DODAG; a versatile new cationic lipid that mediates efficient delivery of pDNA and siRNA.
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-alpha-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).
Mével
Mathieu
M
Imperial College Genetic Therapies Centre, Department of Chemistry, Flowers Building, Armstrong Road, Imperial College London, London, SW7 2AZ, UK.
Kamaly
Nazila
N
Carmona
Sergio
S
Oliver
Morag H
MH
Jorgensen
Michael R
MR
Crowther
Carol
C
Salazar
Felix H
FH
Marion
Patricia L
PL
Fujino
Masato
M
Natori
Yukikazu
Y
Thanou
Maya
M
Arbuthnot
Patrick
P
Yaouanc
Jean-Jacques
JJ
Jaffrès
Paul Alain
PA
Miller
Andrew D
AD
D000818:Animals; D002412:Cations / Q000737:chemistry; D002460:Cell Line; D002470:Cell Survival; D004247:DNA / Q000008:administration & dosage*; D004151:Dipeptides / Q000737:chemistry*; D006515:Hepatitis B virus / Q000235:genetics; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D051379:Mice; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000737:chemistry; D010957:Plasmids / Q000008:administration & dosage*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D014162:Transfection
D002412:Cations; D004151:Dipeptides; D008081:Liposomes; C550435:N',N'-dioctadecyl-N-4,8-diaza-10-aminodecanoylglycine amide; D034741:RNA, Small Interfering; D004247:DNA