title: DODAG; a versatile new cationic lipid that mediates efficient delivery of pDNA and siRNA.
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-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).
authors.affiliation: Imperial College Genetic Therapies Centre, Department of Chemistry, Flowers Building, Armstrong Road, Imperial College London, London, SW7 2AZ, UK.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Mével
authors.forename: Nazila
authors.initials: N
authors.lastname: Kamaly
authors.forename: Sergio
authors.initials: S
authors.lastname: Carmona
authors.forename: Morag H
authors.initials: MH
authors.lastname: Oliver
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jorgensen
authors.forename: Carol
authors.initials: C
authors.lastname: Crowther
authors.forename: Felix H
authors.initials: FH
authors.lastname: Salazar
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Marion
authors.forename: Masato
authors.initials: M
authors.lastname: Fujino
authors.forename: Yukikazu
authors.initials: Y
authors.lastname: Natori
authors.forename: Maya
authors.initials: M
authors.lastname: Thanou
authors.forename: Patrick
authors.initials: P
authors.lastname: Arbuthnot
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Yaouanc
authors.forename: Paul Alain
authors.initials: PA
authors.lastname: Jaffrès
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Miller
mesh_terms: 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
chemical_list: D002412:Cations; D004151:Dipeptides; D008081:Liposomes; C550435:N',N'-dioctadecyl-N-4,8-diaza-10-aminodecanoylglycine amide; D034741:RNA, Small Interfering; D004247:DNA