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.

Improved Bone Regeneration Using Biodegradable Polybutylene Succinate Artificial Scaffold in a Rabbit Model

The treatment of extensive bone loss represents a great challenge for orthopaedic and reconstructive surgery. Most of the time, those treatments consist of multiple-stage surgeries over a prolonged period, pose significant infectious risks and carry the possibility of rejection. In this study, we investigated if the use of a polybutylene succinate (PBS) micro-fibrillar scaffold may improve bone regeneration in these procedures. In an in vivo rabbit model, the healing of two calvarial bone defects was studied. One defect was left to heal spontaneously while the other was treated with a PBS scaffold. Computed tomography (CT) scans, histological and immunohistochemical analyses were performed …

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

Nanofibrillar scaffold resists to bile and urine action: experiences in pigs

Biomaterial-based-scaffolds’ functions are to replace anatomical and functional features loss of an injured tissue. They can replace native tissue after their reabsorption. Material and methods. In our experimental procedures we utilized the PHEA-PLA+PCL scaffold in 2 female pigs to assess its resistance to bile and urine. Results. Both pigs survived to surgical procedures. After a month fibres appeared unchanged in term of form and dimension at electronic microscopy. Cells and ECM factors were founded inside the scaffold in a microscopical evaluation. Conclusion. Planar and tubular scaffolds were colonized by cells and extracellular matrix elements. The study conducted on pig suggested tha…

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 …

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…

Multicomponent solid dispersion a new generation of solid dispersion produced by spray-drying

Abstract The term “multicomponent solid dispersion” is widely used in recent literature to describe solid formulations consisting of a special excipient's mixture and active molecules finely dispersed. However, this term has not yet been defined. In this review, we aimed to improve the definition of multicomponent solid dispersions as a new generation of solid dispersions capable to improve both formulation issues and the therapeutic effect of the final dosage form. As it is well-known the use of solid dispersions to improve drug dissolution rate and solubility, this review describes the field of solid dispersions as well as the formulation strategies available for their production. In part…

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

BIOLOGICAL STUDIES ON POLYASPARTAMIDE COPOLYMERS AS GENE CARRIER

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

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…

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

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(…

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

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

NANOTECHNOLOGIES FOR BIOMEDICAL APLICATIONS

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

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-…

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.

Phospholipid-polyaspartamide micelles for pulmonary delivery of corticosteroids

A novel drug delivery system for beclomethasone dipropionate (BDP) has been constructed through self-assembly of a pegylated phospholipid-polyaminoacid conjugate. This copolymer was obtained by chemical reaction of α,β-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethyleneglycol)2000] (DSPE-PEG(2000)-NH(2)). Benefiting from the amphiphilic structure with the hydrophilic shell based on both PHEA and PEG and many hydrophobic stearoyl tails, PHEA-PEG(2000)-DSPE copolymer was able to self assemble into micelles in aqueous media above a concentration of 1.23 × 10(-7)M, determined by fluorescence studies. During the self-assembling …

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…

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 …

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…

POLYMERIC MICELLES BASED ON A PHOSPHOLIPID/ POLYASPARTAMIDIC COPOLYMER FOR BECLOMETHASONE DIPROPIONATE DELIVERY TO THE LUNGS

Polybutylene Succinate Processing and Evaluation as a Micro Fibrous Graft for Tissue Engineering Applications

A microfibrous tubular scaffold has been designed and fabricated by electrospinning using poly (1,4-butylene succinate) as biocompatible and biodegradable material. The scaffold morphology was optimized as a small diameter and micro-porous conduit, able to foster cell integration, adhesion, and growth while avoiding cell infiltration through the graft’s wall. Scaffold morphology and mechanical properties were explored and compared to those of native conduits. Scaffolds were then seeded with adult normal human dermal fibroblasts to evaluate cytocompatibility in vitro. Haemolytic effect was evaluated upon incubation with diluted whole blood. The scaffold showed no delamination, and mech…

Kinetic studies of the interaction between DNA and polycations based on polyasparthylhydrazide

Abstract In the present paper, a systematic kinetic study on the interaction between interpolyelectrolytes such as positive-charged polymers and DNA was carried out. In particular, a qualitative–quantitative kinetic investigation on the interaction between copolymers of the α,β-poly(aspartylhydrazide) and DNA calf thymus filaments was performed. This study gives a new model starting from a well known “pseudo-phase model”, and permits to give a qualitative explanation about the trends of experimentally observed kinetic constants by varying the concentration of one of the two poly-electrolytes. Moreover, this study permits to verify the dependence of the binding constants KPAHy–CPTA and KDNA …

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…

Influence of Polyvinyl Alcohol (PVA) on PVA-Poly-N-hydroxyethyl-aspartamide (PVA-PHEA) Microcrystalline Solid Dispersion Films

AbstractThis study was conducted to formulate buccal films consisting of polyvinyl alcohol (PVA) and poly-N-hydroxyethyl-aspartamide (PHEA), to improve the dissolution of the drug through the oral mucosa. Ibuprofen sodium salt was used as a model drug, and the buccal film was expected to enhance its dissolution rate. Two different concentrations of PVA (5% w/v and 7.5% w/v) were used. Solvent casting was used to prepare films, where a solution consisting of drug and polymer was cast and allowed to dry. Attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM) were used to investigate the pr…

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…

POLYMERIC MICELLES FOR DRUG TARGETING TO THE BRAIN

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…

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(…

NEW GENERATION OF BIOCOMPATIBLE GRAFT COPOLYMERS FOR THE PRODUCTION OF NANODEVICES

COMPOSIZIONE FARMACEUTICA OFTALMICA CONTENENTE COPOLIMERI ANFIFILICI DELLA POLIASPARTAMMIDE

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 …

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

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…

NOVEL COMPOSED GALACTOSYLATED NANODEVICES CONTAINING A RIBAVIRIN PRODRUG AS HEPATIC CELL-TARGETED CARRIERS FOR HCV TREATMENT

In this paper, we describe the preparation of liver-targeted nanoparticles potentially able to carry to hepatocytes a ribavirin (RBV) prodrug, exploiting the presence of carbohydrate receptors in the liver (i.e., ASGPR in hepatocytes). These particles were obtained starting from a galactosylated phospholipid-polyaminoacid conjugate. This latter was obtained by chemical reaction of ALPHA, BETA -poly(N-2-hydroxyethyl) (2-aminoethylcarbamate)-DL-aspartamide (PHEA-EDA) with 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl) sodium salt (DPPE), and subsequent reaction with lactose, obtaining PHEA-EDA-DPPE-GAL copolymer. To enhance the entrapment into obtained nanostructures, a hydroph…

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

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…

Streptomyces coelicolor Vesicles: Many Molecules To Be Delivered

ABSTRACT Streptomyces coelicolor is a model organism for the study of Streptomyces, a genus of Gram-positive bacteria that undergoes a complex life cycle and produces a broad repertoire of bioactive metabolites and extracellular enzymes. This study investigated the production and characterization of membrane vesicles (MVs) in liquid cultures of S. coelicolor M145 from a structural and biochemical point of view; this was achieved by combining microscopic, physical and -omics analyses. Two main populations of MVs, with different sizes and cargos, were isolated and purified. S. coelicolor MV cargo was determined to be complex, containing different kinds of proteins and metabolites. In particul…

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…

Hyaluronan‐coated poly(propylene imine) dendrimers as biomimetic nanocarriers of doxorubicin

A coating technology based on low molecular weight hyaluronic acid (HA) and ferulic acid (FA) was applied to the coating of low generation poly(propylene imine) dendrimers through a biocompatible hexa(ethylene glycol) spacer. The ensuing HA-FA-HEG-PPID dendrimeric materials showed interesting loading capability (between 7.65% and 9.08%) regarding anticancer agent doxorubicin, and their interactions with the drug appeared to hamper the drug release in the physiological environment. Thus, the stable nanostructured loaded delivery systems were able to internalize into cells expressing the HA receptor CD44 and to demonstrate high cytotoxicity comparable to that shown by equivalent amounts of fr…

A new pH responsive polymer based on inulin for siRNA Delivery

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…

Ferritin-Coated SPIONs as New Cancer Cell Targeted Magnetic Nanocarrier

Superparamagnetic iron oxide nanoparticles (SPIONs) may act as an excellent theragnostic tool if properly coated and stabilized in a biological environment, even more, if they have targeting properties towards a specific cellular target. Humanized Archaeoglobus fulgidus Ferritin (HumAfFt) is an engineered ferritin characterized by the peculiar salt-triggered assembly-disassembly of the hyperthermophile Archaeoglobus fulgidus ferritin and is successfully endowed with the human H homopolymer recognition sequence by the transferrin receptor (TfR1 or CD71), overexpressed in many cancer cells in response to the increased demand of iron. For this reason, HumAfFt was successfully used in this stud…

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

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…

DRUG RELEASE FROM alpha,beta-POLYASPARTYLHYDRAZIDE DERIVATIVES POLYMERS AND INTERACTION WITH A BIOMEMBRANE MODEL

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…

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…

Site-specific halloysite functionalization by polydopamine: A new synthetic route for potential near infrared-activated delivery system

Abstract Halloysite nanotubes (HNTs) represent a versatile core structure for the design of functional nanosystems of biomedical interest. However, the development of selective methodologies for the site-controlled functionalization of the nanotubes at specific sites is not an easy task. This study aims to accomplish a procedure for the site-selective/specific, “pin-point”, functionalization of HNTs with polydopamine (HNTs@PDA). This goal was achieved, at pH 6.5, by exploiting the basicity of ZnO nanoparticles anchored on the HNTs external surface (HNTs@ZnO) to induce a punctual polydopamine polymerization and coating. The morphology and the chemical composition of the nanomaterial was demo…

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…

Influence of functionalization on interaction and drug release from α,β-polyaspartylhydrazide derivatives to a biomembrane model: evaluation by differential scanning calorimetry technique

Abstract A comparative study on the ability of various polymers to interact with a biomembrane model was carried out by differential scanning calorimetry (DSC). The investigated samples were a water soluble polymer, the α,β-polyaspartylhydrazide (PAHy) and its derivatives containing polyethylene glycol (PEG2000) (sample PAHy–PEG2000), or hexadecylamine (C16) (sample PAHy–C16) or both compounds (sample PAHy–PEG2000–C16). Some samples are able to arrange themselves as micellar structures and to interact potentially with the membrane surface so as to favor the release of the drug near the target membrane and consequently to improve drug adsorption processes. First, the interaction of all polym…

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

SUPERPARAMAGNETIC HYDROPHOBIC POLYASPARTAMIDE NANOPARTICLES FOR ANTICANCER DRUG DELIVERY

NEW PEGYLATED POLYHYDROXYETHYLASPARTAMIDE-SPERMINE COPOLYMER AS GENE DELIVERY SYSTEM

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…

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 …

Electrospun PHEA-PLA/PCL Scaffold for Vascular Regeneration: A Preliminary in Vivo Evaluation

Abstract Background There is increasing interest in the development of vessel substitutes, and many studies are currently focusing on the development of biodegradable scaffolds capable of fostering vascular regeneration. We tested a new biocompatible and biodegradable material with mechanical properties similar to those of blood vessels. Methods The material used comprises a mixture of α,β-poly(N-2-hydroxyethyl)- d,l -aspartamide (PHEA) and polylactic acid (PLA), combined with polycaprolactone (PCL) by means of electrospinning technique. Low-molecular-weight heparin was also linked to the copolymer. A tubular PHEA-PLA/PCL sample was used to create an arteriovenous fistula in a pig model wit…

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…

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…

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

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…

NOVEL REVERSIBLY STABLE THIOPOLYCATIONS BASED ON POLYASPARTAMIDE

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…

NEW POLYASPARTAMIDIC COPOLYMERS BEARING SPERMINE SIDE CHAINS FOR GENE THERAPY

Anti-Arrhenian behaviour of conductivity in octanoic acid–bis(2-ethylhexyl)amine systems: a physico-chemical study

