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Lipid nanoparticles for hepatic delivery of small interfering RNA.

Abstract
Clinical application of small interfering RNA (siRNA) requires safe and efficient delivery in vivo. Here, we report the design and synthesis of lipid nanoparticles (LNPs) for siRNA delivery based on cationic lipids with multiple tertiary amines and hydrophobic linoleyl chains. LNPs incorporating the lipid containing tris(2-aminoethyl)amine (TREN) and 3 linoleyl chains, termed TRENL3, were found to have exceptionally high siRNA transfection efficacy that was markedly superior to lipofectamine, a commercial transfection agent. In addition, inclusion of polyunsaturated fatty acids, such as linoleic acid and linolenic acid in the formulation further enhanced the siRNA delivery efficiency. TRENL3 LNPs were further shown to transport siRNA into the cytosol primarily via macropinocytosis rather than clathrin-mediated endocytosis. The new LNPs have demonstrated preferential uptake by the liver and hepatocellular carcinoma in mice, thereby leading to high siRNA gene-silencing activity. These data suggest potential therapeutic applications of TRENL3 mediated delivery of siRNA for liver diseases.
AuthorsBo Yu, Shu-Hao Hsu, Chenguang Zhou, Xinmei Wang, Megan C Terp, Yun Wu, Lesheng Teng, Yicheng Mao, Feng Wang, Weiming Xue, Samson T Jacob, Kalpana Ghoshal, Robert J Lee, Ly J Lee
JournalBiomaterials (Biomaterials) Vol. 33 Issue 25 Pg. 5924-34 (Sep 2012) ISSN: 1878-5905 [Electronic] Netherlands
PMID22652024 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
CopyrightCopyright © 2012 Elsevier Ltd. All rights reserved.
Chemical References
  • Colloids
  • Ethylenediamines
  • Fatty Acids, Unsaturated
  • Lipids
  • RNA, Small Interfering
  • tris(2-aminoethyl)amine
Topics
  • Animals
  • Cell Line
  • Colloids
  • Down-Regulation
  • Drug Delivery Systems (methods)
  • Ethylenediamines (chemistry)
  • Fatty Acids, Unsaturated (chemistry)
  • Humans
  • Lipids (chemistry)
  • Liver (metabolism)
  • Liver Neoplasms (metabolism)
  • Mice
  • Mice, Inbred ICR
  • Nanoparticles (chemistry, ultrastructure)
  • RNA Stability
  • RNA, Small Interfering (administration & dosage, metabolism)
  • Tissue Distribution

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