title: Novel histidine-conjugated galactosylated cationic liposomes for efficient hepatocyte-selective gene transfer in human hepatoma HepG2 cells.
abstract: To enhance gene transfection to hepatocytes by cationic liposomes, it is necessary to overcome a number of barriers existing in the process from administration to gene expression. Recently we and other group have demonstrated that the escape of plasmid DNA (pDNA)/cationic liposome complexes (lipoplexes) from the endosome to cytoplasm was rate limiting. In this study, to enhance transfection efficiency by promoting the release of lipoplexes from the endosome to cytoplasm, we proposed utilizing the "proton sponge effect". Here, we synthesized a novel pH-sensitive histidine-modified galactosylated cholesterol derivative (Gal-His-C4-Chol), for a more efficient gene delivery to hepatocytes. Liposomes containing Gal-His-C4-Chol showed much greater transfection activity than conventional Gal-C4-Chol liposomes based on a receptor-mediated mechanism in HepG2 cells. Hence, this finding should contribute to the development of gene therapy using cationic liposomes toward their clinical application.
authors.affiliation: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Shigeta
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kawakami
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Higuchi
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Okuda
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yagi
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Yamashita
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Hashida
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D037263:Asialoglycoprotein Receptor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002412:Cations; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002782:Cholestenes / Q000378:metabolism; D002788:Cholesterol Esters / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D003593:Cytoplasm / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism; D017930:Genes, Reporter; D006020:Glycopeptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008081:Liposomes; D008113:Liver Neoplasms / Q000378:metabolism*; D008156:Luciferases; D008353:Mannitol / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D010316:Particle Size; D014162:Transfection / Q000379:methods*
chemical_list: C520332:3-(4-(1-amino-2-(galactosylthio)ethyl-histidylamino)butylcarbamoyloxy)cholesterol; D037263:Asialoglycoprotein Receptor; D002412:Cations; D002782:Cholestenes; D002788:Cholesterol Esters; D006020:Glycopeptides; D008081:Liposomes; C506719:cholesten-5-yloxy-N-(4-((1-imino-2-D-thiogalactosylethyl)amino)butyl)formamide; D008353:Mannitol; D004247:DNA; D008156:Luciferases