title: Tumor regression in mice by delivery of Bcl-2 small interfering RNA with pegylated cationic liposomes.
abstract: The pharmacokinetics and antitumor activity of pegylated small interfering RNA (siRNA)/cationic liposome complexes were studied after systemic administration to mice. We designed pegylated-lipid carriers for achieving increased plasma concentrations of RNA and hence improved accumulation of RNA in tumors by the enhanced permeability and retention effect. We compared the pharmacokinetics of siRNA complexed with liposomes incorporating pegylated lipids with longer (C-17 or C-18), shorter (C-12 to C-16), or unsaturated (C-18:1) acyl chains. When longer acyl chains were used, the plasma concentrations of siRNA obtained were dramatically higher than when shorter or unsaturated chains were used. This may be explained by the higher gel-to-liquid-crystalline phase-transition temperature (Tc) of lipids with longer acyl chains, which may form more rigid liposomes with reduced uptake by the liver. We tested a siRNA that is sequence specific for the antiapoptotic bcl-2 mRNA complexed with a pegylated liposome incorporating a C-18 lipid (PEG-LIC) by i.v. administration in a mouse model of human prostate cancer. Three-fold higher accumulation of RNA in the tumors was achieved when PEG-LIC rather than nonpegylated liposomes was used, and sequence-specific antitumor activity was observed. Our siRNA/PEG-LIC complex showed no side effects on repeated administration and the strength of its antitumor activity may be attributed to its high uptake by the tumors. Pegylation of liposomes improved the plasma retention, uptake by s.c. tumors, and antitumor activity of the encapsulated siRNA. PEG-LIC is a promising candidate for siRNA cancer therapy.
authors.affiliation: Discovery Research Laboratories, Nippon Shinyaku Co Ltd, Tsukuba, Japan. s.sonoke@po.nippon-shinyaku.co.jp
authors.forename: Satoru
authors.initials: S
authors.lastname: Sonoke
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ueda
authors.forename: Kae
authors.initials: K
authors.lastname: Fujiwara
authors.forename: Yohei
authors.initials: Y
authors.lastname: Sato
authors.forename: Kazuchika
authors.initials: K
authors.lastname: Takagaki
authors.forename: Kazuko
authors.initials: K
authors.lastname: Hirabayashi
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Ohgi
authors.forename: Junichi
authors.initials: J
authors.lastname: Yano
mesh_terms: D000818:Animals; D001483:Base Sequence; D002412:Cations; D045744:Cell Line, Tumor; D020868:Gene Silencing; D006801:Humans; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D002412:Cations; D008081:Liposomes; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering