Rational design of cationic lipids for siRNA delivery

  • Nat Biotechnol. 2010 Feb;28(2):172-6. doi: 10.1038/nbt.1602.
Sean C Semple  1 ,  Akin Akinc ,  Jianxin Chen ,  Ammen P Sandhu ,  Barbara L Mui ,  Connie K Cho ,  Dinah W Y Sah ,  Derrick Stebbing ,  Erin J Crosley ,  Ed Yaworski ,  Ismail M Hafez ,  J Robert Dorkin ,  June Qin ,  Kieu Lam ,  Kallanthottathil G Rajeev ,  Kim F Wong ,  Lloyd B Jeffs ,  Lubomir Nechev ,  Merete L Eisenhardt ,  Muthusamy Jayaraman ,  Mikameh Kazem ,  Martin A Maier ,  Masuna Srinivasulu ,  Michael J Weinstein ,  Qingmin Chen ,  Rene Alvarez ,  Scott A Barros ,  Soma De ,  Sandra K Klimuk ,  Todd Borland ,  Verbena Kosovrasti ,  William L Cantley ,  Ying K Tam ,  Muthiah Manoharan ,  Marco A Ciufolini ,  Mark A Tracy ,  Antonin de Fougerolles ,  Ian MacLachlan ,  Pieter R Cullis ,  Thomas D Madden ,  Michael J Hope
Affiliations
PMID: 20081866 DOI: 10.1038/nbt.1602
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.

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