This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sonoke, S. Articles by Yano, J. Search for Related Content PubMed PubMed Citation Articles by Sonoke, S. Articles by Yano, J.

Tumor Regression in Mice by Delivery of Bcl-2 Small Interfering RNA with Pegylated Cationic Liposomes

Discovery Research Laboratories, Nippon Shinyaku Co. Ltd., Tsukuba, Japan

Requests for reprints: Satoru Sonoke, Discovery Research Laboratories, Nippon Shinyaku Co. Ltd., 3-14-1 Sakura, Tsukuba, Ibaraki 305-0003, Japan. Phone: 81-29-850-6242; Fax: 81-29-850-6217; E-mail: s.sonoke{at}po.nippon-shinyaku.co.jp.

Key Words: siRNA • pegylation • cationic liposome • Bcl-2

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. [Cancer Res 2008;68(21):8843–51]

This article has been cited by other articles:

				S. Jiang, M. K. Gnanasammandhan, and Y. Zhang Optical imaging-guided cancer therapy with fluorescent nanoparticles J R Soc Interface, September 16, 2009; (2009) rsif.2009.0243v1. [Abstract] [Full Text] [PDF]