New copolymers graft of α,β-poly(N-2-hydroxyethyl)-d,l-aspartamide obtained from atom transfer radical polymerization as vector for gene delivery

Abstract New cationic α,β-poly(N-2-hydroxyethyl)- d , l -aspartamide (PHEA) graft copolymers were synthesized by ATRP, using diethylamino ethyl methacrylate (DEAEMA) as monomer for polymerization, yielding polycations (PHEA-pDEAEMA) able to condense DNA. Then, consecutive ATRP conditions were set up on PHEA-pDEAEMA to obtain copolymers containing also hydrophilic chains (PHEA-IB-pDMAEMA-pPEGMA) able to improve biocompatibility of polyplexes and to provide them stealth properties. Agarose gel studies showed that the copolymers effectively condensed plasmid DNA to form polyplexes. Light scattering studies were used to analyze the size and the ζ -potential of these polyplexes, showing that cop…

AN OPHTHALMIC PHARMACEUTICAL COMPOSITION CONTAINING AMPHIPHILIC POLYASPARTAMIDE COPOLYMERS.

Viscosimetric investigation of the interaction between sodium dodecylsulfate micelles and a polymer drug carrier

Abstract The viscosities of aqueous sodium dodecyl sulfate solutions with and without α,β-poly( N -hydroxyethyl)- dl -aspartamide (PHEA), at 15, 25 and 35°C are reported. The viscosities of SDS and of PHEA aqueous solutions are discussed in terms of the parameter D [D = ( η η 0 − 1)/φ] describing the non-ideal behavior of SDS micelles and of PHEA macromolecules. The viscosities of SDS plus PHEA aqueous solutions, discussed in terms of the parameter F [ F = η rel ( PHEA ) + η rel ( SDS ) − η rel ( SDS + PHEA )] M , demonstrate the occurrence of interactions between SDS micelles and the PHEA macromolecule. Both D and F are scarcely influenced by temperature variation.

Novel inulin-based mucoadhesive micelles loaded with corticosteroids as potential transcorneal permeation enhancers

In this work a new copolymer of inulin (INU) derivatized with ethylendiamine (EDA) and retinoic acid (RA), named INU-EDA-RA, was synthetized, characterized and employed to produce micelles as carriers for topical administration of corticosteroids for the potential treatment of diseases of posterior eye segment. Spectroscopic analysis confirmed a molar derivatization degree of 11.30 and 4.30% in EDA and RA, respectively. INU-EDA-RA micelles are capable of strong mucoadhesive interactions which result time-independent and stable over time but concentration depending. Moreover micelles are able to encapsulate efficiently from 3 to 13% (w/w) of lipophilic drugs, as dexamethasone, triamcinolone …

Reaction of α,β-poly(N-hydroxyethyl)-DL-aspartamide with derivatives of carboxylic acids

Radiosensitizing effect of Curcumin loaded lipid nanoparticles in breast cancer cells

Lipid nanocarriers containing esters prodrugs of Flurbiprofen. Preparation, physical-chemical characterization and biological studies.

In this paper, the preparation, chemical-physical, technological and in vitro characterization of nanostructured lipid carriers (NLC) carrying R-flurbiprofen ester prodrugs, were analyzed for a potential pharmaceutical application. R-flurbiprofen was chosen as a model drug because it has been found to play an effective role in counteracting secretases involved in neurodegenerative diseases, although it does not cross the Blood Brain Barrier (BBB). In this study, two R-flurbiprofen ester prodrugs (ethyl and hexyl) were successfully synthesized and entrapped into non-pegylated and pegylated NLC. The obtained systems showed average diameters in the colloidal size range, negative zeta potential…

In situ forming hydrogels of new amino hyaluronic acid/benzoyl-cysteine derivatives as potential scaffolds for cartilage regeneration

A new chemical strategy is described to link ethylenediamino (EDA) groups to primary hydroxyl groups of hyaluronic acid (HA) and the obtained derivatives have been characterized by 1H-NMR and 13C-NMR analyses. Such HA–EDA derivatives have been exploited to control the functionalization degree in benzoyl-cysteine (BC) groups, chosen as moieties able to allow both self-assembling in aqueous media and an oxidative crosslinking. In particular, the kinetics of oxidation of thiol groups in HA–EDA–BC derivatives has been studied in Dulbecco's Phosphate Buffer Solution (DPBS) pH 7.4 by colorimetric assays and rheological measurements. Mechanical properties of chemical hydrogels obtained after oxida…

SELF-ASSEMBLING POLY(HYDROXYETHYL ASPARTAMIDE)-GRAFT POLYMETHACRYLATE COPOLYMERS OBTAINED BY ATOM TRANSFER RADICAL POLYMERIZATION

Interpenetrating composite biomaterials of hyaluronic acid derivatives and silk fibroin

New hydrogel matrices based on chemical crosslinked α,β -polyas parthydrazide: Synthesis, characterization and in vivo biocompatibility studies

New swellable micromatrices of α,β-polyasparthydrazide (PAHy) crosslinked with glutaraldehyde were prepared. The effect of crosslinking agent concentration was evaluated. In particular, crosslinking density affected aqueous dynamic swelling and glass-transition temperature of the material. The structure of prepared networks was also studied by scanning electron microscopy and X-ray analysis. Finally, biocompatibility of PAHy derivatives was investigated in vivo by subcutaneous implantation and in oral administration to laboratory animals.

Fluorinated and pegylated polyaspartamide derivatives to increase solubility and efficacy of Flutamide

New fluorinated amphiphilic copolymers based on a biocompatible polyaspartamide have been prepared in order to obtain polymeric micelles useful for delivering anticancer drugs. In particular, α,β-poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA) has been derivatized with polyethylene glycol (PEG(2000)) and ethylendiamine (EDA). Both these portions form the hydrophilic part of the copolymer, while the hydrophobic moiety is given by 1,2,4-oxadiazoles: 5-pentafluorophenyl-3-perfluoroheptyl-1,2,4-oxadiazole (PPOX) or 3-carboxyethyl-5-pentadecafluoroheptyl-1,2,4-oxadiazole (CPOX). Copolymers named PHEA-PEG(2000)-EDA-PPOX and PHEA-PEG(2000)-EDA-CPOX have been prepared with various degrees of derivati…

pH-sensitive hydrogel based on a novel photocross-linkable copolymer.

A pH sensitive hydrogel has been prepared by a UV irradiation technique. Starting polymer was the PHM (poly hydroxyethylaspartamide methacrylated) obtained from polyaspartamide (PHEA) partially derivatized with methacrylic anhydride (MA). This new copolymer has been further derivatized with succinic anhydride (SA) to obtain PHM-SA that has been cross-linked by UV irradiation to form a pH sensitive hydrogel. The network, recovered after washing as a powder, has been been characterized by FT-IR spectrophotometry and particle size distribution analysis. Moreover, to have information about water affinity of the prepared sample, swelling measurements have been carried out in aqueous media mimick…

Core-Shell Arginine-Containing Chitosan Microparticles for Enhanced Transcorneal Permeation of Drugs

Chitosan oligosaccharide (C) was functionalized with L-arginine (A) and short hydrocarbon chains (C-8) to design an amphiphilic copolymer, henceforth CAC(8), leading to microparticles (MPs) consisting of an arginine-decorated hydrophilic shell and inner hydrophobic domains allowing the encapsulation of high amount hydrophobic drugs such as sorafenib tosylate (>10% w/w). L-arginine side chains were selected in order to impart the final MPs enhanced transcorneal penetration properties, thus overcoming the typical biological barriers which hamper the absorption of drugs upon topical ocular administration. The mucoadhesive properties and drug release profile of the CAC(8) MPs (CAC(8)-MPs) were …

PEGYLATED POLYASPARTAMIDE–POLYLACTIDE BASED NANOPARTICLES PENETRATING CYSTIC FIBROSIS ARTIFICIAL MUCUS

Here, the preparation of mucus-penetrating nanoparticles for pulmonary administration of ibuprofen in patients with cystic fibrosis is described. A fluorescent derivative of α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide is synthesized by derivatization with rhodamine, polylactide, and poly(ethylene glycol), to obtain polyaspartamide− polylactide derivatives with different degrees of pegylation. Starting from these copolymers, fluorescent nanoparticles with different poly(ethylene glycol) content, empty and loaded with ibuprofen, showed spherical shape, colloidal size, slightly negative ζ potential, and biocompatibility toward human bronchial epithelial cells. The high surface poly(ethylene gly…

Amoxicillin-loaded polyethylcyanoacrylate nanoparticles: influence of PEG coating on the particle size, drug release rate and phagocytic uptake.

Polyethyleneglycol (PEG)-coated polyethylcyanoacrylate (PECA) nanoparticles loaded with amoxicillin were prepared and the influence of the PEG coating on the particle size, zeta potential, drug release rate and phagocytic uptake by murine macrophages was studied. Experimental results show that this colloidal drug delivery system could be useful for intravenous or oral administration. The profile of amoxicillin release from PECA nanoparticles system was studied under various conditions similar to those of some corporeal fluids. In all these experiments, amoxicillin release in the free form was studied by HPLC analysis. Experimental results showed that at pH 7.4 drug release rises when molecu…

Preparation of Polymeric Nanoparticles by Photo-Crosslinking of an Acryloylated Polyaspartamide in w/o Microemulsion

Biodegradable polymeric nanoparticles have been prepared by UV irradiation of an acryloylated water soluble polymer by an inverse microemulsion. The starting polymer was a α,β‐poly(N‐2‐hydroxyethyl)‐D,L‐aspartamide (PHEA) partially functionalized with glycidyl methacrylate (GMA) in order to introduce reactive vinyl groups in the side chain. The PHEA‐GMA copolymer obtained (PHG) was crosslinked by UV irradiation of the inverse microemulsion prepared by mixing an aqueous solution of PHG with propylene carbonate (PC)/ethyl acetate (EtOAc) in the presence of sorbitan trioleate (SPAN 85) as surfactant. Nanoparticles obtained were characterized by FTIR spectrophotometry, transmission electron mic…

Biocompatible hydrogels based on hyaluronic acid cross-linked with a polyaspartamide derivative as delivery systems for epithelial limbal cells.

The aim of this work was to evaluate the potential use of hydrogels based on hyaluronic acid (HA) chemically cross-linked with α,β-poly(N-2-hydroxyethyl) (2-aminoethylcarbamate)-D,L-aspartamide (PHEA-EDA) as substitutes for the amniotic membrane able to release limbal cells for corneal regeneration. Hydrogels, shaped as films, with three different molar ratios (X) between PHEA-EDA and HA (X = 0.5, 1.0 and 1.5) have been investigated. First, it has been evaluated their swelling ability, hydrolytic resistance in simulated physiological fluid and cell compatibility by using human dermal fibroblasts chosen as a model cell line. Then adhesion studies in comparison with collagen gel, have been pe…

POLYSACCHARIDE-POLYAMINOACID HYDROGEL FILMS FOR POTENTIAL CORNEAL CELL RELEASE

Disclosing the emissive surface traps in green-emitting carbon nanodots

Abstract The bright photoluminescence of surface-functionalized carbon nanoparticles, known as carbon nanodots (CDs), has been studied for more than a decade because of its fundamental photo-physical interest and strong technological potential. However, the essential nature of the electronic states involved in their typical light emission remains very elusive. Here, we provide conclusive evidence that surface carboxylic moieties are the key to CD fluorescence. The synergy of nanosecond and femtosecond optical studies, cryogenic fluorescence, computational investigations and chemical engineering of a strategically chosen model CD system, allows to demonstrate that their visible-light transit…

COMPOSITE NANOPARTICLES FOR I.V. DRUG ADMINISTRATION

In-situ forming gel-like depot of a polyaspartamide-polylactide copolymer for once a week administration of Sulpiride

Abstract Objectives An in-situ forming gel-like depot, prepared by using an appropriate polyaspartamide-polylactide graft copolymer, has been employed to release in a sustained way sulpiride. Methods α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide-g-polylactic acid (PHEA-g-PLA) has been used as a polymer component. Its physicochemical properties make possible to dissolve it in N-methyl-2-pyrrolidone, with the obtainment of a solution able to form a gel-like depot once injected into a physiological medium. Cell compatibility of PHEA-g-PLA depot has been investigated, using murine dermal fibroblasts as cell model. 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazo…

Folate targeted coated SPIONs as efficient tool for MRI

The development of more sensitive diagnostic tools allowing an early-stage and highly efficient medical imaging of tumors remains a challenge. Magnetic nanoparticles seem to be the contrast agents with the highest potential, if properly constructed. Therefore, in this study, hybrid magnetic nanoarchitectures were developed using a new amphiphilic inulin-based graft copolymer (INU-LAPEG-FA) as coating material for 10-nm spinel iron oxide (magnetite, Fe3O4) superparamagnetic nanoparticles (SPION). Folic acid (FA) covalently linked to the coating copolymer in order to be exposed onto the nanoparticle surface was chosen as the targeting agent because folate receptors are upregulated in many can…

Nuovi derivati poliaspartammidici per la veicolazione di proteine della terapia antitumorale

NANOSTRUCTURED LIPID CARRIERS CONTAINING RILUZOLE AND PHARMACEUTICAL FORMULATIONS CONTAINING SAID PARTICLES

The present invention concerns the preparation, the physical-chemical, technological and pharmaceutical characterization of Riluzole-loaded nanoparticle vectors. The chosen production technology permitted to obtain these systems in a reproducible way, with high yields and low costs. In particular, a novel formulation of Riluzole loaded into lipid nanoparticles was developed which is able to carry to the Central Nervous System a higher amount of drug in comparison with the free drug. In vivo results demonstrated that the administration on rats of these formulation permits to obtain a lower deposit of Riluzole in organs such as liver, spleen, heart and kidneys; the consequence is a reduction …

SYNTHESIS AND CHARACTERIZATION OF NEW AMPHIPHILIC COPOLYMERS BASED ON A POLY(HYDROXYETHYL)-D,L-ASPARTAMIDE (PHEA) FOR THE COATING OF GOLD NANOPARTICLES TO BE USED AS ANTIMICROBIAL AGENTS ACTIVATED BY NIR IRRADIATION

BIOLOGICAL STUDIES ON POLYASPARTAMIDE COPOLYMERS AS GENE CARRIER

Polyaspartamide based microparticles for Tobramycin delivery to the lung in FC therapy

Cationic polyaspartamide-based nanocomplexes mediate siRNA entry and down-regulation of the pro-inflammatory mediator high mobility group box 1 in airway epithelial cells

Abstract High-mobility group box 1 (HMGB1) is a nonhistone protein secreted by airway epithelial cells in hyperinflammatory diseases such as asthma. In order to down-regulate HMGB1 expression in airway epithelial cells, siRNA directed against HMGB1 was delivered through nanocomplexes based on a cationic copolymer of poly(N-2-hydroxyethyl)- d,l -aspartamide (PHEA) by using H441 cells. Two copolymers were used in these experiments bearing respectively spermine side chains (PHEA-Spm) and both spermine and PEG2000 chains (PHEA-PEG-Spm). PHEA-Spm and PHEA-PEG-Spm derivatives complexed dsDNA oligonucleotides with a w/w ratio of 1 and higher as shown by a gel retardation assay. PHEA-Spm and PHEA-P…

NEW BIODEGRADABLE HYDROGELS BASED ON INULIN AND alpha,beta-POLYASPARTYLHYDRAZIDE DESIGNED FOR COLONIC DRUG DELIVERY:IN VITRO RELEASE OF THE PEPTIDES GLUTATHIONE AND OXYTOCIN

Polyaspartamide-g-Polylactide graft cpolymers able to form nanoparticles obtained by a novel synthetic strategy.

Development of a simple, biocompatible and cost-effective Inulin-Diethylenetriamine based siRNA delivery system

Small interfering RNAs (siRNAs) have the potential to be of therapeutic value for many human diseases. So far, however, a serious obstacle to their therapeutic use is represented by the absence of appropriate delivery systems able to protect them from degradation and to allow an efficient cellular uptake. In this work we developed a siRNA delivery system based on inulin (Inu), an abundant and natural polysaccharide. Inu was functionalized via the conjugation with diethylenetriamine (DETA) residues to form the complex Inu-DETA. We studied the size, surface charge and the shape of the Inu-DETA/siRNA complexes; additionally, the cytotoxicity, the silencing efficacy and the cell uptake-mechanis…

Composite nanoparticles based on hyaluronic acid chemically cross-linked with alpha,beta-polyaspartylhydrazide.

In this paper, new composite nanoparticles based on hyaluronic acid (HA) chemically cross-linked with alpha,beta polyaspartylhydrazide (PAHy) were prepared by the use of a reversed-phase microemulsion technique. HA-PAHy nanoparticles were characterized by FT-IR spectroscopy, confirming the occurrence of the chemical cross-linking, dimensional analysis, and transmission electron micrography, showing a sub-micrometer size and spherical shape. Zeta potential measurements demonstrated the presence of HA on the nanoparticle surface. A remarkable affinity of the obtained nanoparticles toward aqueous media that simulate some biological fluids was found. Stability studies showed the absence of chem…

Gold nanostar–polymer hybrids for siRNA delivery: Polymer design towards colloidal stability and in vitro studies on breast cancer cells

To overcome the low bioavailability of siRNA (small interfering RNA) and to improve their transfection efficiency, the use of non-viral delivery carriers is today a feasible approach to transform the discovery of these incredibly potent and versatile drugs into clinical practice. Polymer-modified gold nanoconstructs (AuNCs) are currently viewed as efficient and safe intracellular delivery carriers for siRNA, as they have the possibility to conjugate the ability to stably entrap and deliver siRNAs inside cells with the advantages of gold nanoparticles, which can act as theranostic agents and radiotherapy enhancers through laser-induced hyperthermia. In this study, AuNCs were prepared by coat…

Inhalable Formulation Based on Lipid–Polymer Hybrid Nanoparticles for the Macrophage Targeted Delivery of Roflumilast

Here, novel lipid-polymer hybrid nanoparticles (LPHNPs), targeted to lung macrophages, were realized as potential carriers for Roflumilast administration in the management of chronic obstructive pulmonary disease (COPD). To achieve this, Roflumilast-loaded fluorescent polymeric nanoparticles, based on a polyaspartamide-polycaprolactone graft copolymer, and lipid vesicles, made from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-distearoyl-sn-glycero-phosphoethanolamine-N-(polyethylene glycol)-mannose, were properly combined using a two-step method, successfully obtaining Roflumilast-loaded hybrid fluorescent nanoparticles (Man-LPHFNPs@Roflumilast). These exhibit colloidal size and a ne…

New biodegradable hydrogels based on a photo-cross-linkable polyaspartamide and poly(ethylene glycol) derivatives. Release studies of an anticancer drug

The functionalization of α,β-poly(N-2-hydroxyethyl)-dl-aspartamide (PHEA) with glycidyl methacrylate (GMA) gives rise to a water-soluble photosensitive copolymer PHEA-GMA (PHG). Aqueous solutions of PHG alone or in combination with various concentrations of poly(ethylene glycol) dimethacrylate or poly(ethylene glycol) diacrylate (PEGDA) have been exposed to a source of UV rays at 313 nm in order to obtain polymeric networks. All samples have been prepared both as water-swellable microparticles and as gel systems. Microparticles have been characterised by Fourier transform IR spectrophotometry, dimensional analysis and swelling measurements in aqueous media mimicking biological fluids. In vi…

A new hyaluronic acid pH sensitive derivative obtained by ATRP for potential oral administration of proteins

Atom transfer radical polymerization (ATRP) has been successfully employed to obtain a new derivative of hyaluronic acid (HA) able to change its solubility as a function of external pH and then to be potentially useful for intestinal release of bioactive molecules, included enzymes and proteins. In particular, a macroinitiator has been prepared by linking 2-bromo-2-methypropionic acid (BMP) to the amino groups of ethylenediamino derivative of tetrabutyl ammonium salt of HA (HA-TBA-EDA). This macroinititor, named HA-TBA-EDA-BMP has been used for the ATRP of sodium methacrylate (MANa) using a complex of Cu(I) and 2,2'-bipyridyl (Byp) as a catalyst. The resulting copolymer, named HA-EDA-BMP-MA…

Effect of alkyl derivatization of gellan gum during the fabrication of electrospun membranes

Electrospun nanofibers based on polysaccharides represent a consolidated approach in Tissue Engineering and Regenerative Medicine (TERM) and nanomedicine as a drug delivery system (DDS). In this work, two chemical derivatives of a low molecular weight gellan gum (96.7 kDa) with aliphatic pendant tails were processed by electrospinning technique into non-woven nanofibrous mats. In order to generate spinnable blends, it was necessary to associate poly vinyl alcohol (PVA). The relationships between the physicochemical properties and the processability via electrospinning technique of gellan gum alkyl derivatives (GG-C8 and GG-C12 having a degree of alkyl chain derivatization of 17 mol % and 1…

Combining inulin multifunctional polycation and magnetic nanoparticles: Redox-responsive siRNA-loaded systems for magnetofection

Superparamagnetic Iron Oxide Nanoparticles (SPIONs) are recognized as one of the most promising agents for theranostic applications. Among methods designed for siRNA delivery, magnetofection, that is, nucleic acid cell uptake under the influence of a magnetic field acting on magnetic nucleic acid vectors, is emerging as a unique approach to combining advantages such as strong improvement of the kinetics of the delivery process and the possibility of localizing nucleic acid delivery to an area where the magnetic field is applied. This paper reports on the preparation of siRNA loaded magnetoplexes&mdash

Hybrid Gold/Silica/Quantum-Dots supramolecular-nanostructures encapsulated in polymeric micelles as potential theranostic tool for targeted cancer therapy

Abstract Efficient theranostic tools are today more and more frequently represented by the nano-sized systems. In this paper, polymeric micelles were produced and exploited to encapsulate both an antitumor drug (Doxorubicin) and gold core–shell quantum dots nanoparticles (Au-SiO2/QDs). α,β-poly(N-hydroxyethyl)- dl -aspartamide (PHEA) was functionalized with lipoic acid (LA), polyethylenglycol (PEG), and folic acid (FA) pendant moieties to obtain a synthetic derivative (PHEA-LA-PEG-FA) able to self assemble in aqueous medium giving rise to the formation of polymeric micelles exposing on their surface both targeting groups (FA) and hydrophilic chains (PEG). The drug carrying ability of PHEA-L…

A Par j1/Par J2-polymeric nanoaggragates as a new tool for allergy vaccination

HYDROGELS OF HYALURONIC ACID AND alpha, beta-POLYASPARTYLHYDRAZIDE AND THEIR BIOMEDICAL AND PHARMACEUTICAL USES

Compositions and products based on the chemical crosslinking of hyaluronic acid with a polyfunctional polymer having a protein-like structure, bearing hydrazido pendent groups along the polymeric chain. The polymer is preferably, alpha-beta-polyaspartylhydrazide, a biocompatible macromolecule. The materials obtained after crosslinking, specifically hydrogels, undergo a reduced chemical and enzymatic degradation, unlike the starting hyaluronic acid, and they can be used to prepare systems for applications in the biomedical and pharmaceutical field.

Amphiphilic derivatives of a polyaspartamide: their aggregation and solubilization ability

Abstract The self-aggregation and solubilization capability of a series of amphiphilic copolymers obtained by derivatisation of polymeric chain of α,β-poly(N-2-hydroxyethyl)- dl -aspartamide (PHEA) with polyethylene glycols (PEG, being different molecular weight 2000 or 5000 Da, PEG2000 and PEG5000, respectively) and/or hexadecylamine alkyl chain (C16), namely PHEA–PEG2000, PHEA–PEG5000, PHEA–C16, PHEA–PEG2000–C16 and PHEA–PEG5000–C16, have been evidenced by performing systematic tensiometric and spectrophotometric studies. All measurements have been performed at 25.0 °C over a wide copolymer concentration range. The tensiometric results have shown that, for all copolymers studied, the surf…

Interaction Between drug loaded Polyaspartamide-polylactide-polisorbate based micelles and cell membrane models: a calorimetric study

Amphiphilic biodegradable copolymers, for their ability to self-assemble into micelle-like aggregates, with a suitable loading capacity, are of emerging interest for the delivery of water-insoluble drugs. α,β-Poly[(N-hydroxyethyl)-dl-aspartamide] (PHEA) is suitable to obtain amphiphilic graft copolymers. These copolymers can be obtained starting from PHEA-ethylenediamine (PHEA-EDA) which is functionalized with polysorbate 80 (PS₈₀, like targeting residues to the brain) and polylactide (PLA, like hydrophobic chains) in order to obtain polymeric micelles of PHEA-EDA-PS₈₀-PLA potentially useful to release drugs to the central nervous system. In this paper, the interaction and absorption of PHE…

SCAFFOLD A STRUTTURA POLISACCARIDICA/POLIAMINOACIDICA PER IL RILASCIO SOSTENUTO DI DNA

Cationic Solid-lipid nanoparticles as DNA carriers.

PEG-benzofulvene copolymer hydrogels for antibody delivery.

A new amphiphilic copolymer have been synthesized starting from the hydrosoluble polyaspartylhydrazide (PAHy) polymer, by grafting both hydrophilic PEG(2000) chains and hydrophobic palmitic acid (C(16)) moieties on polymer backbone, and the structure of obtained PAHy-PEG(2000)-C(16) copolymer have been characterized by 2D (1)H/(13)C NMR experiments. PAHy-PEG(2000)-C(16) copolymer showed the ability of self-assembling in aqueous media giving a core-shell structure and resulted potentially useful for encapsulating and dissolving hydrophobic drug. The formation of micellar core-shell structure has been investigated by 2D (1)H NMR NOESY experiments. The presence of cross-peaks for protons of C(…

Novel Biocompatible Cationic Copolymers Based on Polyaspartylhydrazide Being Potent as Gene Vector on Tumor Cells

Introduction. The reaction between !,"-poly(aspartylhydrazide) (PAHy), a water soluble synthetic polymer and 3-(carboxypropyl)trimethyl-ammonium chloride (CPTACl) produced copolymers bearing permanent positive charges (PAHy–CPTA) with molecular weight of 10 kDa and PAHy–CPTA copolymers differing in positive charge amount (18–58%) were chosen for biological investigations. Materials and methods. Biophysical properties of DNA/PAHy–CPTA polyplexes were evaluated in terms of DNA condensation, zeta potential and size distribution. Cytotoxicity studies on Neuro2A murine neuroblastoma cells evidenced absence of toxicity of these copolymers up to 300 2g/ml unlike linear polyethylenimine (LPEI) that…

TABLET DI ACIDO IALURONICO FUNZIONALIZZATO CON CATENE IDROFOBICHE PER IL RILASCIO LOCOREGIONALE DI PACLITAXEL

DEVELOPMENT OF LIPID NANOSTRUCTURES CONTAINING A PARIETARIA POLLEN ALLERGEN.

Ionizing radiation induced synthesis of polymers and blends with different structures

Impiego di vettori policationici a base poliamminoacidica per la veicolazione di siRNA nel trattamento della in-stent restenosi

NEW HYALURONAN-BASED HYDROGEL AS RESOBABLE ANTIBACTERIAL COATING FOR PREVENTION OF IMPLANT-RELATED INFECTION IN ORTHOPAEDICS

SYNTHESIS OF INULIN-GRAFT COPOLYMERS VIA GRAFTING- FROM ATRP TECHNIQUE. A NEW FRONTIER FOR MODIFICATION OF NATURAL POLYSACCHARIDES

NANOTECHNOLOGIES FOR BIOMEDICAL APLICATIONS

INULIN BASED HYDROGEL FOR ORAL DELIVERY OF FLUTAMIDE: PREPARATION, CHARACTERIZATION AND IN VIVO RELEASE STUDIES

The ability of a hydrogel obtained by crosslinking INUDV and PEGBa to facilitate sustained release of flutamide is examined. The hydrogel is prepared in pH = 7.4 PBS and no toxic solvents or catalysts are used. It is recovered in microparticulate form and its size distribution is determined. Mucoadhesive properties are evaluated in vitro by reproducing gastrointestinal conditions. Flutamide is loaded into the hydrogel using a post-fabrication encapsulation procedure that allows a drug loading comparable to that of market tablets. Drug-loaded microparticles are orally administered to cross-bred dogs and the in vivo study demonstrates their ability to prolong the half-life of the principal ac…

Biocompatible polymeric micelles with polysorbate 80 for use in brain targeting.

In this paper, the synthesis and characterization of novel amphiphilic graft copolymers based on an alpha,beta-poly(N-2-hydroxyethyl)-D, L-aspartamide (PHEA) backbone and D, L-polylactic acid (PLA) hydrophobic side chains are reported. These copolymers were obtained starting from PHEA-ethylenediamine (PHEA-EDA), which was functionalized with polysorbate 80 (PS(80)) and/or PLA in order to obtain the PHEA-EDA-PS(80)-PLA and PHEA-EDA-PLA samples, respectively. The degrees of derivatization, DD(PS80) and DD(PLA), of PHEA-EDA-PS80-PLA, calculated by (1)H-NMR, resulted in being 1.2 +/- 0.03 mol% and 0.54 +/- 0.05 mol%, respectively, while that of PHEA-EDA-PLA was found to be 0.60 +/- 0.05 mol%. S…

BIOCOMPATIBLE MICELLES BASED ON AMPHIPHILIC POLYASPARTMIDE-SQUALENE DERIVATIVES AS POTENTIAL COLLOIDAL DRUG CARRIERS

Uptake of silica covered Quantum Dots into living cells: Long term vitality and morphology study on hyaluronic acid biomaterials

Quantum Dots (QDs) are promising very bright and stable fluorescent probes for optical studies in the biological field but water solubility and possible metal bio-contamination need to be addressed. In this work, a simple silica-QD hybrid system is prepared and the uptake in bovine chondrocytes living cells without any functionalization of the external protective silica shield is demonstrated. Moreover, long term treated cells vitality (up to 14 days) and the transfer of silica-QDs to the next cell generations are here reported. Confocal fluorescence microscopy was also used to determine the morphology of the so labelled cells and the relative silica-QDs distribution. Finally, we employ sil…

Carbon Nanodots as Functional Excipient to Develop Highly Stable and Smart PLGA Nanoparticles Useful in Cancer Theranostics

Theranostic systems have attracted considerable attention for their multifunctional approach to cancer. Among these, carbon nanodots (CDs) emerged as luminescent nanomaterials due to their exceptional chemical properties, synthetic ease, biocompatibility, and for their photothermal and fluorescent properties useful in cancer photothermal therapy. However, premature renal excretion due to the small size of these particles limits their biomedical application. To overcome these limitations, here, hybrid poly(lactic-co-glycolic acid) (PLGA-CDs) nanoparticles with suitable size distribution and stability have been developed. CDs were decisive in the preparation of polymeric nanoparticles, not on…

Swellable microparticles containing Suprofen: evaluation of in vitro release and photochemical behaviour

Suprofen, an anti-inflammatory drug was incorporated in polymer networks based on biocompatible macromolecules, such as alpha,beta-polyasparthydrazide (PAHy) and alpha,beta-poly(N-hydroxyethyl)-DL-aspartamide (PHEA) crosslinked by glutaraldehyde or gamma-rays, respectively. Swelling tests carried out in aqueous media showed that pH value affects the swelling degree of the prepared hydrogels. In vitro release tests were performed in simulated gastrointestinal fluids (pH 1/6.8) using the pH variation method and in phosphate-buffered saline, pH 7.4. Experimental data indicated that Suprofen was released in a sustained way both from PAHy and PHEA microparticles. Further, incorporation of Suprof…

Scaffolds of Hyaluronan crosslinked with alpha,beta-polyaspartylhydrazide for uses in tissue engineering field

BIOCOMPATIBLE POLYAMINOACID-BASED POLYCATIONS AS NON-VIRAL VECTORS FOR GENE THERAPY OF CYSTIC FIBROSIS.

Mucoadhesive Solid Lipid Microparticles (SLM) for sustained release of corticosteroids to the lungs

Pulmonary delivery is the preferred route of drug administration in the treatment of many respiratory disease, such as asthma and chronic obstructive pulmonary disease (COPD). Over the years, several kinds of carriers have been studied for sustained release of corticosteroids and bronchodilators to the lungs. Solid Lipid Microparticles (SLM) due to their biocompatibility and size (3-5 µm) can reach the bronchial epithelium directly, circumvent first pass metabolism and avoid systemic toxicity [1,2]. In this work we describe the preparation and the characterization of two different systems subjected to chitosan and alginate coating for sustained release of fluticasone propionate (FP) into th…

Synthesis and biopharmaceutical characterisation of new poly(hydroxyethylaspartamide) copolymers as drug carriers.

