DODAG; a versatile new cationic lipid that mediates efficient delivery of pDNA and siRNA

Mathieu Mével, Nazila Kamaly, Sergio Carmona, Morag Oliver, Michael R. Jorgensen, Carol Crowther, Felix H. Salazar, Patricia L. Marion, Masato Fujino, Yukikazu Natori, Maya Thanou, Patrick Arbuthnot, Jean-Jacques Yaouanc, Paul Alain Jaffrés, Andrew D. Miller

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

We report the syntheses of novel cationic lipids comprised of cholesteryl-moieties linked to guanidinium functional groups, and also cationic lipids comprising a dialkylglycylamide moiety conjugated with a polyamine or a guanidinium functional group. In plasmid DNA (pDNA) transfection studies, these cationic lipids were formulated into cationic liposomes with the neutral co-lipid dioleoyl-L-α-phosphatidylethanolamine (DOPE) or with a recently reported neutral lipophosphoramidate derivative of histamine (MM27). We observe that cationic liposomes prepared from the cationic lipid N′,N′-dioctadecyl-N-4,8-diaza-10-aminodecanoylglycine amide (DODAG) and DOPE frequently mediate the highest levels of transfection in vitro in all three different cell lines studied (OVCAR-3, IGROV-1 and HeLa) both in the presence or absence of serum. In addition, in vitro cellular toxicity was found to be minimal. Alternatively, we observe that DODAG alone forms lipoplex nanoparticles with small interfering RNA (siRNA) that are able to mediate the functional delivery of two previously validated anti-hepatitis B virus (HBV) — siRNAs to murine liver in vivo with minimal observable liver toxicity and immune stimulation. Specific knock-down of HBV infection parameters (virion and hepatic mRNA levels) is observed that is at least equivalent to the impact of extensive treatment with lamivudine (a licensed antiviral drug).
Original languageEnglish
JournalJournal of Controlled Release
Volume143
Issue number2
Pages (from-to)222-232
ISSN0168-3659
Publication statusPublished - 2010
Externally publishedYes

Keywords

  • Cationic lipids
  • Nucleic acid delivery
  • Liposomes
  • Nanoparticles
  • Guanidinium lipids
  • Polyamines
  • Transfection
  • RNA Interference

Cite this

Mével, M., Kamaly, N., Carmona, S., Oliver, M., Jorgensen, M. R., Crowther, C., Salazar, F. H., Marion, P. L., Fujino, M., Natori, Y., Thanou, M., Arbuthnot, P., Yaouanc, J-J., Jaffrés, P. A., & Miller, A. D. (2010). DODAG; a versatile new cationic lipid that mediates efficient delivery of pDNA and siRNA. Journal of Controlled Release, 143(2), 222-232.