Developing lipid nanoparticle-based siRNA therapeutics for hepatocellular carcinoma using an integrated approach.
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.
Corresponding Author: Yu Shen, Cancer Research, Global Pharmaceutical and Analytical Sciences, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 20064. yu.shen@abbott.com.
Leiming
L
Li
Rongqi
R
Wang
Denise
D
Wilcox
Aparna
A
Sarthy
Xiaoyu
X
Lin
Xiaoli
X
Huang
Lu
L
Tian
Prasad
P
Dande
Robert D
RD
Hubbard
Todd M
TM
Hansen
Carol
C
Wada
Xiaobin
X
Zhao
William M
WM
Kohlbrenner
Stephen W
SW
Fesik
Yu
Y
Shen
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008114:Liver Neoplasms, Experimental; D051379:Mice; D016513:Mice, SCID; D053758:Nanoparticles; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000633:toxicity
D034741:RNA, Small Interfering