RAFT-synthesized graft copolymers that enhance pH-dependent membrane destabilization and protein circulation times

JOURNAL OF CONTROLLED RELEASE

卷:155

Article; Proceedings Paper

Crownover, Emily¹  Duvall, Craig L.²  Convertine, Anthony¹  Hoffman, Allan S.¹  Stayton, Patrick S.¹ 

[1] Univ Washington, Dept Bioengn, Ctr Intracellular Delivery Biol, Seattle, WA 98195 USA

[2] Vanderbilt Univ, Dept Biomed Engn, Nashville, TN 37235 USA

关键词: Circulation half-life;    pH-responsive polymer;    Protein therapeutics;    Drug delivery;   

DOI  :  10.1016/j.jconrel.2011.06.013

来源: Elsevier

【 摘 要 】

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 40 kDa 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. (C) 2011 Elsevier B.V. All rights reserved.

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