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

  1. Dr. Muthusamy Jayaraman2,*,
  2. Dr. Steven M. Ansell1,
  3. Dr. Barbara L. Mui1,
  4. Dr. Ying K. Tam1,
  5. Dr. Jianxin Chen1,
  6. Dr. Xinyao Du1,
  7. Dr. David Butler2,
  8. Dr. Laxman Eltepu2,
  9. Dr. Shigeo Matsuda2,
  10. Dr. Jayaprakash K. Narayanannair2,
  11. Dr. Kallanthottathil G. Rajeev2,
  12. Dr. Ismail M. Hafez3,
  13. Dr. Akin Akinc2,
  14. Dr. Martin A. Maier2,
  15. Dr. Mark A. Tracy2,
  16. Dr. Pieter R. Cullis3,
  17. Dr. Thomas D. Madden1,
  18. Dr. Muthiah Manoharan2,
  19. Dr. Michael J. Hope1,*

Article first published online: 10 JUL 2012

DOI: 10.1002/anie.201203263

Issue

Angewandte Chemie International Edition

Angewandte Chemie International Edition

Volume 51, Issue 34, pages 8529–8533, August 20, 2012

Additional Information

How to Cite

Jayaraman, M., Ansell, S. M., Mui, B. L., Tam, Y. K., Chen, J., Du, X., Butler, D., Eltepu, L., Matsuda, S., Narayanannair, J. K., Rajeev, K. G., Hafez, I. M., Akinc, A., Maier, M. A., Tracy, M. A., Cullis, P. R., Madden, T. D., Manoharan, M. and Hope, M. J. (2012), Maximizing the Potency of siRNA Lipid Nanoparticles for Hepatic Gene Silencing In Vivo . Angew. Chem. Int. Ed., 51: 8529–8533. doi: 10.1002/anie.201203263

Author Information

  1. 1

    AlCana Technologies, Vancouver, BC (Canada) http://www.alnylam.com

  2. 2

    Alnylam Pharmaceuticals, Cambridge, MA (USA)

  3. 3

    Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC (Canada)

*Alnylam Pharmaceuticals, Cambridge, MA (USA)

  1. †

    This work was supported in part by the Canadian Institutes for Health Research (CIHR) through U/I grant FRN 59836. We would like to thank John Maraganore for helpful comments.

Publication History

  1. Issue published online: 14 AUG 2012
  2. Article first published online: 10 JUL 2012
  3. Manuscript Received: 27 APR 2012

Funded by

  • Funded Access
  • Canadian Institutes for Health Research
  • CIHR. Grant Number: FRN 59836

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Keywords:

  • drug delivery;
  • gene silencing;
  • ionizable amino lipids;
  • liposomes;
  • siRNA
Thumbnail image of graphical abstract

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.

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