Maximizing the Potency of siRNA Lipid Nanoparticles for Hepatic Gene Silencing In Vivo (pages 8529–8533)
Dr. Muthusamy Jayaraman, Dr. Steven M. Ansell, Dr. Barbara L. Mui, Dr. Ying K. Tam, Dr. Jianxin Chen, Dr. Xinyao Du, Dr. David Butler, Dr. Laxman Eltepu, Dr. Shigeo Matsuda, Dr. Jayaprakash K. Narayanannair, Dr. Kallanthottathil G. Rajeev, Dr. Ismail M. Hafez, Dr. Akin Akinc, Dr. Martin A. Maier, Dr. Mark A. Tracy, Dr. Pieter R. Cullis, Dr. Thomas D. Madden, Dr. Muthiah Manoharan and Dr. Michael J. Hope
Version of Record online: 10 JUL 2012 | DOI: 10.1002/anie.201203263
Special (lipid) delivery: The role of the ionizable lipid pKa in the in vivo delivery of siRNA by lipid nanoparticles has been studied with a large number of head group modifications to the lipids. A tight correlation between the lipid pKa value and silencing of the mouse FVII gene (FVII ED50) was found, with an optimal pKa range of 6.2–6.5 (see graph). The most potent cationic lipid from this study has ED50 levels around 0.005 mg kg−1 in mice and less than 0.03 mg kg−1 in non-human primates.