Developing Lipid Nanoparticle-Based siRNA Therapeutics for Hepatocellular Carcinoma Using an Integrated Approach

2013 
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 non-toxic 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 with an imperfect delivery platform. In this study, we presented 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 do not trigger liver toxicity upon target knockdown, and the selection of potent and non-immunogenic siRNA molecules against the target. The resulting siRNA-containing lipid nanoparticles produced significant anti-tumor efficacy in orthotopic hepatocellular carcinoma models, and thus, represent a promising starting point for the development of siRNA therapeutics for hepatocellular carcinoma.
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