Intracellular Delivery of Active Proteins by Polyphosphazene Polymers.

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TitleIntracellular Delivery of Active Proteins by Polyphosphazene Polymers.
Publication TypeJournal Article
Year of Publication2021
AuthorsQamar, B, Solomon, M, Marin, A, Fuerst, TR, Andrianov, AK, Muro, S
JournalPharmaceutics
Volume13
Issue2
Date Published2021 Feb 10
ISSN1999-4923
Abstract

Achieving intracellular delivery of protein therapeutics within cells remains a significant challenge. Although custom formulations are available for some protein therapeutics, the development of non-toxic delivery systems that can incorporate a variety of active protein cargo and maintain their stability, is a topic of great relevance. This study utilized ionic polyphosphazenes (PZ) that can assemble into supramolecular complexes through non-covalent interactions with different types of protein cargo. We tested a PEGylated graft copolymer (PZ-PEG) and a pyrrolidone containing linear derivative (PZ-PYR) for their ability to intracellularly deliver FITC-avidin, a model protein. In endothelial cells, PZ-PYR/protein exhibited both faster internalization and higher uptake levels than PZ-PEG/protein, while in cancer cells both polymers achieved similar uptake levels over time, although the internalization rate was slower for PZ-PYR/protein. Uptake was mediated by endocytosis through multiple mechanisms, PZ-PEG/avidin colocalized more profusely with endo-lysosomes, and PZ-PYR/avidin achieved greater cytosolic delivery. Consequently, a PZ-PYR-delivered anti-F-actin antibody was able to bind to cytosolic actin filaments without needing cell permeabilization. Similarly, a cell-impermeable Bax-BH3 peptide known to induce apoptosis, decreased cell viability when complexed with PZ-PYR, demonstrating endo-lysosomal escape. These biodegradable PZs were non-toxic to cells and represent a promising platform for drug delivery of protein therapeutics.

DOI10.3390/pharmaceutics13020249
Alternate JournalPharmaceutics
PubMed ID33578893
Grant ListR01 HL98416 / NH / NIH HHS / United States
SAF2017-91909-EXP / / Ministerio de Ciencia, Innovación y Universidades /
IBBR Seed Grant / / University of Maryland MPower Program /