Facile Synthesis of Multivalent Folate-Block Copolymer Conjugates via Aqueous RAFT Polymerization: Targeted Delivery of siRNA and Subsequent Gene Suppression†
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- 作者：Adam W. York‡ ; ; Yilin Zhang§ ; ; Andrew C. Holley‡ ; ; Yanlin Guo ; Faqing Huang*§ ; ; Charles L. McCormick*‡ ;
- 刊名：Biomacromolecules
- 出版年：2009
- 出版时间：April 13, 2009
- 年：2009
- 卷：10
- 期：4
- 页码：936-943
- 全文大小：225K
- 年卷期：v.10,no.4(April 13, 2009)
- ISSN：1526-4602
文摘
Cell specific delivery of small interfering ribonucleic acid (siRNA) using well-defined multivalent folate-conjugated block copolymers is reported. Primary amine functional, biocompatible, hydrophilic-block-cationic copolymers were synthesized via aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization. N-(2-hydroxypropyl)methacrylamide) (HPMA), a permanently hydrophilic monomer, was copolymerized with a primary amine containing monomer, N-(3-aminopropyl)methacrylamide (APMA). Poly(HPMA) confers biocompatibility, while APMA provides amine functionality, allowing conjugation of folate derivatives. HPMA-stat-APMA was chain extended with a cationic block, poly(N-[3-(dimethylamino)propyl]methacrylamide), to promote electrostatic complexation between the copolymer and the negatively charged phosphate backbone of siRNA. Notably, poly(HPMA) stabilizes the neutral complexes in aqueous solution, while APMA allows the conjugation of a targeting moiety, thus, dually circumventing problems associated with the delivery of genes via cationically charged complexes (universal transfection). Fluorescence microscopy and gene down-regulation studies indicate that these neutral complexes can be specifically delivered to cancer cells that overexpress folate receptors.