This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-08-3945v1 69/16/6531    most recent 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 Google Scholar Articles by Yagi, N. Articles by Nagai, R. PubMed PubMed Citation Articles by Yagi, N. Articles by Nagai, R.

A Nanoparticle System Specifically Designed to Deliver Short Interfering RNA Inhibits Tumor Growth In vivo

¹ Department of Cardiovascular Medicine; ² Global COE Program, Comprehensive Center of Education and Research for Chemical Biology of the Diseases; ³ Translational Systems Biology and Medicine Initiative; ⁴ Center for Disease Biology and Integrative Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan; ⁵ Kyowa Hakko Kirin Co., Ltd., Drug Formulation Research and Development Laboratories, Shizuoka, Japan; and ⁶ PRESTO, Japan Science and Technology Agency, Saitama, Japan

Requests for reprints: Ichiro Manabe, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, Japan. Phone: 81-3-3815-5411; Fax: 81-3-3818-6673; E-mail: manabe-tky{at}umin.ac.jp.

Key Words: nanoparticle • siRNA • drug delivery system • anticancer therapeutics • liposome

Use of short interfering RNA (siRNA) is a promising new approach thought to have a strong potential to lead to rapid development of gene-oriented therapies. Here, we describe a newly developed, systemically injectable siRNA vehicle, the "wrapsome" (WS), which contains siRNA and a cationic lipofection complex in a core that is fully enveloped by a neutral lipid bilayer and hydrophilic polymers. WS protected siRNA from enzymatic digestion, providing a long half-life in the systemic circulation. Moreover, siRNA/WS leaked from blood vessels within tumors into the tumor tissue, where it accumulated and was subsequently transfected into the tumor cells. Because the transcription factor KLF5 is known to play a role in tumor angiogenesis, we designed KLF5-siRNA to test the antitumor activity of siRNA/WS. KLF5-siRNA/WS exhibited significant antitumor activity, although neither WS containing control scrambled-siRNA nor saline containing KLF5-siRNA affected tumor growth. KLF5-siRNA/WS inhibited Klf5 expression within tumors at both mRNA and protein levels, significantly reducing angiogenesis, and we detected no significant acute or long-term toxicity. Our findings support the idea that siRNA/WS can be used to knock down specific genes within tumors and thereby exert therapeutic effects against cancers. [Cancer Res 2009;69(16):6531–8]