title: Therapeutic effect for liver-metastasized tumor by sequential intravenous injection of anionic polymer and cationic lipoplex of siRNA.
abstract: Previously, we developed a novel siRNA transfer method to the liver by sequential intravenous injection of anionic polymer and cationic liposome/siRNA complex (cationic lipoplex). In this study, we investigated whether siRNA delivered by this sequential injection could significantly suppress mRNA expression of the targeted gene in liver metastasis and inhibit tumor growth. When cationic lipoplex was intravenously injected into mice bearing liver metastasis of human breast tumor MCF-7 at 1 min after intravenous injection of chondroitin sulfate C (CS) or poly-l-glutamic acid (PGA), siRNA was accumulated in tumor-metastasized liver. In terms of a gene silencing effect, sequential injections of CS or PGA plus cationic lipoplex of luciferase siRNA could reduce luciferase activity in liver MCF-7-Luc metastasis. Regarding the side effects, sequential injections of CS plus cationic lipoplex did not exhibit hepatic damage or induction of inflammatory cytokines in serum after repeated injections, but sequential injections of PGA plus cationic lipoplex did. Finally, sequential injections of CS plus cationic lipoplex of protein kinase N3 siRNA could suppress tumor growth in the mice bearing liver metastasis. From these findings, sequential injection of CS and cationic lipoplex of siRNA might be a novel systemic method of delivering siRNA to liver metastasis.
authors.affiliation: a Institute of Medicinal Chemistry, Hoshi University , Shinagawa-ku, Tokyo , Japan and.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Hattori
authors.affiliation: a Institute of Medicinal Chemistry, Hoshi University , Shinagawa-ku, Tokyo , Japan and.
authors.forename: Shohei
authors.initials: S
authors.lastname: Arai
authors.affiliation: a Institute of Medicinal Chemistry, Hoshi University , Shinagawa-ku, Tokyo , Japan and.
authors.forename: Takuto
authors.initials: T
authors.lastname: Kikuchi
authors.affiliation: b Laboratory of Cell Regulation, Department of Pharmaceutical Sciences , Graduate School of Biomedical Sciences, Nagasaki University , Nagasaki , Japan.
authors.forename: Kei-Ichi
authors.initials: KI
authors.lastname: Ozaki
authors.affiliation: a Institute of Medicinal Chemistry, Hoshi University , Shinagawa-ku, Tokyo , Japan and.
authors.forename: Kumi
authors.initials: K
authors.lastname: Kawano
authors.affiliation: a Institute of Medicinal Chemistry, Hoshi University , Shinagawa-ku, Tokyo , Japan and.
authors.forename: Etsuo
authors.initials: E
authors.lastname: Yonemochi
mesh_terms: D000818:Animals; D000838:Anions; D002412:Cations; D002784:Cholesterol / Q000737:chemistry; D002809:Chondroitin Sulfates / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry; D020868:Gene Silencing; D006801:Humans; D007275:Injections, Intravenous; D008081:Liposomes; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary*; D049409:Luciferases, Firefly / Q000235:genetics; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011099:Polyglutamic Acid / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000838:Anions; D002412:Cations; D004337:Drug Carriers; D005229:Fatty Acids, Monounsaturated; D008081:Liposomes; D011108:Polymers; D000644:Quaternary Ammonium Compounds; D034741:RNA, Small Interfering; D011099:Polyglutamic Acid; D002809:Chondroitin Sulfates; D002784:Cholesterol; D049409:Luciferases, Firefly; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane
keywords: Chondroitin sulfate; gene silencing; liposome; liver metastasis; poly-l-glutamic acid; siRNA delivery