Rational design of cationic lipids for siRNA delivery (original) (raw)

References

  1. de Fougerolles, A.R. Delivery vehicles for small interfering RNA in vivo. Hum. Gene Ther. 19, 125–132 (2008).
    Article CAS PubMed Google Scholar
  2. Whitehead, K.A., Langer, R. & Anderson, D.G. Knocking down barriers: advances in siRNA delivery. Nat. Rev. Drug Discov. 8, 129–138 (2009).
    Article CAS PubMed Google Scholar
  3. Judge, A.D. et al. Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice. J. Clin. Invest. 119, 661–673 (2009).
    Article CAS PubMed PubMed Central Google Scholar
  4. Judge, A.D. et al. Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat. Biotechnol. 23, 457–462 (2005).
    Article CAS PubMed Google Scholar
  5. Morrissey, D.V. et al. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat. Biotechnol. 23, 1002–1007 (2005).
    Article CAS PubMed Google Scholar
  6. Zimmermann, T.S. et al. RNAi-mediated gene silencing in non-human primates. Nature 441, 111–114 (2006).
    Article CAS PubMed Google Scholar
  7. Akinc, A. et al. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nat. Biotechnol. 26, 561–569 (2008).
    Article CAS PubMed PubMed Central Google Scholar
  8. Frank-Kamenetsky, M. et al. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc. Natl. Acad. Sci. USA 105, 11915–11920 (2008).
    Article CAS PubMed Google Scholar
  9. Hafez, I.M., Maurer, N. & Cullis, P.R. On the mechanism whereby cationic lipids promote intracellular delivery of polynucleic acids. Gene Ther. 8, 1188–1196 (2001).
    Article CAS PubMed Google Scholar
  10. Xu, Y. & Szoka, F.C. Jr. Mechanism of DNA release from cationic liposome/DNA complexes used in cell transfection. Biochemistry 35, 5616–5623 (1996).
    Article CAS PubMed Google Scholar
  11. Zelphati, O. & Szoka, F.C. Jr. Mechanism of oligonucleotide release from cationic liposomes. Proc. Natl. Acad. Sci. USA 93, 11493–11498 (1996).
    Article CAS PubMed Google Scholar
  12. Torchilin, V.P. Recent approaches to intracellular delivery of drugs and DNA and organelle targeting. Annu. Rev. Biomed. Eng. 8, 343–375 (2006).
    Article CAS PubMed Google Scholar
  13. Semple, S.C. et al. Efficient encapsulation of antisense oligonucleotides in lipid vesicles using ionizable aminolipids: formation of novel small multilamellar vesicle structures. Biochim. Biophys. Acta 1510, 152–166 (2001).
    Article CAS PubMed Google Scholar
  14. Maurer, N. et al. Spontaneous entrapment of polynucleotides upon electrostatic interaction with ethanol-destabilized cationic liposomes. Biophys. J. 80, 2310–2326 (2001).
    Article CAS PubMed PubMed Central Google Scholar
  15. Heyes, J., Palmer, L., Bremner, K. & Maclachlan, I. Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids. J. Control. Release 107, 276–287 (2005).
    Article CAS PubMed Google Scholar
  16. Semple, S.C., Chonn, A. & Cullis, P.R. Interactions of liposomes and lipid-based carrier systems with blood proteins: Relation to clearance behaviour in vivo. Adv. Drug Deliv. Rev. 32, 3–17 (1998).
    Article CAS PubMed Google Scholar
  17. Bailey, A.L. & Cullis, P.R. Modulation of membrane fusion by asymmetric transbilayer distributions of amino lipids. Biochemistry 33, 12573–12580 (1994).
    Article CAS PubMed Google Scholar
  18. Cullis, P.R. & de Kruijff, B. The polymorphic phase behaviour of phosphatidylethanolamines of natural and synthetic origin. A 31P NMR study. Biochim. Biophys. Acta 513, 31–42 (1978).
    Article CAS PubMed Google Scholar
  19. Epand, R.M., Robinson, K.S., Andrews, M.E. & Epand, R.F. Dependence of the bilayer to hexagonal phase transition on amphiphile chain length. Biochemistry 28, 9398–9402 (1989).
    Article CAS PubMed Google Scholar
  20. Sekijima, Y., Kelly, J.W. & Ikeda, S. Pathogenesis of and therapeutic strategies to ameliorate the transthyretin amyloidoses. Curr. Pharm. Des. 14, 3219–3230 (2008).
    Article CAS PubMed Google Scholar
  21. Cullis, P.R., Hope, M.J. & Tilcock, C.P. Lipid polymorphism and the roles of lipids in membranes. Chem. Phys. Lipids 40, 127–144 (1986).
    Article CAS PubMed Google Scholar
  22. Heyes, J., Hall, K., Tailor, V., Lenz, R. & MacLachlan, I. Synthesis and characterization of novel poly(ethylene glycol)-lipid conjugates suitable for use in drug delivery. J. Control. Release 112, 280–290 (2006).
    Article CAS PubMed Google Scholar
  23. Jeffs, L.B. et al. A scalable, extrusion-free method for efficient liposomal encapsulation of plasmid DNA. Pharm. Res. 22, 362–372 (2005).
    Article CAS PubMed Google Scholar

