Journal
BIOMACROMOLECULES
Volume 10, Issue 4, Pages 936-943Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bm8014768
Keywords
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Funding
- Mississippi Functional Genomics Network [NCRR P20RR016476]
- MRSEC [DMR-0213883]
- NIH [CA120566]
- Robert M. Hearin Foundation
- NATIONAL CANCER INSTITUTE [R21CA120566] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [P20RR016476] Funding Source: NIH RePORTER
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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.
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