Abstract Four new poly(hydroxyethylaspartamide)-based copolymers bearing (a) poly(ethylene glycol) 2000, (b) poly(ethylene glycol) 5000, (c) poly(ethylene glycol) 2000 and hexadecylalkyl, (d) poly(ethylene glycol) 5000 and hexadecylalkyle, as pendant groups were synthesised. The copolymers were obtained by partial aminolysis of polysuccinimide with poly(ethylene glycol) and hexadecylalkyl amino derivatives followed by reaction with ethanolamine. Naked polyhydroxyaspartamide was obtained by polysuccinimide reaction with ethanolamine. The nuclear magnetic resonance, infrared, light scattering and elemental analysis allowed for the extensive physico-chemical characterisation of the carriers. T…

Innovative polymer - and lipid - based nanotechnologies for drug and nucleic acid delivery

Preparation and Characterization of Inulin Coated Gold Nanoparticles for Selective Delivery of Doxorubicin to Breast Cancer Cells

A novel folate-targeted gold-based nanosystem for achieving selectivity towards folate receptor FR positive cells is proposed, by virtue of the fact that the FR is a molecularly targeted entity overexpressed in a wide spectrum of solid tumors. A new inulin-folate derivative INU-FA has been synthesized to act as coating agent for 40 nm gold nanoparticles. The obtained polymer-coated gold nanoparticles [email protected] were characterized in terms of hydrodynamic radius, shape, zeta potential, and aqueous stability and were loaded with doxorubicin [email protected]/Doxo. Its release capability was tested in different release media. The selectivity of [email protected]/Doxo system towards FRs-…

SUPRAMOLECULAR ASSOCIATION OF RECOMBINANT HUMAN GROWTH HORMONE WITH HYDROPHOBIZED POLYHYDROXYETHYLASPARTAMIDES

Abstract The protein delivery properties of polymer supramolecular assemblies were investigated by using recombinant human growth hormone (rh-GH) and two polyhydroxyethylaspartamide (PHEA) derivatives: (a) PHEA-C 16 obtained by PHEA random grafting with hexadecylalkylamine; (b) PHEA-PEG 5000 -C 16 obtained by PHEA random co-grafting with hexadecylalkylamine and 5 kDa poly(ethylene glycol). The two polymers possessed similar self-assembling properties: critical micelle concentration (CMC) and particle size. The protein loading (protein/polymer, w/w, %) was 12.1 ± 1.3% and 8.5 ± 0.4% with PHEA-C 16 and PHEA-PEG 5000 -C 16 , respectively. The rh-GH/polymer association constant calculated by Sc…

Hydrogels for potential colon drug release by thiol-ene conjugate addition of a new inulin derivative.

Inulin was chosen as a starting polymer for biocompatible, pH-sensitive and biodegradable hydrogels. Three INUDVSA-TT hydrogels were obtained by crosslinking inulin derivatives with trimethylolpropane tris(3-mercaptopropionate) under varying conditions. The resulting hydrogels were cell compatible, as demonstrated by MTS and trypan blue exclusion assays acting on Caco-2 cells, and were biodegraded by inulinase and esterase, thus suggesting their use as colonic drug delivery systems. 2-Methoxyestradiol, an anti-cancer drug, was soaked in INUDVSA-TT hydrogels and its in vitro release and apoptotic effect on Caco-2 cells were evaluated.

NANODEVICES FOR THE TARGETED DRUG AND GENE DELIVERY

Near-Infrared Light Responsive Folate Targeted Gold Nanorods for Combined Photothermal-Chemotherapy of Osteosarcoma.

Folate-targeted gold nanorods (GNRs) are proposed as selective theranostic agents for osteosarcoma treatment. An amphiphilic polysaccharide based graft-copolymer (INU-LA-PEG-FA) and an amino derivative of the α,β-poly(N-2-hydroxyethyl)-d,l-aspartamide functionalized with folic acid (PHEA-EDA-FA), have been synthesized to act as coating agents for GNRs. The obtained polymer-coated GNRs were characterized in terms of size, shape, zeta potential, chemical composition, and aqueous stability. They protected the anticancer drug nutlin-3 and were able to deliver it efficiently in different physiological media. The ability of the proposed systems to selectively kill tumor cells was tested on U2OS…

Inulin-Ethylenediamine Coated SPIONs Magnetoplexes: A Promising Tool for Improving siRNA Delivery.

An inulin based polycation (Inu-EDA) has been synthesized by the grafting of ethylenediamine molecules onto inulin backbone. The obtained inulin copolymer has been though to coat SPIONs (IC-SPIONs) and obtain stable magnetoplexes by complexation of IC-SPIONs with a model duplexed siRNA, for improving oligonucleotide transfection efficiency.The physical-chemical characteristics of IC-SPIONs and IC-SPIONs/siRNA magnetoplexes have been investigated by scanning and transmission electron microscopies, dynamic light scattering, FT-IR and qualitative surface elementary analysis. Cell compatibility and internalization in vitro of IC-SPIONs have been evaluated by MTS and fluorescence microscopy resp…

Ciprofloxacin releasing gellan gum/polydopamine based hydrogels with near infrared activated photothermal properties.

Abstract In this work, with the aim to obtain a wound dressing hydrogel, an amine derivative of gellan gum was crosslinked in the presence of 4arm-polyethylenglycole-vinylsulfone. Through this easy and reproducible chemical procedure, a hydrogel with advanced elastic properties and hydrolytic resistance under physiological conditions was obtained. The incorporation of different quantities of polydopamine in the gelling solutions allows to obtain different hydrogels with marked photothermal properties when irradiated with a laser in the near infrared at 810 nm. The organic nanoparticles, reacting with the amino groups of the polysaccharide derivative, contribute to increase the storage modul…

SINTESI E CARATTERIZZAZIONE DI UN NUOVO DERIVATO DEL PHEA PER IL DIREZIONAMENTO ATTIVO DI FARMACI AL SISTEMA NERVOSO CENTRALE (SNC)

Polymeric Nanocarriers for Magnetic Targeted Drug Delivery: Preparation, Characterization, and in Vitro and in Vivo Evaluation

In this paper the preparation of magnetic nano- carriers (MNCs), containing superparamagnetic domains, is reported, useful as potential magnetically targeted drug delivery systems. The preparation of MNCs was performed by using the PHEA-IB-p(BMA) graft copolymer as coating material through the homogenization−solvent evaporation method. Magnetic and nonmagnetic nanocarriers containing flutamide (FLU-MNCs) were prepared. The prepared nanocarriers have been exhaustively characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), and magnetic measurements. Biological evaluation was performed by in vitro cytotoxicity and cell uptake tests and in vivo biodistribution …

Hyaluronic Acid-g-Copolymers: Synthesis, Properties, and Applications

The aim of this chapter is to review hyaluronic acid (HA) graft copolymers focusing in the description of chemical strategies employed for their synthesis, characterization procedures, and applications in biomedical and pharmaceutical field. Usually biocompatible synthetic polymers and peptides with therapeutic activity are grafted to HA to modify in appropriate way the physicochemical properties of the starting polysaccharide for a specific purpose and at the same time to exploit its biological role, biocompatibility, and targeting ability toward cells with receptors for HA. The use of such HA graft copolymers in the production of nanocarriers or hydrogels for modified drug release and sca…

Tamoxifen-loaded polymeric micelles: preparation, physico-chemical characterization and in vitro evaluation studies.

Several samples of polymeric micelles, formed by amphiphilic derivatives of PHEA, obtained by grafting into polymeric backbone of PEGs and/or hexadecylamine groups (PHEA-PEG-C(16) and PHEA-C(16)) and containing different amount of Tamoxifen, were prepared. All Tamoxifen-loaded polymeric micelles showed to increase drug water solubility. TEM studies provided evidence of the formation of supramolecular core/shell architectures containing drug, in the nanoscopic range and with spherical shape. Samples with different amount of encapsulated Tamoxifen were subjected to in vitro cytotoxic studies in order to evaluate the effect of Tamoxifen micellization on cell growth inhibition. All samples of T…

New injectable depot systems based on alpha,beta-poly(N-2-hydroxyethyl)-D,L-aspartammide copolymers

BIOADHESIVE PROPERTIES OF A POLYAMINOACIDIC HYDROGEL: EVALUATION BY ATR FT-IR SPECTROSCOPY

The bioadhesive properties of a novel chemical hydrogel based on a polymer of protein-like structure, have been investigated by using ATR FT-IR spectroscopy. In particular, the copolymer PHG obtained by partial derivatization of PHEA with GMA was chemically crosslinked by UV irradiation at 313 nm. Crosslinked PHG was treated with water to obtain a swelled sample, named PHG-UV gel, that was brought into contact with a phosphate buffer/citric acid solution at pH 7.0 in the absence or in the presence of mucin at various concentrations (0.01, 0.1 and 1 wt.-%). Preliminary dynamic swelling studies have evidenced the occurrence of an interaction between the PHG-UV gel and the glycoprotein. This r…

NANOPARTICLES OBTAINED FROM HYALURONIC ACID AND POLYASPARTYLHYDRAZIDE

Fluoropolymer Based on a Polyaspartamide containing 1,2,4-Oxadiazole Units: A Potential Artificial Oxygen (O2) Carrier

Abstract In this preliminary work we have prepared a fluorinated polymer capable of solubilizing an appreciable amount of O(2) and, at the same time, maintaining a higher water solubility than perfluoroalkanes investigated as injectable O(2) carriers. In particular, we describe the synthesis and characterization of a new macromolecular conjugate obtained by derivatization of alpha,beta-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) with 5-pentafluorophenyl-3-perfluoroheptyl-1,2,4-oxadiazole, called PHEA-F. This new water soluble fluoropolymer was prepared in high yield using a simple procedure. It was characterized by FT-IR and UV-vis spectrophotometry, (19)F-NMR and SEC measurements. O(2) so…

Polyanion–tobramycin nanocomplexes into functional microparticles for the treatment of Pseudomonas aeruginosa infections in cystic fibrosis

Aim: Efficacy of antibiotics in cystic fibrosis (CF) is compromised by the poor penetration through mucus barrier. This work proposes a new ‘nano-into-micro’ approach, used to obtain a combinatorial effect: achieve a sustained delivery of tobramycin and overcome mucus barrier. Methods: Mannitol microparticles (MPs) were loaded with a tobramycin polymeric nanocomplex and characterized in presence of CF artificial mucus. Results & discussion: MPs are able to alter the rheological properties of CF artificial mucus, enhancing drug penetration into it and allowing a prolonged drug release. MPs resulted to be effective in Pseudomonas aeruginosa infections if compared with free tobramycin. Co…

Biomaterials for Biotechnological and Pharmaceutical application

An asymmetric electrospun membrane for the controlled release of ciprofloxacin and FGF-2: Evaluation of antimicrobial and chemoattractant properties.

Here, an asymmetric double-layer membrane has been designed and fabricated by electrospinning as a tool for a potential wound healing application. A hydrophobic layer has been produced by using a polyurethane-polycaprolactone (PU-PCL) copolymer and loaded with the antibacterial ciprofloxacin whereas an ion responsive hydrophilic layer has been produced by using an octyl derivative of gellan gum (GG-C8) and polyvinyl alcohol (PVA) and loaded with the growth factor FGF-2. This study investigated how the properties of this asymmetric membrane loaded with actives, were influenced by the ionotropic crosslinking of the hydrophilic layer. In particular, the treatment in DPBS and the crosslinking i…

Antibacterial hydrogel and use thereof in orthopedics.

BIOCOMPATIBLE POLYCATIONS FOR GENE DELIVERY

HYALURONIC ACID DERIVATIVE MICELLES AS OCULAR PLATFORMS TO DRUG RELEASE AND CORNEAL PERMEATION

In traditional ocular formulations, only small amount of the administered drug penetrates the cornea to reach the intraocular tissue. One approach to improve the drug ocular bioavailability was to develop colloidal drug delivery systems. Polymeric micelles seem to be very promising for their capacity to dissolve a variety of hydrophobic drugs by enhancing their water solubility and so their bioavailability. They are able to increase ocular drug permeability due to interact with the complex corneal structure. Considering the advantages to use mucoadhesive polymer to increase drug residence time on the ocular surface, the aim of this work was to prepare hyaluronic acid-based micelles as a pla…

Micromaterials lipid-based for topic release of fluticasone propionate for the COPD treatment

Mucus and Cell-Penetrating Nanoparticles Embedded in Nano-into-Micro Formulations for Pulmonary Delivery of Ivacaftor in Patients with Cystic Fibrosis

Here, mucus-penetrating nanoparticles (NPs) for pulmonary administration of ivacaftor in patients with cystic fibrosis (CF) were produced with the dual aim of enhancing ivacaftor delivery to the airway epithelial cells, by rapid diffusion through the mucus barrier, and at the same time, promoting ivacaftor lung cellular uptake. Pegylated and Tat-decorated fluorescent nanoparticles (FNPs) were produced by nanoprecipitation, starting from two synthetic copolymers, and showed nanometric sizes (∼70 nm), a slightly negative ζ potential, and high cytocompatibility toward human bronchial epithelium cells. After having showed the significant presence of poly(ethylene glycol) chains and Tat protein …

Functionalization of a polyaspartamide with glycidyl methacrylate: A useful method to prepare hydrogels through gamma irradiation

α-β-Poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) was derivatized with glycidyl methacrylate (GMA). Aqueous solutions of the obtained copolymer PHEA-GMA (PHG) were irradiated by gamma rays with a dose rate of 0.5 KGy/h and at zero °C in the presence or in the absence of N,N'-methylenebisacrylamide (BIS). New hydrogel systems were obtained and characterized by FT-IR analyses and swelling measurements in aqueous medium at different pH values.

Effect of pH on the transfer kinetics of an anti-inflammatory drug from polyaspartamide hydrogels to a lipid model membrane

Abstract The release of a nonsteroidal anti-inflammatory drug (NSAID), 4-biphenylacetic acid (BPAA), from α,β-poly( N -hydroxyethyl)- dl -aspartamide (PHEA) hydrogels was tested at different pHs (4 and 7.4) by measuring the drug transfer from loaded hydrogel to dimyristoylphosphatidylcholine (DMPC) liposomes (multilamellar vesicles, MLV), chosen as a biomembrane model. This drug transfer was compared with the transfer from powdered drug and with drug classical. The perturbing effect of pure BPAA on the thermotropic behaviour of DMPC liposomes, in terms of transition temperature shift (Δ T m ) and enthalpy changes (Δ H ), was analysed at different pHs (4 and 7.4) by differential scanning cal…

Sustained release of silibinin to the posterior segment of the eye by mucoadhesive NLC

Amphiphilic inulin graft co-polymers as self assembling micelles for doxorubicin delivery

This paper reports the synthesis and characterization of a new amphiphilic inulin graft copolymer able to self-assemble in water into a micelle type structure and to deliver the anticancer model drug doxorubicin. For this aim, inulin was chemically modified in the side chain with primary amine groups (INU-EDA) and these were used as reactive moieties for the conjugation of poly ethylene glycol 2000 and succinyl-ceramide. The CMC of obtained amphiphilic inulin derivatives (INU-ceramide and INU-ceramide-PEG2000) was measured by means of fluorescence analysis using pyrene as the fluorescent probe. The obtained micelles were characterized by DLS and AFM analysis and the ability to release the l…

Enhanced pulmonary delivery of Salmeterol Xinafoate (SX) by mucoadhesive microparticles

Ibuprofen containing mucus-penetrating nanoparticles as therapeutic tool for the treatment of inflammation in Cystic Fibrosis

CONTROLLED RELEASE OF IgG BY NOVEL UV INDUCED POLYSACCHARIDE/POLY(AMINO ACID)HYDROGELS

The development of new protein and peptide drugs needs new delivery systems able to entrap such drugs in safe conditions without affecting their structure and biological activity. In this context, the present work reports a new approach to load IgG, used as a model of therapeutic proteins such as anti-TNF-alpha monoclonal antibodies, into a polymeric system able to release the entrapped IgG in a controlled manner. In particular, new polysaccharide/poly(amino acid) UV induced hydrogels are proposed as colon delivery systems for human IgG. The poly(amino acid), alpha,beta-poly[N-(2-hydroxyethyl)-D,L-aspartamide], has been functionalized with methacrylic anhydride, while the polysaccharide, in…

Development of nimesulide loaded solid lipid nanoparticles.

Solid-lipid nanoparticles for gene delivery to cells.

POLYMERIC MICELLES FOR DRUG TARGETING TO THE BRAIN

Nuovi Sistemi Polimerici a base di Polisaccaridi/Poliamminoacidici per il Rilascio Colon Specifico Di Farmaci

HYALURONIC ACID-graft-ELASTIN BASED SCAFFOLDS FOR POTENTIAL TISSUE ENGINEERING APPLICATIONS

Hyaluronan Graft Copolymers Bearing Fatty-Acid Residues as Self-Assembling Nanoparticles for Olanzapine Delivery

In order to evaluate the potential of a technology platform based on hyaluronan copolymers grafted with propargylated ferulate fluorophores (HA-FA-Pg) in the development of drug delivery systems, the propargyl groups of HA-FA-Pg derivatives were employed with oleic acid (OA) or stearic acid (SA) residues across a biocompatible hexa(ethylene glycol) (HEG) spacer. The designed materials (i.e., HA-FA-HEG-OA or HA-FA-HEG-SA) showed clear-cut aggregation features in an aqueous environment, as confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM), generating nanoaggregate systems. In fact, HA-FA-HEG-OA and HA-FA-HEG-SA derivatives showed the property to create sel…

Synthesis of polymeric derivatives of isoniazid: characterization and in vitro release from a water-soluble adduct with polysuccinimide.

Coupling of isoniazid with polysuccinimide afforded a water-insoluble polymeric pro-drug; by reaction with ethanolamine it was chemically transformed in a water-soluble adduct. The in vitro release of isoniazid from the drug-polymer adduct was studied by using an artificial stomach wall lipid membrane. The transfer rate constant from simulated gastric juice to simulated plasma was defined and compared with that of an equivalent dose of pure drug.

IDROGELI DI ACIDO IALURONICO E alfa,beta-POLIASPARTILIDRAZIDE E LORO APPLICAZIONI IN CAMPO BIOMEDICO E FARMACEUTICO

From Genesis to Revelation: The Role of Inflammatory Mediators in Chronic Respiratory Diseases and their Control by Nucleic Acid-based Drugs.

Asthma, chronic obstructive pulmonary disease, cystic fibrosis, and idiopathic pulmonary fibrosis, are among the most common chronic diseases and their prevalence is increasing. Each of these diseases is characterized by the secretion of cytokines and pro-inflammatory molecules which are thought to play a critical role in their pathogenesis. Moreover, immune cells, particularly neutrophils, macrophages and dendritic cells as well structural cells such as epithelial and airway smooth muscle cells are also involved in the pathogenic cycle of these diseases. There is a pressing need for the development of new therapies for these pulmonary diseases, particularly as no existing treatment has bee…

Biotin-Containing Reduced Graphene Oxide-Based Nanosystem as a Multieffect Anticancer Agent: Combining Hyperthermia with Targeted Chemotherapy

Among the relevant properties of graphene derivatives, their ability of acting as an energy-converting device so as to produce heat (i.e., thermoablation and hyperthermia) was more recently taken into account for the treatment of solid tumors. In this pioneering study, for the first time, the in vitro RGO-induced hyperthermia was assessed and combined with the stimuli-sensitive anticancer effect of a biotinylated inulin-doxorubicin conjugate (CJ-PEGBT), hence, getting to a nanosystem endowed with synergic anticancer effects and high specificity. CJ-PEGBT was synthesized by linking pentynoic acid and citraconic acid to inulin. The citraconylamide pendants, used as pH reversible spacer, were …

NEW SELF-ASSEMBLING POLYASPARTYLHYDRAZIDE COPOLYMER MICELLES FOR ANTICANCER DRUG DELIVERY.

A new amphiphilic copolymer have been synthesized starting from the hydrosoluble polyaspartylhydrazide (PAHy) polymer, by grafting both hydrophilic PEG(2000) chains and hydrophobic palmitic acid (C(16)) moieties on polymer backbone, and the structure of obtained PAHy-PEG(2000)-C(16) copolymer have been characterized by 2D (1)H/(13)C NMR experiments. PAHy-PEG(2000)-C(16) copolymer showed the ability of self-assembling in aqueous media giving a core-shell structure and resulted potentially useful for encapsulating and dissolving hydrophobic drug. The formation of micellar core-shell structure has been investigated by 2D (1)H NMR NOESY experiments. The presence of cross-peaks for protons of C(…

Hyaluronic acid based microparticles for applications in regenerative medicine

A large catabolic plasmid carries the genes for the dehalogenation of 4-chlorobenzoate in arthrobacter ramosus FG1

Blend scaffolds with polyaspartamide/polyester structure fabricated via TIPS and their RGDC functionalization to promote osteoblast adhesion and proliferation

Target of this work was to prepare a RGDC functionalized hybrid biomaterial via TIPS technique to achieve a more efficient control of osteoblast adhesion and diffusion on the three-dimensional (3D) scaffolds. Starting from a crystalline poly(l-lactic acid) (PLLA) and an amorphous alpha,beta-poly(N-2-hydroxyethyl) (2-aminoethylcarbamate)-d,l-aspartamide-graft-polylactic acid (PHEA-EDA-g-PLA) copolymer, blend scaffolds were characterized by an appropriate porosity and pore interconnection. The PHEA-EDA-PLA interpenetration with PLLA improved hydrolytic susceptibility of hybrid scaffolds. The presence of free amino groups on scaffolds allowed to tether the cyclic RGD peptide (RGDC) via Michael…

Hyaluronic acid based hydrogels for antibiotics and enzymes release: from academic research to industry

Conclusion: HA-g-PDLLA hydrogel is suitable to coat a prosthesis remaining adherent to it and distributing itself in the bone cavity. The hydrogel has been proven effective in a rabbit model of highly contaminated implant. In vivo studies have demonstrated how the intraoperative coating of implants with DAC is safe and feasible. HA-EDA-MA hydrogel is able to protect PEP from alteration during storage and it seems a good candidate for a potential once-daily oral formulation in the treatment of celiac disease.

NEW GENERATION OF BIOCOMPATIBLE GRAFT COPOLYMERS FOR THE PRODUCTION OF NANODEVICES

Addition reactions of azoesters with 2-thioquinazolinones

Reaction between diethyl azodicarboxylate (I) and 1,2,3,4-tetrahydro-2-thioquinazolin-4-one (II), as a cyclic model of thiourea, both in alcoholic medium and in inert solvents has been investigated. By carrying out the reaction in an inert solvent, it was possible to isolate an intermediate. Evidence is presented that the intermediate, in turn, was converted into the final products. Structures were unequivocally assigned by mass spectrometry.

Perfluorocarbon functionalized hyaluronic acid derivatives as oxygenating systems for cell culture

A set of new hyaluronic acid (HA) derivatives was obtained by binding fluorinated oxadiazole (OXA) moieties to an amino derivative of the polysaccharide (HA-EDA). The obtained HA-EDA-OXA biomaterials are potentially able to improve oxygenation into a scaffold for tissue engineering purposes. The oxygen solubility in aqueous dispersions of the obtained derivatives showed that polymers were able to improve oxygen uptake and maintenance in the medium. The HA-EDA-OXA was employed to form a hydrogel in situ by reaction with a vinyl sulphone derivative of inulin, under physiological conditions. The influence of the presence of OXA moieties on the mechanical properties of the obtained hydrogels as…

COMPOSIZIONE FARMACEUTICA OFTALMICA CONTENENTE COPOLIMERI ANFIFILICI DELLA POLIASPARTAMMIDE

SYNTHESIS AND CHARACTERIZATION OF AMPHIPHILIC GRAFT COPOLYMERS BASED ON alpha,beta-POLY(N-2-HYDROXYETHYL)-D,L-ASPARTAMIDE AS CARRIER FOR DRUG DELIVERY

Development of New Targeted Inulin Complex Nanoaggregates for siRNA Delivery in Antitumor Therapy.

Here, a novel strategy of formulating efficient polymeric carriers based on the already described INU-IMI-DETA for gene material whose structural, functional, and biological properties can be modulated and improved was successfully investigated. In particular, two novel derivatives of INU-IMI-DETA graft copolymer were synthesized by chemical functionalisation with epidermal growth factor (EGF) or polyethylenglycol (PEG), named INU-IMI-DETA-EGF and INU-IMI-DETA-PEG, respectively, in order to improve the performance of already described “inulin complex nanoaggregates” (ICONs). The latter were thus prepared by appropriately mixing the two copolymers, by varying each component from 0 to 100 wt%…

Evaluation of biodegradability of novel polymeric nanoparticles based on amphiphilic polylactide-polyaspartamide derivatives.

Hyaluronic acid and alpha-elastin based hydrogel for three dimensional culture of vascular endothelial cells

Abstract The aim of this work was to demonstrate that employing a copolymer of hyaluronic acid and α-elastin (HA-EDA-g-α-elastin) is possible to produce a scaffold able to support the adhesion and growth of human vascular endothelial cells (HUVEC) thanks to its ability to incorporate and control the diffusion of vascular endothelial growth factor (VEGF). HA-EDA-g-α-elastin was crosslinked with low molecular weight hyaluronic acid (HALMW) to obtain a hydrogel that gives rise to the formation of three dimensional sponge after the freeze drying process. The physicochemical features the obtained material along with its ability to act as a support for the three dimensional culture of endothelial…

Dexamethasone dipropionate loaded nanoparticles of α-elastin-g-PLGA for potential treatment of restenosis.

A graft copolymer of α-elastin with poly(lactic-co-glycolic) acid (PLGA) has been synthesized and successfully employed to produce nanoparticles. Exploiting the known biological activity of α-elastin to promote the maintenance of smooth muscle cells (SMCs) contractile phenotype and the antiproliferative effect of glucocorticoids, the aim of this research was to produce drug-loaded nanoparticles suitable for potential treatment of restenosis. In particular, nanoparticles of α-elastin-g-PLGA with a mean size of 200 nm have been produced and loaded with dexamethasone dipropionate (10% w/w), chosen as a model drug that inhibits proliferation of vascular SMCs. These nanoparticles are able to pro…

POLYMERIC NANOPARTICLES OBTAINED BY PHOTOCROSSLINKING OF AN ACRYLOYLATED POLYASPARTAMIDE IN INVERSE EMULSION

Photocycle of Excitons in Nitrogen-Rich Carbon Nanodots: Implications for Photocatalysis and Photovoltaics

Nitrogen-rich carbon nanodots have emerged as promising nanomaterials for a wide range of applications where a highly emissive and photoactive material with low toxicity and cost-effectiveness is required. One of their hallmarks is indeed a bright, tunable fluorescence of excitonic nature. Disentangling the origin of their optical absorption and fluorescence properties and uncovering relaxation channels and interactions with solvents are some of the most debated issues in the field. Uncovering these aspects is essential for targeted applications, especially in the fields of photocatalysis but also photovoltaics and optoelectronics. Here, we present dedicated transient absorption measurement…

Hyaluronic acid and beta cyclodextrins films for the release of corneal epithelial cells and dexamethasone

In this work we prepared hydrogels based on hyaluronic acid and β-cyclodextrins to sustain the release of both corneal epithelial cells and dexamethasone. This steroid is administered as eye drops several times per day to reduce the risk of rejection in the post operative period after the cornea transplantation and cell release techniques. Hydrogels were produced by crosslinking an amino derivative of hyaluronic acid, with the divinyl sulfone derivative of β-cyclodextrins, this last employed as a crosslinker and solubilizing agent. Drug release studies revealed that dexamethasone containing samples are able to extend the release of this drug for at least five days. Biological studies, condu…

Polycations based on polyasparthylhydrazide for gene therapy

MODIFICATION OF HYDROPHOBIC SURFACE WITH POLYASPARTAMIDE-BASED POLYCATIONS FOR BIOMEDICAL APPLICATION

A convenient way for the achievement of polymer-based solid materials for specific biomedical applications is grafting the appropriate macromolecules onto the surfaces in order to confer them specific properties. To date many approaches have been used to covalently modify polymeric surfaces, and among them chemoselective coupling reactions, usually referred as “click” reactions, gained much attention thanks to simple procedure with high reaction rate under mild reaction conditions (at normal temperature and pressure) [1]. In particular, radical-initiated thiol-yne “photo-click” chemistry has been demonstrated as an effective way to functionalize efficiently surfaces. This method gives also …

Disentangling size effects and spectral inhomogeneity in carbon nanodots by ultrafast dynamical hole-burning.

Carbon nanodots (CDs) are a novel family of nanomaterials exhibiting unique optical properties. In particular, their bright and tunable fluorescence redefines the paradigm of carbon as a "black" material and is considered very appealing for many applications. While the field keeps growing, understanding CDs fundamental properties and relating them to their variable structures becomes more and more critical. Two crucial problems concern the effect of size on the electronic structure of CDs, and to what extent their optical properties are influenced by structural disorder. Furthermore, it remains largely unclear whether traditional concepts borrowed from the photo-physics of semiconductor qua…

Spray-Drying, Solvent-Casting and Freeze-Drying Techniques: a Comparative Study on their Suitability for the Enhancement of Drug Dissolution Rates.

Purpose Solid dispersions (SDs) represent the most common formulation technique used to increase the dissolution rate of a drug. In this work, the three most common methods used to prepare SDs, namely spray-drying, solvent-casting and freezedrying, have been compared in order to investigate their effect on increasing drug dissolution rate. Methods Three formulation strategies were used to prepare a polymer mixture of polyvinyl-alcohol (PVA) and maltodextrin (MDX) as SDs loaded with the following three model drugs, all of which possess a poor solubility: Olanzapine, Dexamethasone, and Triamcinolone acetonide. The SDs obtained were analysed and compared in terms of drug particle size, drug-lo…

FOLATE-MEDIATED TARGETING OF POLYMERS AS COMPONENTS OF COLLOIDAL DRUG DELIVERY SYSTEMS

Photothermal nanofibrillar membrane based on hyaluronic acid and graphene oxide to treat Staphylococcus aureus and Pseudomonas aeruginosa infected wounds.

Here we reported the fabrication of an electrospun membrane based on a hyaluronic acid derivative (HA-EDA) to be used as a bandage for the potential treatment of chronic wounds. The membrane, loaded with graphene oxide (GO) and ciprofloxacin, showed photothermal properties and light-triggered drug release when irradiated with a near-infrared (NIR) laser beam. Free amino groups of HA-EDA derivative allowed autocrosslinking of the elec- trospun membrane; thus, a substantial enhancement in the hydrolytic resistance of the patch was obtained. In vitro antibacterial activity studies performed on Staphylococcus aureus and Pseudomonas aeruginosa revealed that such electrospun membranes, due to the…

Nanoaggregates Based on New Poly-Hydroxyethyl-Aspartamide Copolymers for Oral Insulin Absorption

The aim of this work was to produce copolymers with an appropriate hydrophilic/hydrophobic balance able to form nanoaggregates with protein molecules and to be used as ideal materials in the field of oral peptide/protein delivery. New anionic polymers obtained by the conjugation of carboxy-bearing ligands, like succinic anhydride and/or cysteine, to hydrophobized α,β-poly(N-2-hydroxyethyl)-dl-aspartamide (PHEA) copolymers have been synthesized and characterized. Starting copolymer was synthesized by the partial derivatization of hydroxyl groups on the PHEA backbone with butylamine (C4) (obtaining the PHEA-C4 copolymer, bearing a butyl moiety). The consecutive reaction of PHEA-C4 with succin…

Evaluation of polyalkylcyanoacrylate nanoparticles as a potential drug carrier: preparation, morphological characterization and loading capacity.

Some physicochemical behaviours were investigated of polyethyl- (PECA) and polyisobutylcyanoacrylate (PICA), which, in recent years, have been proposed as nanoparticle colloidal systems for drug carrying. We observed the influence of preparation conditions, such as pH value and surfactant concentration, on parameters such as particle size and polymer molecular weight. Lower operating pH values (0-2) resulted in smaller nanoparticles than those prepared at pH 5.5. The polymer molecular weight was also a function of pH: low molecular weight at low pH and vice-versa. The surfactant concentration positively influenced main particle size and polymer molecular weight. These trends were independen…

65) LUNG LOCALIZATION OF AEROSOLISED BECLOMETHASONE DIPROPIONATE-LOADED NANOPARTICLES AND THEIR POSSIBLE ROLE IN ENHANCING ANTI-INFLAMMATION ACTION ON BRONCHIAL CELLS

Micelles of hyaluronic acid-hexadecylamine derivatives for ocular release of hydrophobic durgs

The topical route is the ideal way to release drugs to the eye. Unfortunately, the low ocular drug bioavailability associated with this route of administration, makes not very efficient the treatment of several ocular diseases. Nowadays, polymeric micelles occupy a significant role in the field of ocular drug delivery thanks to the advantages that they offer in comparison with the administration of drugs in the free form. Indeed, polymeric micelles are suitable for delivering hydrophobic drugs and they seem to be very promising in ocular drug delivery for their high kinetic and thermodynamic stability. Also, micellar systems are able to give a controlled drug release and to act as absorptio…

Nanostructured Lipid Carriers-Containing Anticancer Compounds: Preparation, Characterization, and Cytotoxicity Studies

This article describes the development of nanostructured lipid carriers (NLC) as colloidal carriers for two antitumor compounds that possess a remarkable antineoplastic activity. But their limited stability and low solubility in water could give a very low parenteral bioavailability. Results revealed an enhancement of the cytotoxicity effect of drug-loaded NLC on human prostate cancer (PC-3) and human hepatocellular carcinoma (HuH-6, HuH-7) cell lines with respect to that of both free drugs. Results of characterization studies strongly support the potential application of these drugs-loaded NLC as prolonged delivery systems for lipophilic drugs by several administration routes, in particula…

Microfibers of a Hyaluronic Acid Derivative to Mimic Blood Vessels

Inulin derivatives obtained via enhanced microwave synthesis as potential drug delivery system.