Pure surfactant liquids and their binary mixtures, owing to the amphiphilic nature of the molecules involved, can exhibit nano-segregation and peculiar transport properties. The structural and dynamic properties of octanoic acid (OA)–bis(2-ethylhexyl)amine (BEEA) liquid mixtures at various compositions have been studied by Wide Angle X-ray Scattering (WAXS), 1H-NMR and broadband dielectric spectroscopy as a function of temperature. It was found that the self-assembly occurs via proton exchange between the OA COOH group and the BEEA NH one; such self-assembled local structures are affected anisotropically by a temperature increase so that the thermal dilatation is more marked in a direction …

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

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…

Synthesis of Novel Folic Acid-Functionalized Biocompatible Block Copolymers by Atom Transfer Radical Polymerization for Gene Delivery and Encapsulation of Hydrophobic Drugs

Two synthetic routes to folic acid (FA)-functionalized diblock copolymers based on 2-(methacryloyloxy)- ethyl phosphorylcholine [MPC] and either 2-(dimethylamino)ethyl methacrylate [DMA] or 2-(diisopropylamino) ethyl methacrylate [DPA] were explored. The most successful route involved atom transfer radical polymerization (ATRP) of MPC followed by the tertiary amine methacrylate using a 9-fluorenylmethyl chloroformate (Fmoc)-protected ATRP initiator. Deprotection of the Fmoc groups produced terminal primary amine groups, which were conjugated with FA to produce two series of novel FA-functionalized biocompatible block copolymers. Nonfunctionalized MPC-DMA diblock copolymers have been previou…

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 …

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.

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 …

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

Design, Synthesis and Characterization of a Visible-Light-Sensitive Molecular Switch and Its PEGylation Towards a Self-Assembling Molecule.

HBDI-like chromophores represent a novel set of biomimetic switches mimicking the fluorophore of the green fluorescent protein that are currently studied with the hope to expand the molecular switch/motor toolbox. However, until now members capable of absorbing visible light in their neutral (i. e. non-anionic) form have not been reported. In this contribution we report the preparation of an HBDI-like chromophore based on a 3-phenylbenzofulvene scaffold capable of absorbing blue light and photoisomerizing on the picosecond timescale. More specifically, we show that double-bond photoisomerization occurs in both the E-to-Z and Z-to-E directions and that these can be controlled by irradiating …

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…

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…

Montmorillonite nanodevices for the colon metronidazole delivery.

The adsorption profiles of the antibiotic metronidazole (MNE) into the K10-montmorillonite (MMT-K10) clay and the subsequent release have been investigated as a function of pH and MNE/MMT-K10 ratio, in order to evaluate the potential of the MNE/MMT-K10 hybrids as controlled drug delivery system. The adsorption mechanism has been first elucidated by performing complementary equilibrium and kinetic studies and through the X-ray diffractometry (XRD) characterization of the obtained composite materials. The gathered results allowed us to propose a mechanism consisting of a multi-step pathway involving the neutral and the cationic form of the drug, which interact with different sites of the clay…

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

pH responsive polycation inulin derivative for siRNA Delivery

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

Densely PEGylated polybenzofulvene brushes for potential applications in drug encapsulation

The technique of grafting side chains onto a linear polymeric backbone is commonly used to confer to the new polymeric material with desired properties, such as tunable solubility, ionic charge, biocompatibility, or specific interactions with biological systems. In this paper, two new polybenzofulvene backbones were assembled by spontaneous polymerization of the appropriate benzofulvene monomers (4,6-PO-BF3k and 4&rsquo

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 …

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 …

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

Nanoreactors for the multi-functionalization of poly-histidine fragments

Water-soluble MBHA derivatives were found to self-assemble in a water environment to generate aggregates showing core–shell architectures. The aggregates appeared to be capable of working as nanoreactors performing a multi-functionalization of poly-histidine fragments, which after an initial interaction with the solvated oligo(ethylene glycol) shell reach the reactive core.