Download references

Acknowledgements

The authors thank K. McClintock for assistance with animal studies. The authors also thank the Centre for Drug Research and Development at the University of British Columbia for use of the NMR facilities and M. Heller for his expert assistance in setting up the 31P-NMR experiments.

Author information

Author notes

  1. Jianxin Chen, Barbara L Mui, Ying K Tam, Thomas D Madden & Michael J Hope
    Present address: Present address: Alcana Technologies, Vancouver, British Columbia, Canada.,
  2. Sean C Semple and Akin Akinc: These authors contributed equally to this work.

Authors and Affiliations

  1. Tekmira Pharmaceuticals, Burnaby, British Columbia, Canada
    Sean C Semple, Jianxin Chen, Ammen P Sandhu, Barbara L Mui, Connie K Cho, Derrick Stebbing, Erin J Crosley, Ed Yaworski, Kieu Lam, Lloyd B Jeffs, Merete L Eisenhardt, Sandra K Klimuk, Ying K Tam, Ian MacLachlan, Thomas D Madden & Michael J Hope
  2. Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA
    Akin Akinc, Dinah W Y Sah, J Robert Dorkin, June Qin, Kallanthottathil G Rajeev, Lubomir Nechev, Muthusamy Jayaraman, Martin A Maier, Michael J Weinstein, Qingmin Chen, Rene Alvarez, Scott A Barros, Soma De, Todd Borland, Verbena Kosovrasti, William L Cantley, Muthiah Manoharan, Mark A Tracy & Antonin de Fougerolles
  3. Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada
    Ismail M Hafez, Kim F Wong, Mikameh Kazem & Pieter R Cullis
  4. Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada
    Masuna Srinivasulu & Marco A Ciufolini

Authors

  1. Sean C Semple
    You can also search for this author inPubMed Google Scholar
  2. Akin Akinc
    You can also search for this author inPubMed Google Scholar
  3. Jianxin Chen
    You can also search for this author inPubMed Google Scholar
  4. Ammen P Sandhu
    You can also search for this author inPubMed Google Scholar
  5. Barbara L Mui
    You can also search for this author inPubMed Google Scholar
  6. Connie K Cho
    You can also search for this author inPubMed Google Scholar
  7. Dinah W Y Sah
    You can also search for this author inPubMed Google Scholar
  8. Derrick Stebbing
    You can also search for this author inPubMed Google Scholar
  9. Erin J Crosley
    You can also search for this author inPubMed Google Scholar
  10. Ed Yaworski
    You can also search for this author inPubMed Google Scholar
  11. Ismail M Hafez
    You can also search for this author inPubMed Google Scholar
  12. J Robert Dorkin
    You can also search for this author inPubMed Google Scholar
  13. June Qin
    You can also search for this author inPubMed Google Scholar
  14. Kieu Lam
    You can also search for this author inPubMed Google Scholar
  15. Kallanthottathil G Rajeev
    You can also search for this author inPubMed Google Scholar
  16. Kim F Wong
    You can also search for this author inPubMed Google Scholar
  17. Lloyd B Jeffs
    You can also search for this author inPubMed Google Scholar
  18. Lubomir Nechev
    You can also search for this author inPubMed Google Scholar
  19. Merete L Eisenhardt
    You can also search for this author inPubMed Google Scholar
  20. Muthusamy Jayaraman
    You can also search for this author inPubMed Google Scholar
  21. Mikameh Kazem
    You can also search for this author inPubMed Google Scholar
  22. Martin A Maier
    You can also search for this author inPubMed Google Scholar
  23. Masuna Srinivasulu
    You can also search for this author inPubMed Google Scholar
  24. Michael J Weinstein
    You can also search for this author inPubMed Google Scholar
  25. Qingmin Chen
    You can also search for this author inPubMed Google Scholar
  26. Rene Alvarez
    You can also search for this author inPubMed Google Scholar
  27. Scott A Barros
    You can also search for this author inPubMed Google Scholar
  28. Soma De
    You can also search for this author inPubMed Google Scholar
  29. Sandra K Klimuk
    You can also search for this author inPubMed Google Scholar
  30. Todd Borland
    You can also search for this author inPubMed Google Scholar
  31. Verbena Kosovrasti
    You can also search for this author inPubMed Google Scholar
  32. William L Cantley
    You can also search for this author inPubMed Google Scholar
  33. Ying K Tam
    You can also search for this author inPubMed Google Scholar
  34. Muthiah Manoharan
    You can also search for this author inPubMed Google Scholar
  35. Marco A Ciufolini
    You can also search for this author inPubMed Google Scholar
  36. Mark A Tracy
    You can also search for this author inPubMed Google Scholar
  37. Antonin de Fougerolles
    You can also search for this author inPubMed Google Scholar
  38. Ian MacLachlan
    You can also search for this author inPubMed Google Scholar
  39. Pieter R Cullis
    You can also search for this author inPubMed Google Scholar
  40. Thomas D Madden
    You can also search for this author inPubMed Google Scholar
  41. Michael J Hope
    You can also search for this author inPubMed Google Scholar

Contributions

J.C., M.A.C., P.R.C., T.D.M., M.J.H. and K.F.W. designed and advised on novel lipids. J.C., K.F.W. and M.S. synthesized novel lipids. M.J.H., T.D.M., J.C., K.F.W., M.M., K.G.R., M.A.M., M.T. and M.J. analyzed and interpreted lipid data. T.D.M., M.J.H. and M.A.T. co-directed novel lipid synthesis and screening program. S.C.S. designed and directed rodent in vivo studies. S.C.S., S.K.K., B.L.M., K.L., M.L.E., M.K., A.P.S., Y.K.T., S.A.B., W.L.C., M.J.W. and E.J.C. generated rodent in vivo data, including Factor VII and tolerability analyses. L.N., V.K., T.B., R.A., Q.C. and D.W.Y.S. developed novel siRNAs targeting TTR. R.A. and A.A. designed and directed NHP in vivo studies. S.C.S., S.K.K., A.A., B.L.M., I.M., A.P.S., Y.K.T., R.A., T.B., D.W. Y. S., S.A.B., J.Q., J.R.D. and A.d.F. analyzed and interpreted in vivo data. B.L.M., K.L., A.P.S., S.K.K., S.C.S. and E.J.C. generated and characterized preformed vesicle formulations with novel lipids. D.S. and C.K.C. developed methods and designed and conducted HPLC lipid analyses of preformed vesicle formulations. E.Y. and L.B.J. prepared SNALP formulations. P.R.C. directed biophysical studies and advised on methods. A.P.S., I.M.H., S.D. and K.W. performed biophysical characterization studies (p_K_a, NMR, differential scanning calorimetric) of novel lipids and formulations. M.J.H., P.R.C., T.D.M., A.P.S., I.M.H. and K.F.W. analyzed biophysical data. S.C.S., M.J.H., A.A. and P.R.C. co-wrote the manuscript. T.D.M., M.M., M.A.M., M.A.T. and A.D.F. reviewed and edited the manuscript. S.C.S., M.J.H., A.A., P.R.C., I.M. and A.D.F. were responsible for approval of the final draft.

Corresponding authors

Correspondence toSean C Semple or Akin Akinc.

Ethics declarations

Competing interests

Authors are employees of Alnylam, Tekmira, or Alcana or receive funding from Alnylam.

Supplementary information

Rights and permissions

About this article

Cite this article

Semple, S., Akinc, A., Chen, J. et al. Rational design of cationic lipids for siRNA delivery.Nat Biotechnol 28, 172–176 (2010). https://doi.org/10.1038/nbt.1602

Download citation