PHOTOCROSSLINKING OF DEXTRAN AND POLYASPARTAMIDE DERIVATIVES: A COMBINATION SUITABLE FOR COLON- SPECIFIC DRUG DELIVERY.

The aim of this study was to prepare and characterize novel hydrogels with polysaccharide–polyaminoacid structure, able to undergo an enzymatic hydrolysis in the colon and potentially useful for treating inflammatory bowel diseases (IBD). Starting materials were methacrylated dextran (DEX-MA) and methacrylated α,β-poly(N-2-hydroxyethyl)-DL-aspartamide (PHM). These polymers were photocrosslinked by exposure of their aqueous solutions at 313 nm without photoinitiators. Different samples, shaped as microparticles, were obtained as a function of polymer concentration and irradiation time. FT-IR analysis confirmed the occurrence of a co-crosslinking between DEX-MA and PHM in all experimental con…

Synthesis of Biocompatible and Biodegradable Polyamidoamines Microgels via a Simple and Reliable Statistical Approach.

Polyamidoamines (PAAs) are biocompatible and biodegradable polymers with a huge potential as biomaterials for pharmaceutical applications. They are obtained by the step-wise aza-Michael polyaddition of bifunctional or multifunctional amines with bisacrylamides in water. To the best of our knowledge, no synthetic protocols leading to hyperbranched PAAs as well as PAA microgels have been published so far. To fill this gap, a statistical approach was established in this work to fine-tune the aza-Michael polyaddition stoichiometry when a multifunctional co-monomer (bf) is added to a mixture of bifunctional monomers with complementary functions (a2 + b2), possibly even in presence of a monofunct…

Reversibly stable thiopolyplexes for intracellular delivery of genes.

Novel polyaspartamide non-viral carriers for gene therapy were synthesized by introducing, on the same polymer backbone, positively charged groups, for electrostatic interactions with DNA, and thiol groups for the formation of disulfide bridges between polymer chains. The introduction of thiols was aimed to have a vector with low redox potential sensitivity: disulfide crosslinking in fact, being stable in extracellular environment, allowed either to have stable complexes in plasma, that can protect DNA from metabolism, or to be reduced inside the cell, where the excess of glutathion in reduced form maintains a low redox potential. The consequent destabilization of the complex after disulfid…

New folate-functionalized biocompatible block copolymer micelles as potential anti-cancer drug delivery systems

Abstract The main objective of this study was to synthesize novel folic acid-functionalized diblock copolymer micelles and evaluate their solubilization of two poorly water-soluble anti-tumor drugs, tamoxifen and paclitaxel, which suffer from low water solubility and/or poor hydrolytic stability. The diblock copolymer consisted of a permanently hydrophilic block comprising 2-(methacryloyloxy)ethyl phosphorylcholine (MPC) residues and a pH-sensitive hydrophobic block comprising 2-(diisopropylamino)ethyl methacrylate (DPA) residues. Folic acid (FA) was conjugated to the end of the MPC block so that this group was located on the micelle periphery. Tamoxifen- and paclitaxel-loaded micelles were…

A new pH responsive polymer based on inulin for siRNA Delivery

Cationic solid lipid nanoparticles complexed with genetic material for liver tumor treatment

Concept Gene therapy is a growing field of medicine with great potential for the treatment of several diseases and it is based on the delivery of nucleic acids (DNA, RNA, etc.,) to specific cells. To achieve their therapeutic effects, the nucleic acids need to cross several biological barriers and be protected from the degradation by nucleases, present in biological fluids and intracellular compartments, to successfully gain access to their intracellular targets. To overcome these hurdles, it is necessary to deliver the genetic material with biocompatible carriers able to facilitate its translocation across the cell membranes and protect it from being degraded while circulating in the blood…

New hydrogel matrices containing an anti-inflammatory agent. Evaluation of in vitro release and photoprotective activity.

In the present work. the preparation and characterization of hydrogels based on alpha,beta-polyaspartylhydrazide (PAHy) chemically crosslinked with ethyleneglycol diglycidylether (EGDGE) containing Tolmetin sodium salt, are reported. In particular, these samples have been prepared both as water swellable microparticles and as gels at two different crosslinking degrees. The incorporation of Tolmetin sodium salt in PAHy-EGDGE microparticles has been performed after the crosslinking reaction by a soaking procedure or during the formation of the network. The influence of drug loading procedure on Tolmetin release has been evaluated by performing in vitro release study in simulated gastrointesti…

Injectable in situ forming microgels of hyaluronic acid-g-polylactic acid for methylprednisolone release

Abstract A hydrophobic derivative of hyaluronic acid (HA), obtained by grafting polylactic acid (PLA) to the polysaccharide, has been exploited to produce injectable in situ forming microgels. First of all, self assembling properties of HA-g-PLA copolymer have been evaluated by determining the critical aggregation concentration (CAC) value, then this copolymer has been dissolved in a mixture water/NMP 5:2 v/v with a concentration greater than CAC. When solutions at 1% or 2% w/v were injected into Dulbecco phosphate buffer solution (DPBS) pH 7.4, microgels promptly are formed. Their stability in DPBS pH 7.4 in the absence or in the presence of hyaluronidase and cell compatibility have been e…

Isolation of Gram positive n-alkane degraders from a hydrocarbon contaminated sicilian shoreline

Drug release from alpha,beta-poly(N-2-hydroxyethyl)-DL-aspartamide-based microparticles.

Abstract Spherical pH-sensitive microparticles have been prepared by reverse phase suspension polymerization technique. Starting polymer has been α , β -poly( N -2-hydroxyethyl)- dl -aspartamide (PHEA) partially derivatized with glycidylmethacrylate (GMA). PHEA-GMA copolymer (PHG) has been crosslinked in the presence of acrylic acid (AA) or methacrylic acid (MA) at various concentration. The obtained microparticles have been characterized by FT-IR spectrophotometry, particle size distribution analysis and scanning electron microscopy. In order to have information about water affinity of the prepared samples, swelling measurements have been carried out in aqueous media which simulate some bi…

CATIONIC SLN AS TARGETING DRUG DELIVERY SYSTEMS

Nanoscience and nanotechnology have received much attention in the last decade and they actually form one of the most important fields of technology and innovation. Due to rapid progresses in nanotechnology and biotechnology, nanoparticles have come to be seen as a viable vehicle for the delivery and release of drugs and nucleic acids. Within this field, the use of solid lipid nanoparticles (SLNs) is of particular importance. In particular, cationic SLN are promising non-viral gene delivery carriers suitable for systemic and topic administration. The surface of these nanoparticles is positively charged and the negatively charged nucleic acids are complexed to the their surface. The obtained…

ANTIBACTERIAL HYDROGEL AND USE THEREOF IN ORTHOPEDICS.

Composizione farmaceutica a rilascio controllato e/o programmato

Polybenzofulvene derivatives bearing dynamic binding sites as potential anticancer drug delivery systems.

In order to obtain new advanced functional materials capable of recognizing drug molecules, the polybenzofulvene backbone of molecular brush poly-6-MOEG-9-TM-BF3k has been functionalized with a “synthetic dynamic receptor” composed of two 1-adamantylurea moieties linked together by means of a dipropyleneamino bridge as in Meijer's bis(adamantylurea) pincer (BAUP). This functional material, bearing synthetic receptors potentially capable of recognizing/loading and then delivering drug molecules, was used to prepare colloidal drug delivery systems (by means of soft interaction with BAUP) for delivering the model anti-cancer drug doxorubicin (DOXO). The resulting nanostructured drug delivery s…

Double-Network-Structured Graphene Oxide-Containing Nanogels as Photothermal Agents for the Treatment of Colorectal Cancer.

Here, we reported the production of hyaluronic acid/polyaspartamide-based double-network nanogels for the potential treatment of colorectal carcinoma. Graphene oxide, thanks to the huge aromatic surface area, allows to easily load high amount of irinotecan (33.0% w/w) and confers to the system hyperthermic properties when irradiated with a near-infrared (NIR) laser beam. We demonstrate that the release of antitumor drug is influenced both by the pH of the external medium and the NIR irradiation process. In vitro biological studies, conducted on human colon cancer cells (HCT 116), revealed that nanogels are uptaken by the cancer cells and, in the presence of the antitumor drug, can produce a…

Design of New Polyaspartamide Copolymers for siRNA Delivery in Antiasthmatic Therapy

Here, a novel protonable copolymer was realized for the production of polyplexes with a siRNA (inhibitor of STAT6 expression in asthma), with the aim of a pulmonary administration. The polycation was synthesized by derivatization of &alpha

Microfibers and Nanoparticles with Controlled Dimensions of a Hyaluronic Acid Derivative

Microfluidics is defined as the technology that deals with the precise control and manipulation of small quantities of fluids constrained in micro-channels of small cross-sectional dimensions [1]. Microfluidics has recently emerged as a very promising route for the production of polymeric fibers at the micro and nanoscale, providing a fine control over fiber shape, size, chemical anisotropy and biological activity [2]. Furthermore, the ability to manipulate nanoliter volumes of liquid and to control mixing and reaction precisely, opens up the possibility of creating smart targeted drug delivery systems as nanoparticles, especially with uniform and narrow size distribution [3]. This work des…

Derivati polianionici di una poliaspartammide: sintesi e caratterizzazione di idrogeli stimolo-sensibili

Studies of macromolecular prodrugs of zidovudine.

Abstract The current problems in controlling severe viral infections such as AIDS as well as the lack of effective and safe therapeutic measures for such diseases have caused interest in systems such as macromolecular prodrugs potentially able to solve heavier drawbacks of conventional antiviral therapy. This review focuses on various approaches proposed in the literature in this field. Neoglycoproteins and synthetic protein-like structure polymers have been mainly proposed. In the first group, the possibility of incorporating into the polymeric structures a determined amount of sugar molecules make them interesting candidates for targeting of infected blood cells. The conjugate of zidovudi…

Polyhydroxyethylaspartamide-based micelles for ocular drug delivery

In this paper three copolymers of polyhydroxyethylaspartamide (PHEA), bearing in the side chains polyethylene glycol (PEG) and/or hexadecylamine (C(16)) (PHEA-PEG, PHEA-PEG-C(16) and PHEA-C(16) respectively) have been studied as potential colloidal drug carriers for ocular drug delivery. The physical characterization of all three PHEA derivatives, using the Langmuir trough (LT) and micellar affinity capillary electrophoresis (MACE) techniques allowed to assume that whereas alone PHEA backbone is an inert polymer with respect to the interactions with lipid membranes and drug complexation, when PHEA chains are grafted with long alkyl chains like C(16) or in combination C(16) chains and hydrop…

Polymeric micelles containing squalenoyl chains for the delivery of drugs to the central nervous system

ChemInform Abstract: Reaction of 2-Acetyltetralone with Some Esters of Benzoic Acid.

In order to investigate the pharmacological screening of a number of pyran-4-ones their synthesis by cyclization with sulphuric acid of the corresponding 1,3,5-triketones has been carried out with high yields. In the course of preparation of the latter the reaction of 2-acetyltetralone with some esters of benzoic acid derivatives has been studied and in particular, for a number of them, an interesting nucleophilic substitution of a chlorine atom with an alkoxy group on a benzenic nucleus has been evidenced.

Molecular characterization of α,β-poly(N-2-hydroxyethyl)-dl-aspartamide derivatives as potential self-assembling copolymers forming polymeric micelles

A family of graft copolymers derivatives obtained from α,β-poly(N-2-hydroxyethyl)-dl-aspartamide (PHEA) have been studied as potential self-assembling macromolecules forming stable polymeric micelles at low critical micellar concentration. These polymers are obtained grafting on PHEA poly(ethylene glycol) (PEG) (Mw 5000 g/mol) (PHEA–PEG), hexadecylamine (PHEA–C16) or both moieties (PHEA–PEG–C16). The PHEA derivatives were characterised by a multi-angle light scattering (MALS) photometer on line to a size exclusion chromatography system in obtaining the molar mass distribution of the polymers. In addition, to investigate the capacity to form micellar aggregates in aqueous medium the MALS pho…

SOLUBLE AND WATER-SWELLABLE POLYAMINOACIDIC CONSTRUCTS FOR DRUG DELIVERY

Injectable in situ forming hydrogels based on natural and synthetic polymers for potential application in cartilage repair

In this work we prepared two new hyaluronic acid (HA) based in situ forming hydrogels for the potential treatment of articular cartilage damages. In particular the amino derivative of HA (HA-EDA) and its graft copolymer with α-elastin (HA-EDA-g-α-elastin) were crosslinked, in mild physiological conditions via Michael-type addition, with α,β-poly(N-2-hydroxyethyl)-dl-aspartamide (PHEA) derivatized with divinylsulfone (DV). The swelling and degradation profile of the obtained hydrogels as well as the metabolic activity of incorporated bovine articular chondrocytes were investigated. Histological analysis and scanning electron microscopy (SEM) were performed to analyze the morphology of cells …

SPERMINATED POLYASPARTAMIDE COPOLYMERS AS VECTORS FOR GENE THERAPY

PHEA-Dox nanoparticles as pH-sensitive model for drug delivery in tumour treatment.

PHEA-Dox nanoparticles as pH-sensitive model for drug delivery in tumour treatment. S. Camporaa, G. Adamoa, N. Maurob, C. Scialabbab, M. Licciardib, G. Giammonab and G. Ghersia. aDipartmento di “Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche” (STEBICEF), Università di Palermo, Viale delle Scienze Ed. 16, 90128 Palermo, Italy. bLaboratory of Biocompatible Polymers, Dipartmento di “Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche” (STEBICEF), Università di Palermo, Via Archirafi, 32 90123 Palermo, Italy. Classical chemotherapeutic applications, using molecules such as doxorubicin (Dox), have side effects due to an unspecific action. In order to obtain a specific release of…

Carbon Nanodots for On Demand Chemophotothermal Therapy Combination to Elicit Necroptosis: Overcoming Apoptosis Resistance in Breast Cancer Cell Lines

Background: Engineered luminescent carbon nanodots (CDs) are appealing nanomaterials for cancer image-guided photothermal therapy combining near infrared (NIR)&ndash

Chemical stiffening of constructs between polymeric microparticles based on a hyaluronic acid derivative and mesenchymal stem cells: rheological and in vitro viability studies

Our research group has recently developed microparticles of a hyaluronic acid derivative used for bottom-up growth of microparticles/human mesenchymal stem cells (hMSCs). In this work, we investigated a strategy to increase the stiffening of aggregated constructs between microparticles and hMSCs. In particular, we applied a Michael-type crosslinking procedure between microparticles to allow a chemically driven and cell-compatible stiffening of constructs. Two batches of microparticles were functionalized with thiol and maleimide groups, respectively, and were then mixed to allow chemical crosslinking. The adhesion of hMSCs was controlled through addition of the adhesive peptide cyclo(-Arg-G…

Biocompatible Hydrogels Based on Hyaluronic Acid Cross-Linked with a Polyaspartamide Derivative as Delivery Systems for Epithelial Limbal Cells

Effect of actively targeted copolymer coating on solid tumors eradication by gold nanorods-induced hyperthermia.

Efforts in the field of anticancer therapy are increasingly focusing on the development of localized and selective treatments. Photothermal therapy (PTT) can lead to a spatially confined death of cancer cells, exploiting an increasing in temperature generated after UV-NIR irradiation of peculiar materials. Herein, a new actively targeted gold-based drug delivery system, named PHEA-LA-Fol-AuNRs/Iri, was explored for hyperthermia and chemotherapy colon cancer treatment. Gold nanorods were stabilized using a folate-derivative of α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA-LA-PEG-FA) as coating agent and then loaded with the antineoplastic drug irinotecan (Iri). The efficacy of empty and i…

A Fibrillar Biodegradable Scaffold for Blood Vessels Tissue Engineering

In recent years there has been a growing interest for the development of tubular scaffolds employed to assist the replacement of small blood vessels. Materials designed for this purpose need to be biodegradable, have good mechanical properties and improve cell adhesion, proliferation and differentiation. To obtain biomaterials with these properties, electrospinning seems to be one of the most useful technique. Several biodegradable synthetic polymers or constituents of the extracellular matrix (ECM) have been electrospun showing optimal mechanical properties and biodegradability. However, such polymers are lacking in versatile chemical structure affordable to immobilize growth factors or ch…

Inulin-based polymer coated SPIONs as potential drug delivery systems for targeted cancer therapy

This paper deal with the synthesis and characterization of PEGylated squalene-grafted-inulin amphiphile capable of self-assembling and self-organizing into nanocarriers once placed in aqueous media. It was exploited as coating agent for obtaining doxorubicin loaded superparamagnetic iron oxide nanoparticles (SPIONs) endowed with stealth like behavior and excellent physicochemical stability. Inulin was firstly modified in the side chain with primary amine groups, followed in turn by conjugation with squalenoyl derivatives through common amidic coupling agents and PEGylation by imine linkage. Polymer coated SPIONs were so obtained by spontaneous self-assembling of inulin copolymer onto magnet…

SYNTHESIS AND PHYSICO-CHEMICAL CHARACTERIZATION OF NEW PHEA-GRAFT COPOLYMERS OBTAINED BY ARTP

Sintesi di nuovi copolimeri graft di acido ialuronico,polietilenglicole ed acido lattico

SUPERPARAMAGNETIC HYDROPHOBIC POLYASPARTAMIDE NANOPARTICLES FOR ANTICANCER DRUG DELIVERY

NEW PEGYLATED POLYHYDROXYETHYLASPARTAMIDE-SPERMINE COPOLYMER AS GENE DELIVERY SYSTEM

EVALUATION OF BIODEGRADABILITY ON POLYSPARTAMIDE-POLYLACTIC ACID BASED NANOPARTICLES BY CHEMICAL HYDROLYSIS STUDIES POLYMER DEGRADATION AND STABILITY

Here, the synthesis of two graft copolymers based on α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA) and poly(lactic acid) (PLA), the O-(2-aminoethyl)-O′-galactosyl polyethylene glycol (GAL-PEG-NH2) or the methoxypolyethylene glycol amine (H2N-PEG-OCH3) is described. Starting from the obtained PHEA-PLA-PEG-GAL and PHEA-PLA-PEG copolymers, polymeric nanoparticles were prepared by high pressure homogenization–solvent evaporation method. To demonstrate their biodegradability as a function of the matrix composition, a chemical stability study was carried out until 21 days by incubating systems in two media mimicking physiological compartments (pH 7.4 and pH 5.5). The degradability of both nan…

PHOTOCROSSLINKED POLYMERIC NANOPARTICLES OBTAINED FROM AN ACRYLOYLATED POLYASPARTAMIDE

Heparin functionalized polyaspartamide/polyester scaffold for potential blood vessel regeneration

An interesting issue in tissue engineering is the development of a biodegradable vascular graft able to substitute a blood vessel and to allow its complete regeneration. Here, we report a new scaffold potentially useful as a synthetic vascular graft, produced through the electrospinning of α,β-poly(N-2-hydroxyethyl) (2-aminoethylcarbamate)-D,L-aspartamide-graft-polylactic acid (PHEA-EDA-g-PLA) in the presence of polycaprolactone (PCL). The scaffold degradation profile has been evaluated as well as the possibility to bind heparin to electrospun fibers, being it a known anticoagulant molecule able to bind growth factors. In vitro cell compatibility has been investigated using human vascular e…

Photo-Cross-Linked Hydrogels with Polysaccharide−Poly(amino acid) Structure:  New Biomaterials for Pharmaceutical Applications

The aim of this work has been the preparation and characterization of novel hydrogels with polysaccharide-poly(amino acid) structure having suitable physicochemical properties for pharmaceutical applications. In the first step, hyaluronic acid (HA) and alpha,beta-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) have been derivatized with methacrylic anhydride (AMA), thus obtaining HA-AMA and PHM derivatives, respectively. In the second step, aqueous solutions of both these derivatives have been irradiated at 313 nm to obtain chemical hydrogels. The hydrogel obtained by irradiating for 15 min an aqueous solution containing 4% w/v of HA-AMA and 4% w/v of PHM resulted in the highest yield. Its swe…

SMART HYDROGELS FOR DRUG DELIVERY

Salmeterol Xinafoate (SX) loaded into mucoadhesive solid lipid microparticles for COPD treatment

Chronic obstructive pulmonary disease (COPD) is one of the main health problems worldwide. It is characterised by chronic inflammation in the lungs that leads to progressive, chronic, largely irreversible airflow obstruction. The use of long-acting β agonists remain today the frontline treatment for COPD with the aim of minimizing side effects and enhancing therapeutic usefulness. To this purpose, in this paper, mucoadhesive solid lipid microparticles (SLMs) containing a long-acting β-2 agonist, Salmeterol Xinafoate (SX) were prepared, characterised (size, z-potential, aerodynamic diameter, turbidimetric evaluations, drug loading and entrapping efficiency) and tested in a model of bronchial…

Polyaminoacid–doxorubicin prodrug micelles as highly selective therapeutics for targeted cancer therapy

An amphiphilic copolymer carrying high-dose doxorubicin (21% on a weight basis), PHEA–EDA–P,C–Doxo, was prepared by coupling doxorubicin with a biocompatible polyaminoacid through a pH-sensitive spacer. Additional derivatization with 4-pentynoic acid endows it with self-assembling properties by means of π–π stacking. These micelles can be triggered to promptly release drug in lysosomes (∼40% in 12 h) through pH-dependent micelle hydrolysis after uptake. In vitro tests on co-cultures of cancer (MDA-MB 231) and normal (HB-2) breast cells proved that the conjugate was selectively internalized into the former rather than normal cells, exploiting the caveolae-dependent endocytosis pathway, expla…

SPIONs embedded in polyamino acid nanogels to synergistically treat tumor microenvironment and breast cancer cells.

Abstract The extremely complex tumor microenvironment (TME) in humans is the major responsible for the therapeutic failure in cancer nanomedicine. A new concept of disease-driven nanomedicine, henceforth named “Theranomics”, which attempts to target cancer cells and TME on the whole, represents an attractive alternative. Herein, a nanomedicine able to co-deliver doxorubicin and a tumor suppressive proteolytic protein such as collagenase-2 was developed. We successfully obtained superparamagnetic nanogels (SPIONs/Doco@Col) via the intermolecular azide-alkyne Huisgen cycloaddition. We demonstrated that a local ECM degradation and remodeling in solid tumors by means of collagenase-2 could enha…

HYALURONAN/POLYASPARTAMIDE BASED BIOMATERIALS AS GENE ACTIVATED MATRICES

Bioadhesive disk based on photo-crosslinkable polyaspartamide derivative for drug delivery

Correlating Rheological Properties of a Gellan Gum-Based Bioink: A Study of the Impact of Cell Density.

Here, for the production of a bioink-based gellan gum, an amino derivative of this polysaccharide was mixed with a mono-functionalized aldehyde polyethyleneglycol in order to improve viscoelastic macroscopic properties and the potential processability by means of bioprinting techniques as confirmed by the printing tests. The dynamic Schiff base linkage between amino and aldehyde groups temporally modulates the rheological properties and allows a reduction of the applied pressure during extrusion followed by the recovery of gellan gum strength. Rheological properties, often related to printing resolution, were extensively investigated confirming pseudoplastic behavior and thermotropic and io…

SOLID LIPID NANOPARTICLES (SLN) AS DRUG CARRIERS FOR NEUROPROTECTIVE AGENTS: PREPARATION, CHARACTERIZATION AND RELEASE STUDIES

Understanding the role of graphene oxide in the capture and eradication of circulating tumor cells

The capture of circulating cancer cells on functional biomaterials is expected to control metastatic spread of a tumor, which is related to good probability containing the progression of disease burden. (1) The physicochemical characteristics of a biomaterial surface highly affect cell recruitment and adhesion, which is of great importance in such applications. Here, we designed a poly(caprolactone)-based nanocompsite scaffold, henceforth PCLMF-GO, to simultaneously recruit and kill circulating cancer cells by tuning physicochemical features of the scaffold surface through nitrogen plasma activation and hetero-phase graphene oxide (GO) covalent functionalization. Nitrogen plasma activation …

RHEOLOGICAL AND RELEASE PROPERTIES OF FUNCTIONALIZED INULIN HYDROGELS

α,β-poly(asparthylhydrazide)–glycidyltrimethylammonium chloride copolymers (PAHy–GTA): novel polymers with potential for DNA delivery

Hydrophilic polycations form complexes when mixed with plasmids. Following functionalisation with glycidyltrimethylammonium chloride (GTA) alpha,beta-poly(asparthylhydrazide) (PAHy), a water-soluble synthetic macromolecule, becomes polycationic and potentially useful for systemic gene delivery. Initially the biocompatibility of PAHy and PAHy-GTA derivatives with different degrees of positive charge substitution were studied and it was shown that PAHy-GTA was neither haemolytic nor cytotoxicity up to 1 mg/ml. After intravenous injection (125)I-labelled PAHy-GTA derivative containing 46 mol% (PAHy-GTA(b)) of trimethylammonium groups did not accumulate in the liver (4.1+/-0.9% of the recovered…

Multifibrillar bundles of a self-assembling hyaluronic acid derivative obtained through a microfluidic technique for aortic smooth muscle cell orientation and differentiation

A hyaluronic acid derivative that is able to physically crosslink in a saline aqueous environment was employed for the production of fibers with a mean diameter of 50 μm using a microfluidic technique. The microfibers were collected in a tailored rotating collector and assembled to form multifibrillar bundles. The orientation of the microfibers on the collected bundles was evaluated by microCT analysis. The bundles were biofunctionalized by physical addition of fibronectin or chemical tethering of a cyRGDC peptide to achieve control of Aortic Smooth Muscle Cell (AoSMC) attachment, elongation and alignment. The mechanical performances of these bundles were evaluated by elongation tests, rela…

Galactosylated polyaspartamide copolymers for siRNA targeted delivery to hepatocellular carcinoma cells

The limited efficacy of available treatments for hepatocellular carcinoma (HCC) requires the development of novel therapeutic approaches. We synthesized a novel cationic polymer based on α,β-poly-(N-2-hydroxyethyl)-D,L-aspartamide (PHEA) for drug delivery to HCC cells. The copolymer was synthesized by subsequent derivatization of PHEA with diethylene triamine (DETA) and with a polyethylene glycol (PEG) derivative bearing galactose (GAL) molecules, obtaining the cationic derivative PHEA-DETA-PEG-GAL. PHEA-DETA-PEG-GAL has suitable chemical-physical characteristics for a potential systemic use and can effectively deliver a siRNA (siE2F1) targeted against the transcription factor E2F1, a gen…

Self-organized environment-sensitive inulin–doxorubicin conjugate with a selective cytotoxic effect towards cancer cells

An inulin-based random copolymer bearing high dose doxorubicin (18.45% on a weight basis), INU-EDA-P, C-DOXO, was prepared by coupling doxorubicin with inulin though a citraconylamide bridge used as a pH sensitive spacer. A further conjugation with pentynoic acid via an amidic bond led to the hydrophobization of the copolymer which allows the acquisition of a self-assembling ability at low concentration (0.33 mg mL(-1)) combining both Pi-Pi stacking and London interactions. Drug release studies were carried out at different pH demonstrating a remarkable pH dependency, where the maximum release rate was observed at pH mimicking cancer tissue and lysosomal environments. Besides, by measuring …

Graphene oxide containing hyaluronic acid based nanogels for the potential treatment of colorectal cancer

Here, we reported the production of graphene oxide (GO) containing nanogels produced by a top-down procedure employing as a starting biomaterial an amino derivative of hyaluronic acid named HA-EDA. This derivative was reacted, in the presence of single layer GO, with α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide-((2-aminoethyl)-carbamate)-divinyl sulfone (PHEA-DVS) employed as a macromolecular crosslinking agent. The so obtained hydrogel was homogenized by ultra-turrax and high pressure homogenizer and nanogels with Z-average of 390 nm and PDI of 0.22 were obtained. These nanogels were employed to incorporate Irinotecan (IT), an antitumor drug used in the treatment of colorectal carcinoma. It …

Lipid nanoparticles as delivery vehicles for the Parietaria judaica major allergen Par j 2

Maria Luisa Bondì1,*, Giovanna Montana2,*, Emanuela Fabiola Craparo3, Roberto Di Gesù3, Gaetano Giammona3, Angela Bonura2, Paolo Colombo21Istituto per lo Studio dei Materiali Nanostrutturati, 2Istituto di Biomedicina ed Immunologia Molecolare, Consiglio Nazionale delle Ricerche, 3Laboratory of Biocompatible Polymers, Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari Stembio, Università di Palermo, Palermo, Italy *These authors contributed equally to this workAbstract: Parietaria pollen is one of the major causes of allergic reaction in southern Europe, affecting about 30% of all allergic patients in this area. Specific immunotherapy is the only…

Hyaluronic acid, elastin and heparin containing scaffolds for the treatment of skin chronic wounds

POLYMERIC MICELLES AS TUNABLE OFF-ON-OFF pH WINDOW BIOSENSORS.

Reactions of azoesters and dimethyl acetylenedicarboxylate with 3-methyl-1,2,4-triazole-5-thione

The addition of dimethyl acetylenedicarboxylate to 3-methyl-1,2,4-triazole-5-thione (1), both in alcoholic medium and in inert solvents, has been investigated. When 1 was allowed to react with diethyl azodicarboxylate a disulfide 5 was obtained.

Peculiar mechanism of solubilization of a sparingly water soluble drug into polymeric micelles. Kinetic and equilibrium studies.

Complementary kinetic and equilibrium studies on the solubilization process of the sparingly water soluble tamoxifen (TAM) drug in polymeric aqueous solutions have been performed by using the spectrophotometric method. In particular, the amphiphilic copolymers obtained by derivatization of polymeric chain of poly(N-2-hydroxyethyl)-dl-aspartamide, PHEA, with poly(ethylene glycol)s, PEG (2000 or 5000 Da), and/or hexadecylamine chain, C16, namely PHEA-PEG2000-C16, PHEA-PEG5000-C16, PHEA-C16, have been employed. Preliminary to the kinetic and equilibrium data quantitative treatment, the molar absorption coefficient of TAM in polymeric micelle aqueous solution has been determined. By these studi…

Galactosylated Polymer/Gold Nanorods Nanocomposites for Sustained and Pulsed Chemo-Photothermal Treatments of Hepatocarcinoma

In this paper, we propose a rational design of a hybrid nanosystem capable of locally delivering a high amount of hydrophobic anticancer drugs (sorafenib or lenvatinib) and heat (hyperthermia) in a remote-controlled manner. We combined in a unique nanosystem the excellent NIR photothermal conversion of gold nanorods (AuNRs) with the ability of a specially designed galactosylated amphiphilic graft copolymer (PHEA-g-BIB-pButMA-g-PEG-GAL) able to recognize hepatic cells overexpressing the asialoglycoprotein receptor (ASGPR) on their membranes, thus giving rise to a smart composite nanosystem for the NIR-triggered chemo-phototherapy of hepatocarcinoma. In order to allow the internalization of A…

Self-assembling and auto-crosslinkable hyaluronic acid hydrogels with a fibrillar structure

Abstract A hyaluronic acid derivative bearing pendant l -benzoyl-cysteine portions (with a derivatization degree equal to 10 mol.%) was synthesized by linking N,N′-dibenzoyl- l -cystine to the polysaccharide and then reducing its disulfide bridge to thiol groups. The formation of π–π stacking interactions between the benzoyl moieties was studied by fluorescence spectroscopy as a function of polymer concentration and oxidation time. The efficiency of oxidation of thiol groups to disulfide bridges occurring in phosphate buffer pH 7.4, was determined by colorimetric assays. The hydrogel formed by means of oxidative crosslinking has shown the presence of fibrillar aggregates as detected by ligh…

Microfibrillar polymeric ocular inserts for triamcinolone acetonide delivery.

Abstract Despite eye drops generally represent the most convenient, simple and patient-friendly formulations to treat ocular diseases, they suffer from poor retention on the ocular surface and low drug bioavailability leading to the necessity of prolonged and continuous treatment over time. Therefore, ocular insert could represent an innovative way to benefit from ocular topical administration while minimizing all the relevant limitation related to this route of administration. Polymeric non-erodible mucoadhesive ocular inserts should be comfortable and should rapidly adhere on the ocular surface, remain in situ for prolonged period, assure a reproducible and controlled drug release as well…

Photocrosslinking of dextran and polyaspartamide derivatives: a combination suitable for colon-specific drug delivery.

Abstract The aim of this study was to prepare and characterize novel hydrogels with polysaccharide–polyaminoacid structure, able to undergo an enzymatic hydrolysis in the colon and potentially useful for treating inflammatory bowel diseases (IBD). Starting materials were methacrylated dextran (DEX-MA) and methacrylated α,β-poly(N-2-hydroxyethyl)- dl -aspartamide (PHM). These polymers were photocrosslinked by exposure of their aqueous solutions at 313 nm without photoinitiators. Different samples, shaped as microparticles, were obtained as a function of polymer concentration and irradiation time. FT-IR analysis confirmed the occurrence of a co-crosslinking between DEX-MA and PHM in all exper…

Hydrophilic and hydrophobic copolymers of a polyasparthylhydrazide bearing positive charges as vector for gene therapy

BACKGROUND: The design of polymeric vectors for gene delivery provided with specific properties is one of the most critical aspects for a successful gene therapy. These polymers should be biocompatible as well as able to carry efficiently DNA to target tissues and to transfect it into cells. RESULTS: The formation of complexes of poly[(α,β-asparthylhydrazide)–poly(ethylene glycol)] and poly[(α,β-asparthylhydrazide)–hexadecylamine] copolymers functionalised with glycidyltrimethylammonium chloride (PAHy–PEG-GTA and PAHy–C16-GTA, respectively) with DNA was studied. The effects of the introduction of hydrophilic (PEG) or hydrophobic (C16) moieties on the chains of PAHy–GTA copolymers, such as t…

SINTESI E CARATTERIZZAZIONE DI NUOVI POLICATIONI DELLA POLIASPARTILIDRAZIDE IDROFOBIZZATI UTILIZZABILI PER IL DRUG E IL GENE DELIVERY

Drug release from α,β-poly(N-2-hydroxyethyl)-DL-aspartamide based microparticles

Spherical pH-sensitive microparticles have been prepared by reverse phase suspension polymerization technique. Starting polymer has been alpha,beta-poly(N-2-hydroxyethyl)-dl-aspartamide (PHEA) partially derivatized with glycidylmethacrylate (GMA). PHEAGMA copolymer (PHG) has been crosslinked in the presence of acrylic acid (AA) or methacrylic acid (MA) at various concentration. The obtained microparticles have been characterized by FT-IR spectrophotometry, particle size distribution analysis and scanning electron microscopy. In order to have information about water affinity of the prepared samples, swelling measurements have been carried out in aqueous media which simulate some biological f…

HYALURONAN CROSS-LINKED WITH alpha,beta-POLYASPARTYLHYDRAZIDE BASED SCAFFOLDS FOR TISSUE ENGINEERING

Inulin-Based Polymeric Micelles Functionalized with Ocular Permeation Enhancers: Improvement of Dexamethasone Permeation/Penetration through Bovine Corneas

Ophthalmic drug delivery is still a challenge due to the protective barriers of the eye. A common strategy to promote drug absorption is the use of ocular permeation enhancers, while an innovative approach is the use of polymeric micelles. In the present work, the two mentioned approaches were coupled by conjugating ocular permeation enhancers (PEG2000, carnitine, creatine, taurine) to an inulin-based co-polymer (INU-EDA-RA) in order to obtain self-assembling biopolymers with permeation enhancer properties for the hydrophobic drug dexamethasone (DEX). Inulin derivatives were properly synthetized, were found to expose about 2% mol/mol of enhancer molecules in the side chain, and resulted abl…

PRODUCTION OF MICELLES FROM HYALURONIC ACID AMPHIPHILIC DERIVATIVES FOR TARGETED RELEASE OF DOXORUBICIN

NOVEL REVERSIBLY STABLE THIOPOLYCATIONS BASED ON POLYASPARTAMIDE

DNA PLASMID DELIVERY INTO HEPATOCELLULAR CARCINOMA CELLS BY COMPLEXATION WITH SOLID LIPID NANOPARTICLES

Medicated hydrogels of hyaluronic acid derivatives for use in orthopedic field

NEW AMPHIPHILIC HYALURONIC ACID COPOLYMERS BEARING PEG AND PLA CHAINS

Hydrogels containing 5-Fluorouracil obtained by γ-irradiation. Synthesis, characterization and in vitro release studies

The functionalization of α,β-poly(N-2-hydroxyethyl)-dl-aspartamide (PHEA) with glycidyl methacrylate (GMA) gives rise to a water-soluble copolymer PHEA-GMA (PHG) containing double bonds and ester groups in the side chain. Aqueous solutions of PHG alone or in combination with N,N′ methylenbisacrylamide (BIS) have been exposed to a γ-ray source at different irradiation doses in order to obtain polymeric networks. All samples have been prepared both as water-swellable microparticles and as gel systems. Microparticles have been characterized by FT-IR spectrophotometry and swelling measurements in aqueous media mimicking biological fluids. The effect of irradiation dose and BIS presence on rheol…

SYNTHESIS, PHYSICO-CHEMICAL AND BIOLOGICAL CHARACTERIZATION OF A PACLITAXEL MACROMOLECULAR PRODRUG

Paclitaxel was attached to poly(hydroxyethylaspartamide) via a succinic spacer arm by a two-step protocol: (1) synthesis of 2'-O-succinyl-paclitaxel; (2) synthesis of PHEA-2'-O-succinyl-paclitaxel. The 2'-O-succinyl-paclitaxel derivative and the macromolecular conjugate were characterized by UV, IR, NMR and mass spectrometry analysis. The reaction yields were over 95% and the purity of products over 98%. Paclitaxel release and degradation from 2'-O-succinyl-paclitaxel occurred at a faster rate at pH 5.5 than 7.4. After 30 h of incubation at pH 5.5 and 7.4 the released free paclitaxel was about 40 and 20%, respectively. In plasma both drug release and degradation were found to occur at a hig…

A NOVEL POLYSACCHARIDE/POLYAMINOACID pH-SENSITIVE AND BIODEGRADABLE HYDROGEL: PREPARATION AND CHARACTERIZATION

Heparin functionalized polyaspartamide/polyester scaffold for potential blood vessel regeneration

A hyaluronic acid/cyclodextrin based injectable hydrogel for local doxorubicin delivery to solid tumors

Localized delivery of anticancer drugs is often the most useful therapeutic approach for the treatment of solid tumors. The use of injectable polymeric systems that maximize drug concentration in the proximal area of the tumor represents an extremely advantageous therapeutic strategy. Here, the development of an injectable in situ forming hydrogel was accomplished by exploiting the azo-type Michael reaction between an amine derivative of hyaluronic and vinylsulfone functionalized -cyclodextrins complexing doxorubicin. This injectable system can be easily prepared and administered with timelines compatible with normal operating room procedures, as demonstrated by rheological tests. In vitro…

A fluorescent molecular sensor for pH windows in traditional and polymeric biocompatible micelles: comicellization of anionic species to shift and reshape the ON window.

A new approach is presented to obtain fluorescent sensors for pH windows that work in water and under biomimetic conditions. A single molecule that features all-covalently linked components is used, thus making it capable of working as a fluorescent sensor with an OFF/ON/OFF response to pH value. The components are a tertiary amine, a pyridine, and a fluorophore (pyrene). The forms with both protonated bases or both neutral bases quench the pyrene fluorescence, whereas the form with the neutral pyridine and protonated amine groups is fluorescent. The molecular sensor is also equipped with a long alkyl chain to make it highly hydrophobic in all its protonated and unprotonated forms, that is,…

NEW POLYASPARTAMIDIC COPOLYMERS BEARING SPERMINE SIDE CHAINS FOR GENE THERAPY

NANOSTRUCTURED LIPID CARRIER (NLC) CONTAINING FERULIC ACID: PREPARATION, CARACTERIZATION AND CYTOTOXICITY STUDIES

SYNTHESIS OF NOVEL GRAFT COPOLYMERS OF HYALURONAN, POLYETHYLENEGLYCOL AND POLYLACTIC ACID

SYNTHESIS, CHARACTERIZATION AND IN VITRO CYTOTOXICITY STUDIES OF A MACROMOLECULAR CONJUGATE OF PACLITAXEL BEARING OXYTOCIN AS TARGETING MOIETY.

The present study describes the experimental synthetic procedure and the characterization of a new polyaspartamide macromolecular prodrug of paclitaxel, bearing oxytocin residues as targeting moieties. In vitro stability studies of bioconjugate, performed in media mimicking biological fluids (buffer solutions at pH 7.4 and 5.5) and in human plasma, evidenced the high stability of the targeting portion (oxytocin)-polymer linkage and the ability of this conjugate to release linked paclitaxel in a prolonged way in plasma. Moreover, preliminary in vitro antiproliferative studies, carried out on MCF-7 cells, that are oxytocin receptor positive cells, showed that the polymeric conjugate has the s…

Polymer-based systems for controlled release and targeting of drugs

The current need to find new advanced approaches to carry biologically active substances (conventional organic drugs, peptides, proteins (such as antibodies), and nucleic acid-based drugs (NABDs such as siRNA and miRNA)) in the body fluids, to realize targeted therapies and even personalized ones, goes hand in hand with research on the performance of new materials to better realize appropriate drug vectors [...]

Cationic solid-lipid nanoparticles as vector for RNA delivery

in vitro biological evaluation of folate-functionalized block copolymer micelles for selective anti-cancer drug delivery.

The main objective of this study was to evaluate the ability of folic acid-functionalized diblock copolymer micelles to improve the delivery and uptake of two poorly water-soluble anti-tumor drugs, tamoxifen and paclitaxel, to cancer cells through folate receptor targeting. The diblock copolymer used in this study comprised a hydrophilic poly[2-(methacryloyloxy)ethyl phosphorylcholine] (MPC) block, carrying at the chain end the folate targeting moiety, and a pH-sensitive hydrophobic poly[2-(diisopropylamino)ethyl methacrylate] (DPA) block (FA-MPC-DPA). The drug-loading capacities of tamoxifen- and paclitaxel-loaded micelles were determined by high performance liquid chromatography and the m…

SCAFFOLDS BASED ON HYALURONIC ACID AND POLYAMINOACIDS AS ARTIFICIAL ECM SUBSTITUTES

SOLID LIPID NANOPARTICLES CONTAINING AN ANTIOXIDANT COMPOUND IN ALZHEIMER’S DISEASE

Solid Lipid Nanoparticles Containing Nimesulide: Preparation, Characterization and Cytotoxicity Studies

The prospect of improved cancer therapy using Solid Lipid Nanoparticles (SLNs) as drug delivery system is promising. Sev- eral obstacles frequently encountered with anticancer compounds, such as poor drug solubility, are overcome by delivering them using SLN. Moreover, the intravenous administration of drugs into SLNs can potentially enhance drug blood circulation time and improve drug per- formance by inducing accumulation into tumours by enhanced permeability and retention (EPR) effect. This paper deals with the devel- opment of SLN containing nimesulide, a non-steroidal anti-inflammatory drug with antitumour effect and low solubility in water. Here, SLNs carrying nimesulide were prepared…

Polyhydroxyethylaspartamide-spermine copolymers: Efficient vectors for gene delivery

Abstract Aim of this paper was that to prepare biocompatible, polyaspartamide based copolymers containing spermine or spermine/hydrophobic side chains able to condense nucleic acids and to transfect mammalian cells. Copolymers were prepared starting from α,β-poly-(N-2-hydroxyethyl)- d , l -aspartamide (PHEA) and exploiting the reactive hydroxyl groups in the polymeric side chains by subsequent activation reactions to obtain PHEA-Spermine (PHEA-Spm) and PHEA-Spermine-Butyramide (PHEA-Spm-C4). Molecular, physico-chemical and biological characterization of copolymers and interpolyelectrolyte complexes with plasmid DNA was performed. Experimental results evidenced that these copolymers are able…

Branched High Molecular Weight Glycopolypeptide With Broad-Spectrum Antimicrobial Activity for the Treatment of Biofilm Related Infections.

There are few therapeutic options to simultaneously tackle Staphylococcus aureus and Pseudomonas aeruginosa, two of the most relevant nosocomial and antibiotic-resistant pathogens responsible for implant, catheters and wound severe infections. The design and synthesis of polymers with inherent antimicrobial activity have gained increasing attention as a safe strategy to treat multi-drug-resistant microbes. Here, we tested the activity of a new polymeric derivative with glycopolypeptide architecture (PAA-VC) bearing l-arginine, vancomycin, and colistin as side chains acting against multiple targets, which give rise to a broad spectrum antimicrobial activity favorably combining specific and n…

Enhanced adhesion and in situ photothermal ablation of cancer cells in surface-functionalized electrospun microfiber scaffold with graphene oxide

The physicochemical characteristics of a biomaterial surface highly affect the interaction with living cells. Recently, much attention has been focused on the adhesion properties of functional biomaterials toward cancer cells, since is expected to control metastatic spread of a tumor, which is related to good probability containing the progression of disease burden. Here, we designed an implantable poly(caprolactone)-based electrospun microfiber scaffold, henceforth PCLMF-GO, to simultaneously capture and kill cancer cells by tuning physicochemical features of the hybrid surface through nitrogen plasma activation and hetero-phase graphene oxide (GO) covalent functionalization. The surface i…

ANTI-INFLAMMATORY AND ANTIBIOTIC DRUG DELIVERY THROUGH THE MUCOSAL BARRIER IN THE AIRWAYS

Novel polyaminoacidic copolymers as nonviral gene vectors

Human gene therapy is one of the most promising methods developed in recent years, providing great potential for the treatment of a variety of diseases. Complexes formed between DNA and cationic polymers are attracting increasing attention as novel synthetic vectors for the delivery of genes. We have synthesized polycations with quaternary ammonium groups in their side chains for self-assembly with calf thymus DNA. This paper describes the functionalization of α,β-polyasparthydrazide (PAHy), a synthetic macromolecule having many potential applications in the field of biomedical sciences, with glycidyltrimethylammonuim chloride (GTA) in order to introduce positive charges into their chains. …

Polyaspartamide-graft- Polymethacrylate Nanoparticles for Doxorubicin Delivery

A new PHEA-IB-PMANa + copolymer has been synthesized and its pH-induced self-assembly has been investigated in an aqueous medium. PHEA-IB-PMANa + formed nanoparticles with diameters from 25 to 50 nm upon protonation of the carboxylic acid moieties dislocated along the grafted polymethacrylate sodium salt side chains. The physico-chemical characterization of the nanoparticles was performed using light scattering, zeta-potential measurements, SEM, and AFM. Doxorubicin-loaded nanoparticles were prepared and drug release profiles were evaluated under conditions mimicking physiological media. A biological characterization was carried out by testing the cytotoxicity on Caco-2 cells, and cellular …

Molecular characterization of α,β-poly[( N -hydroxyethyl)- dl –aspartamide] by light scattering and viscometry studies

Abstract α,β-poly[(N-hydroxyethyl)- dl -aspartamide] (PHEA) is a new synthetic polymer which is of interest in biomedical applications. In this paper, the molecular characterization of PHEA by multi-angle laser light scattering and viscometry off-line and on-line to a size exclusion chromatography system is reported. These techniques furnish an exhaustive and consistent characterization of the PHEA polymer. The fractionation of the PHEA macromolecules was relatively simple. Using an aqueous mobile phase of medium ionic strength, the elution was substantially regular and the macromolecules were not aggregate. The molar mass M of four PHEA samples approximately ranges from 46 to 53 K g/mol, t…

Production of hyaluronic acid derivative microfibers with controlled dimension as potential drug delivery system

Spray dried hyaluronic acid microparticles for adhesion controlled aggregation and potential stimulation of stem cells

Spray-dried microparticles of a derivative of hyaluronic acid (HA) have been engineered to obtain a controlled aggregation with Human Mesenchymal Stem Cells (hMSCs) into 3D constructs. We demonstrated the utility of chemical functionalization of a native constituent of the extracellular matrix to improve processing performances and to control on stem cell adhesion and differentiation. Native hyaluronic acid (HA), cell adhesive peptides (RGD), transforming growth factor β3, dexamethasone are biological agents potentially suitable for chondrogenic stimulation of hMSCS. However unmodified HA suffers of drawbacks in terms of stability and versatility of processing. Functionalization strategies…

New hyaluronic acid based brush copolymers synthesized by atom transfer radical polymerization.

Abstract In this work, an efficient method for the synthesis of hyaluronic acid based brush copolymers using atom transfer radical polymerization (ATRP) has been reported. At first, two different hyaluronic acid (HA) based macroinitiators have been prepared and then they have been used for the polymerization via ATRP of hydrophilic or hydrophobic molecules carrying vinyl portions. In particular, by linking 2-bromo-2-methylpropionic acid (BMP) to the primary hydroxyl groups of tetrabutyl ammonium salt of HA (HA–TBA) or to amino groups of the ethylenediamino derivative of HA–TBA (HA–TBA–EDA), two macroinitiators (HA–TBA–BMP and HA–TBA–EDA–BMP) have been obtained. Then they have been used for …

Inulin coated plasmonic gold nanoparticles as a tumor-selective tool for cancer therapy.

Preferential uptake by cancer cells of PEG-inulin coated gold nanoparticles loaded with the drug doxorubicin.

NANOSTRUCTURED LIPID CARRIERS (NLC) FOR POORLY-WATER SOLUBLE DRUGS: PREPARATION, CHARACTERISATION AND IN VITRO RELEASE STUDIES

POLY-HYDROXYETHYLASPARTAMIDE SUPRAMOLECULAR SYSTEMS FOR PROLONGED rh-GH delivery

NUOVI SISTEMI SOPRAMOLECOLARI VESCICOLARI CONTENENTI COPOLIMERI DELLA POLIASPARTILIDRAZIDE PER LA VEICOLAZIONE DI AGENTI ANTITUMORALI

Evaluation of mucoadhesive properties of α,β-poly(N-hydroxyethyl)-dl-aspartamide and α,β-poly(aspartylhydrazide) using ATR–FTIR spectroscopy

Abstract The mucoadhesive properties of α,β poly( N -hydroxyethyl)- dl -aspartamide (PHEA) and α,β-polyaspartylhydrazide (PAHy) have been investigated using attenuated total reflection infrared (ATR–FTIR) spectroscopy. In particular, films based on these polymers have been contacted with a mucin solution at pH 7 and, the interfacial interaction and interpenetration between the glycoprotein and PHEA or PAHy have been studied by analysing the ATR–FTIR spectra. A diffusion model using a solution of Ficks' second law has been employed to determine the diffusion coefficient of water into polymeric films as a consequence of interdiffusion which occurs at the polymer film/mucin solution interface.

Polybutylene succinate artificial scaffold for peripheral nerve regeneration

Regeneration and recovery of nerve tissues are a great challenge for medicine, and positively affect the quality of life of patients. The development of tissue engineering offers a new approach to the problem with the creation of multifunctional artificial scaffolds that act on various levels in the damaged tissue, providing physical and biochemical support for the growth of nerve cells. In this study, the effects of the use of a tubular scaffold made of polybutylene succinate (PBS), surgically positioned at the level of a sciatic nerve injured in rat, between the proximal stump and the distal one, was investigated. Scaffolds characterization was carried out by scanning electron microscopy …

INULIN DERIVATIVE CROSSLINKED WITH tri-THIO: NEW pH-SENSITIVE AND BIODEGRADABILE HYDROGELS

VETTORI NANOPARTICELLARI LIPIDICI CONTENENTI RILUZOLO E COMPOSIZIONI FARMACEUTICHE CHE LI CONTENGONO

Delivery of shRNA plasmid DNA by cationic solid lipid nanoparticles for gene silencing in human hepatocarcinoma cells

Nano into Micro Formulations of Tobramycin for the Treatment of Pseudomonas aeruginosa Infections in Cystic Fibrosis.

Here, nano into micro formulations (NiMs) of tobramycin for the treatment of Pseudomonas aeruginosa airway infections in cystic fibrosis (CF) are described. NiMs were produced by spray drying a solution containing polymers or sugars and a nanometric polyanion–tobramcyin complex (PTC), able to achieve a prolonged antibiotic release. NiMs properties were compared to TOBIPodhaler(Novartis), the only one commercially available dry powder inhalatory formulation based on porous microparticles. Produced NiMs showed adequate characteristics for pulmonary administration, as spherical shape, micrometric size, and high cytocompatibility toward human bronchial epithelial cells. Contrarily to TOBIPodhal…

Chemical hydrogels based on a hyaluronic acid-graft-α-elastin derivative as potential scaffolds for tissue engineering

In this work hyaluronic acid (HA) functionalized with ethylenediamine (EDA) has been employed to graft α-elastin. In particular a HA-EDA derivative bearing 50 mol% of pendant amino groups has been successfully employed to produce the copolymer HA-EDA-g-α-elastin containing 32% w/w of protein. After grafting with α-elastin, remaining free amino groups reacted with ethylene glycol diglycidyl ether (EGDGE) for producing chemical hydrogels, proposed as scaffolds for tissue engineering. Swelling degree, resistance to chemical and enzymatic hydrolysis, as well as preliminary biological properties of HA-EDA-g-α-elastin/EGDGE scaffold have been evaluated and compared with a HA-EDA/EGDGE scaffold. T…

Nanometric ion pair complexes of tobramycin forming microparticles for the treatment of Pseudomonas aeruginosa infections in cystic fibrosis

Abstract Sustained pulmonary delivery of tobramycin from microparticles composed of drug/polymer nanocomplexes offers several advantages against traditional delivery methods. Namely, in patients with cystic fibrosis, microparticle delivery can protect the tobramycin being delivered from strong mucoadhesive interactions, thus avoiding effects on its diffusion toward the infection site. Polymeric ion-pair complexes were obtained starting from two synthetic polyanions, through impregnation of their solid dissociated forms with tobramycin in aqueous solution. The structure of these polymeric systems was characterized, and their activities were examined against various biofilm-forming Pseudomona…

NOVEL PAHY-GRAFT COPOLYMERS AS MICELLAR DRUG CARRIER FOR ANTICANCER DRUGS

Preparation and characterization of lipid nanoparticles as potential carriers for ester prodrugs of flurbiprofen

EMPLOYMENT OF CATIONIC SOLID-LIPID NANOPARTICLES AS RNA CARRIERS

Gene transfer represents an important advance in the treatment of both genetic and acquired diseases. In this article, the suitability of cationically modified solid-lipid nanoparticles (SLN) as a nonviral vector for gene delivery was investigated, in order to obtain stable materials able to condense RNA. Cationic SLN were produced by microemulsion using Compritol ATO 888 as matrix lipid, Pluronic F68 as tenside, and dimethyldioctadecylammonium bromide (DDAB) as cationic lipid. The resulting particles were approximately 100 nm in size and showed a highly positive surface charge (+41 mV) in water. Size and shape were further characterized by scanning electron microscopy (SEM) measurements. M…

New Biodegradable Hydrogels Based on Inulin and α,β-Polyaspartylhydrazide Designed for Colonic Drug Delivery: In Vitro Release of Glutathione and Oxytocin.

Succinic derivatives of inulin (INU-SA) with two different degrees of derivatization (20% and 30%, mol/mol) were cross-linked with α,β-polyaspartylhydrazide (PAHy) to obtain INUPAHy hydrogels. Cross-linking was performed using N-ethyl-N-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N-hydroxysulfosuccinimide (NHSS) as coupling agents and by varying the reaction time (4 h, 8 h and 24 h). All samples prepared were characterized by FT-IR analysis and swelling measurements in different media. In vitro assays, performed in the presence of inulinase, demonstrated the degradability of the prepared hydrogels. Cell compatibility was evaluated using Caco-2 cells through both direct and …

MODIFIED PEPTIDE RELEASE FROM NEW IN SITU GEL FORMING COPOLYMERS BASED ON POLYLACTIDE AND POLYASPARTAMIDE

Inulin Derivatives Obtained Via Enhanced Microwave Synthesis for Nucleic Acid Based Drug Delivery

A new class of therapeutic agents with a high potential for the treatment of different socially relevant human diseases is represented by Nucleic Acid Based Drugs (NABD), including small interfering RNAs (siRNA), decoy oligodeoxynucleotides (decoy ODN) and antisense oligonucleotides (ASOs). Although NABD can be engineered to be specifically directed against virtually any target, their susceptibility to nuclease degradation and the difficulty of delivery into target tissues severely limit their use in clinical practice and require the development of an appropriate nanostructured delivery system. For delivery of NABD, Inulin (Inu), a natural, water soluble and biocompatible polysaccharide, wa…

Synthesis and characterization of water-swellable?,?-polyasparthydrazide derivatives

α, β-polyasparthydrazide (PAHy) was crosslinked by glutaraldehyde to form water-swellable materials possessing a three-dimensional molecular network. Different crosslinking degrees were prepared varying glutaraldehyde/PAHy ratio and samples containing 5-fluorouracil were obtained by incorporating the drug into the polymer networks during the crosslinking reaction. All samples were characterized by swelling tests, thermal, x-ray and SEM analysis. Their microstructure was observed through scanning electron microscopy. Furthermore, for samples containing the anticancer drug,in vitro release studies were performed in pH 7.4 buffer solution.

Polyaspartamide based hydrogel with cell recruitment properties for the local administration of hydrophobic anticancer drugs

Abstract By exploiting the chemical versatility and the high water dispersibility of α,β-poly(N-2-hydroxyethyl)D,L-aspartamide, in this work, two different polymer derivatives were synthesized for the first time. Obtained macromolecules were characterized and used to produce hydrogels exploitable for the local release of hydrophobic anticancer drugs. The first derivative, bearing pendant β-cyclodextrins, was employed to solubilize tamoxifen, chosen as a model drug, and to produce a water soluble supramolecular complex, as evidenced through tamoxifen phase solubility studies. The second derivative, bearing pendant Cyclo(Arginine-Glyicine-Asparagine-D-Phenilyalanine-Cysteine) peptide moieties…

Physicochemical and Rheological Characterization of Different Low Molecular Weight Gellan Gum Products and Derived Ionotropic Crosslinked Hydrogels

A series of four different low molecular weight gellan gum products was obtained by alkaline hydrolysis with the aim to investigate the impact of the molecular weight on the rheological properties of the polysaccharide aqueous dispersions and on the physicochemical characteristics of derived ionotropic crosslinked hydrogels. In particular, thermo-rheological analysis was conducted on aqueous dispersions to study the influence of molecular weight on the thermogelation properties typical of the native polysaccharide while strain sweep experiments were conducted to establish if aqueous dispersion shows a viscoelastic behavior. The effect of different Ca2+ on the rheological properties of hydro…

Cholesterol-Inulin Conjugates for Efficient SN38 Nuclear Delivery: Nanomedicines for Precision Cancer Therapy

An amphiphilic inulin-thiocholesterol conjugate (INU-Cys-TC) was strategically designed as a biodegradable core-shell nanocarrier of 7-ethyl-10-hydroxy-camptothecin (SN38) to enhance its solubility and stability in aqueous media, thus exploiting its brilliant anticancer effect. INU-Cys-TC was designed to have the hydrophilic inulin backbone (external shell) partially functionalized with hydrophobic thiocholesterol moieties (internal core) through a biodegradable disulfide bond due to cysteamine bridges. Thiocholesterol moieties impair redox-sensitive self-assembling abilities, yielding to nano-sized micelles in aqueous media capable of efficiently encapsulating a high amount of SN38 (DL = 8…

Polymeric prodrug for release of an antitumoral agent by specific enzymes.

The clinical usefulness of antitumor chemotherapy has been strongly limited by the lack of specificity of most anticancer drugs, which act also against healthy cells. The aim of this work was to design, synthesize, and evaluate a macromolecular prodrug of Cytarabine, a known antitumor drug, which is a specific substrate for plasmin enzyme whose concentration is high in various kinds of tumor mass as a result of plasminogen activator secretion. alpha,beta-Poly(N-hydroxyethyl)-DL-aspartamide (PHEA), a known synthetic and biocompatible polyamino acid, was used as a drug carrier, and Cytarabine was linked to PHEA by D-Val-Leu-Lys spacer synthesized beginning from Cbz-D-Val-LeuOH dipeptide and N…

Micelles of hyaluronic acid-hexadecylamine derivatives for ocular release of hydrophobic drugs

Kinetics of Molecule Transfer between Lipid Vesicles and β-Cyclodextrins

Abstract We propose a calorimetric method based on the van't Hoff model of depression of the freezing temperature to investigate slow kinetics involving lipid vesicles (liposomes) and drug–β-cyclodextrin (Cyd) complexes. Some nonsteroidal antiinflammatory drugs (NSAIDs) were examined and standard phospholipid liposomes were used in our experiments. Three different kinetic processes were investigated: (a)9Transfer of drugs from water-soluble Cyd-complexes to void liposomes. (b)9Uptake of drugs from the surface of liposomes by free Cyd dissolved in the aqueous phase. (c)9Exchange of drugs from loaded to void vesicles, and the effect of free Cyd in enhancing such a transfer. Most experiments w…

New biodegradable hydrogels based on a photocrosslinkable modified polyaspartamide: synthesis and characterization

Abstract α,β-Poly( N -2-hydroxyethyl)- dl -aspartamide (PHEA), a synthetic water-soluble biocompatible polymer, was derivatized with glycidyl methacrylate (GMA), in order to introduce in its structure chemical residues having double bonds and ester groups. The obtained copolymer (PHG) contained 29 mol% of GMA residues. PHG aqueous solutions at various concentrations ranging from 30 to 70 mg/ml were exposed to a source of UV rays at λ 254 nm in the presence or in the absence of N , N ′-methylenebisacrylamide (BIS); the formation of compact gel phases was observed beginning from 50 mg/ml. The obtained networks were characterized by FT-IR spectrophotometry and swelling measurements which evide…

Amphiphilic polyaspartamide copolymer-based micelles for rivastigmine delivery to neuronal cells

A novel polysorbate-80 (PS(80))-attached amphiphilic copolymer comprising a hydrophilic α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA) backbone and hydrophobic squalenyl-C(17) (Sq(17)) portions was synthesized and characterized; the formation of polymeric micelles was also evaluated. Rivastigmine free-base (Riv), a hydrophobic drug employed to treat Alzheimer's disease, was chosen as model drug to investigate micelle's ability to incorporate hydrophobic molecules and target them to neuronal cells. Micelle formation was studied through analyses including fluorescence spectroscopy and 2D (1)H-NMR NOESY experiments. Finally, the capacity of Riv-loaded micelles, versus free drug, to penetrat…

Synthesis, characterisation and properties of α,β-poly(N-2-hydroxyethyl)-dl-aspartamide-graft-maleic anhydride precursors and their stimuli-responsive hydrogels

Abstract A family of poly(amino acid)-maleic anhydride hydrogels were designed and synthesized. Water soluble polymeric precursors were prepared by partially substituting the hydroxyl groups of the α,β-poly( N -2-hydroxyethyl)- dl -aspartamide backbone with maleic anhydride, so as to provide double bonds for crosslinking and carboxylic acid groups for pH and electric field responsiveness. Reaction conditions (reactive mixture composition and catalysis) were systematically varied in order to obtain PHEA–MA precursors with different and reliable graft-maleic anhydride levels. PHEA–MA precursors were characterised by titration, Nuclear Magnetic Resonance ( 1 H NMR), Fourier-Transformed Infrare…

Dexamethasone Dipropionate Loaded Nanoparticles Of -Elastin-G-Plga For Potential Treatment Of Restenosis

PREPARATION, CHARACTERIZATION AND IN VITRO EVALUATION OF TAMOXIFEN-LOADED POLYMERIC MICELLES

NANOPARTICELLE LIPIDICHE SOLIDE CATIONICHE COME VETTORI NON VIRALI DEL DNA

Synthesis, mechanical and thermal rheological properties of new gellan gum derivatives

New derivatives of gellan gum (GG) were prepared by covalent attachment of octadecylamine (C18- NH2) to polysaccharide backbone via amide linkage by using bis(4-nitrophenyl) carbonate (4-NPBC) as a coupling agent. The effect of the alkyl chain grafted onto hydrophilic backbone of high molecular weight GG was investigated in terms of physicochemical properties and ability of new derivatives to form hydrogels. A series of hydrogels was obtained in solutions with different kind and concentration of ions and their stability and mechanical properties were evaluated. The obtained derivatives resulted soluble at temperature lower than starting GG and physicochemical properties of obtained hydrogel…

Synthesis and evaluation of thermo-rheological behaviour and ionotropic crosslinking of new gellan gum-alkyl derivatives.