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…

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…

Physicochemical Properties of A New PEGylated Polybenzofulvene Brush for Drug Encapsulation

A new polymer brush was synthesized by spontaneous polymerization of benzofulvene macromonomer 6-MOEG-9-T-BF3k bearing a nona(ethylene glycol) side chain linked to the 3-phenylindene scaffold by means of a triazole heterocycle. The polymer structure was studied by SEC-MALS, NMR spectroscopy, and MALDI-TOF MS techniques, and the results supported the role of oligomeric initiatory species in the spontaneous polymerization of polybenzofulvene derivatives. The aggregation features of high molecular weight poly-6-MOEG-9-T-BF3k-FE were investigated by pyrene fluorescence analysis, dynamic light scattering studies, and transmission electron microscopy, which suggested a tendency towards the format…

Sistemi sopramolecolari cationici innovativi per la veicolazione polmonare dei bioattivi.

NEW PHEA POLYCATIONIC DERIVATIVES FOR GENE DELIVERY

Novel Lipid and Polymeric Materials as Delivery Systems for Nucleic Acid Based Drugs

Nucleic acid based drugs (NADBs) are short DNA/RNA molecules that include among others, antisense oligonucleotides, aptamers, small interfering RNAs and micro-interfering RNAs. Despite the different mechanisms of actions, NABDs have the ability to combat the effects of pathological gene expression in many experimental systems. Thus, nowadays, NABDs are considered to have a great therapeutic potential, possibly superior to that of available drugs. Unfortunately, however, the lack of effective delivery systems limits the practical use of NABDs. Due to their hydrophilic nature, NABDs cannot efficiently cross cellular membrane; in addition, they are subjected to fast degradation by cellular and…

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

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.

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

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…

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…

Engineered Ferritin with Eu3+ as a Bright Nanovector: A Photoluminescence Study

Ferritin nanoparticles play many important roles in theranostic and bioengineering applications and have been successfully used as nanovectors for the targeted delivery of drugs due to their ability to specifically bind the transferrin receptor (TfR1, or CD71). They can be either genetically or chemically modified for encapsulating therapeutics or probes in their inner cavity. Here, we analyzed a new engineered ferritin nanoparticle, made of the H chain mouse ferritin (HFt) fused with a specific lanthanide binding tag (LBT). The HFt-LBT has one high affinity lanthanide binding site per each of the 24 subunits and a tryptophane residue within the tag that acts as an antenna able to transfer …

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…

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

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.

COPOLYMERS FOR PROTEIN ORAL DELIVERY

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

Kinetic studies of the interaction between DNA and polycations based on polyaspartylhydrazide

Metallic core nano-devices as drug delivery systems

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…

COPOLYMER CONJUGATES FOR DRUG TARGETING

Polyaspartamide-graft-polymethacrylate nanoparticles for doxorubicin delivery

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 …

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…

Preparation and Characterization of Gold Nanorods Coated with Gellan Gum and Lipoic Acid

Gold nanorods (AuNRs) can combine therapeutic hyperthermia with diagnostic features, representing a smart choice to address personalized cancer treatments. In this regard, a crucial quest is the selection of the right biocompatible coating agent able to stabilize them in the physiological environment, further endowing the possibility to load bioactive molecules and/or targeting moieties. Therefore, AuNRs optical properties can be successfully merged with advantageous materials features to obtain selective photothermal therapy (PTT) systems. Here, the natural materials lipoic acid (LA) and the polysaccharide gellan gum (GG) were chosen to prepare three types of stabilized gold nanorods, usin…

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.

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…

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

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…

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 …

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

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…

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…

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…

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 …

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

Identification of microplastics using 4‐dimethylamino‐4′‐nitrostilbene solvatochromic fluorescence

In this work, we introduce the use of 4-dimethylamino-4'-nitrostilbene (DANS) fluorescent dye for applications in the detection and analysis of microplastics, an impendent source of pollution made of synthetic organic polymers with a size varying from less than 5 mm to nanometer scale. The use of this dye revealed itself as a versatile, fast and sensitive tool for readily discriminate microplastics in water environment. The experimental evidences herein presented demonstrate that DANS efficiently absorbs into a variety of polymers constituting microplastics, and its solvatochromic properties lead to a positive shift of the fluorescence emission spectrum according to the polarity of the poly…

