title: Shrinkage of a rapidly growing tumor by drug-loaded polymersomes: pH-triggered release through copolymer degradation.
abstract: Carrier-mediated delivery of drugs into the cytosol is often limited by either release from the carrier or release from an internalizing endolysosome. Here, loading, delivery, and cytosolic uptake of drug mixtures from degradable polymersomes are shown to exploit both the thick membrane of these block copolymer vesicles and their aqueous lumen as well as pH-triggered release within endolysosomes. Our initial in vivo studies demonstrate growth arrest and shrinkage of rapidly growing tumors after a single intravenous injection of polymersomes composed of poly(ethylene glycol)-polyester. Vesicles are shown to break down into membrane-lytic micelles within hours at 37 degrees C and low pH, although storage at 4 degrees C allows retention of drug for over a month. It is then shown that cell entry of the polymersomes into endolysosomes is followed by copolymer-induced endolysosomal rupture with release of cytotoxic drugs. Above a critical poration concentration (CCPC) that is easily achieved within endolysosomes and that scales with copolymer proportions and molecular weight, the copolymer micelles are seen to disrupt lipid membranes and thereby enhance drug activity. Neutral polymersomes and related macrosurfactant assemblies can thus create novel pathways within cells for controlled release and delivery.
authors.affiliation: Chemical and Biomolecular Engineering, Center for Molecular Modeling, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Fariyal
authors.initials: F
authors.lastname: Ahmed
authors.forename: Refika I
authors.initials: RI
authors.lastname: Pakunlu
authors.forename: Goundla
authors.initials: G
authors.lastname: Srinivas
authors.forename: Aaron
authors.initials: A
authors.lastname: Brannan
authors.forename: Frank
authors.initials: F
authors.lastname: Bates
authors.forename: Michael L
authors.initials: ML
authors.lastname: Klein
authors.forename: Tamara
authors.initials: T
authors.lastname: Minko
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Discher
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000648:ultrastructure; D003198:Computer Simulation / Q000706:statistics & numerical data; D004317:Doxorubicin / Q000627:therapeutic use*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D017404:In Situ Hybridization, Fluorescence; D008247:Lysosomes / Q000378:metabolism; D008561:Membrane Fusion; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D017239:Paclitaxel / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D008823:Micelles; D011092:Polyethylene Glycols; D004317:Doxorubicin; D017239:Paclitaxel