Abstract This paper reports the synthesis and the physicochemical characterization of two series of gellan gum (GG) derivatives functionalized with alkyl chains with different number of carbon, from 8 to 18. In particular, low molecular weight gellan gum samples with 52.6 or 96.7 kDa, respectively, were functionalized with octylamine (C8), dodecylamine (C12) and octadecylamine (C18) by using bis(4-nitrophenyl) carbonate (4-NPBC) as a coupling agent. Thermo-rheological and ionotropic crosslinking properties of these gellan gum-alkyl derivatives were evaluated and related to the degree of derivatization in alkyl chains. Results suggested as length and degree of derivatization differently infl…

In situ forming hydrogels of hyaluronic acid and inulin derivatives for cartilage regeneration.

An in situ forming hydrogel obtained by crosslinking of amino functionalized hyaluronic acid derivatives with divinylsulfone functionalized inulin (INU-DV) has been here designed and characterized. In particular two hyaluronic acid derivatives bearing respectively a pendant ethylenediamino (EDA) portion (HA-EDA) and both EDA and octadecyl pendant groups (HA-EDA-C18) were crosslinked through an azo-Michael reaction with INU-DV. Gelation time and consumption of DV portions have been evaluated on hydrogel obtained using HA-EDA and HA-EDA-C18 derivatives with a concentration of 3% w/v and a ratio 80/20 w/w respect to the crosslinker INU-DV. The presence of pendant C18 chains improves mechanical…

Mechanical Characterization of Polysaccharide/polyaminoacid Hydrogels as Potential Scaffolds for Tissue Regeneration

The mechanical properties of hydrogel scaffolds based on hyaluronic acid (HA) that were chemically crosslinked with α,β-poly(N-2-hydroxyethyl)(2-aminoethylcarbamate)-D,L-aspartamide (PHEA-EDA) were investigated. Variation of these properties as a function of three different PHEA-EDA amounts used to crosslink HA has been related to the reaction efficiency evaluated using a colorimetric assay. Moreover, the amount of unreacted amino groups that was still present in the hydrogels was related to the attachment behavior of human dermal fibroblasts to the hydrogel surface. The mechanical data and biological results suggest the suitability of the investigated hydrogels as scaffolds for the regener…

Developing Antibiofilm Fibrillar Scaffold with Intrinsic Capacity to Produce Silver Nanoparticles

The development of biomedical systems with antimicrobial and antibiofilm properties is a difficult medical task for preventing bacterial adhesion and growth on implanted devices. In this work, a fibrillar scaffold was produced by electrospinning a polymeric organic dispersion of polylactic acid (PLA) and poly(α,β-(N-(3,4-dihydroxyphenethyl)-L-aspartamide-co-α,β-N-(2-hydroxyethyl)-L-aspartamide) (PDAEA). The pendant catechol groups of PDAEA were used to reduce silver ions in situ and produce silver nanoparticles onto the surface of the electrospun fibers through a simple and reproducible procedure. The morphological and physicochemical characterization of the obtained s…

Solid lipid nanoparticles containing tamoxifen characterization and in vitro antitumoral activity.

Solid lipid nanoparticles (SLNs) containing tamoxifen, a nons- teroidal antiestrogen used in breast cancer therapy, were prepared by microemulsion and precipitation techniques. Tamoxifen loaded SLNs seem to have dimensional properties useful for parenteral administration, and in vitro plasmatic drug release studies demon- strated that these systems are able to give a prolonged release of the drug in the intact form. Preliminary study of antiproliferative ac- tivity in vitro, carried out on MCF-7 cell line (human breast cancer cells), demonstrated that SLNs, containing tamoxifen showed an antitumoral activity comparable to free drug. The results of char- acterization studies and of in vitro …

pH responsive polycation inulin derivative for siRNA Delivery

Ocular tolerability and in vivo bioavailability of poly(ethylene glycol) (PEG)-coated polyethyl-2-cyanoacrylate nanosphere-encapsulated acyclovir.

Acyclovir-loaded polyethyl-2-cyanoacrylate (PECA) nanospheres were prepared by an emulsion polymerization process in the micellar phase and characterized. The influence of the presence of nonionic surfactant as well as other substances [i.e., 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and poly(ethylene glycol) (PEG)], on formulation parameters and loading capacity was investigated. In particular, the presence of PEG resulted in an increase of mean size and size distribution. To obtain PEG-coated PECA nanospheres with a mean size of200 nm, Pluronic F68 at concentrations1.5% (w/v) should be used during preparation. The presence of PEG also resulted in a change in zeta potential, from -25…

DIFFERENTIAL SCANNING CALORIMETRY STUDY ON DRUG RELEASE FROM AN INULIN-BASED HYDROGEL AND ITS INTERACTION WITH A BIOMEMBRANE MODEL:pH AND LOADING EFFECT

Inulin has been derivatized with methacrylic anhydride (MA) and succinic anhydride (SA) to obtain a methacrylated/succinilated derivative (INU-MA-SA) able to produce a pH sensitive hydrogel after UV irradiation. The hydrogel was characterized and loaded with diflunisal (10.4, 17 and 24%, w/w) chosen as a model drug. The drug release from INU-MA-SA-based hydrogel to a biomembrane model made by unilamellar vesicles of dimyristoylphosphatidyl-choline (DMPC) was investigated at pH 4.0 and 7.4 by differential scanning calorimetry (DSC) that appears to be a suitable technique to follow the transfer kinetics of a drug from a controlled release system to a biomembrane model. The drug release from t…

New amphiphilic copolymers based on a poly(hydroxyethylaspartamide): coating of Au nanostars to obtain antimicrobial photothermal/delivering systems activated by NIR irradiation

Preparation, characterization and biological evaluation of Nanostructured Lipid Carriers (NLCs) conteining sorafenib

Vettori polimerici della poliaspartammide coniugati a bisfosfonati per il direzionamento di farmaci alle ossa.

SOLID LIPID NANOPARTICLES (SLNs) CONTAINING FERULIC ACID AGAINST OXIDATIVE STRESS IN NEURODEGENERATIVE DISEASES

Smart copolymer coated SPIONs for colon cancer chemotherapy

Human colon cancer is one of the higher aggressive solid tumors, whose high mortality, much like many other solid tumors, results from metastasis formation. To reduce this high mortality, more effective chemotherapy, allowing a specific tumor accumulation and an efficient early-stage medical imaging as well, are still needed. At this regard, stimuli-responsive nanocarriers for anticancer drug delivery are promising strategy in cancer therapy. For this purpose, a dual targeted redox-responsive drug delivery system, prepared by coating superparamagnetic nanoparticles (SPIONs) with the amphiphilic copolymer INU-LA-PEG-FA and loading doxorubicin (DOXO-SPIONs) was investigated as tool for solid …

Synthesis, characterization and foaming of PHEA-PLLA, a new graft copolymer for biomedical engineering

Abstract In this study a chemical grafting procedure was set up in order to link high molecular weight poly L-lactic acid (PLLA) chains to the hydrophilic α,β-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) backbone. A graft copolymer named PHEA-g-PLLA (or simply PHEA–PLLA) was obtained bearing a degree of derivatization of 1.0 mol.% of PLLA as grafted chain. This new hybrid derivative offers both the opportune crystallinity necessary for the production of scaffolds trough a thermally induced phase separation (TIPS) technique and the proper chemical reactivity to perform further functionalizations with bio-effectors and drugs. PHEA–PLLA porous scaffolds for tissue engineering applications were…

Poly(hydroxyethylaspartamide) derivatives as colloidal drug carrier systems

Abstract Poly(hydroxyethylaspartamide) (PHEA) derivatives bearing at the polyaminoacidic backbone poly(ethyleneglycol) (2000 or 5000 Da) or both poly(ethyleneglycol) and hexadecylalkylamine as pendant moieties were investigated as polymeric colloidal drug carriers. The ability of the PHEA derivatives to solubilize hydrophobic drugs was investigated using paclitaxel, amphotericin B and methotrexate. The results demonstrated that the drug solubility depends on both macromolecule composition and drug physicochemical properties. In particular, PEG/hexadecylalkylamine co-grafting increased significantly the solubilization properties of PHEA for the considered drugs while the conjugation of PEG o…

Using Polymeric Scaffolds for Vascular Tissue Engineering

With the high occurrence of cardiovascular disease and increasing numbers of patients requiring vascular access, there is a significant need for small-diameter (<6 mm inner diameter) vascular graft that can provide long-term patency. Despite the technological improvements, restenosis and graft thrombosis continue to hamper the success of the implants. Vascular tissue engineering is a new field that has undergone enormous growth over the last decade and has proposed valid solutions for blood vessels repair. The goal of vascular tissue engineering is to produce neovessels and neoorgan tissue from autologous cells using a biodegradable polymer as a scaffold. The most important advantage of …

Medicated hydrogels of hyaluronic acid derivatives for use in orthopedic field.

Physical hydrogels have been obtained from hyaluronic acid derivatized with polylactic acid in the presence or in the absence of polyethylene glycol chains. They have been extemporarily loaded with antibacterial agents, such as vancomycin and tobramycin. These medicated hydrogels have been used to coat titanium disks (chosen as simple model of orthopedic prosthesis) and in vitro studies in simulated physiological fluid have been performed as a function of time and for different drug loading and polymer concentration values. Sterilization process performed on the hydrogels does not change their rheological behavior and release properties as well as the chemical structure of starting copolyme…

CROSSLINKED HYALURONAN WITH A PROTEIN-LIKE POLYMER: NOVEL FILMS FOR BIOMEDICAL APPLICATION

Chemical stiffening of constructs between polymeric microparticles based on a hyaluronic acid derivative and mesenchymal stem cells: rheological and in vitro viability studies

Hyaluronan alkyl derivatives-based electrospun membranes for potential guided bone regeneration: Fabrication, characterization and in vitro osteoinductive properties

Item does not contain fulltext The aim of the work was to determine the effects of the chemical functionalization of hyaluronic acid (HA) with pendant aliphatic tails at different lengths and free amino groups in terms of chemical reactivity, degradation rate, drug-eluting features, and surface properties when processed as electrospun membranes (EM) evaluating the osteoinductive potential for a possible application as guided bone regeneration (GBR). To this end, a series of HA derivatives with different aliphatic tails (DD-Cx mol% ≈ 12.0 mol%) and decreasing derivatization of free amino groups (DD(EDA) mol% from 70.0 to 30.0 mol%) were first synthesized, namely Hn. Then dexamethasone-loaded…

Polymeric drug delivery micelle-like nanocarriers for pulmonary administration of beclomethasone dipropionate

In this paper, the potential of novel polymeric micelles as drug delivery systems for Beclomethasone Dipropionate (BDP) administration into the lung is investigated. These nanostructures are obtained starting from α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA), which was subsequently functionalized with O-(2-aminoethyl)-O’-methylpolyethylenglycole (PEG2000), ethylenediamine (EDA) and lipoic acid (LA), obtaining PHEA-PEG2000-EDA-LA graft copolymer. Empty and drug-loaded micelles possess adequate chemical-physical characteristics for pulmonary administration such as spherical shape, slightly positive surface charge and mean size of about 200 nm. Besides, BDP-loaded micelles, obtained …

Production of polymeric micro- and nanostructures with tunable properties as pharmaceutical delivery systems

Abstract The production of novel graft copolymers based on poly-e-caprolactone (PCL) and polyaspartamide are useful to realize structures for potential biomedical applications. Here, the synthesis of pegylated PCL/polyhydroxyethyl aspartamide (PHEA) graft copolymers (PHEA-g-SUCC-PCL-g-PEG) with tunable composition, was achieved by followpling a synthetic strategy that involved first the grafting of preformed PCL on PHEA backbone, then polyethylen glycol (PEG), by using 1,1′-carbonyldiimidazole (CDI) to speed up the condensation reaction. Graft copolymers with a Derivatization Degree (DD) in PCL ranging between 1.1 and 4.4 mol% were obtained, and processable with different technologies for t…

LIPID NANOPARTICLE SYSTEMS CONTAINING CURCUMIN: PREPARATION AND CHARACTERIZATION

Mucoadhesive micelles based on inulin derivative for ocular release of corticosteroids

Ferulic Acid-Loaded Lipid Nanostructures as Drug Delivery Systems for Alzheimers Disease: Preparation, Characterization and Cytotoxicity Studies

PHEA-graft-polybutylmethacrylate copolymer microparticles for delivery of hydrophobic drugs.

Abstract Polymeric microparticles encapsulating two model hydrophobic drugs, beclomethasone dipropionate (BDP) and flutamide (FLU) were prepared by using the high pressure homogenization-solvent evaporation method starting from a oil-in-water emulsion. For the preparation of polymeric microparticles a α,β-poly(N-2-hydroxyethyl)- d , l -aspartamide (PHEA) graft copolymer with comb like structure was properly synthesized via grafting from atom transfer radical polymerization (ATRP) technique, by using two subsequent synthetic steps. In the first step a polymeric multifunctional macroinitiator was obtained by the conjugation of a proper number of 2-bromoisobutyryl bromide (BIB) residues to the…

Nanosystem for diagnosis and photothermal treatment of tumors

The invention relates to a nanosystem for the diagnosis, image-guided treatment of tumors and monitoring of the tumor microenvironment. The nanosystem is a contrast agent comprising a polymer shell based on a hyaluronic acid nanogel, super-parameg-netic iron oxide nanoparticles (SPIONs) and carbon nanoparticles (CDs).

Construction and evaluation of sponge scaffolds from hyaluronic acid derivatives for potential cartilage regeneration

A two or one pot synthesis has been used for the reaction of hyaluronic acid (HA) with octadecylamine (C-18) and hydrazine (Hy). In both cases, the chemical derivatization involved primary hydroxyl groups of hyaluronic acid and not its carboxyl groups, whose presence is important for receptor interaction. In this way, Hy-HA-C-18 derivatives have been obtained with appropriate hydrophobic and hydrophilic character. Their ability to form homogeneous physical hydrogels has been evaluated as well as the possibility to obtain porous sponges through salt leaching technology. Sponges showing the highest porosity, potentially compatible with cell entrapment, have been characterized with regard to t…

Bisphosphonate-polyaspartamide conjugates as bone targeted drug delivery systems.

Poly-hydroxy-aspartamide was used as a backbone to synthesize bisphosphonate derivatives thus achieving macromolecular carriers to be potentially used as targeting agents for bone drug delivery. Molecules bearing bisphosphonate groups, such as aminobisphosphonate (ABP) and neridronate (NRD), have been conjugated to polyaspartamide (α,β-poly(N-2-hydroxyethyl)-dl-aspartamide, PHEA), with or without a spacer (succinic acid or 6-aminocaproic acid) thus obtaining PHEA-succinate-ABP and PHEA-caproylcarbamate-ABP and PHEA-ABP and PHEA-NRD, respectively. Bisphosphonate-polymer conjugates were physico-chemically characterized using size exclusion chromatography and 1H-NMR; and their in vitro and e…

PHEA-graft-polymethacrylate supramolecular aggregates for protein oral delivery

Abstract Salmon calcitonin (sCT) is characterized by a poor oral availability. A new copolymer, β-poly(N-2-hydroxyethyl)-graft-{N-2-ethylene[2-poly(methacrylic acid sodium salt)isobutyrate]}- d , l -aspartamide (PHEA-IB-p(MANa + )), was designed for the oral administration of sCT through the formation of supramolecular aggregates (SAs) based on electrostatic interactions. Several sCT/PHEA-IB-p(MANa + ) weight ratios were characterized by turbidimetry, DLS, zeta potential, and microscopy analysis. After the incubation of sCT/PHEA-IB-p(MANa + ) complex with digestive enzymes, 10% (w/w) of loaded sCT was released in the native form. In vitro investigation was carried out to determine the copol…

Evaluation of thermoresponsive properties and biocompatibility of polybenzofulvene aggregates for leuprolide delivery

Abstract In this study, a polybenzofulvene derivative named poly-6-MOEG-9-BF3k, was evaluated as polymeric material for the production of injectable thermoresponsive nano-aggregates able to load low molecular weight peptidic drug, like the anticancer leuprolide. Thermoresponsive behavior of poly-6-MOEG-9-BF3k was studied in aqueous media by evaluating scattering intensity variations by means of DLS in function of temperature. Zeta potential measurements and SEM observations were also carried out. Moreover, critical aggregation temperature of the poly-6-MOEG-9-BF3k polymer was evaluated by pyrene fluorescence analysis. Then, the ability of prepared thermoresponsive aggregates to protect this…

PEGylated graphene oxide (GO-PEG) as new carrier for chemotherapeutic agent delivery

Graphene, a single layer of sp2 -hybridized carbon atoms arranged in a honeycomb two-dimensional (2-D) crystal lattice, has evoked enormous interest throughout the scientific community since its first appearance in 2004. Due to its unique structure and geometry, graphene possesses remarkable physical–chemical properties (including large specific surface area and biocompatibility) that enable it to be an ideal material for several of applications, ranging from quantum physics, nanoelectronics, energy research, catalysis and engineering of nanocomposites and biomaterials. In the area of nanomedicine, graphene and its derivatives can be exploited for a broad range of applications, including a …

Sistemi sopramolecolari cationici innovativi per la veicolazione polmonare dei bioattivi.

Biodegradable and pH-sensitive hydrogels for potential colon-specific drug delivery: Characterization and in vitro release studies

A novel pH-sensitive and biodegradable composite hydrogel, based on a methacrylated and succinic derivative of dextran, named Dex-MA-SA, and a methacrylated and succinic derivative of alpha,beta-poly( N-2-hydroxyethyl)- DL-aspartamide (PHEA), named PHM-SA, was produced by photocross-linking. The goal was to obtain a colon-specific drug delivery system, exploiting both the pH-sensitive behavior and the colon-specific degradability. The hydrogel prepared with a suitable ratio between the polysaccharide and the polyaminoacid was characterized regarding its swelling behavior in gastrointestinal simulated conditions, chemical and enzymatic degradability, interaction with mucin, and cell compatib…

NEW PHEA POLYCATIONIC DERIVATIVES FOR GENE DELIVERY

Realization of polyaspartamide-based nanoparticles and in vivo lung biodistribution evaluation of a loaded gucocorticoid after aerosolization in mice

Abstract In this study, novel polymeric nanoparticles (NPs) were developed and their potential as carriers for beclomethasone dipropionate (BDP) into the lung after aerosolization was demonstrated by in vivo studies in mice. In particular, these NPs were obtained starting from two polyaspartamide-based copolymers which were synthesized by chemical reaction of α,β-poly(N-2-hydroxyethyl)- dl -aspartamide (PHEA) and its pegylated derivative (PHEA-PEG2000) with poly(lactic acid) (PLA). To obtain nanosized particles, the high pressure homogenization (HPH)—solvent evaporation method was followed by using an organic phase containing both PHEA-PLA and PHEA-PEG2000-PLA (at a weight ratio equal to 1:…

Hepatocyte-targeted fluorescent nanoparticles based on a polyaspartamide for potential theranostic applications

Abstract Here, the synthesis of a galactosylated amphiphilic copolymer bearing rhodamine (RhB) moieties and its use for the preparation of polymeric fluorescent nanoparticles for potential applications in therapy and diagnosis are described. To do this, firstly, a fluorescent derivative of α,β-poly( N -2-hydroxyethyl)- d , l -aspartamide (PHEA) was synthesized by chemical reaction with RhB, and with polylactic acid (PLA), to obtain PHEA-RhB-PLA. Then, the derivatization of PHEA-RhB-PLA with GAL-PEG-NH 2 allows obtaining PHEA-RhB-PLA-PEG-GAL copolymer, with derivatization degrees in -PLA and -PEG-GAL equal to 1.9 mol% and 4.5 mol%, respectively. Starting from this copolymer, liver-targeted f…

ATRP AS AN EFFICIENT METHOD TO PRODUCE BRUSH COPOLYMERS OF HYALURONIC ACID

Ultrafast Interface Charge Separation in Carbon Nanodot-Nanotube Hybrids

Carbon dots are an emerging family of zero-dimensional nanocarbons behaving as tunable light harvesters and photoactivated charge donors. Coupling them to carbon nanotubes, which are well-known electron acceptors with excellent charge transport capabilities, is very promising for several applications. Here, we first devised a route to achieve the stable electrostatic binding of carbon dots to multi- or single-walled carbon nanotubes, as confirmed by several experimental observations. The photoluminescence of carbon dots is strongly quenched when they contact either semiconductive or conductive nanotubes, indicating a strong electronic coupling to both. Theoretical simulations predict a favo…

A Hydrogel Based on a Polyaspartamide: Characterization and Evaluation of In-vivo Biocompatibility and Drug Release in the Rat

Abstract This paper deals with the characterization of a new microparticulate hydrogel obtained by gamma irradiation of α,β-poly[N-(2-hydroxyethyl)-dl-aspartamide] (PHEA). When enzymatic digestion of PHEA hydrogel was evaluated using various concentrations of pepsin and α-chymotrypsin no degradation occurred within 24 h. In-vivo studies showed that this new material is biocompatible after oral administration to rats. PHEA hydrogel was also studied as a system for delivery of diflunisal, an anti-inflammatory drug. In-vitro release studies in simulated gastrointestinal juice (pH 1 or 6.8) showed that most of the drug was released at pH 6.8. In-vivo studies indicated that diflunisal-loaded PHE…

Near-Infrared, Light-Triggered, On-Demand Antiinflammatories and Antibiotics Release by Graphene Oxide/Elecrospun PCL Patch for Wound Healing

Very recently, significant attention has been focused on the adsorption and cell adhesion properties of graphene oxide (GO), because it is expected to allow high drug loading and controlled drug release, as well as the promotion of cell adhesion and proliferation. This is particularly interesting in the promotion of wound healing, where antibiotics and anti-inflammatories should be locally released for a prolonged time to allow fibroblast proliferation. Here, we designed an implantable patch consisting of poly(caprolactone) electrospun covered with GO, henceforth named GO&ndash

Microgels of polyaspartamide and poly(ethylene glycol) derivatives obtained by γ-irradiation

Abstract The copolymer PHG based on α , β -poly( N -2-hydroxyethyl)- dl -aspartamide (PHEA) functionalized with glycidyl methacrylate has been exposed in aqueous solution to a γ -ray source at different irradiation doses (2, 2.5 and 3.5 kGy), alone or in combination with poly(ethylene glycol)dimethacrylate (PEGDMA) or poly(ethylene glycol)diacrylate (PEGDA). The irradiation produces microgel systems that have been characterized by viscosity measurements. Lyophilization of microgels gives rise to samples able to swell instantaneously in water whereas their treatment with acetone produces swellable microparticles that have been characterized.

Curcumin entrapped into lipid nanosystems inhibits neuroblastoma cancer cell growth and activates Hsp70 protein

Curcumin is a natural anti-cancer compound utilized on a wide variety of human cancer cell lines and animal carcinogenesis models. However, its clinical application has been limited for its minimal systemic bioavailability. Nanoparticle-based drug delivery approaches have the potential for rendering hydrophobic molecules such as curcumin dispersible in aqueous media, thus overtaking the limits of its poor solubility. In this paper, we reported the preparation and chemical-physical characterization of Nanostructured Lipid Carriers (NLC) containing curcumin, based on Imwitor, Compritol or Precirol as lipid matrix. By in vitro experiments, we have demonstrated that these nano-systems are able …

Printable Thermo- and Photo-stable Poly(D,L-lactide)/Carbon Nanodots Nanocomposites via Heterophase Melt-Extrusion Transesterification

We propose for the first time an one-pot synthesis of carbon nanodots-poly(D,L-lactide) (CDs-PLA) nanocomposites, obtained by a simple reactive melt-extrusion process involving polar surface groups of multicolor CDs and ester bonds of PLA chains. Apart from providing an excellent method to produce polyester-coated CDs, our protocol allows obtaining perfect PLA@CDs blends giving rise to homogeneous extruded PLA@CDs filaments (ePLA@CDs) suitable for 3D printing applications (e.g., additive manufacturing for biomaterials and biodegradable encoded polymer ink technology). We demonstrate that ePLA@CDs filaments can be used to build a huge range of fluorescent objects with increasing architectura…

INNOVATIVE CATIONIC SUPRAMOLECULAR VESICULAR AGGREGATES (SVAs) FOR THE PULMONARY TISSUE SELECTIVE TARGETING

NANOPARTICLES CONTAINING RIVASTIGMINE FOR THE TREATMENT OF ALZHEIMER DISEASE

COMPOSITE BIOMATERIALS OF HYALURONIC ACID AND A PROTEIN-LIKE POLYMER FOR TISSUE ENGINEERING

Cell Uptake Enhancement of Folate Targeted Polymer Coated Magnetic Nanoparticles

Dual targeted drug delivery systems represent a potential platform for developing efficient vector to tumor sites. In this study we evaluated a folate- and magnetic-targeted nanocarriers based on 10 nm iron oxide nanodomais coated with the properly synthesized and characterized folic acid (FA)-functionalized amphiphilic copolymer PHEA-PLA-PEG-FA. FA was chemically conjugated to one end of diamino-polyethylene glycol of 2000 Da, in order to ensure its exposition on the polymer coated magnetic nanoparticles (MNPs-FA). The prepared nanoparticles have been exhaustively characterized by different methods, including DLS, SEM, FT-IR and magnetic measurements. Magnetic nanoparticles showed dimensio…

SYNTHESIS AND CHARACTERIZATION OF POLYAMINOACIDIC POLYCATIONS FOR GENE DELIVERY

The properties as non viral gene vector of a protein-like polymer, the alpha,beta-poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA) were exploited after its derivatization with 3-(carboxypropyl)trimethyl-ammonium chloride (CPTA) as molecule bearing a cationic group, in order to obtain stable polycations able to condense DNA. PHEA was firstly functionalized with aminic pendant groups by reaction with ethylenediamine (EDA) obtaining the alpha,beta-poly(N-2-hydroxyethyl)(2-aminoethylcarbamate)-d,l-aspartamide (PHEA-EDA) copolymer. We demonstrated that polymer functionalization degree is easily modulable by varying reaction conditions, so allowing to produce two PHEA-EDA derivatives at different mo…

Microfibers obtained by electrospinning of alpha, beta poly(N-2-hydroxyethyl)-DL-aspartamide-g-polylactic acid for potential use in tissue reconstruction

Electrospinning of α,β-poly(N-2-hydroxyethyl)-dl-aspartamide-graft-polylactic acid to produce a fibrillar scaffold

Abstract α,β-Poly( N -2-hydroxyethyl)- dl -aspartamide grafted with polylactic acid (PHEA- g -PLA) is a biocompatible and biodegradable amphiphilic copolymer that has been already employed to prepare a drug delivery system. In this study we have prepared for the first time a fibrillar scaffold from PHEA- g -PLA by the electrospinning of a solution of this copolymer in a mixture of N , N -dimethyl formamide (DMF) and acetone (80:20 vol/vol). The average diameter and the morphology of electrospun fibers were detected by scanning electron microscopy. Chemical degradation studies in phosphate buffer solution pH 7.4 have been performed until 15 days in order to obtain a preliminary information a…

COMPARATIVE-STUDY ON INCLUSION-COMPOUNDS OF 4-BIPHENYLACETIC ACID WITH BETA-CYCLODEXTRIN, HYDROXYPROPYLATED-BETA-CYCLODEXTRINS, AND METHYLATED-BETA-CYCLODEXTRINS

AbstractThe inclusion behavior of Hydroxypropyl-β-Cyclodextrin (HP-β-Cyd) and of methylated-β-Cyclodextrins, heptakis-(2,6-di-O-methyl)-β-Cyclodextrin (DM-β-Cyd) and heptakis-(2,3,6-tri-O-methyl)-β-Cyclodextrin (TM-β-Cyd), in solution and solid state was compared with that of natural β-Cyclodextrin (β-Cyd) using an anti-inflammatory drug, 4-biphenylacetic acid (BPAA), as a guest molecule. The solubility of BPAA with β-Cyd and β-Cyd derivatives in aqueous solution were determined. Stability constants were calculated by phase solubility method at various pH values and temperatures. The formation of inclusion complexes with β-Cyd and β-Cyd derivatives in the solid slate were confirmed by infra…

Polysaccharide/polyaminoacid composite scaffolds for modified DNA release.

Abstract In this work composite polymeric films or sponges, based on hyaluronic acid (HA) covalently crosslinked with α,β-poly(N-2-hydroxyethyl)(2-aminoethylcarbamate)- d , l -aspartamide (PE), have been prepared and characterized as local gene delivery systems. In particular, HA/PE scaffolds have been loaded with PE/DNA interpolyelectrolyte complexes, employing PE as a macromolecular crosslinker for HA and as a non-viral vector for DNA. In vitro studies showed that HA/PE films and sponges have high compatibility with human dermal fibroblasts and they give a sustained DNA release, whose trend can be easily tailored by varying the crosslinking ratio between HA and PE. Electrophoresis analysi…

When Functionalization of PLA Surfaces Meets Thiol−Yne Photochemistry: Case Study with Antibacterial PolyaspartamideDerivatives

International audience; In this work we wish to report on the covalent functionalization of polylactide (PLA) surfaces by photoradical thiol–yne to yield antibacterial surfaces. At first, hydrophilic and hydrophobic thiol fluorescent probes are synthesized and used to study and optimize the conditions of ligation on alkyne-PLA surfaces. In a second part, a new antibacterial polyaspartamide copolymer is covalently grafted. The covalent surface modification and the density of surface functionalization are evaluated by SEC and XPS analyses. No degradation of PLA chains is observed, whereas covalent grafting is confirmed by the presence of S2p and N1s signals. Antiadherence and antibiofilm acti…

Inhalable nano into micro dry powders for ivacaftor delivery: The role of mannitol and cysteamine as mucus-active agents.

In this paper the innovative approach of Nano into micro (NiM9 was developed to produce Nanoparticles loaded Ivacaftor to incorporate into mannitol or mannitol/cysteamine micromatrices for drug pulmonary administration in CF. Nanoparticles composed by a mixture of two polyhydrohydroxyethtylaspartamide copolymers containing a loading of Ivacaftor of 15.5 % w/w were produced. These Nanoparticles were incorporated into microparticles to obtain NiM that were characterized in terms of size and size distribution, interaction with CF-AM by rheological and turbidimetric studies as well as by aerodynamic diameter measurements. Finally the activity of Ivacaftor into these NiM was evaluated by in vitr…

Polymeric nanoparticles for siRNA delivery: Production and applications

Gene therapy through the use of siRNA and a polymeric carrier are becoming an efficient therapeutic option to conventional pharmaceutical formulations for the treatment of deadly diseases, such as cancer, pulmonary, ocular and neurodegenerative diseases. However, several considerations regarding the stability, formulation, and efficacy have to be faced up until these systems could be considered to be a marketable pharmaceutical products for to extend siRNA application to clinical practice. This review is focused on the key challenges of siRNA therapeutics, with special attention on the faced obstacles and on the formulation-related difficulties, providing a list of requirements needed for o…

Microfluidic production of hyaluronic acid derivative microfibers to control drug release

"Available online 4 July 2016"

NEW POLYSACCHARIDE DERIVATIVES FOR THE POTENTIAL TREATMENT OF IRON DEFICIENCY ANAEMIA

Polyaspartamide-Doxorubicin Conjugate as Potential Prodrug for Anticancer Therapy

Purpose To synthesize a new polymeric prodrug based on ?,?- poly(N-2-hydroxyethyl)(2-aminoethylcarbamate)-d,l-aspartamide copolymer bearing amine groups in the side chain (PHEA-EDA), covalently linked to the anticancer drug doxorubicin and to test its potential application in anticancer therapy. Methods The drug was previously derivatized with a biocompatible and hydrophilic linker, leading to a doxorubicin derivative highly reactive with amino groups of PHEA-EDA. The PHEAEDA- DOXO prodrug was characterized in terms of chemical stability. The pharmacokinetics, biodistribution and cytotoxicity of the product was investigated in vitro and in vivo on human breast cancer MCF-7 and T47D cell lin…

Hyaluronan-coated polybenzofulvene brushes as biomimetic materials

Hyaluronic acid (HA) forms pericellular coats in many cell types that are involved in the early stages of cell adhesion by interacting with the CD44 receptor. Based on the largely recognized overexpression of the CD44 receptor in tumor tissues, a polybenzofulvene molecular brush has been enveloped into hyaluronan shells to obtain a tri-component polymer brush (TCPB) composed of intrinsically fluorescent backbones bearing nona(ethylene glycol) arms terminated with low molecular weight HA macromolecules. The nanoaggregates obtained in TCPB water dispersions were characterized on the basis of dimensions, zeta potential, and in vitro cell toxicity. This biomimetic multifunctional material beari…

CROSSLINKED HYALURONAN WITH A PROTEIN-LIKE POLYMER: NOVEL BIORESORBABLE FILMS FOR BIOMEDICAL APPLICATIONS

In this work, novel hydrogel films based on hyaluronan (HA) chemically crosslinked with the alpha,beta-poly(N-2-hydroxyethyl) (2-aminoethylcarbamate)-D,L-aspartamide (PHEA-EDA) were produced by solution casting method. The goal was to exploit both the biological key role of HA in tissue repair and regeneration, and the versatility of a synthetic protein-like polymer as the PHEA-EDA, in order to obtain biomaterials with physicochemical and biological properties suitable for a clinical use. By varying the molar ratio between the PHEA-EDA amino groups and HA carboxyl groups, three different films were obtained and characterized. Particularly FTIR, swelling, hydrolysis, and enzymatic degradatio…

ANTICANCER RELEASING FILMS AND POROUS SCAFFOLDS BASED ON PHYSICALLY ASSEMBLED HYALURONIC ACID DERIVATIVES

Inulin cationic derivatives obtained via enhanched microwave synthesis for nucleic acid based drugs delivery

Procedimento per la produzione di derivati funzionalizzati dell'acido ialuronico e relativi idrogeli

POLY-HYDROXYETHYLASPARTAMIDES SUPRAMOLECULAR SYSTEMS FOR rh-GH DELIVERY

Reaction of 2-acetyltetralone with some esters of benzoic acid

In order to investigate the pharmacological screening of a number of pyran-4-ones their synthesis by cyclization with sulphuric acid of the corresponding 1,3,5-triketones has been carried out with high yields. In the course of preparation of the latter the reaction of 2-acetyltetralone with some esters of benzoic acid derivatives has been studied and in particular, for a number of them, an interesting nucleophilic substitution of a chlorine atom with an alkoxy group on a benzenic nucleus has been evidenced.

Improvements in Rational Design Strategies of Inulin Derivative Polycation for siRNA Delivery.

The advances of short interfering RNA (siRNA)-mediated therapy provide a powerful option for the treatment of many diseases, including cancer, by silencing the expression of targeted genes involved in the progression of the pathology. On this regard, a new pH-responsive polycation derived from inulin, Inulin-g-imidazole-g-diethylenetriamine (INU-IMI-DETA), was designed and employed to produce INU-IMI-DETA/siRNA "Inulin COmplex Nanoaggregates" (ICONs). The experimental results showed that INU-IMI-DETA exhibited strong cationic characteristics and high solubility in the pH range 3-5 and self-aggregation triggered by pH increase and physiological salt concentration. INU-IMI-DETA showed as well…

Novel hydrogels based on a polyasparthydrazide. Synthesis and characterization

α,β-polyasparthydrazide (PAHy), a synthetic water-soluble biocompatible polymer, was chemically crosslinked with ethyleneglycol diglycidylether (EGDGE), in order to obtain water swellable microparticies. These were characterized by means of FT-IR spectrophotometry and by means of particle size distribution analysis. The mean pore size of the prepared gels as various crosslinking ratios and the fractal dimensions were determined by light scattering measurements. Swelling measurements gave evidence of the high affinity of PAHy-EGDGE microparticles towards aqueous media at different pH values. The physical state of the prepared networks was evaluated by means of X-rays diffractometry and therm…

A Nanoparticulate Drug-Delivery System for Rivastigmine: Physico-Chemical and in vitro Biological Characterization

The preparation and characterization of surface-PEGylated polymeric nanoparticles are described. These systems were obtained by UV irradiation of PHM and PHM-PEG 2000 as an inverse microemulsion, using an aqueous solution of the PHM/PHM-PEG 2000 copolymer mixture as the internal phase and triacetin saturated with water as the external phase, and characterized by dimensional analysis, zeta-potential measurements and XPS. in vitro biological tests demonstrated their cell compatibility and their ability to escape from phagocytosis. Rivastigmine was encapsulated into the nanoparticle structure and drug-release profiles from loaded samples were investigated in PBS at pH = 7.4 and human plasma.

Effect of?-cyclodextrin complexation on the photohaemolitic activity induced by Ketoprofen and Naproxen sensitization

Red blood cell lysis photosensitized by two non-steroidal anti-inflammatory drugs Naproxen (NAP) and Ketoprofen (KPF) was investigated in the presence of β-cyclodextrin (β-Cyd). The photohaemolysis was inhibited by the addition of β-Cyd both for NAP and, to a lesser extent, for KPF. The protective action was found only in a restricted range of concentration of β-Cyd. Higher amounts of β-Cyd interfered with the resistance of the cell to the osmotic shock induced by the photosensitization process. The complexing action of β-Cyd was ascertained through UV-vis absorption spectroscopy, induced circular dichroism and emission spectroscopy. The isolated complexes Naproxen-β-Cyd (NAP-β-Cyd) and Ket…

COPOLYMERS FOR PROTEIN ORAL DELIVERY

Microfluidic Fabrication of Physically Assembled Nanogels and Micrometric Fibers by Using a Hyaluronic Acid Derivative

The employ of a hyaluronic acid (HA) derivative, bearing octadecyl (C18) and ethylenediamine (EDA) groups, for microfluidic fabrication of nanogels and microfibers is reported in this study. Two HA-EDA-C18 derivatives (125 and 320 kDa) having ionic strength sensitive properties are synthesized and characterized. The control of the rheological properties of HA-EDA-C18 aqueous dispersions by formation of inclusion complexes with hydroxypropyl-β-cyclodextrins (HPCD) is described. Reversibility of C18/HPCD complexation and physical crosslinking is detected in media with different ionic strength through oscillation frequency tests. HA-EDA-C18 125 kDa is employed for nanogel fabrication. Control …

Polyaspartamide-based nanoparticles loaded with fluticasone propionate and the in vitro evaluation towards cigarette smoke effects

This paper describes the evaluation of polymeric nanoparticles (NPs) as a potential carrier for lung administration of fluticasone propionate (FP). The chosen polymeric material to produce NPs was a copolymer based on α,β-poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA) whose backbone was derivatised with different molecules, such as poly(lactic acid) (PLA) and polyethylenglycol (PEG). The chosen method to produce NPs from PHEA-PLA-PEG2000 was the method based on high-pressure homogenization and subsequent solvent evaporation by adding Pluronic F68 during the process and trehalose before lyophilisation. Obtained colloidal FP-loaded NPs showed a slightly negative surface charge and nanometric d…

Inulin-Based Hydrogel for Oral Delivery of Flutamide: Preparation, Characterization, and in vivo Release Studies

The ability of a hydrogel obtained by crosslinking INUDV and PEGBa to facilitate sustained release of flutamide is examined. The hydrogel is prepared in pH 7.4 PBS and no toxic solvents or catalysts are used. It is recovered in microparticulate form and its size distribution is determined. Mucoadhesive properties are evaluated in vitro by reproducing gastrointestinal conditions. Flutamide is loaded into the hydrogel using a post-fabrication encapsulation procedure that allows a drug loading comparable to that of market tablets. Drug-loaded microparticles are orally administered to cross-bred dogs and the in vivo study demonstrates their ability to prolong the half-life of the principal acti…

Hydrogels of methacrylic hyaluronic acid derivatives for oral enzyme therapy in celiac disease

Hyaluronic acid, celiac disease

Polyaspartamide-polylactide electrospun scaffolds for potential topical release of Ibuprofen.

In this work, the production and characterization of electrospun scaffolds of the copolymer α,β-poly(N-2-hydroxyethyl)-DL-aspartamide-graft-polylactic acid (PHEA-g-PLA), proposed for a potential topical release of Ibuprofen (IBU), are reported. The drug has been chemically linked to PHEA-g-PLA and/or physically mixed to the copolymer before electrospinning. Degradation studies have been performed as a function of time in Dulbecco phosphate buffer solution pH 7.4, for both unloaded and drug-loaded scaffolds. By using an appropriate ratio between drug physically blended to the copolymer and drug-copolymer conjugate, a useful control of its release can be obtained. MTS assay on human dermal fi…

A hyaluronic acid derivative as a coating film for an electrospun cell releasing system in the treatment of corneal wounds

The transparency of the cornea is maintained by the stem cells of the corneal epithelium in the limbal region; damage to the limbus may cause partial or total limbal stem cell deficiency that, may lead to blindness. The transplantation of cells is crucial to regenerate the damaged areas. The techniques currently employed consist in cadaveric corneal transplantation or in the use of amniotic membrane as a carrier for delivering cultured limbal stem cells to the cornea. Both these approaches show severe drawbacks such as the potential reject of the transplanted cornea and the risk of viral disease transmissions. Here we report the production of an electrospun device that could be exploited as…

PHYSICO-CHEMICAL CHARACTERIZATION OF AMPHIPHILIC DERIVATIVES OF A POLYASPARTAMIDE

COMPOSIZIONE A RILASCIO MODIFICATO pH DIPENDENTE

Engineering Oral Mucosal Polymeric Patches for Treatment of Childhood-Onset Schizophrenia

Mesoporous silicate as matrix for drug delivery systems of non-steroidal antinflammatory drugs

Publisher Summary The suitability of a mesoporous silicate matrix as a drug-delivery system has been evaluated using different nonsteroid anti-inflammatory agents as model drugs. This type of matrix can trap the bioactive agents by a soaking procedure and then release them in conditions mimicking the biological fluids. The high affinity of these matrices for water makes them potentially biocompatible. A matrix impregnated with diflunisal can offer a good potential as a system for the controlled drug release. In fact, only 20% of the drug is released at the gastric level allowing, in this way, the reduction of side effects related to the oral administration of nonsteroidal anti-inflammatory …

Influence of different parameters on drug release from hydrogel systems to a biomembrane model. Evaluation by differential scanning calorimetry technique

A comparative study on the drug release capacity of four water swellable polymeric systems was carried out by differential scanning calorimetry (DSC). The polymeric systems chosen were alpha,beta-polyaspartahydrazide (PAHy) crosslinked by glutaraldehyde (GLU) (PAHy-GLU) or by ethyleneglycoldiglycidylether (EGDGE), (PAHy-EGDGE), polyvinylalcohol (PVA) crosslinked by glutaraldehyde (PVA-GLU) and alpha,beta-poly(N-hydroxyethyl)-DL-aspartamide (PHEA) by gamma irradiation (PHEA-gamma matrices). The degree of crosslinking for PAHy-GLU, PAHy-EGDGE and PVA-GLU samples was about 0.4 and 0.8. These hydrogels were characterized as free of drugs and were loaded with diflunisal (DFN) (approximately 2.5%…

PHEA‐PLLA: A New Polymer Blend For Tissue Engineering Applications

One of most important features that a material should have in order to be utilized for tissue engineering applications is its biocompatibility and its chemical surface. These properties are required for a high degree of cell adhesion on the scaffold. Poly‐L‐lactid acid (PLLA) is a biocompatible synthetic polymer approved by the Food and Drug Administration for human clinical applications. It has been largely employed, in the last years, as a constituent of surgical and implantable devices. PHEA is a biocompatible water‐soluble synthetic polymer, with a protein‐like structure, whose use as a drug carrier and as starting material for many other biomedical and pharmaceutical applications has b…

BRAIN-TARGETED SOLID LIPID NANOPARTICLES CONTAINING RILUZOLE: PREPARATION, CHARACTERIZATION AND BIODISTRIBUTION

Aim: Developments within nanomedicine have revealed a great potential for drug delivery to the brain. In this study nanoparticulate systems as drug carriers for riluzole, with sufficiently high loading capacity and small particle size, were prepared to a reach therapeutic drug level in the brain. Materials & method: Solid lipid nanoparticles containing riluzole have great potential as drug-delivery systems for amyotrophic lateral sclerosis and were produced by using the warm oil-in-water microemulsion technique. The resulting systems obtained were approximately 88 nm in size and negatively charged. Drug-release profiles demonstrated that a drug release was dependent on medium pH. Biodi…

NEW IN SITU FORMING HYALURONIC ACID SCAFFOLDS WITH A FIBRILLAR STRUCTURE

Metallic core nano-devices as drug delivery systems

Rheological characterization and release properties of inulin-based hydrogels

Abstract In the present study the rheological properties of hydrogels obtained through UV irradiation of an aqueous solution of methacrylated inulin (INUMA) alone or in the presence of four different crosslinkers, have been recorded as a function of irradiation time, at two different wavelengths (320 and 365 nm) and fixed frequency and amplitude by oscillatory experiments. Each hydrogel has been analyzed by measurements of the frequency-dependency of the elastic modulus, G ′, in the linear viscoelastic region. The amount of polymeric chains giving an elastic response has been correlated to the chemical nature of the crosslinker used together with INUMA. Finally the release properties of the…

Folate-mediated targeting of polymeric conjugates of gemcitabine.

The synthesis of two new macromolecular prodrugs for active tumor targeting was set up. Gemcitabine (2'-deoxy-2',2'-difluorocytidine) was conjugated to alpha,beta-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) through succinyl or diglycolyl hydrolysable spacers. The targeting agent folic acid was attached to the macromolecular backbone through the aminocaproic spacer. The two conjugates [PHEA-(5'-succinylgemcitabine)-1'-carboxypentyl-folamide and PHEA-(5'-diglycolyl-gemcitabine)-1'-carboxypentyl-folamide], were purified and extensively characterised by spectroscopic (UV, IR and NMR) and chromatographic analyses to determine the correct chemical structure, the purity degree and the reaction yi…

INULIN-BASED HYDROGELS: RHEOLOGICAL EVALUATION AND IN VITRO DRUG RELEASE STUDIES

COPOLYMER CONJUGATES FOR DRUG TARGETING

FIBRILLAR SCAFFOLD BASED ON ELECTROSPUN alpha,beta-POLY(N-2-HYDROXYETHYL)-DL-ASPARTAMIDE-GRAFT-POLYLACTIC ACID COPOLYMER.

In vitro evaluation of glycol chitosan based formulations as oral delivery systems for efflux pump inhibition.

Recently, we have reported that glycol chitosan (GCS) was able to reverse the P- glycoprotein (P-gp) efflux pump. The objective of the present study was to evaluate the potential of two GCS-based dosage forms (aqueous solution or nanoparticle suspension) for oral administration of the P-gp substrate Rho-123. A further aim of the present study was to assess the effect of the glycol chitosan-4-thiobutylamidine thiomer (GCS-TBA) on P-gp activity considering that the corresponding thiomer of chitosan series is a well-known P-gp inhibitor. Pre-treatment of Caco-2 cell monolayer with a GCS solution or GCS-based nanoparticles increased the absorptive transport of Rho-123 across the monolayer of 1.…

Polyaspartamide-graft-polymethacrylate nanoparticles for doxorubicin delivery

Galactosylated micelles for a ribavirin prodrug targeting to hepatocytes.

Polymeric micelles potentially able to carry to hepatocytes a ribavirin (RBV) prodrug, exploiting the presence of carbohydrate receptors, that is, ASGPR, were prepared starting from a galactosylated polylactide-polyaminoacid conjugate. This latter was obtained by chemical reaction of α,β-poly(N-2-hydroxyethyl) (2-aminoethylcarbamate)-dl-aspartamide (PHEA-EDA) with polylactic acid (PLA), and subsequent reaction with lactose, obtaining PHEA-EDA-PLA-GAL copolymer. To enhance the entrapment into obtained nanostructures, a hydrophobic RBV prodrug, that is, RBV tripalmitate, was synthesized and its capability to release RBV in the presence of an adequate enzymatic activity was demonstrated. Liver…

Cationic Supramolecular Vesicular Aggregates for Pulmonary Tissue Selective Delivery in Anticancer Therapy

The biopharmaceutical properties of supramolecular vesicular aggregates (SVAs) were characterized with regard to their physicochemical features and compared with cationic liposomes (CLs). Neutral and cationic SVAs were synthesized using two different copolymers of poly(aspartyl hydrazide) by thin-layer evaporation and extrusion techniques. Both copolymers were self-assembled in pre-formulated liposomes and formed neutral and cationic SVAs. Gemcitabine hydrochloride (GEM) was used as an anticancer drug and loaded by a pH gradient remote loading procedure, which significantly increased drug loading inside the SVAs. The resulting average size of the SVAs was 100 nm. The anticancer activity of …

Macromolecular Prodrugs Based on Synthetic Polyaminoacids: Drug Delivery and Drug Targeting in Antitumor Therapy

In the last twenty years a depth study on potential pharmaceutical applications of synthetic polymers at proteinlike structure as carrier for macromolecular prodrug production has been performed in academia and in industry. In particular α,β-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA), α,β-polyaspartylhydrazide (PAHy), poly(glutamic acid) (PGA), poly(aspartic acid) (PAA) and polylysine (PLL) have been extensively studied in this field. In the present review, the use of PHEA, PAHy, PGA as starting materials to prepare macromolecular prodrugs is reported and drug delivery and targeting aspects have been considered.

ENTRAPMENT OF TYRPHOSTIN AG 14-78 INTO LIPID NANOPARTICLES IMPROVES ITS ANTITUMOR ACTIVITY AGAINST HUMAN HEPATOCARCINOMA CELLS

HYDROGELS BASED ON DEXTRAN AND POLYASPARTAMIDE METHACRYLIC DERIVATIVES

Novel cationic polyaspartamide with covalently linked carboxypropyl-trimethyl ammonium chloride as a candidate vector for gene delivery

Abstract The non-viral gene vector properties of a protein-like polymer, the α,β-poly(N-2-hydroxyethyl)- d , l -aspartamide (PHEA) were investigated after its derivatization with 3-(carboxypropyl)trimethyl-ammonium chloride (CPTA) as molecule bearing cationic groups, in order to obtain stable polycations able to condense DNA. PHEA was firstly functionalized with hydrazide pendant groups by reaction with hydrazine monohydrate (HYD), obtaining the polyhydrazide α,β-poly(N-2-hydroxyethyl/carbazate)- d , l -aspartamide (PHEA–HYD). In this paper we reported that polymer functionalization degree can be easily modulated by varying reaction conditions, so allowing us to produce two PHEA derivatives…

Evaluation of biodegradability on polyaspartamide-polylactic acid based nanoparticles by chemical hydrolysis studies

Here, the synthesis of two graft copolymers based on ?,?-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA) and poly(lactic acid) (PLA), the O-(2-aminoethyl)-O'-galactosyl polyethylene glycol (GAL-PEG-NH2) or the methoxypolyethylene glycol amine (H2N-PEG-OCH3) is described. Starting from the obtained PHEA-PLA-PEG-GAL and PHEA-PLA-PEG copolymers, polymeric nanoparticles were prepared by high pressure homogenization-solvent evaporation method. To demonstrate their biodegradability as a function of the matrix composition, a chemical stability study was carried out until 21 days by incubating systems in two media mimicking physiological compartments (pH 7.4 and pH 5.5). The degradability of both nan…

New hyaluronic acid based brush copolymers synthesized by atom transfer radical polymerization

COLLOIDAL VECTORS WITH POLYAMINOACID STRUCTURE FOR ORAL RELEASE OF PEPTIDES AND PROTEINS AND METHOD FOR THEIR PRODUCTION

The present invention concerns colloidal vectors with polyaminoacid structure for oral release of peptides and proteins and a method for their production. Specifically, the invention concerns systems for the release of active substances, specifically peptides and proteins, by means of their incorporation in nanoparticles, nano-aggregates or complexes based on properly derivatized synthetic polyaminoacids. These polymeric systems are proposed to release peptide drugs or proteins from oral dosage forms in an effective manner, besides increasing the physicochemical stability of proteins in liquid or solid pharmaceutical dosage forms.

Dielectric Behavior of Aqueous Solutions of α,β-Poly(aspartyl hydrazide) and α,β-Poly(N-hydroxyethyl aspartamide): An Investigation of the Structural and Dynamic Properties

The dielectric properties of aqueous solutions of α,β-poly(aspartyl hydrazide) (PAHy) and of α,β-poly( N-hydroxyethyl aspartamide) (PHEA) were measured at 25 ° C in the frequency range of 100 MHz to 15 GHz using a time domain reflection method (TDR). Single time relaxation processes were found at 2 GHz and 15 GHz, respectively. The low frequency dispersion was inter preted in terms of the dynamics of polymeric segments based on the dielectric relaxation strength and the relaxation time. The high frequency process which is attributed to the rotational relaxation of water, indicated that water mole cules surrounding the polymeric backbone and in the pure state have a similar rotational behav…

Photothermal Ablation of Cancer Cells Using Folate-Coated Gold/ Graphene Oxide Composite

Objective: A new tumor targeted polymer-coated gold/graphene hybrid has been developed for achieving simultaneously thermoablation and chemoterapy of folate receptor-positive cancer cells. Methods: The gold/graphene hybrid was prepared by depositing gold nanospheres onto graphene oxide and coating it with an inulin-folate conjugate. Paclitaxel was loaded by sonication. The hybrid was characterized by UV-Vis spectroscopy, DSC analysis and SEM microscopy. The cytotoxicity, thermoablation and anticancer activity were evaluated in vitro on MCF-7 and 16 HBE. Results: In vitro tests showed that the paclitaxel-loaded hybrid improved the effectiveness of the drug especially after photothermal treat…

Biomedical Applications of Polylactide (PLA) and Its Copolymers.

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SUPRAMOLECULAR LIPIDIC AGGREGATES (SLAs) AS DELIVERY DEVICES FOR ANTICANCER THERAPY

β-C3N4 Nanocrystals: Carbon Dots with Extraordinary Morphological, Structural, and Optical Homogeneity

Carbon nanodots are known for their appealing optical properties, especially their intense fluorescence tunable in the visible range. However, they are often affected by considerable issues of optical and structural heterogeneity, which limit their optical performance and limit the practical possibility of applying these nanoparticles in several fields. Here we developed a synthesis method capable of producing a unique variety of carbon nanodots displaying an extremely high visible absorption strength (ε > 3 × 106 M(dot)−1 cm−1) and a high fluorescence quantum yield (73%). The high homogeneity of these dots reflects in many domains: morphological (narrow size distribution), structural (q…

Polyaspartylhydrazide Copolymer-Based Supramolecular Vesicular Aggregates as Delivery Devices for Anticancer Drugs

In this paper we report on three different hydrophilic copolymers based on alpha,beta-polyaspartylhydrazide (PAHy) bearing butyric groups in the side chain (C 4) (PAHy-C 4) or a combination of butyric groups and positive charged residues ((carboxypropyl)trimethylammonium chloride, CPTACl) (PAHy-C 4-CPTA) that were synthesized and used for the preparation of new supramolecular vesicular aggregates (SVAs) containing gemcitabine as an antitumor drug. Gemcitabine-loaded SVAs containing synthesized PAHy derivatives were characterized from the physicochemical and technological point of view and the in vitro toxicity and anticancer activity on two different human cancer cell lines, i.e., CaCo-2 (h…

Pegylated nanoparticles based on a polyaspartamide. Preparation, physico-chemical characterization and intracellular uptake

Nanoparticles with different surface PEGylation degree were prepared by using as starting material alpha,beta-poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA). PHEA was functionalized with a PEG amino-derivative for obtaining PHEA-PEG(2000) copolymer. Both PHEA and PHEA-PEG(2000) were derivatized with methacrylic anhydride (MA) for obtaining poly(hydroxyethylaspartamide methacrylated) (PHM) and poly(hydroxyethylaspartamide methacrylated)-PEGylated (PHM-PEG(2000)), respectively. Nanoparticles were obtained by UV irradiation of an inverse microemulsion, using as internal phase an aqueous solution of PHM alone or of the PHM/PHM-PEG(2000) mixture at different weight ratio and as external phase a m…

Conformational analysis of α,β-poly(N-hydroxyethyl)-dl-aspartamide (PHEA) and α,β-polyasparthydrazide (PAHy) polymers in aqueous solution

Abstract α,β-Poly(N-hydroxyethyl)- dl -aspartamide (PHEA) and α,β-polyasparthydrazide (PAHy) are synthetic polymers previously studied for biomedical applications. We report here the results of a small-angle X-ray scattering analysis carried out on these two macromolecules in aqueous solution. The data obtained indicate that the two polymers assume remarkably different conformations in aqueous solution, although the backbone is supposed to be the same for the two chains. PHEA can be represented by a random coil conformation, whereas PAHy can be described in terms of an elliptical cylinder characterized by an almost planar structural arrangement with the backbone refolded on itself in a fash…

POLYASPARTAMIDE-POLYLACTIDE GRAFT COPOLYMERS WITH TUNABLE PROPERTIES FOR THE REALIZATION OF FLUORESCENT NANOPARTICLES FOR IMAGING

Here, the synthesis and the characterization of novel amphiphilic graft copolymers with tunable properties, useful in obtaining polymeric fluorescent nanoparticles for application in imaging, are described. These copolymers are obtained by chemical conjugation of rhodamine B (RhB) moieties, polylactic acid (PLA), and O-(2-aminoethyl)-O'-methyl poly(ethylene glycol) (PEG) on α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA). In particular, PHEA is first functionalized with RhB to obtain PHEA-RhB with a derivatization degree in RhB (DDRhB ) equal to 0.55 mol%. By varying the reaction conditions, different amounts of PLA are grafted on PHEA-RhB to obtain PHEA-RhB-PLA with DDPLA equal to 1.9, 4…

Synthesis and characterization of polyaspartamide copolymers obtained by ATRP for nucleic acid delivery

Abstract Nucleic acid molecules such as small interfering RNAs (siRNAs) and plasmidic DNAs (pDNAs) have been shown to have the potential to be of therapeutic value in different human diseases. Their practical use is however compromised by the lack of appropriate release systems. Delivered as naked molecules, siRNAs/pDNAs are rapidly degraded by extracellular nucleases thus considerably reducing the amount of molecule which can reach the target cells. Additionally, the anionic charge of the phosphate groups present on the siRNAs/pDNAs backbone, disfavors the interaction with the negatively charged surface of the cell membrane. In this paper we describe the generation of a novel polymer able …

Polyaspartamide-polylactide electrospun scaffolds for potential topical release of ibuprofen

Novel water-swellable beads based on an acryloylated polyaspartamide

Spherical polymeric microparticles have been prepared by a reverse-phase suspension polymerization technique. The starting polymer was α,β-poly (N-2-hydroxyethyl)-dl-aspartamide (PHEA) partially functionalised with glycidylmethacrylate (GMA) in order to introduce reactive vinyl groups in the side chain. The PHEA–GMA copolymer obtained (PHG) was cross-linked in a mixture of water/hexane–carbon tetrachloride in the presence of sorbitan trioleate (Span 85) as surfactant and ammonium persulfate/N,N,N′,N′-tetramethylethylenediamine as initiator system. The reaction was also carried out in the presence of N,N′-dimethylacrylamide as comonomer or N,N′-ethylenebisacrylamide as a cross-linking agent.…

Amphiphilic Copolymers Based on Poly[(hydroxyethyl)-d,l-aspartamide]: A Suitable Functional Coating for Biocompatible Gold Nanostars

Novel amphiphilic copolymers have been synthesized based on a biocompatible poly(hydroxyethylaspartamide) (PHEA) backbone, bearing both anchoring groups for gold nanoparticles, such as thiols and disulfide, and conjugable moieties, such as amino groups, the latter as points suitable for appending further functional agents. The strategy was to functionalize α,β-poly[(N-2- hydroxyethyl)-d,l-aspartamide] (PHEA) with PEG2000-NH2 and with ethylenediamine (EDA) obtaining a partially pegylated copolymer with a large number of pendant primary amino groups. A fraction of the latter was conjugated with molecules bearing terminal thiol moieties such as 12-mercaptododecanoic acid (MDA) and disulfide gr…

PEGYLATED POLYPLEXES BASED ON POLYHYDROXYETHYLASPARTAMIDE AS GENE DELIVERY SYSTEM

FOLATE RECEPTOR-TARGETED SUPRAMOLECULAR VESICULAR AGGREGATES (SVAS)FOR ANTICANCER THERAPY

DERIVATI CATIONICI DELL’INULINA OTTENUTI MEDIANTE L’IMPIEGO DELLE MICROONDE PER LA VEICOLAZIONE DI FARMACI A BASE DI ACIDI NUCLEICI

Cationic copolymers of ?,?-poly-(N-2-hydroxyethyl)-DL-aspartamide (PHEA) and ?,?-polyasparthylhydrazide (PAHy): synthesis and characterization

In the present study the derivatization of two water-soluble synthetic polymers, α,β-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) and α,β-polyasparthylhydrazide (PAHy), with glycidyltrimethylammonium chloride (GTA) is described. This reaction permits the introduction of positive charges in the macromolecular chains of PHEA and PAHy in order to make easier the electrostatic interaction with DNA. Different parameters affect the reaction of derivatization, such as GTA concentration and reaction time. PHEA reacts partially and slowly with GTA; on the contrary the reaction of PAHy with GTA is more rapid and extensive. The derivatization of PHEA and PAHy with GTA is a convenient method to introdu…

Folate-targeted supramolecular vesicular aggregates based on polyaspartyl-hydrazide copolymers for the selective delivery of antitumoral drugs.

Supramolecular vesicular aggregates (SVAs) have the advantage of combining the safe and biocompatible properties of colloidal vesicular carriers based on phospholipids with those of polymeric materials, i.e. polyaspartyl-hydrazide (PAHy) copolymers. To provide SVAs with a certain tumour selectivity, folate moieties were chemically conjugated to PAHy copolymers. Physicochemical properties (mean sizes, polydispersity index and zeta potential) of folate-targeted SVAs (FT-SVAs) loaded with gemcitabine were evaluated. The antiproliferative and anticancer activity of gemcitabine-loaded FT-SVAs was evaluated against two cancer cell lines, i.e. MCF-7 cells which over-express the folate receptor and…

MICROFIBERS OBTAINED BY ELECTROSPINNING OF alpha,beta-POLY(N-2-HYDROXYETHYL)-DL-ASPARTAMIDE-g-POLYLACTID ACID FOR POTENTIAL USE IN TISSUE RECONSTRUCTION

A Click Chemistry-Based “Grafting Through” Approach to the Synthesis of a Biorelevant Polymer Brush

A new biorelevant polymer brush showing a polybenzofulvene backbone was synthesized by a ‘‘grafting through’’ approach based on click chemistry and spontaneous polymerization reactions. The easy polymerization of the relatively complex monomer (6-MOEG-9-TM-BF3k) suggests the existence of a particularly efficient recognition process capable of pre-organizing the monomer molecules for the spontaneous polymerization. 13C-NMR spectroscopy as well as UV-vis and fluorescence spectroscopy suggested for poly-6-MOEG-9-TM-BF3k the features of a vinyl (1,2) p-stacked polymer. The new polybenzofulvene derivative was found to interact with water at room temperature to give clear water solutions, but TEM…

Fabrication of silver nanoparticles by a diethylene triamine-hyaluronic acid derivative and use as antibacterial coating

In this work a synthetic protocol for the functionalization of hyaluronic acid with diethylenetriamine (DETA) was standardized. HA-DETA derivatives were characterized by NMR and proton carbon correlation analysis HSQC and HMBC to confirm chemical structure. A selected derivative was used to set up a green fabrication procedure for HA-DETA capped silver nanoparticles with the aim to achieve a polymeric based coating with potential application in the treatment of medical devices associated infections. Data from UV-visible spectroscopy, electron scanning and transmission microscope (STEM), photoelectric spectroscopy (XPS) and rheological characterization were combined to characterize the HA-DE…

A multifunctional peptidomimetic macromolecule to fight polymicrobial infections

Multicomponent solid dispersion as a formulation strategy to improve drug permeation: A case study on the anti-colorectal cancer irinotecan

Abstract Multicomponent solid dispersions (MSD)s are frequently proposed as efficient drug delivery systems to improve drug solubility and bioavailability. In this study, the effects of specific excipients, such as mannitol, inulin, poly(methyl methacrylate-co-methacrylic)acid (PMMA) and cellulose acetate phthalate (CAP) have been tested to potentially improve irinotecan (IRN) permeation in the intestinal tract with the intention to protect the drug from the gastric environment. MSDs were formulated as microparticles by Spray-Drying technique. Raw materials and microparticles have been characterized by FTIR analysis to determine hydrogen bonding. SEM images were recorded to investigate morp…

Hyaluronic Acid-Based Micelles as Ocular Platform to Modulate the Loading, Release, and Corneal Permeation of Corticosteroids

The aim of this work is to prepare hyaluronic acid-based micelles as a platform to load corticosteroid drugs and to improve their corneal permeation after administration on the ocular surface. Three amphiphilic derivatives of hyaluronic acid (HA) are synthesized using different amounts of hexadecylamine (C16 -NH2 ). HAC16 a, HAC16 b, and HAC16 c derivatives are able to form micelles by the cosolvent evaporation method and to entrap corticosteroids (dexamethasone, triamcinolone, triamcinolone acetonide). HAC16 a and HAC16 b micelles show the best results in terms of drug loading and particle size. They are also able to improve drug release compared to free drug solution or suspension. In add…

Curcumin delivered by solid lipid nanoparticles potentiates radiation effects in MCF7 cancer cells

Novel Gamma-crosslinked Hydrogels for Intelligent Release of Actives

COMPOSITE SCAFFOLD FOR TISSUE ENGINEERING

Novel cationic copolymers of a polyasparthylhydrazide: synthesis and characterization.

