Effects of complement depletion on the pharmacokinetics and gene delivery mediated by cationic lipid-DNA complexes.
We show that lipoplexes activate complement in human serum in vitro and deplete complement when administered intravenously (i.v.) to mice. This raised the possibility that complement proteins might alter gene expression mediated by lipoplex in animals. To investigate this phenomenon, complement levels were depleted to less than 5% in ICR mice by intraperitoneal (i.p.) injection of cobra venom factor and anti-C3 antibodies. The pharmacokinetics and distribution of radio labeled DOTAP-cholesterol (1.0:0.9 molar ratio)-DNA (5:1 positive charge ratio) complexes containing 131I-labeled p-hydroxybenzamidine phosphatidylethanolamine and 125I-labeled DNA were measured in mice after i.v. administration. Greater than 75% of the injected lipoplex appeared in the lungs 5 min following injection. The lipid and DNA were eliminated from the lungs at a constant ratio. Distribution in various organs was not affected by complement depletion. Expression of luciferase was highest in the lungs and showed a dose-dependent increase as the amount of DNA injected increased from 3 to 60 microg. Reporter gene expression was not affected by complement depletion. In addition, complement depletion had no effect on either the distribution or gene expression in the heart, spleen, or liver. We conclude that cationic lipid-DNA complexes interact with serum complement proteins upon i.v. injection in mice, but this interaction does not influence the lipofection efficiency or systemic distribution of the lipoplex.
Barron
L G
LG
Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco 94143-0446, USA.
Meyer
K B
KB
Szoka
F C
FC
D000818:Animals; D002412:Cations; D002784:Cholesterol / Q000276:immunology / Q000493:pharmacokinetics*; D003176:Complement C3 / Q000276:immunology*; D015926:Complement C3a / Q000276:immunology; D003169:Complement Inactivator Proteins / Q000494:pharmacology; D004247:DNA / Q000276:immunology / Q000493:pharmacokinetics*; D004337:Drug Carriers; D004546:Elapid Venoms / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000276:immunology / Q000493:pharmacokinetics*; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D006801:Humans; D008081:Liposomes / Q000276:immunology; D008156:Luciferases / Q000235:genetics; D008168:Lung / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D000644:Quaternary Ammonium Compounds / Q000276:immunology / Q000493:pharmacokinetics*
D002412:Cations; D003176:Complement C3; D003169:Complement Inactivator Proteins; D004337:Drug Carriers; D004546:Elapid Venoms; D005229:Fatty Acids, Monounsaturated; D008081:Liposomes; D000644:Quaternary Ammonium Compounds; C016310:cobra venom factor; D015926:Complement C3a; D004247:DNA; D002784:Cholesterol; D008156:Luciferases; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane