ABSTRACT
Novel oppositely charged polyphosphazene polyelectrolytes containing grafted poly(ethylene glycol) (PEG) chains were synthesized as modular components for the assembly of biodegradable PEGylated protein delivery vehicles. These macromolecular counterparts, which contained either carboxylic acid or tertiary amino groups, were then formulated at near physiological conditions into supramolecular assemblies of nanoscale level, below 100 nm. Nanocomplexes with electroneutral surface charge, as assessed by zeta potential measurements, were stable in aqueous solutions, which suggests their compact polyelectrolyte complex "core"-hydrophilic PEG "shell" structure. Investigation of PEGylated polyphosphazene nanocomplexes as agents for noncovalent PEGylation of the therapeutic protein l-asparaginase (L-ASP) in vitro demonstrated their ability to dramatically reduce protein antigenicity, as measured by antibody binding using enzyme linked immunosorbent assay (ELISA). Encapsulation in nanocomplexes did not affect enzymatic activity of L-ASP, but improved its thermal stability and proteolytic resistance. Gel permeation chromatography (GPC) experiments revealed that all synthesized polyphosphazenes exhibited composition controlled hydrolytic degradability in aqueous solutions at neutral pH and showed greater stability at lower temperatures. Overall, novel hydrolytically degradable polyphosphazene polyelectrolytes capable of spontaneous self-assembly into PEGylated nanoparticulates in aqueous solutions can potentially enable a simple and effective approach to modifying therapeutic proteins without the need for their covalent modification.
Subject(s)
Antineoplastic Agents/administration & dosage , Asparaginase/administration & dosage , Nanoparticles/chemistry , Organophosphorus Compounds/chemistry , Polyelectrolytes/chemistry , Polyethylene Glycols/chemistry , Polymers/chemistry , HydrolysisABSTRACT
A series of biodegradable drug delivery polymers with intrinsic multifunctionality have been designed and synthesized utilizing a polyphosphazene macromolecular engineering approach. Novel water-soluble polymers, which contain carboxylic acid and pyrrolidone moieties attached to an inorganic phosphorus-nitrogen backbone, were characterized by a suite of physicochemical methods to confirm their structure, composition, and molecular sizes. All synthesized polyphosphazenes displayed composition-dependent hydrolytic degradability in aqueous solutions at neutral pH. Their formulations were stable at lower temperatures, potentially indicating adequate shelf life, but were characterized by accelerated degradation kinetics at elevated temperatures, including 37 °C. It was found that synthesized polyphosphazenes are capable of environmentally triggered self-assembly to produce nanoparticles with narrow polydispersity in the size range of 150-700 nm. Protein loading capacity of copolymers has been validated via their ability to noncovalently bind avidin without altering biological functionality. Acid-induced membrane-disruptive activity of polyphosphazenes has been established with an onset corresponding to the endosomal pH range and being dependent on polymer composition. The synthesized polyphosphazenes facilitated cell-surface interactions followed by time-dependent, vesicular-mediated, and saturable internalization of a model protein cargo into cancer cells, demonstrating the potential for intracellular delivery.
Subject(s)
Carboxylic Acids/chemistry , Drug Delivery Systems/methods , Nanoparticles/chemistry , Pyrrolidinones/chemistry , Animals , Avidin/metabolism , Biological Transport , Cell Line, Tumor , Drug Compounding , Epithelial Cells/cytology , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Erythrocytes/cytology , Erythrocytes/drug effects , Fluorescein-5-isothiocyanate/analogs & derivatives , Fluorescein-5-isothiocyanate/metabolism , Humans , Hydrogen-Ion Concentration , Hydrolysis , Nanoparticles/ultrastructure , Organophosphorus Compounds/chemical synthesis , Organophosphorus Compounds/pharmacology , Particle Size , Polymers/chemical synthesis , Polymers/pharmacology , SwineABSTRACT
We report the functionalization of hexagonal boron nitride (hBN) with polymer chains. These chains are grown by atom transfer radical polymerization (ATRP) from hBN following thermal treatment. When used as a nanofiller, the material shows improved dispersion resulting in significantly improved toughness as compared to pristine hBN without polymer functionalization. The polymer functionalized BN is also characterized by TGA, FTIR and FESEM.
ABSTRACT
In the crystal structure of the title compound, [Cu(2)Br(2)(C(9)H(14)N(2)S)(2)], the mol-ecule resides about a crystallographic inversion center. The coordination sphere around each copper ion has a distorted tetra-hedral geometry, with ligation by two bridging bromide ions, an amine N atom and an imine N atom. The thio-phene ring is disordered over two sites, with occupancies of 0.719â (3) and 0.281â (3). Weak C-Hâ¯π inter-actions feature in the crystal packing.
