title: Unsaturated cationic ortho esters for endosome permeation in gene delivery.
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 (DOTAP).
authors: Department of Pharmaceutics and Medicinal Chemistry, University of the Pacific, Stockton, California 95211, USA.
authors: Haigang
authors: H
authors: Chen
authors: Huizhen
authors: H
authors: Zhang
authors: Charles M
authors: CM
authors: McCallum
authors: Francis C
authors: FC
authors: Szoka
authors: Xin
authors: X
authors: Guo
mesh_terms: D000818:Animals; D002412:Cations; D002460:Cell Line; D004247:DNA / Q000008:administration & dosage; D004149:Dioxoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D017930:Genes, Reporter; D000882:Haplorhini; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007425:Intracellular Membranes / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics; D010539:Permeability; D010714:Phosphatidylethanolamines / Q000737:chemistry; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D014162:Transfection / Q000379:methods*
chemical_list: C410262:1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; C523900:2-(methoxy-(1,2-dioleylglyceroxy)methoxy)-N,N,N-trimethylammonium; C523901:2-(methoxy-2-(1',2'-dioleylglyceroxy)dioxolane-4-yl)methyl-N,N,N-trimethylammonium; D002412:Cations; D004149:Dioxoles; D004952:Esters; D008081:Liposomes; D010714:Phosphatidylethanolamines; D000644:Quaternary Ammonium Compounds; D004247:DNA; D049409:Luciferases, Firefly