| Breaking down Endolysosomal Barriers for Drug Delivery with Degradable Polymersomes | ||
| Fariyal Ahmed, Bioengineering, University of Pennsylvania, 220 South 33rd Street, Room 112 Towne Bldg., Philadelphia, PA 19104-6391, Goundla Srinivas, Univ.Pennsylvania, Dept.Chemistry, Philadelphia, PA 19104, Aaron Brannan, Department of Chemical Engineering & Material Science, University of Minnesota, Minneapolis, MN 55455, Michael L. Klein, Chemistry, Univ.Pennsylvania, 112 Towne Bldg, Philadelphia, PA 19104, Frank S. Bates, University of Minnesota, 421 Washington Avenue SE, Minneapolis, MN 55455 and Dennis E. Discher, Chemical & Biomolecular Engineering, University of Pennsylvania, 220 South 33rd Street, Room 112 Towne Bldg., Philadelphia, PA 19104-6391 Carrier-mediated entry of cytotoxic drugs into a cell's cytoplasm is often limited by release from the carrier as well as endosomal release after internalization. Here we demonstrate by molecular simulation and experiment that degradable, non-ionic polymersomes of PEG-(polyester) foster endosome rupture and release of cytotoxic drugs doxorubicin (DOX) and paclitaxel (TAX). These drugs are typical – soluble and insoluble – anticancer agents. We characterize the stability, delivery and intracellular toxicity of DOX- and TAX-loaded nano-polymersomes with breast and lung cancer cell lines that take up the vesicles. While degradable polymersome formulations retain their load for over a month at 4°C, they exhibit facilitated release at 37°C and low pH. Copolymer degradation fosters endosomal escape through copolymer-induced disruption of the lipid membrane, enhancing intracellular drug release and cytotoxicity up to 40-fold relative to free drug. More generally, the results show that macro-surfactants, which are increasingly being applied, will interact with cell membranes Extended Abstract Status: Not Uploaded | ||