title: RAFT-synthesized graft copolymers that enhance pH-dependent membrane destabilization and protein circulation times.
abstract: Here we describe a new graft copolymer architecture of poly(propylacrylic acid) (polyPAA) that displays potent pH-dependent, membrane-destabilizing activity and in addition is shown to enhance protein blood circulation kinetics. PolyPAA containing a single telechelic alkyne functionality was prepared via reversible addition-fragmentation chain transfer (RAFT) polymerization with an alkyne-functional chain transfer agent (CTA) and coupled to RAFT polymerized poly(azidopropyl methacrylate) (polyAPMA) through azide-alkyne [3 + 2] Huisgen cycloaddition. The graft copolymers become membrane destabilizing at endosomal pH values and are active at significantly lower concentrations than the linear polyPAA. A biotin terminated polyPAA graft copolymer was prepared by grafting PAA onto polyAPMA polymerized with a biotin functional RAFT CTA. The blood circulation time and biodistribution of tritium labeled avidin conjugated to the polyPAA graft copolymer was characterized along with a clinically utilized 40kDa branched polyethylene glycol (PEG) also possessing biotin functionalization. The linear and graft polyPAA increase the area under the curve (AUC) over avidin alone by 9 and 12 times, respectively. Furthermore, polyPAA graft copolymer conjugates accumulated in tumor tissue significantly more than the linear polyPAA and the branched PEG conjugates. The collective data presented in this report indicate that the polyPAA graft copolymers exhibit robust pH-dependent membrane-destabilizing activity, low cytotoxicity, significantly enhanced blood circulation time, and increased tumor accumulation.
authors.affiliation: Center for Intracellular Delivery of Biologics, Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Crownover
authors.forename: Craig L
authors.initials: CL
authors.lastname: Duvall
authors.forename: Anthony
authors.initials: A
authors.lastname: Convertine
authors.forename: Allan S
authors.initials: AS
authors.lastname: Hoffman
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Stayton
mesh_terms: D000179:Acrylates / Q000737:chemistry*; D000180:Acrylic Resins / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry; D001360:Avidin / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry; D001386:Azides / Q000737:chemistry*; D001710:Biotin / Q000737:chemistry; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D057930:Click Chemistry; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects; D006367:HeLa Cells; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008051:Lipid Bilayers / Q000737:chemistry; D008689:Methacrylates / Q000737:chemistry*; D051379:Mice; D015394:Molecular Structure; D011108:Polymers / Q000737:chemistry*; D013997:Time Factors; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000179:Acrylates; D000180:Acrylic Resins; D000970:Antineoplastic Agents; D001386:Azides; D004337:Drug Carriers; D008051:Lipid Bilayers; D008689:Methacrylates; D011108:Polymers; C571439:poly(azidopropyl methacrylate); C501628:poly(propyl acrylic acid); D001360:Avidin; D001710:Biotin