Developing lipid nanoparticle-based siRNA therapeutics for hepatocellular carcinoma using an integrated approach.

Li L, Wang R, Wilcox D, Sarthy A, Lin X, Huang X, Tian L, Dande P, Hubbard RD, Hansen TM, Wada C, Zhao X, Kohlbrenner WM, Fesik SW, Shen Y
Mol Cancer Ther. 2013 12 (11): 2308-18

PMID: 23943805 · DOI:10.1158/1535-7163.MCT-12-0983-T

Successful siRNA therapeutics requires the optimal integration of multiple components, including an efficient delivery system, a disease indication that is appropriate for siRNA-based therapy, and a potent and nontoxic siRNA against a robust therapeutic target. Although all currently available delivery systems have limitations, it is important to recognize that a careful selection of the disease indication, therapeutic target, and siRNA molecule could partially compensate for deficiencies associated with the delivery system and makes it possible to advance a therapeutic siRNA regimen. In this study, we present the development of siRNA therapeutics for hepatocellular carcinoma using an integrated approach, including the development of an efficient lipid nanoparticle delivery system, the identification of a robust therapeutic target that does not trigger liver toxicity upon target knockdown, and the selection of potent and nonimmunogenic siRNA molecules against the target. The resulting siRNA-containing lipid nanoparticles produced significant antitumor efficacy in orthotopic hepatocellular carcinoma models, and, thus, represent a promising starting point for the development of siRNA therapeutics for hepatocellular carcinoma.

©2013 AACR.

MeSH Terms (14)

Animals Carcinoma, Hepatocellular Cell Line, Tumor Drug Delivery Systems Female Genetic Therapy Hep G2 Cells Humans Liver Neoplasms Liver Neoplasms, Experimental Mice Mice, SCID Nanoparticles RNA, Small Interfering

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