Display options
Cite
Mihaila R, Ruhela D, Keough E, et al. Mathematical Modeling: A Tool for Optimization of Lipid Nanoparticle-Mediated Delivery of siRNA. Mol Ther Nucleic Acids. 2017;7:246-255doi: 10.1016/j.omtn.2017.04.003.
Mihaila, R., Ruhela, D., Keough, E., Cherkaev, E., Chang, S., Galinski, B., Bartz, R., Brown, D., Howell, B., & Cunningham, J. J. (2017). Mathematical Modeling: A Tool for Optimization of Lipid Nanoparticle-Mediated Delivery of siRNA. Molecular therapy. Nucleic acids, 7246-255. https://doi.org/10.1016/j.omtn.2017.04.003
Mihaila, Radu, et al. "Mathematical Modeling: A Tool for Optimization of Lipid Nanoparticle-Mediated Delivery of siRNA." Molecular therapy. Nucleic acids vol. 7 (2017): 246-255. doi: https://doi.org/10.1016/j.omtn.2017.04.003
Mihaila R, Ruhela D, Keough E, Cherkaev E, Chang S, Galinski B, Bartz R, Brown D, Howell B, Cunningham JJ. Mathematical Modeling: A Tool for Optimization of Lipid Nanoparticle-Mediated Delivery of siRNA. Mol Ther Nucleic Acids. 2017 Jun 16;7:246-255. doi: 10.1016/j.omtn.2017.04.003. Epub 2017 Apr 12. PMID: 28624200; PMCID: PMC5415968.
Copy Download .nbib Format: NLM
Share it on

Mol Ther Nucleic Acids. 2017 Jun 16;7:246-255. doi: 10.1016/j.omtn.2017.04.003. Epub 2017 Apr 12.

Mathematical Modeling: A Tool for Optimization of Lipid Nanoparticle-Mediated Delivery of siRNA.

Molecular therapy. Nucleic acids

Radu Mihaila, Dipali Ruhela, Edward Keough, Elena Cherkaev, Silvia Chang, Beverly Galinski, René Bartz, Duncan Brown, Bonnie Howell, James J Cunningham

Affiliations

  1. Sirna Therapeutics, 1700 Owens Street, Fourth Floor, San Francisco, CA 94158, USA. Electronic address: [email protected].
  2. Sirna Therapeutics, 1700 Owens Street, Fourth Floor, San Francisco, CA 94158, USA.
  3. Department of RNA Therapeutics, Merck Sharp & Dohme Corp., West Point, PA 19486, USA.
  4. Department of Mathematics, University of Utah, Salt Lake City, UT 84112, USA.

PMID: 28624200 PMCID: PMC5415968 DOI: 10.1016/j.omtn.2017.04.003

Abstract

Lipid nanoparticles (LNPs) have been used to successfully deliver small interfering RNAs (siRNAs) to target cells in both preclinical and clinical studies and currently are the leading systems for in vivo delivery. Here, we propose the use of an ordinary differential equation (ODE)-based model as a tool for optimizing LNP-mediated delivery of siRNAs. As a first step, we have used a combination of experimental and computational approaches to develop and validate a mathematical model that captures the critical features for efficient siRNA-LNP delivery in vitro. This model accurately predicts mRNA knockdown resulting from novel combinations of siRNAs and LNPs in vitro. As demonstrated, this model can be effectively used as a screening tool to select the most efficacious LNPs, which can then further be evaluated in vivo. The model serves as a starting point for the future development of next generation models capable of capturing the additional complexity of in vivo delivery.

Copyright © 2017 Elena Cherkaev, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA. Published by Elsevier Inc. All rights reserved.

Keywords: RNA interference; cellular pharmacokinetics; intracellular trafficking; lipid nanoparticles; mathematical modeling; siRNA

References

  1. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3338-40 - PubMed
  2. N Engl J Med. 2013 Aug 29;369(9):819-29 - PubMed
  3. Int J Pharm. 2011 Nov 25;420(1):118-21 - PubMed
  4. Mol Biosyst. 2015 Oct;11(10):2680-9 - PubMed
  5. Science. 2006 Jan 13;311(5758):195-8 - PubMed
  6. J Clin Oncol. 2014 Dec 20;32(36):4141-8 - PubMed
  7. Expert Opin Drug Deliv. 2012 Feb;9(2):171-82 - PubMed
  8. J Med Chem. 2010 Nov 25;53(22):7887-901 - PubMed
  9. Mol Pharm. 2014 May 5;11(5):1424-34 - PubMed
  10. Nucleic Acids Res. 2006 Jan 12;34(1):322-33 - PubMed
  11. Mol Pharm. 2009 May-Jun;6(3):763-71 - PubMed
  12. Proc Natl Acad Sci U S A. 2012 Feb 21;109 (8):3137-42 - PubMed
  13. Nat Struct Mol Biol. 2005 May;12(5):469-70 - PubMed
  14. Lancet. 2014 Jan 4;383(9911):60-8 - PubMed
  15. Nat Rev Drug Discov. 2004 Apr;3(4):318-29 - PubMed
  16. Nat Biotechnol. 2013 Jul;31(7):638-46 - PubMed
  17. RNA. 2010 Dec;16(12):2553-63 - PubMed
  18. Mol Ther. 2011 Dec;19(12):2186-200 - PubMed
  19. Biotechnol Prog. 2008 Jan-Feb;24(1):23-8 - PubMed
  20. Nature. 2001 May 24;411(6836):494-8 - PubMed
  21. Annu Rev Biochem. 2002;71:375-403 - PubMed
  22. RNA. 2004 May;10(5):766-71 - PubMed
  23. Pharm Res. 2007 Mar;24(3):438-49 - PubMed
  24. Nature. 2006 May 4;441(7089):111-4 - PubMed
  25. J Mol Diagn. 2000 May;2(2):84-91 - PubMed
  26. Nat Biotechnol. 2015 Aug;33(8):870-6 - PubMed
  27. Biophys J. 2003 May;84(5):3307-16 - PubMed
  28. RNA. 2003 Sep;9(9):1034-48 - PubMed
  29. Cancer Discov. 2013 Apr;3(4):406-17 - PubMed
  30. Nat Cell Biol. 2006 Nov;8(11):1195-203 - PubMed
  31. Nanomedicine. 2013 May;9(4):504-13 - PubMed
  32. Nat Biotechnol. 2010 Feb;28(2):172-6 - PubMed
  33. Int J Clin Pharmacol Ther. 2012 Jan;50(1):76-8 - PubMed
  34. J Cell Sci. 2010 Apr 15;123(Pt 8):1183-9 - PubMed
  35. Mol Ther. 2011 Mar;19(3):567-75 - PubMed
  36. Nucleic Acids Res. 1995 Jul 25;23(14):2677-84 - PubMed
  37. Gene Ther. 2001 Aug;8(15):1188-96 - PubMed
  38. Biochem J. 2011 Apr 15;435(2):475-87 - PubMed

Publication Types