期刊
JOURNAL OF CONTROLLED RELEASE
卷 143, 期 2, 页码 222-232出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2009.12.001
关键词
Cationic lipids; Nucleic acid delivery; Liposomes; Nanoparticles; Guanidinium lipids; Polyamines; Transfection; RNA interference
资金
- EPSRC
- ImuThes Ltd
- Mitsubishi Chemical Corporation
- South African Innovation Fund
- National Research Foundation
- European Union [LSHB-CT-2004-005276]
- CANSA
- South African Poliomyelitis Research Foundation
- Engineering and Physical Sciences Research Council [EP/F003188/1] Funding Source: researchfish
- EPSRC [EP/F003188/1] Funding Source: UKRI
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-phosphatidylethano-lamine (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). (C) 2009 Elsevier B.V. All rights reserved.
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