PEGYLATED POLYASPARTAMIDE–POLYLACTIDE BASED NANOPARTICLES PENETRATING CYSTIC FIBROSIS ARTIFICIAL MUCUS

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

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

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

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

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

MRI-visible nanoparticles from hydrophobic gadolinium poly(ε-caprolactone) conjugates

International audience; In this work we report on the synthesis of two hydrophobic and degradable gadolinium poly(ε-caprolactone) conjugates and their use for the preparation of MRI-visible nanoparticles intended for diagnosis applications. Advantage has been taken from functional poly(ε-caprolactone)s (PCL) bearing propargyl (PCL-yne) or amine groups (P(CL-co-NH2VL)) to yield conjugates by following two strategies. In a first approach, an azido-chelate of gadolinium (Gd(III)) has been conjugated by CuAAC to PCL-yne to yield a polymeric chelate containing 2.6 wt% of Gd(III). In a second approach, a dianhydride Gd(III)-ligand was reacted with P(CL-co-NH2VL) to yield, after complexation with …

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

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

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

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

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

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

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

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

Galactosylated polyaspartamide copolymers for siRNA targeted delivery to hepatocellular carcinoma cells

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

PREPARAZIONE, CARATTERIZZAZIONE E STUDI DI DEGRADAZIONE CHIMICA DI NUOVI SISTEMI POLIMERICI NANOPARTICELLARI A BASE DI COPOLIMERI ANFIFILICI DI UNA α,β-POLI(N-2-IDROSSIETIL)-D,L-ASPARTAMMIDE

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

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

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

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

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

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

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

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

Polymeric nanoparticles for siRNA delivery: Production and applications

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

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

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

MRI-Visible Poly(ε-caprolactone) with Controlled Contrast Agent Ratios for Enhanced Visualization in Temporary Imaging Applications

International audience; Hydrophobic macromolecular contrast agents (MMCAs) are highly desirable to provide safe and efficient magnetic resonance (MR) visibility to implantable medical devices. In this study, we report on the synthesis and evaluation of novel biodegradable poly(ε-caprolactone)-based MMCAs. Poly(α-propargyl-ε-caprolactone-co-ε-caprolactone)s containing 2, 5, and 10 mol % of propargyl groups have been prepared by ring-opening copolymerization of ε-caprolactone and the corresponding propargylated lactone. In parallel, a diazido derivative of the clinically used diethylenetriaminepentaacetic acid (DTPA)/Gd3+ complex has been synthesized. Finally, MRI-visible poly(ε-caprolactone)…

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

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

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

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

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

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

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

Toward potent antibiofilm degradable medical devices: A generic method for the antibacterial surface modification of polylactide

International audience; The effects of biomaterials on their environment must be carefully modulated in most biomedical applications. Among other approaches, this modulation can be obtained through the modification of the biomaterial surface. This paper proposes a simple and versatile strategy to produce non-leaching antibacterial polylactide (PLA) surfaces without any degradation of the polyester chains. The method is based on a one-pot procedure that provides a "clickable" PLA surface via anionic activation which is then functionalized with an antibacterial quaternized poly(2-(dimethylamino)ethyl methacrylate) (QPDMAEMA) by covalent immobilization on the surface. The anti-adherence and an…