Synthesis and characterization of biodegradable HPMA-oligolysine copolymers for improved gene delivery.
Bioactive peptides, including DNA-binding, endosomal release, and cell targeting peptides, have been integrated into synthetic gene carriers to improve delivery efficiency by enabling the vectors to overcome barriers to gene delivery. Our overall goal is to develop multifunctional, peptide-based polymers that incorporate motifs to condense DNA and facilitate sequential trafficking steps. One approach is to polymerize vinyl-terminated peptides by radical polymerization. In this work, cationic oligolysine peptides were designed to contain vinyl termini with internal reducible linkers. These peptides were copolymerized with HPMA to form biodegradable, DNA-condensing copolymers for gene delivery. The polymerization conditions were optimized by varying the initiator to monomer ratios, macromonomer to comonomer ratios, and reactant concentrations. The synthesized copolymers were shown to possess several important properties required for in vivo gene delivery applications, including (i) efficient DNA binding and condensation, (ii) the ability to stabilize particles against salt-induced aggregation, (iii) the ability to resist extracellular polyplex unpackaging, (iv) biocompatibility and the potential to be degraded into nontoxic components after cellular uptake, and (v) efficient delivery of plasmid to cultured cells.
Burke
Rob S
RS
Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
Pun
Suzie H
SH
D001665:Binding Sites; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008689:Methacrylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D008970:Molecular Weight; D010957:Plasmids / Q000378:metabolism; D011107:Polylysine / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors; D014162:Transfection / Q000379:methods*
D008689:Methacrylates; D011108:Polymers; D011107:Polylysine; D004247:DNA; D008156:Luciferases; C032802:hydroxypropyl methacrylate