title: Polymer nanocarrier system for endosome escape and timed release of siRNA with complete gene silencing and cell death in cancer cells.
abstract: An influenza virus-inspired polymer mimic nanocarrier was used to deliver siRNA for specific and near complete gene knockdown of an osteoscarcom cell line (U-2SO). The polymer was synthesized by single-electron transfer living radical polymerization (SET-LRP) at room temperature to avoid complexities of transfer to monomer or polymer. It was the only LRP method that allowed good block copolymer formation with a narrow molecular weight distribution. At nitrogen to phosphorus (N/P) ratios of equal to or greater than 20 (greater than a polymer concentration of 13.8 μg/mL) with polo-like kinase 1 (PLK1) siRNA gave specific and near complete (>98%) cell death. The polymer further degrades to a benign polymer that showed no toxicity even at polymer concentrations of 200 μg/mL (or N/P ratio of 300), suggesting that our polymer nanocarrier can be used as a very effective siRNA delivery system and in a multiple dose administration. This work demonstrates that with a well-designed delivery device, siRNA can specifically kill cells without the inclusion of an additional clinically used highly toxic cochemotherapeutic agent. Our work also showed that this excellent delivery is sensitive for the study of off-target knockdown of siRNA.
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Gu
authors.forename: Zhongfan
authors.initials: Z
authors.lastname: Jia
authors.forename: Nghia P
authors.initials: NP
authors.lastname: Truong
authors.forename: Indira
authors.initials: I
authors.lastname: Prasadam
authors.forename: Yin
authors.initials: Y
authors.lastname: Xiao
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Monteiro
mesh_terms: D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry*; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D011992:Endosomes / Q000378:metabolism*; D020868:Gene Silencing / Q000187:drug effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015394:Molecular Structure; D053758:Nanoparticles / Q000737:chemistry*; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D004337:Drug Carriers; D011108:Polymers; D034741:RNA, Small Interfering