1. Rational design of cationic lipids for siRNA delivery
- Author
-
Ammen P. Sandhu, Scott A Barros, William Cantley, Ying K. Tam, Masuna Srinivasulu, Verbena Kosovrasti, Akin Akinc, Kieu Lam, Kallanthottathil G. Rajeev, Marco A. Ciufolini, Dinah W.Y. Sah, Soma De, Lloyd Jeffs, Ismail M. Hafez, Qingmin Chen, Thomas D. Madden, Antonin de Fougerolles, Ed Yaworski, June Qin, Mark A Tracy, Pieter R. Cullis, Barbara L. Mui, Jianxin Chen, Michael J. Hope, Martin Maier, Sandra K. Klimuk, Rene Alvarez, Connie K Cho, Michael J Weinstein, Muthiah Manoharan, Kim F. Wong, Mikameh Kazem, Derrick Stebbing, Merete L. Eisenhardt, Ian MacLachlan, Lubomir Nechev, Erin J Crosley, Muthusamy Jayaraman, J. Robert Dorkin, Sean C. Semple, and Todd Borland
- Subjects
Drug Carriers ,Small interfering RNA ,Drug Compounding ,Stable nucleic acid lipid particle ,Biomedical Engineering ,Rational design ,Cationic polymerization ,RNA ,Bioengineering ,Biology ,Pharmacology ,Transfection ,Lipids ,Applied Microbiology and Biotechnology ,Biochemistry ,In vivo ,Cations ,Drug Design ,Nucleic acid ,Molecular Medicine ,Gene silencing ,lipids (amino acids, peptides, and proteins) ,RNA, Small Interfering ,Biotechnology - Abstract
We adopted a rational approach to design cationic lipids for use in formulations to deliver small interfering RNA (siRNA). Starting with the ionizable cationic lipid 1,2-dilinoleyloxy-3-dimethylaminopropane (DLinDMA), a key lipid component of stable nucleic acid lipid particles (SNALP) as a benchmark, we used the proposed in vivo mechanism of action of ionizable cationic lipids to guide the design of DLinDMA-based lipids with superior delivery capacity. The best-performing lipid recovered after screening (DLin-KC2-DMA) was formulated and characterized in SNALP and demonstrated to have in vivo activity at siRNA doses as low as 0.01 mg/kg in rodents and 0.1 mg/kg in nonhuman primates. To our knowledge, this represents a substantial improvement over previous reports of in vivo endogenous hepatic gene silencing.
- Published
- 2010
- Full Text
- View/download PDF