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Article
Unsaturated cationic ortho esters for endosome permeation in gene delivery
Journal of Medicinal Chemistry
  • Haigang Chen, University of the Pacific
  • Huizhen Zhang, University of the Pacific
  • Charles Michael McCallum, University of the Pacific
  • Francis C. Szoka, Jr., University of California, San Francisco
  • Xin Guo, University of the Pacific
Document Type
Article
DOI
10.1021/jm060128c
Publication Date
8-10-2007
Abstract
Two cleavable cationic lipids were designed to trigger the fusogenicity and membrane permeation of their lipoplexes in endosomes via the formation of inverted hexagonal phases (HII). Both lipids contain a cationic head group and an unsaturated hydrophobic dioleylglycerol moiety joined together by a linear or a cyclic ortho ester linker. At pH 7.4, the lipids formed stable complexes with plasmid DNA together with the conelike helper lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). The decrease of pH enhanced the hydrolysis of the ortho ester linkers, which removed the cationic head groups and caused the aggregation of the lipoplexes. At pH 5.5, the cationic lipid N-[2-methyl-2-(1‘,2‘-dioleylglyceroxy)dioxolan-4-yl]methyl-N,N,N-trimethylammonium iodide (2) with a cyclic ortho ester linker showed exceptional pH-sensitivity and triggered its lipoplex to permeate model biomembranes within the time span of endosome processing prior to lysosomal degradation. Lipid 2 significantly improved gene transfection in cultured cells compared to the pH-insensitive control lipid 1,2-dioleoyl-3-trimethylammoniopropane
Citation Information
Haigang Chen, Huizhen Zhang, Charles Michael McCallum, Francis C. Szoka, et al.. "Unsaturated cationic ortho esters for endosome permeation in gene delivery" Journal of Medicinal Chemistry Vol. 50 Iss. 18 (2007) p. 4269 - 4278 ISSN: 0022-2623
Available at: http://works.bepress.com/xin-guo/32/