title: Facile synthesis of multivalent folate-block copolymer conjugates via aqueous RAFT polymerization: targeted delivery of siRNA and subsequent gene suppression.
abstract: 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.
authors.affiliation: Department of Polymer Science, The University of Southern Mississippi, Hattiesburg, Mississippi 39406 USA.
authors.forename: Adam W
authors.initials: AW
authors.lastname: York
authors.forename: Yilin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Holley
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Guo
authors.forename: Faqing
authors.initials: F
authors.lastname: Huang
authors.forename: Charles L
authors.initials: CL
authors.lastname: McCormick
mesh_terms: D000178:Acrylamides / Q000737:chemistry; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002412:Cations / Q000737:chemistry; D016503:Drug Delivery Systems; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000737:chemistry*; D006801:Humans; D007624:KB Cells; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D011108:Polymers / Q000138:chemical synthesis* / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000178:Acrylamides; D002352:Carrier Proteins; D002412:Cations; D058973:Folate Receptors, GPI-Anchored; D011108:Polymers; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D005492:Folic Acid; C032976:N-(2-hydroxypropyl)methacrylamide