Alpha,beta-poly(asparthylhydrazide) (PAHy), a water soluble synthetic polymer, was functionalized by using EDCI chemistry with 3-(carboxypropyl)trimethyl-ammonium chloride (CPTACl) obtaining carboxypropyltrimethyl ammonium copolymers (PAHy-CPTA). Three PAHy-CPTA copolymers at increasing derivatization degrees (38%, 48%, 58%) were chosen for subsequent investigations. The capability of these copolymers to bind, neutralize, and protect DNA against degradation by DNase II was evalued by gel retardation assay and DNA degradation test at pH 5.5. Zeta potential measurements show that all studied polymers are able to neutralize the anionic charge of DNA at polymer/DNA weight ratio in the range of …

Novel cationic solid-lipid nanoparticles as non-viral vectors for gene delivery.

In this paper, the suitability of novel cationic solid-lipid nanoparticles (SLN) as a nonviral transfection agent for gene delivery was investigated. SLN were produced by using the microemulsion method and Compritol ATO 888 as matrix lipid, dimethyldioctadecylammonium bromide as charge carrier and Pluronic F68 as surfactant. Obtained nanoparticles were approximately 120 nm in size and positively charged, with a zeta potential value equal to +45 mV in twice-distilled water. Cationic SLN were able to form stable complexes with DNA and to protect DNA against DNase I digestion. The SLN-DNA complexes were characterized by mean diameter and zeta potential measurements. In vitro studies on human l…

Decagram-Scale Synthesis of Multicolor Carbon Nanodots: Self-Tracking Nanoheaters with Inherent and Selective Anticancer Properties

Carbon nanodots (CDs) are a new class of carbon-based nanoparticles endowed with photoluminescence, high specific surface area, and good photothermal conversion, which have spearheaded many breakthroughs in medicine, especially in drug delivery and cancer theranostics. However, the tight control of their structural, optical, and biological properties and the synthesis scale-up have been very difficult so far. Here, we report for the first time an efficient protocol for the one-step synthesis of decagram-scale quantities of N,S-doped CDs with a narrow size distribution, along with a single nanostructure multicolor emission, high near-infrared (NIR) photothermal conversion efficiency, and sel…

Graphene oxide surface functionalization of polymeric scaffolds for the recruitment and thermal ablation of tumor cells

IDAC: production of resorbable hyaluronic acid hydrogels

Water structure in water/AOT/n-heptane microemulsions by FT-IR spectroscopy

Abstract FT-IR spectra in the OH stretching region of water/sodium bis(2-ethylhexyl) sulfosuccinate (AOT)/n-heptane microemulsions as a function of the water/AOT molar ratio (R) and of the weight fraction (φ) of the micellar phase have been recorded at 25°C. After elimination of the unwanted CH contribution and correction for the water concentration, the shape of the normalized OH bands has been found to be dependent on R and practically independent of φ. The analysis of these bands in terms of “bound” and “bulk” water (representing, as a first approximation, the two water domains within the water pool) allowed the evaluation of the fraction (α) of the “bound” water as a function of R. A…

Effects in cigarette smoke stimulated bronchial epithelial cells of a corticosteroid entrapped into nanostructured lipid carriers

Background Nanomedicine studies have showed a great potential for drug delivery into the lung. In this manuscript nanostructured lipid carriers (NLC) containing Fluticasone propionate (FP) were prepared and their biocompatibility and effects in a human bronchial epithelial cell line (16-HBE) stimulated with cigarette smoke extracts (CSE) were tested. Results Biocompatibility studies showed that the NLC did not induce cell necrosis or apoptosis. Moreover, it was confirmed that CSE increased intracellular ROS production and TLR4 expression in bronchial epithelial cells and that FP-loaded NLC were more effective than free drug in modulating these processes. Finally, the nanoparticles increased…

An allergen-polymeric nanoaggregate as a new tool for allergy vaccination.

Parietaria pollen is one of the major causes of allergic reaction in southern Europe, affecting about 30% of all allergic patients in this area. Specifi immunotherapy is the only treatment able to modify the natural outcome of the disease by restoring a normal immunity against allergens. The preparation of allergen-solid lipid nanoparticles as delivery vehicles for therapeutic proteins, P. judaica major allergen Par j 2, was investigated. The Par j 2 allergen was expressed in a large amount in Escherichia coli and purifid to homogeneity. Its immunological properties were studied by western blotting and enzyme-linked immunosorbent assay inhibition. Solid lipid nanoparticles were obtained by …

VETTORI COLLOIDALI A STRUTTURA POLIAMMINOACIDICA PER IL RILASCIO ORALE DI PEPTIDI E PROTEINE E RELATIVO METODO DI PRODUZIONE

Temperature and polymer crosslinking degree influence on drug transfer from alpha,beta-polyasparthydrazide hydrogel to model membranes. A calorimetric study

Abstract A non-steroidal anti-inflammatory drug, diflunisal, has been chosen as drug model to be incorporated in α , β -polyasparthydrazide (PAHy) matrices to study the effect of polymer crosslinking degrees on the release processes from hydrogel ( X =0.4 and X =0.8) to a model membrane represented by unilamellar vesicles of dipalmitoylphosphatidylcholine. The technique employed to monitor these processes was differential scanning calorimetry that appears to be particularly suitable to follow the transfer kinetics of a drug from a controlled release system to void biomembrane model. The drug release from the two PAHy hydrogels differently crosslinked by glutaraldehyde to the lipidic model w…

Interpenetrated 3D porous scaffolds of silk fibroin with an amino and octadecyl functionalized hyaluronic acid

An ethylenediamine (EDA) and octadecylamine (-C18) hyaluronic acid (HA) derivative, named HA-EDA-C18, has been used for the production of interpenetrated composite biomaterials with silk fibroin. The peculiar ionic strength sensibility of this HA derivative allows the production of porous matrices without the need for chemical crosslinking. Scaffolds have been produced through a salt leaching procedure by exploiting the properties of silk fibroin and HA-EDA-C18 to physically crosslink when forced through a syringe loaded with NaCl. The porosity of the sponges, comprised between 70-80%, was dependent on the amount of each polymer and NaCl size distribution. Moreover, through FT-IR analysis, …

Surfactant effect on the physicochemical characteristics of cationic solid lipid nanoparticles

Solid lipid nanoparticles (SLNs) may be considered as a new approach for therapeutics for many diseases. In addition to drug delivery, their use as non-viral vectors for gene delivery can be obtained by including cationic lipids, which provide a positive surface potential that favors binding to the nucleic acids as DNA, siRNA, miRNA, etc. In fact, the addition of cationic surfactants is indispensable for obtaining nanoparticles with surface positive charge. In this study, three different cationic lipids (dioctadecyl dimethyl ammonium bromide, cetyltrimethyl ammonium bromide, cetylpyridinium chloride) and Brij 76 as nonionic surfactant were employed to formulate Precirol ATO 5 based cSLN usi…

Biodegradable hydrogels obtained by photocrosslinking of dextran and polyaspartamide derivatives

The functionalization of dextran with glycidyl methacrylate (GMA) leads to the formation of a derivative that generates hydrogels for irradiation at 365nm. The effects of various polymer concentrations and irradiation times on the yield and the properties of the obtained hydrogels are reported. The networks have been characterized by FT-IR spectra, dimensional analysis and swelling measurements carried out at different pH values. In vitro studies suggest that all samples undergo a partial chemical hydrolysis, whereas the incubation with dextranases causes a total degradation whose rate depends on the degree of crosslinking. In addition, aqueous solutions of functionalized dextran have been …

New gellan gum-graft-poly(D,L-lactide-co-glycolide) copolymers as promising bioinks: Synthesis and characterization

This research focused on the aim of tackling the urgent demand of printable biomaterials, hence we synthetized and characterized three gellan gum-graft-poly(d,l-lactide-co-glycolide) copolymers (GGm-PLGA a, b and c) which differed in the graft substitution degree. We investigated the effect of the polyester chain grafted onto hydrophilic backbone of gellan gum in terms of physicochemical properties and the ability of the system to print 3D cell laden constructs. In particular, we evaluated thermo-rheological, ionotropic crosslinking, shear thinning, swelling and stability properties of these copolymers and their derived biomaterials and findings related to the degree of functionalization. M…

Nanoparticles of a polyaspartamide-based brush copolymer for modified release of sorafenib: In vitro and in vivo evaluation.

Abstract In this paper, we describe the preparation of polymeric nanoparticles (NPs) loaded with sorafenib for the treatment of hepatocellular carcinoma (HCC). A synthetic brush copolymer, named PHEA-BIB-ButMA (PBB), was synthesized by Atom Trasnfer Radical Polymerization (ATRP) starting from the α-poly( N -2-hydroxyethyl)- d , l -aspartamide (PHEA) and poly butyl methacrylate (ButMA). Empty and sorafenib loaded PBB NPs were, then, produced by using a dialysis method and showed spherical morphology, colloidal size, negative ζ potential and the ability to allow a sustained sorafenib release in physiological environment. Sorafenib loaded PBB NPs were tested in vitro on HCC cells in order to e…

HYDROPHOBIC POLYMER COATED SUPERPARAMAGNETIC NANOPARTICLES FOR ANTICANCER DRUG DELIVERY

HYDROPHOBIC POLYMER COATED SUPERPARAMAGNETI NANOPARTICLES FOR ANTICANCER DRUG DELIVERY LICCIARDI M.1, SCIALABBA C.1, AMATO G.1, CAVALLARO G.1, GIAMMONA G.1,2 1Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari (STEMBIO), University of Palermo, via Archirafi 32, 90123, Palermo, Italy. 2IBF-CNR, via Ugo La Malfa, 153, 90143 Palermo, Italy. Superparamagnetic Fe3O4 nanoparticles have been recently used in drug delivery applications [1-4]. In this study, a novel approach to prepare magnetic polymeric nanoparticles containing superparamagnetic domains and hydrophobic polymeric shell using microemulsion-solvent evaporation method is reported. PHEA-IB-poly(ButMA) copolymer was used as …

Hyaluronic acid based hydrogel and use thereof in surgery

Inulin Derivatives Obtained <i>Via</i> Enhanced Microwave Synthesis for Nucleic Acid Based Drug Delivery

A new class of therapeutic agents with a high potential for the treatment of different socially relevant human diseases is represented by Nucleic Acid Based Drugs (NABD), including small interfering RNAs (siRNA), decoy oligodeoxynucleotides (decoy ODN) and antisense oligonucleotides (ASOs). Although NABD can be engineered to be specifically directed against virtually any target, their susceptibility to nuclease degradation and the difficulty of delivery into target tissues severely limit their use in clinical practice and require the development of an appropriate nanostructured delivery system. For delivery of NABD, Inulin (Inu), a natural, water soluble and biocompatible polysaccharide, wa…

Inulin-iron complexes: a potential treatment of iron deficiency anaemia.

The aim of this work was that to synthesize macromolecular derivatives based on inulin able to complex iron and useful in the treatment of iron deficiency anaemia. Carboxylated or thiolated/carboxylated inulin derivatives were obtained by single or double step reactions, respectively. The first one was obtained by reaction of inulin (INU) with succinic anhydride (SA) alone obtaining INU-SA derivative; the second one was obtained by the reaction of INU with succinic anhydride and subsequent reaction of INU-SA with cysteine; both derivatives were treated with ferric chloride in order to obtain the INU-SA-Fe(III) and INU-SA-Cys-Fe(III) complexes. Both complexes showed an excellent biodegradabi…

NIR LASER-RESPONSIVE FOLATE-TARGETED GOLD NANORODS AS EFFICIENT THERANOSTIC TOOL FOR OSTEOSARCOMA TREATMENT

Folate-targeted gold nanorods (GNRs) are here proposed as selective theranostic agents for osteosarcoma treatment. Taking advantage of the attractive physiochemical and optical properties of GNRs they can be proposed as effective and selective platform to obtain a targeted intracellular drug release, photothermal therapy and cancer imaging, which may improve therapeutic outcomes of osteosarcoma. An amphiphilic polysaccharide graft-copolymer, named INU-LA-PEG-FA, and a folic acid functionalized α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA-FA), have been synthesized to act as coating agents for GNRs. The obtained polymer-coated GNRs were characterized in terms of size, shape, zeta potenti…

Hyaluronic acid and its derivatives in drug delivery and imaging: Recent advances and challenges.

Hyaluronic acid (HA) is a biodegradable, biocompatible, nontoxic, and non-immunogenic glycosaminoglycan used for various biomedical applications. The interaction of HA with the CD44 receptor, whose expression is elevated on the surface of many types of tumor cells, makes this polymer a promising candidate for intracellular delivery of imaging and anticancer agents exploiting a receptor-mediated active targeting strategy. Therefore, HA and its derivatives have been most investigated for the development of several carrier systems intended for cancer diagnosis and therapy. Nonetheless, different and important delivery applications of the polysaccharide have also been described, including gene …

CURCUMIN-LOADED LIPID NANOSTRUCTURES AS DRUG DELIVERY SYSTEMS.

CONTROLLED DELIVERY OF WATER-INSOLUBLE ACTIVE INGREDIENTS IN AIR FROM HYDROGEL MATRICES

INTERACTION OF MACROMOLECULAR PRO-DRUGS WITH LIPID MODEL MEMBRANE - CALORIMETRIC STUDY OF 4-BIPHENYLACETIC ACID LINKED TO ALPHA,BETA-POLY(N-HYDROXYETHYL)-DL-ASPARTAMIDE INTERACTING WITH PHOSPHATIDYLCHOLINE VESICLES

The effect of 4-biphenylacetic acid (BPAA) covalently linked to α,β-poly(N-hydroxyethyl)-dl-aspartamide (PHEA) on the thermotropic properties of dipalmitoylphosphatidylcholine (DPPC) liposomes was investigated by differential scanning calorimetry (DSC). Addition of increasing amounts of PHEA-BPAA adduct to a suspension of phospholipid vesicles modified the thermotropic gel-to-liquid crystalline phase transition by decreasing the enthalpy changes ΔH with concomitant broadening of the peak without variations in the transition temperature (Tm). These effects are interpreted in terms of a deep interaction of BPAA bound to the polymer with the apolar moiety of the lipid bilayer. The amount of dr…

Biocompatible micelles based on squalene portions linked to pegylated polyaspartamide as potential colloidal drug carriers

α,β-Poly(N-Hydroxyethyl)-DL-Aspartamide Hydrogels as Drug Delivery Devices

α,β-poly(N-hydroxyethyl)-DL-aspartamide (PHEA) was exposed to gamma radiation to obtain micromatrices able to swell in an aqueous medium. Crosslinked PHEA was loaded with an anti-inflammatory drug, 4-biphenylacetic acid (BPAA) and the drug dispersion in the network was investigated by X-ray analysis. The BPAA loaded PHEA microparticles were also characterized by dimensional analysis, which showed the presence of quasispherical shapes. The drug release from PHEA hydrogel was studied in vitro in a pH 1.1 (simulated gastric juice) and in a pH 7.4 buffer solution, respectively. The experimental data indicate that an anomalous delivery occurs, but Fickian diffusion through swollen PHEA hydrogel…

TUNABLE SENSOR FOR PH WINDOWS IN BIOCAMPITBLE POLYMERIC MICELLES SISTEM

FERULIC ACID LOADED SOLID LIPID NANOPARTICLES PROTECTS LAN5 NEUROBLASTOMA CELL LINE BY Ab-AMYLOID OXIDATIVE STRESS

POLYMER-BASED THERAPEUTICS FOR THE TREATMENT OF LIVER DISEASES

Sintesi e caratterizzazione di vettori polimerici a base di una poliidrossietilaspartammide ottenuti mediante ATRP per la veicolazione di SiRNA

Mucoadhesive solid lipid microparticles for controlled release of a corticosteroid in the chronic obstructive pulmonary disease treatment.

Therapeutic efficacy of inhaled drugs is limited by rapid clearance from the site of action due to absorption into systemic circulation or metabolic degradation by alveolar macrophages. Drug delivery systems offer new solutions to clinical problems especially in the treatment of pulmonary diseases. In particular, Solid Lipid Microparticles (SLM) in the range of 3-5 µm are suggested as systems for delivery of therapeutics to the lung as, because of their size, they are able to deposit into secondary bronchi, avoiding systemic absorption typical of alveolar regions. Here, we describe two novel different SLMs prepared with chitosan and alginate for sustained release of fluticasone propionate (…

Clever pH-Sensitive Drug-polymer Coniugates For Targeted Cancer Therapy

METHOD TO PRODUCE HYALURONIC ACID FUNCTIONALIZED DERIVATIVES AND FORMATION OF HYDROGELS THEREOF

Production of a Double-Layer Scaffold for the “On-Demand” Release of Fibroblast-like Limbal Stem Cells

The production and characterization of a double layer scaffold, to be used as a system for the “on demand” release of corneal limbal stem cells are here reported. The devices used in the clinics and proposed so far in the scientific literature, for the release of corneal stem cells in the treatment of limbal stem cell deficiency, cannot control the in vivo space-time release of cells since the biomaterial of which they are composed is devoid of stimuli responsiveness features. Our approach was to produce a scaffold composed of two different polymeric layers that give the device the appropriate mechanical properties to be placed on the ocular surface and the possibility of releasing the stem…

Combining Spontaneous Polymerization and Click Reactions for the Synthesis of Polymer Brushes: A "Grafting Onto" Approach

Two novel benzofulvene monomers bearing propargyl or allyl groups have been synthesized by means of readily accessible reactions, and were found to polymerize spontaneously by solvent removal, in the apparent absence of catalysts or initiators, to give the corresponding polybenzofulvene derivatives bearing clickable propargyl or allyl moieties. The clickable propargyl and allyl groups were exploited in appropriate click reactions to develop a powerful and versatile "grafting onto" synthetic methodology for obtaining tailored polymer brushes.

Margination of Fluorescent Polylactic Acid-Polyaspartamide based Nanoparticles in Microcapillaries In Vitro: the Effect of Hematocrit and Pressure.

The last decade has seen the emergence of vascular-targeted drug delivery systems as a promising approach for the treatment of many diseases, such as cardiovascular diseases and cancer. In this field, one of the major challenges is carrier margination propensity (i.e., particle migration from blood flow to vessel walls); indeed, binding of these particles to targeted cells and tissues is only possible if there is direct carrier–wall interaction. Here, a microfluidic system mimicking the hydrodynamic conditions of human microcirculation in vitro is used to investigate the effect of red blood cells (RBCs) on a carrier margination in relation to RBC concentration (hematocrit) and pressure drop…

Modulation of physical and biological properties of a composite PLLA and polyaspartamide derivative obtained via thermally induced phase separation (TIPS) technique.

Abstract In the present study, blend of poly l -lactic acid (PLLA) with a graft copolymer based on α,β-poly(N-hydroxyethyl)- dl -aspartamide and PLA named PHEA-PLA, has been used to design porous scaffold by using Thermally Induced Phase Separation (TIPS) technique. Starting from a homogeneous ternary solution of polymers, dioxane and deionised water, PLLA/PHEA-PLA porous foams have been produced by varying the polymers concentration and de-mixing temperature in metastable region. Results have shown that scaffolds prepared with a polymer concentration of 4% and de-mixing temperature of 22.5 °C are the best among those assessed, due to their optimal pore size and interconnection. SEM and DSC…

Highly Homogeneous Biotinylated Carbon Nanodots: Red-Emitting Nanoheaters as Theranostic Agents toward Precision Cancer Medicine

Very recent red-emissive carbon nanodots (CDs) have shown potential as near-infrared converting tools to produce local heat useful in cancer theranostics. Besides, CDs seem very appealing for clinical applications combining hyperthermia, imaging, and drug delivery in a single platform capable of selectively targeting cancer cells. However, CDs still suffer from dramatic dot-to-dot variability issues such that a rational design of their structural, optical, and chemical characteristics for medical applications has been impossible so far. Herein, we report for the first time a simple and highly controllable layer-by-layer synthesis of biotin-decorated CDs with monodisperse size distribution, …

Rapamycin-Loaded Polymeric Nanoparticles as an Advanced Formulation for Macrophage Targeting in Atherosclerosis

Recently, rapamycin (Rapa) represents a potential drug treatment to induce regression of atherosclerotic plaques

Composite Hydrogels of Alkyl Functionalized Gellan Gum Derivative and Hydroxyapatite/Tricalcium Phosphate Nanoparticles as Injectable Scaffolds for bone Regeneration

An alkyl functionalized gellan gum derivative was here used to produce hydrogels containing hydroxyapatite and tricalcium phosphate nanoparticles as injectable nanostructured scaffolds for bone regeneration. The amphiphilic nature of the polysaccharide derivative along with its thermotropic behavior and ionotropic crosslinking features made possible to produce injectable bone mimetic scaffolds that can be used to release viable cells and osteoinductive biomolecules. The influence of different nanoparticles concentration on the rheological and physicochemical properties of the injectable systems was studied. We found that the presence of inorganic nanoparticles reinforces the three-dimension…

Evaluation of the interaction between a polyaminoacidic hydrogel and mucin by ATR-FTIR spectroscopy

Multicomponent polymeric micelles based on polyaspartamide as tunable fluorescent pH-window biosensors

Abstract PHEA-PEG 5000 -C 16 is a polyaspartamide polymer with appended hydrophilic PEG 5000 functions and hydrophobic n-C 16 units forming biocompatible micelles with a CAC as low as 1.8 × 10 −7  M. The protonation and acidity constants of the polymer's amino and carboxylic groups have been determined by potentiometric titrations at five different concentrations higher than CAC, finding concentration-independent values. Viscosity and polarity of the micellar core have been investigated by means of fluorescent probes, finding local values comparable to those of pure toluene and to the core of sodium dodecyl sulphate micelles, independently on the protonation degree of the polymer. The fluor…

Hyaluronic acid dressing of Hydrophobic Carbon Nanodots: a Self-assembling Strategy of Hybrid Nanocomposites with Theranostic Potential

We propose a rational design of hyaluronic acid-dressed red-emissive carbon dots (CDs), with a well-structured hydrophobic core capable of locally delivering high amount doxorubicin (Doxo) (> 9% w/w) and heat (hyperthermia) in a light stimuli sensitive fashion. We combined in a unique micelle-like superstructure the peculiar optical properties of CDs (NIR photothermal conversion and red fluorescence) with the ability of hyaluronic acid (HA) shell of stabilizing nanomedicines in aqueous environment and recognizing cancer cells overexpressing CD44 receptors on their membranes, thus giving rise to smart theranostic agents useful in cancer imaging and NIR-triggered chemo-phototherapy of solid t…

idrogelo a base di acido ialuronico e suo uso in ortopedia

Cationic solid-lipid nanoparticles for gene delivery.

CHEMICALLY CROSSLINKED HYALURONAN AND alpha,beta-POLYASPARTYLHYDRAZIDE AS NANO-COMPOSITE PARTICLES

POLYMERIC CONJUGATES OF DEXAMETASONE

Hyaluronic Acid-g-Copolymers: Synthesis, Properties, and Applications

NEW AMPHIPHILIC POLY(HYDROXYETHYL)ASPARTAMIDE DERIVATIVES FOR OCULAR DELIVERY

Pefloxacine mesilate- and ofloxacin-loaded polyethylcyanoacrylate nanoparticles: characterization of the colloidal drug carrier formulation.

The entrapment of fluoroquinolones, perfloxacine mesilate (PFX) and ofloxacin (OFX), in polyalkylcyanoacrylate (PECA) nanoparticles could offer some advantages for their biological application; for examples, increasing their bioavailability, controlling the drug time-release in blood, and reducing the formation of bacterial resistance. To load these two drugs in PECA polymeric bulk, the incorporation or adsorption method was performed. These two methods were capable of influencing nanoparticle size, molecular weight, release profile, and drug–polymer association. The incorporation method, particularly for the OFX system, achieved PECA nanoparticle suspensions with a mean size value three ti…

Scaffolds based on hyaluronan crosslinked with a polyaminoacid: Novel candidates for tissue engineering application

New porous scaffolds, with a suitable hydrolytic and enzymatic degradation, useful for tissue engineering applications have been obtained by a carbodiimide mediated reaction between hyaluronan (HA) and a synthetic polymer with a polyaminoacid structure such as α,β-polyaspartylhydrazide (PAHy). Scaffolds with a different molar ratio between PAHy repeating units and HA repeating units have been prepared and characterized from a chemical and physicochemical point of view. Tests of indirect and direct cytotoxicity, cell adhesion, and spreading on these biomaterials have been performed by using murine L929 fibroblasts. The new biomaterials showed a good cell compatibility and ability to allow ce…

SYNTHESIS, CHARACTERIZATION AND RELEASE STUDIES OF NEW pH SENSITIVE MICROPARTICLES

Electrostatic contribution to the interaction of α, β poly (N-hydroxyethyl)-DL-aspartamide with sodium dodecylsulfate micelles

The enthalpic effect due to the interaction between α, β poly(N-hydroxyethyl)-DL-aspartamide (PHEA) and sodium dodecylsulfate (SDS) in aqueous solutions as a function of the surfactant concentration was measured by the calorimetric technique at various NaCl concentrations. A marked influence of the added electrolyte on the PHEA-SDS interaction was observed. An analysis of the experimental enthalpies allows to estimate the electrostatic and the hydrophobic contributions to the enthalpy of interaction between PHEA and SDS micelles. The results were rationalized in terms of effects due to the screening of the charges residing on PHEA and SDS micelles.

Pressure-Dependent Tuning of Photoluminescence and Size Distribution of Carbon Nanodots for Theranostic Anticancer Applications

Carbon nanodots (CDs) have recently attracted attention in the field of nanomedicine because of the biocompatibility, cost-effective nature, high specific surface, good near infrared (NIR) photothermal conversion into heat and tunable fluorescence properties, which have paved the way toward incorporating use of CDs into innovative anticancer theranostic platforms. However, a reliable synthesis of CDs with established and controlled physiochemical proprieties is precluded owing to the lack of full manipulation of thermodynamic parameters during the synthesis, thus limiting their use in real world medical applications. Herein, we developed a robust solvothermal protocol which allow fine contr…

A methacrylic hyaluronic acid derivative for potential application in oral treatment of celiac disease.

Objective: Aim of this work was the synthesis of a methacrylic hyaluronic acid (HA) derivative and the production, via photocrosslinking, of related hydrogels loaded with an endopeptidase intended for a potential oral treatment of celiac disease. Methods: The methacrylic derivative of HA was prepared through a one-pot procedure involving the reaction with ethylenediamine (EDA) and methacrylic anhydride (MA). The obtained derivative, named HA-EDA-MA, was used to prepare photocrosslinked hydrogels loaded with a prolyl endopeptidase derived from Flavobacterium meningosepticum (PEP FM) able to detoxify gliadin. Obtained hydrogels were recovered as gels or freeze-dried powders. Results: Hydrogel…

π-Stacked polymers in drug delivery applications

Abstract Polybenzofulvenes are π-stacked polymers, which can be synthesized by spontaneous polymerization of the corresponding monomers without the use of catalysts or initiators. Therefore, they can be obtained completely free from byproducts, impurities, or harmful substances. The absence of any relevant toxic effects and cell viability impairments allows PEGylated polybenzofulvene brushes to be potentially functional in a wide range of biological, biomedical, and biotechnological applications. Moreover, the properties of these polymers, in terms of interaction with pharmacological active agents and the ability to self-assemble into nanoaggregates or a quite compact physical gel useful as…

MICELLES OF AMPHYPHLIC HYALURONIC ACID DERIVATIVES FOR TARGETED DELIVERY OF DOXORUBICIN

Molecular characterization of α , β -poly(asparthylhydrazide) a new synthetic polymer for biomedical applications

Abstract α , β -Poly(asparthylhydrazide) (PAHy) is a new synthetic polymer that exhibits interesting properties and is a candidate for biomedical applications. In this article the characterization of PAHy polymer by multi-angle laser light scattering (MALS) and single-capillary viscometer (SCV) detectors on-line to a size exclusion chromatography (SEC) system is reported. The SEC–MALS–SCV system furnishes exhaustive and consistent characterization of the PAHy polymer. Further, it is possible to characterize the PAHy polymer through conventional SEC and universal calibration. The universal calibration method gives intrinsic viscosity and dispersity very close to those measured by the absolut…

A facile way to build up branched high functional polyaminoacids with tunable physicochemical and biological properties

Abstract Here, for the first time, branched polyaminoacids bearing α-amino acids as side functions, namely PAA-co-AA and PGA-co-AA, are prepared by heterophase ring opening of polysuccinimide (PSI) with l -arginine or glycine in aqueous environment and at controlled pH. The modulation of the pH of the reaction leads to high-molecular-weight copolymers with tunable functionalization and, as consequence, with tailor-made physicochemical properties. Furthermore, a branched polyaminoacid carrying a preformed bioactive peptide ( l -trileucine) and l -arginine as side pendants, named PATA-co-AA, was synthesized via a similar pathway thus leading to complex biomimetic materials potentially exploit…

FERULIC ACID INHIBITS OXIDATE STRESS AND CELL DEATH INDUCED BY Ab OLIGOMERS: IMPROVED DELIVERY BY SOLID LIPID NANOPARTICLES.

Oxidative stress and dysfunctional mitochondria are among the earliest events in AD, triggering neurodegeneration. The use of natural antioxidants could be a neuroprotective strategy for blocking cell death. Here, the antioxidant action of ferulic acid (FA) on different paths leading to degeneration of recombinant beta-amyloid peptide (rAbeta42) treated cells was investigated. Further, to improve its delivery, a novel drug delivery system (DDS) was used. Solid lipid nanoparticles (SLNs), empty or containing ferulic acid (FA-SNL), were developed as DDS. The resulting particles had small colloidal size and highly negative surface charge in water. Using neuroblastoma cells and rAbeta42 oligome…

Microwave-assisted synthesis of PHEA-oligoamine copolymers as potential gene delivery systems

Aims - Copolymers bearing oligoamines and having buffering capacity in the endosomal pH range seems very promising as non viral vectors in gene delivery, due to the great importance of endosomal escaping for an efficient endocellular DNA release. Aim of this paper was to prepare new copolymers based on α,β-poly-(N-2-hydroxyethyl)-D,L-aspartamide (PHEA) as polymeric backbone and bearing an oligoamine, such as diethylentriamine (DETA) in the side chain and useful for gene delivery. Moreover in order to reduce solvent volume and to make faster the reaction, microwave-assisted has been used. Materials and methods - PHEA copolymers bearing different amount of DETA were prepared by using bis(4-ni…

Preparation and characterization of new hydrogels based on hyaluronic acid and α,β-polyaspartylhydrazide

Abstract Hyaluronic acid (HA) has been crosslinked with α,β-polyaspartylhydrazide (PAHy). The crosslinking reaction has been performed in acidic medium in the presence of various amounts of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC). All obtained samples have been characterized by FT-IR analysis and swelling measurements in double distilled water that have confirmed the occurrence of a chemical linkage between two polymers and the affinity towards aqueous medium of HA–PAHy networks, respectively. In vitro degradation assays have been performed in simulated physiological conditions as well as in the presence of hyaluronidase. Experimental data evidenced that HA–PAHy …

pH-sensitive hydrogel based on a polyaspartamide derivative

A pH-sensitive hydrogel was prepared by UV irradiation technique. Starting polymer was obtained from alpha,beta-poly (N-2-hydroxyethyl)-DL-aspartamide (PHEA) partially derivatized with glycidyl methacrylate (PHG). The PHG copolymer was cross-linked by UV irradiation in the presence of methacrylic acid (MA) to form a pH sensitive hydrogel. The cross-linked matrix shaped as microparticles was characterized by FT-IR spectrophotometry, XPS, X-ray diffraction, SEM and particle size distribution analyses. Moreover, to have information about water affinity of the prepared sample, swelling measurements were carried out in aqueous media mimicking some biological fluids. In order to employ the prepar…

PHARMACEUTICAL NANODEVICES FOR BIOMEDICAL APPLICATIONS

NEW GRAFT COPOLYMERS OF HYALURONIC ACID AND POLYLACTIC ACID: SYNTHESIS AND CHARACTERIZATION

Abstract New graft copolymers have been synthesized, using hyaluronic acid (HA) as a hydrophilic backbone and polylactic acid (PLA) as an aliphatic polyester in order to obtain new polymeric derivatives of HA able to hydrophobically associate in an aqueous medium. Hyaluronic acid with low molecular weight was made soluble in organic solvent by transformation to its tetrabutylammonium (TBA) salt. Using the HA–TBA derivative, the reaction was performed in dimethylsulfoxide adding as a reagent the N -hydroxysuccinimide derivative of PLA. Two HA–PLA graft copolymers have been synthesized and characterized by FT-IR, 1 H NMR spectroscopy and gel permeation chromatography. The interaction between …

Inulin vinyl sulfone derivative cross-linked with bis-amino PEG: new materials for biomedical applications

In this work new hydrogels based on biocompatible polymers such as inulin (INU) and O,O'-bis(2-aminoethyl)polyethyleneglycol (PEGBa) have been prepared and charaterized. In particular, INU has been derivatized with divinyl sulfone (DV) thus obtaining the INUDV derivative, a copolymer bearing double bonds highly reactive towards the conjugate addition by nucleophilic molecules. INUDV has been characterized by FT-IR, 1 H-NMR and SEC analyses that have confirmed the success of the derivatization reaction. With the aim to obtain novel hydrogel systems, INUDV derivative has been cross-linked with PEGBa in phosphate buffer solution pH 7.4. The reaction has been carried out for 4 h at room tempera…

Preparation and Biological Evaluation of Ethylcellulose Microspheres Containing Tolmetin

AbstractTolmetin microspheres were prepared by the coacervation process from the ethylcellulose. Microspheres were obtained both in presence and without protecting colloids, such as polyisobutilene (PIB) or ethyl-vinylacetate copolimers (EVA). The effect of these agents on the preparation, drug content, wall thickness, surface morphology, drug dissolution arid release from microspheres, were evaluated. The dissolution rate analysis was carried out also in the presence of a surfactant (Tween 80) at different pH values.In addition, microspheres containing Tolmetin as a core material were submitted to biological tests, in comparison with the free drug, to evaluate upon experimental models the …

Effects of Homogenization Technique and amount of Surfactants on Physical-Chemical Properties of Nanostructured Lipid Carriers (NLCs).

