1. Biodegradable "Smart" Polyphosphazenes with Intrinsic Multifunctionality as Intracellular Protein Delivery Vehicles.
- Author
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Martinez AP, Qamar B, Fuerst TR, Muro S, and Andrianov AK
- Subjects
- 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, Swine, Carboxylic Acids chemistry, Drug Delivery Systems methods, Nanoparticles chemistry, Pyrrolidinones chemistry
- Abstract
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.
- Published
- 2017
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