title: Small interfering RNA delivery to the liver by intravenous administration of galactosylated cationic liposomes in mice.
abstract: Although small interfering RNA (siRNA) is a potentially useful therapeutic approach to silence the targeted gene of a particular disease, its use is limited by its stability in vivo. For the liver parenchymal cell (PC)-selective delivery of siRNA, siRNA was complexed with galactosylated cationic liposomes. Galactosylated liposomes/siRNA complex exhibited a higher stability than naked siRNA in plasma. After intravenous administration of a galactosylated liposomes/siRNA complex, the siRNA did not undergo nuclease digestion and urinary excretion and was delivered efficiently to the liver and was detected in PC rather than liver non-parenchymal cells (NPC). Endogenous gene (Ubc13 gene) expression in the liver was inhibited by 80% when Ubc13-siRNA complexed with galactosylated liposomes was administered to mice at a dose of 0.29 nmol/g. In contrast, the bare cationic liposomes did not induce any silencing effect on Ubc13 gene expression. These results indicated that galactosylated liposomes/siRNA complex could induce gene silencing of endogenous hepatic gene expression. The interferon responses by galactosylated liposomes/siRNA complex were controlled by optimization of the sequence of siRNA. Also no liver toxicity due to galactosylated liposomes/siRNA complex was observed under any of the conditions tested. In conclusion, we demonstrated the hepatocyte-selective gene silencing by galactosylated liposomes following intravenous administration.
authors.affiliation: GeneCare Research Institute Co. Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-0063, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Sato
authors.forename: Motoki
authors.initials: M
authors.lastname: Takagi
authors.forename: Akira
authors.initials: A
authors.lastname: Shimamoto
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kawakami
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Hashida
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry; D002412:Cations; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D016503:Drug Delivery Systems; D004355:Drug Stability; D005690:Galactose / Q000737:chemistry; D020868:Gene Silencing; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008081:Liposomes / Q000737:chemistry; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008422:Materials Testing; D051379:Mice; D008813:Mice, Inbred ICR; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D001672:Biocompatible Materials; D002412:Cations; D008081:Liposomes; D034741:RNA, Small Interfering; D005690:Galactose