DRUG DELIVERY FROM MUCOADHESIVE DISKS BASED ON A PHOTO-CROSS-LINKABLE POLYASPARTAMIDE DERIVATIVE

Disks for local delivery of amoxicillin to the buccal or gastric cavity were prepared using as starting polymer a polyaspartamide derivative. In particular, α,β-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) was derivatized with glycidyl methacrylate (GMA) in order to synthesize PHG, a photo-cross-linkable and biodegradable polymer that gives rise to the formation of a chemical hydrogel (PHG-UV) by UV irradiation. This hydrogel was shaped as disks whose mucoadhesive properties have been confirmed by swelling measurements in phosphate buffer/citric acid solution at pH 7.0 in the presence of various concentrations of mucin. Swelling ability of PHG-UV disks was also evaluated in simulated saliva…

BIODEGRADABLE POLYASPARTAMIDE-GRAFT-POLYESTER COPOLYMER FOR VASCULAR REGENERATION

Cell uptake enhancement of folate targeted polymer coated magnetic nanoparticles.

Dual targeted drug delivery systems represent a potential platform for developing efficient vector to tumor sites. In this study we evaluated a folate- and magnetic-targeted nanocarriers based on 10 nm iron oxide nanodomais coated with the properly synthesized and characterized folic acid (FA)-functionalized amphiphilic copolymer PHEA-PLA-PEG-FA. FA was chemically conjugated to one end of diamino-polyethylene glycol of 2000 Da, in order to ensure its exposition on the polymer coated magnetic nanoparticles (MNPs-FA). The prepared nanoparticles have been exhaustively characterized by different methods, including DLS, SEM, FT-IR and magnetic measurements. Magnetic nanoparticles showed dimensio…

Beads of Acryloylated Polyaminoacidic Matrices Containing 5-Fluorouracil for Drug Delivery

Spherical polymeric microparticles have been prepared by a reverse phase suspension polymerization technique. The starting polymer was alpha,beta-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA), partially derivatized with glycidylmethacrylate (GMA). PHEA-GMA copolymer (PHG) was crosslinked in the presence of N,N'-dimethylacrylamide (DMAA) or N,N'-ethylenebisacrylamide (EBA). 5-fluorouracil was incorporated into PHG-DMAA or PHG-EBA beads both during and after the crosslinking process. Swelling studies revealed a high affinity toward aqueous medium, influenced by the presence of 5-fluorouracil. The in vitro release study showed that the release rate depends on the chemical structure of the beads…

A POLYCARBOXYLIC/AMINO FUNCTIONALIZED HYALURONIC ACID DERIVATIVE FOR THE PRODUCTION OF pH SENSIBLE HYDROGELS IN THE PREVENTION OF BACTERIAL ADHESION ON BIOMEDICAL SURFACES

A graft copolymer derivative of hyaluronic acid bearing pendant amino and short polymethacrylate portions (HA-EDA-BMP-MANa) has been employed for the production of a pH sensible vancomycin releasing hydrogel and studied in vitro to test its potential anti adhesive property against Staphylococcus aureus colonization. The copolymer obtained through atom transfer radical polymerization bears chargeable (carboxyl and amino groups) portions and it could be formulated as a hydrogel at a concentration of 10% w/v. The HA-EDA-BMP-MANa hydrogels, produced at three different pH values (5, 6 and 7, respectively), were formulated with or without the addition of vancomycin (2% w/v). The vancomycin releas…

Silibilina per il trattamento delle patologie oculari neurodegenerative e formulazioni comprendenti nanostrutture per la sua veicolazione

EVALUATION OF POLYAMINOACIDIC POLYMERS AS GENE TRANFER AGENTS TO RESPIRATORY EPITHELIAL CELLS AND OF THEIR BIOPHYSICAL PROPERTIES IN THE PRESENCE OF CYSTIC FIBROSIS MUCUS

NOVEL THIOLATED COPOLYMER BASED ON POLYASPARTAMIDE: IN VITRO EVALUATION STUDIES

HYDROGELS OF HYALURONIC ACID-GRAFT-alfa-ELASTIN AS EXTRACELLULAR MATRIX SUBSTITUTES

MICELLE POLIMERICHE A BASE DI NUOVI DERIVATI ANFIFILICI DELL’INULINA PER LA SOMMINISTRAZIONE OCULARE TOPICA DI CORTICOSTEROIDI NEL TRATTAMENTO DELLE PATOLOGIE DEGENERATIVE DELLA RETINA

Al giorno d’oggi, la via di somministrazione oftalmica costituisce ancora una sfida per i tecnologi farmaceutici. Si tratta, inoltre, probabilmente di uno degli ambiti che più di ogni altro potrebbe beneficiare dello sviluppo di nuovi Drug Delivery Systems basati sull’utilizzo di nanovettori. Infatti, più del 50% delle patologie oculari maggiormente debilitanti (es. degenerazione maculare legata all’età, retinopatia diabetica ed edema maculare diabetico) ha origine a livello del segmento oculare posteriore. Ad oggi, la terapia intravitreale costituisce il gold standard per garantire il raggiungimento del sito target, ovvero la retina. Tuttavia, la necessità di ricorrere a frequenti somminis…

Self-aggregating amphiphilic derivatives of a polyaspartamide

NLC Containing Fluticasone Propionate for Inhalatory Delivery: Biocompatibility and Drug Antiinflamatory Effect

Par j 1/Par j 2-nanoaggregati: un nuovo strumento per la terapia antiallergica

Coupling of the antiviral agent zidovudine to polyaspartamide and in vitro drug release studies.

A macromolecular prodrug of the known antiretroviral agent zidovudine and alpha, beta-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) was synthesized. A succinic spacer was present between the polymer and the drug, and 1,1'-carbonyldiimidazole was used as the coupling agent. In vitro drug release studies at pH 1.1, 5.5 and 7.4 indicated that limited amounts of intact drug were released from the conjugate. At pH 1.1 and 7.4 succinylzidovudine was released, and this was hydrolysed to give free zidovudine. In the presence of alpha-chymotrypsin, zidovudine was released preferentially in comparison with the succinyl derivative. The amounts of released zidovudine and succinylzidovudine were greater …

POLYMERIC MICELLES AS DRUG DELIVERY SYSTEMS TOWARDS BRAIN TARGETING

THIOPOLYCATIONS BASED ON POLYASPARTAMIDE AS NEW VECTORS FOR GENE THERAPY

Polymeric micelles based on a polyaspartamide copolymer for pulmonary delivery of beclomethasone dipropionate

Calorimetric investigation of the complex formation between surfactants and α-, β- and γ-cyclodextrins

Abstract A calorimetric technique has been used to study complex formation between α-, β- and γ-cyclodextrins (αCD, βCD and γCD) and some surfactants (sodium dodecylsulphate (SDS), hexadecyl trimethylammonium bromide (CTAB) and p-(1,1,3,3-tetramethylbutyl) phenoxypoly(oxyethyleneglycol) (Triton X-100)). The experimental data indicate that some complexes (SDS-αCD, SDS-βCD and CTAB-αCD) are very stable and allow direct determination of their stoichiometry and molar enthalpy of complex formation. Those for other complexes closely fit a model based on an equilibrium reaction between surfactant, cyclodextrin and a single complex. According to the model, data analysis allows determination of the …

New pegylated polyaspartamide-based polyplexes as gene delivery vectors

Aims: To synthesize novel polyhydroxyethylaspartamide (PHEA) copolymers containing spermine (Spm) and polyethylene glycol (PEG) moieties in high yields, with the expectation that this material would show stealth properties and the ability to complex DNA by electrostatic interactions. Materials & methods: PHEA–PEG–Spm copolymer was prepared with a two-step reaction. Chemical, physicochemical and biological characterizations of PHEA–PEG–Spm copolymers and their obtained polyplexes with pDNA were performed. Results: The introduction of spermine in PHEA structure allows to obtain a copolymer bearing in the side chains polyamine moieties capable to interact with DNA. On the other hand, the …

FLUORINATED DERIVATIVES OF A POLYASPARTAMIDE BEARING POLYETHYLENE GLYCOL CHAINS AS OXYGEN CARRIERS

Abstract In this paper the synthesis and characterization of new fluorinated polymers based on a polyaspartamide bearing polyethylene glycol (PEG) chains, are reported. The starting material was the α,β-poly(N-2-hydroxyethyl)- dl -aspartamide (PHEA), a water soluble and biocompatible polymer, that has been derivatized with both polyethylene glycol (with a molecular weight of 2000 Da) and 5-pentafluorophenyl-3-perfluoroheptyl-1,2,4-oxadiazole. By varying the amount of the fluorinated oxadiazole, three samples have been prepared and characterized by FT-IR, 1H NMR, 19F NMR and UV–VIS spectroscopy. Size exclusion chromatography analysis of these copolymers revealed the occurrence of a self-asso…

PREPARATION AND CHARACTERIZATION OF NEW PHEA-GRAFT-POLYMETHACRYLATE NANOPARTICLES.

NEW PEGYLATED NANOPARTICLE SYSTEMS BASED ON POLYASPARTAMIDE DERIVATIVES

NEW PHEA COPOLYMERS BEARING GRAFT POLYMETHACRYLIC ACID CHAINS AS CARRIER FOR ENDOSTATIN

PREPARATION AND IN VITRO CHARACTERIZATION OF NEW HYDROGELS BASED ON INULIN AND ALPHA,BETA-POLYASPARTYLHYDRAZIDE FOR COLONIC DRUG DELIVERY

New biodegradable hydrogels based on an acryloylated polyaspartamide cross-linked by gamma irradiation

Alpha, beta-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA), a synthetic biocompatible macromolecule, was functionalized with glycidyl methacrylate (GMA) in order to introduce in its side chains residues having double bonds and ester groups. The copolymer (PHG), obtained from PHEA and GMA, had a degree of derivatization of 29 mol%. PHG aqueous solutions are cross-linked by gamma radiation at 0 degrees C either in the presence or absence of N,N'-methylenebisacrylamide (BIS) giving rise to new hydrogel systems. In both cases gelation occurs at quite low doses (0.26 and 0.4 kGy, respectively). The obtained networks were characterized by FT-IR spectrophotometry which confirmed that the cross-linki…

MATRICES OF A HYDROPHOBICALLY FUNCTIONALIZED HYALURONIC ACID DERIVATIVE FOR THE LOCOREGIONAL TUMOUR TREATMENT

A hyaluronic acid (HA) derivative bearing octadecylamine and acylhydrazine functionalities has been here employed for the production of a paclitaxel delivering matrix for locoregional chemotherapy. Through a strategy consisting in a powder compression and a plasticization with a mixture water/ethanol, a physically assembled biomaterial, stable in solutions with physiologic ionic strengths, has been produced. Two different drug loading strategies have been adopted, by using paclitaxel as chemotherapic agent, and obtained samples have been assayed in terms of release in enhanced solubility conditions and in vitro and in vivo tumoural cytotoxicity. In particular sample with the best releasing …

A self-sterilizing fluorescent Nanocomposite as versatile material with broad-spectrum Antibiofilm features

Abstract Hematogenous spread of infections from colonized central intravenous catheters or central lines is a long-recognized problem with infection rates of 2 and 6.8 per 1000 days, respectively. Besides, removal of severe microbial colonization of implanted biomaterials is still a challenge and usually requires invasive operations. Hence, on demand self-sterilizing materials are required to avoid explant of colonized biomaterials and improve patient compliance. Moreover, photoluminescence is needed to make trackable biomaterials, which can be easily monitored upon implanting them in the body. Here, we propose the incorporation of near infrared (NIR) sensitive red-emitting carbon nanodot (…

Amphiphilic derivatives of a polyaspartamide: their aggregation and solubilization ability.Tensiometric and spectrophotometric studies

The self-aggregation and solubilization capability of a series of amphiphilic copolymers obtained by derivatisation of polymeric chain of α,β-poly(N-2-hydroxyethyl)-dl-aspartamide (PHEA) with polyethylene glycols (PEG, being different molecular weight 2000 or 5000 Da, PEG2000 and PEG5000, respectively) and/or hexadecylamine alkyl chain (C16), namely PHEA–PEG2000, PHEA–PEG5000, PHEA–C16, PHEA–PEG2000–C16 and PHEA–PEG5000–C16, have been evidenced by performing systematic tensiometric and spectrophotometric studies. All measurements have been performed at 25.0 °C over a wide copolymer concentration range. The tensiometric results have shown that, for all copolymers studied, the surface tension…

DEGRADATION STUDIES OF NOVEL POLYMERIC NANOPARTICLES BASED ON AMPHIPHILIC POLYLACTIC ACID-POLYASPARTAMIDE DERIVATIVES

Chemical conjugation of dexamethasone to a polyaspartamide and in vitro evaluation studies

Two macromolecular conjugates of dexamethasone containing different drug amounts were synthesized using PHEA as the polymeric carrier and a succinic group as spacer. The content of linked drug was equal to 25.3% w/w (conjugate A) and 12.7% w/w (conjugate B). Both polymeric conjugates, unlike the free drug, were water-soluble and the amount of unlinked drug was evaluated to be approximately about 0.01% w/w. Both conjugates were relatively stable in vitro at pH 7.4 whereas in the presence of esterase only the conjugate B was able to release drug under the used experimental conditions. This dissimilar behavior has been attributed to the distinct macromolecular conformations assumed in aqueous …

SELF-ASSEMBLED AMPHIPHILIC HYALURONIC ACID GRAFT COPOLYMERS FOR TARGETED RELEASE OF ANTITUMORAL DRUG

Polymeric micelles obtained by self-assembling of amphiphilic hyaluronic acid (HA) graft copolymers have been prepared and characterized. In particular, hyaluronic acid (HA) has been grafted to polylactic acid (PLA) and polyethylenglycol chains (PEG), then the copolymers able to form micelles in aqueous medium have been chosen to entrap the antitumoral drug Doxorubicin. The critical aggregation concentration of HA-g-PLA or HA-g-PLA-g-PEG micelles has been determined by using pyrene as a fluorescent probe, whereas their shape and size have been evaluated by light scattering measurements, scanning and transmission electron microscopies. The selective cytotoxicity of drug loaded micelles towar…

Hyaluronic Acid Derivative with Improved Versatility for Processing and Biological Functionalization

A hydrophobic/amino functionalized derivative of hyaluronic acid (HA-EDA-C18 ) has been processed by salt leaching technique as porous scaffold without need of chemical crosslinking. Aim of this work is to demonstrate the improved versatility of HA-EDA-C18 in terms of processing and biological functionalization. In particular, the chemical procedure to tether thiol bearing RGD peptide has been described. Moreover, the possibility to load and to control the release of slightly water soluble effectors has been demonstrated by using dexamethasone. First, the swelling and degradation profiles of the scaffolds have been investigated, then the evaluation of metabolic activity of bovine chondrocyt…

HYALURONIC ACID BASED-MICELLES FOR OFF-LABEL USE OF IMATINIB IN RETINOPATHIES TREATMENT

The aim of this work was to obtain polymeric micelles able to cross corneal barrier and to improve the permeation of imatinib free base. Micelles were prepared by using hyaluronic acid (HA) derivatives containing ethylenediamine (EDA), chains of hexadecyl (C16), polyethylene glycol (PEG) and/or L-carnitine (CRN). The resulting samples, named as HA-EDA-C16, HA-EDA-C16-PEG and HA-EDA-C16-CRN micelles, were designed to allow a non-invasive way of administration, i.e. topical ocular instillation. These nanocarriers showed an optimal particle size in aqueous media and mucoadhesive properties. Imatinib-loaded micelles were able to interact with corneal barrier and to promote imatinib transcorneal…

SELF ASSEMBLED AND CROSSLINKED FIBRILLAR SCAFFOLDS FOR CARTILAGE REGENERATION.

Development of stimulus-sensitive electrospun membranes based on novel biodegradable segmented polyurethane as triggered delivery system for doxorubicin

In this work, redox-sensitive polyurethane urea (PUU) based electrospun membranes have been exploited to chemically tether a pH-sensitive doxorubicin derivative achieved by linking a lipoyl hydrazide to the drug via a hydrazone linkage. First, the lipoyl-hydrazone-doxorubicin derivative labelled as LA-Hy-Doxo has been syn- thesized and characterized. Then, the molecule has been tethered, via a thiol-disulfide exchange reaction, to the redox-sensitive PUU (PolyCEGS) electrospun membrane. The redox-sensitive PolyCEGS PUU has been produced by using PCL-PEG-PCL polyol and glutathione-tetramethyl ester (GSSG-OMe)4 as a chain extender. The LA-Hy- Doxo tethered electrospun membrane has showed a du…

Synthesis and characterisation of novel chemical conjugates based on alpha, beta-polyaspartylhydrazide and beta-cyclodextrins

A new family of supramolecular systems based on a synthetic polyaminoacid and cyclic oligosaccharides such as beta-cyclodextrins (beta-CDs) was synthesised. The pharmaceutical potential of these systems arises from the proper combination between the complexing properties of cyclodextrins and the particular pharmacokinetic profile that can be obtained by using macromolecular conjugates with a biocompatible backbone. Five supramolecular conjugates were synthesised by using alpha,beta-polyaspartylhydrazide (PAHy) as a polymeric component and various amounts of two P-CD derivatives. In particular, by reaction of PAHy with beta-CD monoaldehyde, samples named as A(1), A(2) and A(3), bearing, resp…

SIMPLE, BIOCOMPATIBLE AND COST-EFFECTIVE INULIN BASED SIRNA DELIVERY SYSTEMS

Metallic Core Nanocarriers for Multiple Cancer Targeting

Imatinib-Loaded Micelles of Hyaluronic Acid Derivatives for Potential Treatment of Neovascular Ocular Diseases

In this work, new micellar systems able to cross corneal barrier and to improve the permeation of imatinib free base were prepared and characterized. HA-EDA-C-16, HA-EDA-C-16-PEG, and HA-EDA-C-16-CRN micelles were synthesized starting from hyaluronic acid (HA), ethylenediamine (EDA), hexadecyl chains (C-16), polyethylene glycol (PEG), or L-carnitine (CRN). These nanocarriers showed optimal particle size and mucoadhesive properties. Imatinib-loaded micelles were able to interact with corneal barrier and to promote imatinib transcorneal permeation and penetration. In addition, a study was conducted to understand the in vitro imatinib inhibitory effect on a choroidal neovascularization process…

Calorimetric and viscosimetric investigation of the interaction between α,β-polyasparthydrazide and sodium dodecyl sulfate micelles

Abstract The interaction between α,β-polyasparthydrazide (PAHy) and sodium dodecyl sulfate (SDS) micelles in aqueous solution was investigated by calorimetry and viscosimetry. The dependence of the enthalpic effect due to this interaction upon the surfactant concentration was rationalized in terms of a progressive binding of SDS micelles to the polymeric backbone. The analysis of the calorimetric data allow evaluation of the binding ability of SDS micelles to the polymeric chain. The viscosimetric behavior of SDS plus PAHy aqueous solutions, discussed in terms of the parameter F [F = ηrel(PAHy) + ηrel(PAHy) − ηrel(SDS+PAHy)], confirms the occurence of the interaction between SDS micelles an…

Design and development of hyaluronan-functionalized polybenzofulvene nanoparticles as CD44 receptor mediated drug delivery system

A tri-component polymer brush (TCPB), composed of a polybenzofulvene copolymer bearing low molecular weight hyaluronic acid (HA) on the surface of its cylindrical brush-like backbone and oligo-PEG fractions, was employed in the preparation of 350 nm nanostructured drug delivery systems capable of delivering the anticancer drug doxorubicin. The obtained drug delivery systems were characterized on the basis of drug loading and release, dimensions and zeta potential, morphology and in vitro cell activity, and uptake on three different human cell lines, namely the bronchial epithelial 16HBE, the breast adenocarcinoma MCF-7, and the colon cancer HCT116 cells. Finally, the ability of doxorubicin…

In vivo efficacy of verteporfin loaded gold nanorods for combined photothermal/photodynamic colon cancer therapy.

The high incidence of cancer recurrences and the frequent occurrence of multidrug resistance often stem from a poorly selective and inefficient antineoplastic therapy, responsible for the onset of undesired side effects as well. A combination of minimal-invasive approaches could thus be a useful strategy to surmount these shortcomings, achieving a safe and solid cancer therapy. Herein, a multi-therapeutic nanotool was designed by merging the photothermal properties of gold nanorods (AuNRs) with the photodynamic activity of the photosensitizer ver-teporfin. AuNRs were coated with the natural materials lipoic acid and gellan gum (AuNRs_LA,GG) and subse-quently loaded with verteporfin (AuNRs_L…

Hydrophilic and Hydrophobic Polymeric Derivatives of Anti-Inflammatory Agents Such as Alclofenac, Ketoprofen, and Ibuprofen

Macromolecular prodrugs of a hydrophilic polymer [α,β-poly( N- hydroxyethyl)-DL-aspartamide (PHEA)] was used as a drug carrier. Three poly- (HEA)-NSAID adducts were studied: poly(HEA)-Alclofenac, poly(HEA)-Keto profen, and poly(HEA)-Ibuprofen. Prodrugs with different drug content were synthesized both as water-soluble and water-insoluble agents. Hydrolysis of water-soluble adducts in a simulated gastric juice was studied.

Mucoadhesive PEGylated inulin-based self-assembling nanoparticles: In vitro and ex vivo transcorneal permeation enhancement of corticosteroids

Abstract As transcorneal drug delivery is still a challenge, the scope of the present study was to prepare useful nanosystems able to enhance transcorneal permeation/penetration of drugs. Moreover, this work aims to evaluate the effectiveness of inulin-based nanosystems in the specific field of ocular drug delivery and the effect of PEG chains to promote mucoadhesion, stability and transcorneal penetration/permeation enhancer effect of self-assembling nanoparticles in vitro (transwell systems and HCE) and ex vivo (Franz cells and bovine cornea). In particular, inulin was chosen as the starting natural polysaccharide polymer to design a novel amphiphilic derivative named INU-EDA-RA-PEG capab…

In situ gel forming graft copolymers of a polyaspartamide and polylactic acid: Preparation and characterization

Abstract In situ gel forming systems have been prepared by linking polylactic acid (PLA) to a water soluble and polyfunctional polymer, such as α,β-poly( N -2-hydroxyethyl)- d , l -aspartamide (PHEA). Three graft copolymers PHEA–PLA with a different derivatization degree in PLA, have been synthesized and characterized. PHEA–PLA graft copolymer with the highest amount in PLA has been used to prepare solutions in organic solvents able to give rise to gel-like matrices when injected into phosphate buffered saline solution. The chemical degradation of these gels has been evaluated and in vitro tests have been performed to evaluate the cell compatibility of the hydrolysis products. The possibili…

Radiation synthesis of polyaspartamide functionalised hydrogels for sustained release of fragrances

The aim of the present investigation is to assess the possibility of obtaining a biocompatible material device which is able to deliver oil-soluble fragrances in air over a length of time. Aqueous solutions of polyaspartamide functionalised with glycidyl methacrylate have been cross linked through gamma irradiation in the presence of a lipophilic model fragrance, emulsified prior to irradiation. Two emulsification conditions have been considered at two different concentrations of both fragrance and surfactant in water. Chemical hydrogels have been obtained in correspondence to two irradiation absorbed doses and have been characterised for their solubility properties and swelling ability in …

Effects of kind and amount of surfactants on physical-chemical properties of cationic solid lipid nanoparticles (SLN) for the treatment of hepatocellular carcinoma.

New Self-Assembling Polyaspartamide-Based Brush Copolymers Obtained by Atom Transfer Radical Polymerization

A simple and efficient method for the synthesis of polyaspartamide-based brush copolymers using Atom Transfer Radical Polymerization (ATRP) is here presented. The syntheses were performed by using two subsequent steps. In the first step the macroinitiator was obtained by the conjugation of a proper number of 2-bromoisobutyryl bromide (BIB) residues to the R, -poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA) side chains, obtaining the PHEA-BIB copolymer. PHEA-BIB copolymer was used as “multi-functional macroinitiator” for the polymerization via ATRP of hydrophilic methacrylic monomers, such as methacrylic acid (MA), obtaining PHEA-IB-poly(MA) copolymer, sodium methacrylate (MANa+), obtaining PH…

MACROMOLECULAR CONJUGATE OF PACLITAXEL BEARING OXYTOCIN AS TARGETING MOIETY

PREPARAZIONE E CARATTERIZZAZIONE DI UN NUOVO IDROGEL pH-SENSIBILE E BIODEGRADABILE PER IL RILASCIO COLON-SPECIFICO DI FARMACI

UV-photocrosslinking of inulin derivatives to produce hydrogels for drug delivery application.

In this work, INU, a natural polysaccharide, has been chemically modified in order to obtain new photocrosslinkable derivatives. To reach this goal, INU has been derivatized with MA thus obtaining four samples (INU-MA derivatives) as a function of the temperature and time of reaction. An aqueous solution of the derivative INU-MA1 was irradiated by using a UV lamp with an emission range from 250 to 364 nm and without using photoinitiators. The obtained hydrogel showed a remarkable water affinity but it underwent a partial degradation in simulated gastric fluid. To overcome this drawback, INU-MA 1 was derivatized with SA thus obtaining the INU-MA1-SA derivative designed to produce a hydrogel …

POLYMERIC SUPRAMOLECULR SYSTEMS FOR PROTEIN DELIVERY

Biocompatibility and staining properties of CdSe\CdS\SiO2 nanoparticles for in-vitro biomaterials characterization

Semiconductor nanocrystals, known as quantum dots (QDs) display well-tuned emission spectra from ultraviolet to the infrared region. Their photostability is greatly enhanced compared to fluorophores making them suitable for optical bio-imaging. In this work we have studied the cytocompatibility of CdSe\CdS\SiO2 QDs towards bovine articular chondrocytes in order to establish if these nanoparticles could be used as staining system forcells in tissue engineering purposes. Studies of QDs uptake and cell viability were conducted through morphology evaluation and MTS test. The adhesion behavior of chondrocytes deposited onto scaffolds of a derivative of hyaluronic acid functionalized with octadec…

Crosslinked α,β-Polyasparthydrazide Micromatrices for Controlled Release of Anticancer Drugs

The preparation of new hydrogels by the reaction of α,β- polyasparthydrazide and glutaraldehyde is reported. A different crosslinking degree was obtained by varying the ratio crosslinking agent/polymer which influenced the swelling behavior of the gel. 5-Fluorouracil, was incorporated into the matrices during the crosslinking reaction and in vitro release studies were performed in simulated gastric juice (pH 1.1) and pH 7.4 buffer solution. The hydrogels prepared were chemically stable in the dissolution media. The observed data show the potential application of these new matrices for peroral administration of anticancer agents.

Glycosylated macromolecular conjugates of antiviral drugs with a polyaspartamide.

Two new polymeric conjugates for specific liver targeting were prepared by conjugation of sugar moieties and antiviral drugs to alpha, beta-poly[N-2-(hydroxyethyl)-DL-aspartamide] (PHEA). PHEA-galactopyranosylphenylthiocarbamide-mono-O-succinylganciclovir (conjugate 7) and PHEA-mannopyranosylphenylthiocarbamide-O-succinylacyclovir (conjugate 8) were synthesized according to a multi-step procedure which allowed for obtaining high product yield and process standardization. Conjugate 7 contained 7.5 and 8.5% of galactose and ganciclovir (substituent/repeating unit, mol/mol), respectively, and conjugate 8 contained 14.2 and 10.8% of mannose and acyclovir, respectively. In vitro studies demonstr…

Folate-targeted supramolecular vesicular aggregates as a new frontier for effective anticancer treatment in in vivo model.

Abstract Supramolecular vesicular aggregates (SVAs), made up by self-assembling liposomes and polyasparthydrazide co-polymers conjugated to folic acid molecules were extensively investigated in this manuscript as potential active targeting formulation for anticancer drug delivery. Folate-targeted systems (FT-SVAs) were used to treat breast cancer and to further proof the potential in vivo administration of these systems for the therapeutic treatment for several aggressive solid tumors. The physicochemical and technological parameters of FT-SVAs are suitable for their potential in vivo administration. The chemotherapeutic activity of GEM-loaded FT-SVAs was increased during in vivo experiment…

A New Hyaluronic Acid Derivative Obtained from Atom Transfer Radical Polymerization as a siRNA Vector for CD44 Receptor Tumor Targeting

Two derivatives of hyaluronic acid (HA) have been synthesized by atom transfer radical polymerization (ATRP), starting from an ethylenediamino HA derivative (HA-EDA) and by using diethylaminoethyl methacrylate (DEAEMA) as a monomer for polymerization. Both samples, indicated as HA-EDA-pDEAEMA a and b, are able to condense siRNA, as determined by gel retardation assay and resulting complexes show a size and a zeta potential value dependent on polymerization number, as determined by dynamic light scattering measurements. In vitro studies performed on HCT 116 cell line, that over express CD44 receptor, demonstrate a receptor mediated uptake of complexes, regardless of their surface charge.

Electrospun biodegradable materials for vascular regenerative medicine

Objectives: There is a rising interest for the development of small-sized blood vessels substitutes. Several studies have been focused on the development of a biodegradable graft temporarily able to substitute the blood vessels and allow their complete regeneration after a certain time. We tried to develop a biodegradable material, with optimal mechanical characteristics and the capacity to allow cells adhesion, differentiation and proliferation by electrospinning to obtain a nano-fibrillar scaffold starting from a polymeric solution. Methods: We report the in vivo application on rats of two new electrospun biodegradable materials, specifically designed to create tubular structures. Both bi…

Glycidyl methacrylate derivatization of α,β-poly(N-hydroxyethyl)-dl-aspartamide and α,β-polyasparthydrazide

Abstract α,β-Poly(N-hydroxyethyl)- dl -aspartamide (PHEA) and α,β-polyasparthydrazide (PAHy) are two synthetic macromolecules having many potential applications in the field of biomedical sciences. This paper describes the functionalization of PHEA and PAHy with glycidyl methacrylate (GMA), in order to introduce pendant double bonds in their chains. Derivatized PHEA and PAHy (samples PHG and PAG, respectively) at various GMA content have been obtained and characterized. It has been shown that the derivatization reaction can be controlled by varying some parameters as solvent, catalyst, pH, GMA concentration and reaction time. As expected, PAHy reacted more rapidly and more extensively than …

CURCUMIN ENTRAPPED INTO LIPID NANOSYSTEMS IMPROVES INHIBITION OF NEUROBLASTOMA CANCER CELL GROWTH ACTIVATING HSP70 PROTEIN

BIOCOMPATIBLE PHEA-SPERMINE COPOLYMERS FOR GENE DELIVERY

Nanoparticelle polimeriche per il rilascio di molecole bioattive

APPLICAZIONI DI NANOBIOTECNOLOGIE PER LA SALUTE.