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[Cancer Research 65, 8984-8992, October 1, 2005]
© 2005 American Association for Cancer Research

Experimental Therapeutics, Molecular Targets, and Chemical Biology

Sequence-Specific Knockdown of EWS-FLI1 by Targeted, Nonviral Delivery of Small Interfering RNA Inhibits Tumor Growth in a Murine Model of Metastatic Ewing's Sarcoma

Siwen Hu-Lieskovan1, Jeremy D. Heidel2, Derek W. Bartlett2, Mark E. Davis2 and Timothy J. Triche1

1 Department of Pathology, Children's Hospital Los Angeles, Los Angeles, California and 2 Chemical Engineering, California Institute of Technology, Pasadena, California

Requests for reprints: Timothy J. Triche, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Box 43, 4650 Sunset Boulevard, Los Angeles, CA 90027. Phone: 323-669-4516; Fax: 323-667-1123; E-mail: triche{at}usc.edu or Mark E. Davis, Chemical Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125. E-mail: mdavis{at}cheme.caltech.edu.

The development of effective, systemic therapies for metastatic cancer is highly desired. We show here that the systemic delivery of sequence-specific small interfering RNA (siRNA) against the EWS-FLI1 gene product by a targeted, nonviral delivery system dramatically inhibits tumor growth in a murine model of metastatic Ewing's sarcoma. The nonviral delivery system uses a cyclodextrin-containing polycation to bind and protect siRNA and transferrin as a targeting ligand for delivery to transferrin receptor–expressing tumor cells. Removal of the targeting ligand or the use of a control siRNA sequence eliminates the antitumor effects. Additionally, no abnormalities in interleukin-12 and IFN-{alpha}, liver and kidney function tests, complete blood counts, or pathology of major organs are observed from long-term, low-pressure, low-volume tail-vein administrations. These data provide strong evidence for the safety and efficacy of this targeted, nonviral siRNA delivery system.




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