Maximizing the Potency of siRNA Lipid Nanoparticles for Hepatic Gene Silencing In Vivo

• Published in: Angewandte Chemie International Edition Vol. 51; no. 34; pp. 8529 - 8533
• Main Authors: Jayaraman, Muthusamy, Ansell, Steven M., Mui, Barbara L., Tam, Ying K., Chen, Jianxin, Du, Xinyao, Butler, David, Eltepu, Laxman, Matsuda, Shigeo, Narayanannair, Jayaprakash K., Rajeev, Kallanthottathil G., Hafez, Ismail M., Akinc, Akin, Maier, Martin A., Tracy, Mark A., Cullis, Pieter R., Madden, Thomas D., Manoharan, Muthiah, Hope, Michael J.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 20.08.2012; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Amines - chemistry; Animals; Chemistry; Chemistry, Multidisciplinary; Communications; drug delivery; Female; Gene Silencing; Genetic Therapy - methods; Humans; ionizable amino lipids; Kinetics; Lipids; Lipids - administration & dosage; Lipids - chemistry; liposomes; Liposomes - administration & dosage; Liposomes - chemistry; Liver - metabolism; Liver - physiology; Mice; Mice, Inbred C57BL; Nanoparticles; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Optimization; Phospholipids; Physical Sciences; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - chemistry; RNA, Small Interfering - genetics; Science & Technology; siRNA; THERAPEUTICS; CATIONIC LIPIDS; MECHANISM; liposomes; ACIDS; gene silencing; ionizable amino lipids; INTRACELLULAR DELIVERY; siRNA; drug delivery
• ISSN: 1433-7851; 1521-3773
• 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.