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 …

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…

Hyaluronan-Based Graft Copolymers Bearing Aggregation-Induced Emission Flurogens

In order to develop a technology platform based on two natural compounds from biorenewable resources, a short series of hyaluronan (HA) copolymers grafted with propargylated ferulic acid (HA-FA-Pg) were designed and synthesized to show different grafting degree values and their optical properties were characterized in comparison with reference compounds containing the same ferulate fluorophore. Interestingly, these studies revealed that the ferulate fluorophore was quite sensitive to the restriction of intramolecular motion and its introduction into the rigid HA backbone, as in HA-FA-Pg graft copolymers, led to higher photoluminescence quantum yield values than those obtained with the isola…

Enhanced anticancer effect of quercetin microparticles formulation obtained by spray drying

This study unravels a formulation made of food-based microparticles (MPs) able to control the release of quercetin, a natural anticancer compound, which activity is only limited by its poor aqueous solubility and consequent low bioavailability. To solve this issue, a spray-dried micro delivery system was developed using a bench mini spray dryer B290 Buchi. The resulting MPs were only manufactured with foodderived ingredients such as whey proteins and milk, avoiding the use of any other synthetic material. These microparticles were characterised with a testing campaign encompassing either the physical–chemical characterisation with SEM, DSC and DLS, or the technological and biological featur…

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

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

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

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.

Corrigendum to “Folate-mediated targeting of polymeric conjugates of gemcitabine” [Int. J. Pharm. 307 (2006) 258–269]

Photocatalytic activity of N-doped TiO2-based materials embedded with gold NPs for applications in antibacterial photodynamic therapy (aPDT)

Antibacterial photodynamic therapy (aPDT) is a potential treatment for antibiotic-resistant bacterial infections. It is based on the photosensitization of bacterial cells with exogenous agents that, when exposed to light, produce reactive oxygen species (ROS), such as OH-, O2-, H2O2. ROS can induce complex oxidative-reductive chains of reactions, resulting in damage of cellular components in target tissues1. Photocatalysts, like inorganic semiconductor oxides, represent an interesting class of materials to design new strategies for aPTD. As exposed to light of proper wavelengths, photocatalysts induce the formation of electron-hole pairs capable of producing a cascade of reactions suitable …

NEW AMPHIPHILIC POLY(HYDROXYETHYL)ASPARTAMIDE DERIVATIVES FOR OCULAR DELIVERY

Electrospun Polyhydroxyethyl-Aspartamide-Polylactic Acid Scaffold for Biliary Duct Repair: A Preliminary In Vivo Evaluation

Abstract Tissue engineering has emerged as a new approach with the potential to overcome the limitations of traditional therapies. The objective of this study was to test whether our polymeric scaffold is able to resist the corrosive action of bile and to support a cell's infiltration and neoangiogenesis with the aim of using it as a biodegradable tissue substitute for serious bile duct injuries. In particular, a resorbable electrospun polyhydroxyethyl-aspartamide–polylactic acid (90 mol% PHEA, 10 mol% PLA)/polycaprolactone (50:50 w/w) plate scaffold was implanted into rabbit gallbladder to assess the in vivo effects of the lytic action of the bile on the scaffold structure and then as a tu…

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…

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…

PHARMACEUTICAL NANODEVICES FOR BIOMEDICAL APPLICATIONS

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…

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

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

THIOPOLYCATIONS BASED ON POLYASPARTAMIDE AS NEW VECTORS FOR GENE THERAPY

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 …

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

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

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

Metallic Core Nanocarriers for Multiple Cancer Targeting

Novel galactosylated nanoparticles containing a ribavirin prodrug as hepatic cell-targeted carriers for hcv treatment

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…

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 …

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…

Metronidazole/montmorillonite nanodevices for controlled drug delivery

MACROMOLECULAR CONJUGATE OF PACLITAXEL BEARING OXYTOCIN AS TARGETING MOIETY

POLYMERIC SUPRAMOLECULR SYSTEMS FOR PROTEIN DELIVERY

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…

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…

BIOCOMPATIBLE PHEA-SPERMINE COPOLYMERS FOR GENE DELIVERY