Rational Design of Cationic Lipids for siRNA Delivery

Nat Biotechnol. 2010 Feb;28(2):172-6. doi: 10.1038/nbt.1602. Epub 2010 Jan 17.

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.

MeSH terms

  • Cations
  • Drug Carriers / chemistry*
  • Drug Compounding / methods*
  • Drug Design*
  • Lipids / chemistry*
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / chemistry*
  • Transfection / methods*

Substances

  • Cations
  • Drug Carriers
  • Lipids
  • RNA, Small Interfering