title: Synthesis and evaluation of degradable polyurea block copolymers as siRNA delivery agents.
abstract: Chain extension by diisocyanate condensation provides a versatile and convenient means for preparing block copolymers. We have utilized this chemistry to prepare reducible multiblock polycations for siRNA delivery. This approach, an alternative to oxidative coupling, was suitable for preparing multiblock polycations with defined molecular weight and architecture. The polymer, PEG-b-multi-(polyhexylurea-co-oligo-L-lysine)-b-PEG, was capable of electrostatically condensing siRNA to form nano-sized polyplexes across a broad compositional range. We demonstrated that the polyplexes enter the cells via endocytosis and interact with the endosome membrane leading to destabilization and hence endosome escape. Another feature of these polymers is their multiple intra-chain disulfide linkages. This enables weakening of the polyplex via chain scission within the cytosol's reductive environment. In addition to the controlled preparation of the polymer, the polyplexes were capable of delivering siRNA in vitro to silence greater than 50% green fluorescent protein expression with negligible toxicity.
authors.affiliation: CSIRO Materials Science and Engineering, Bayview Avenue, Clayton 3168, Victoria, Australia. Pete.Cass@csiro.au
authors.forename: Peter
authors.initials: P
authors.lastname: Cass
authors.forename: Warren
authors.initials: W
authors.lastname: Knower
authors.forename: Tracey
authors.initials: T
authors.lastname: Hinton
authors.forename: Shuning
authors.initials: S
authors.lastname: Shi
authors.forename: Felix
authors.initials: F
authors.lastname: Grusche
authors.forename: Mark
authors.initials: M
authors.lastname: Tizard
authors.forename: Pathiraja
authors.initials: P
authors.lastname: Gunatillake
mesh_terms: D020341:Absorbable Implants; D000818:Animals; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003460:Crystallization / Q000379:methods; D004058:Diffusion; D004343:Drug Implants / Q000008:administration & dosage / Q000138:chemical synthesis*; D020868:Gene Silencing / Q000502:physiology; D008422:Materials Testing; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics*
chemical_list: D004343:Drug Implants; D053769:Nanocapsules; D011108:Polymers; D034741:RNA, Small Interfering; C045786:polyurea; D011092:Polyethylene Glycols
keywords: Delivery; Polylysine; Polyurea; Reducible; siRNA