In vivo comparative study of lipid/DNA complexes with different in vitro serum stability: effects on biodistribution and tumor accumulation.
To evaluate the in vivo biodistribution and expression of DOTAP-Chol/DNA complexes (lipoplexes) with different in vitro serum stability, quantitative real-time PCR, in vitro luciferase expression and whole body luminescence imaging were used. In general, less tissue biodistribution, lower luciferase expression and whole body luminescence were observed for DOTAP:Chol (mol/mol 1:4)/DNA lipoplexes which had higher in vitro serum stability as compared to DOTAP:Chol (mol/mol 1:1)/DNA lipoplexes. Plasmid DNA biodistribution and expression were mainly confined to the lungs, and the results suggest that in vitro serum stability may serve as a predictor of transfection in the lung. No correlation between plasmid DNA tissue biodistribution and gene expression was observed by simultaneous determination of the level of plasmid DNA tissue biodistribution and gene expression. While high doses of the formulation possessing increased in vitro serum stability did exhibit reduced entrapment in the lung, no corresponding increase in the plasmid levels of other tissues was observed. However, this formulation did show increased accumulation in tumors that was not further enhanced by PEGylation.
Zhang
Ye
Y
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262, USA. Zhangy@sirna.com
Bradshaw-Pierce
Erica L
EL
Delille
Alexandra
A
Gustafson
Daniel L
DL
Anchordoquy
Thomas J
TJ
D000818:Animals; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D002784:Cholesterol / Q000737:chemistry; D004247:DNA / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D005079:Excipients; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry; D005260:Female; D006801:Humans; D008055:Lipids / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D008081:Liposomes; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D049449:Luminescence; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000378:metabolism*; D010957:Plasmids / Q000493:pharmacokinetics; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044967:Serum / Q000737:chemistry; D014018:Tissue Distribution
D005079:Excipients; D005229:Fatty Acids, Monounsaturated; D008055:Lipids; D008081:Liposomes; D000644:Quaternary Ammonium Compounds; D004247:DNA; D002784:Cholesterol; D008156:Luciferases; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane