Polyinosinic acid and polycationic liposomes attenuate the hepatic clearance of circulating plasmid DNA

Minchin, RF, Carpenter, D and Orr, RJ (2001) Polyinosinic acid and polycationic liposomes attenuate the hepatic clearance of circulating plasmid DNA. Journal of Pharmacology And Experimental Therapeutics, 296 3: 1006-1012.

Author Minchin, RF
Carpenter, D
Orr, RJ
Title Polyinosinic acid and polycationic liposomes attenuate the hepatic clearance of circulating plasmid DNA
Journal name Journal of Pharmacology And Experimental Therapeutics   Check publisher's open access policy
ISSN 0022-3565
Publication date 2001-01-01
Sub-type Article (original research)
Volume 296
Issue 3
Start page 1006
End page 1012
Total pages 7
Place of publication Bethesda
Publisher Amer Soc Pharmacology Experimental Therapeutics
Language eng
Abstract DNA that enters the circulation is rapidly cleared both by tissue uptake and by DNase-mediated degradation. In this study, we have examined the uptake of linear plasmid DNA in an isolated perfused liver model and following intra-arterial administration to rats. We found that the DNA was rapidly taken up by the isolated perfused liver without degradation. The single-pass extraction ratio was 0.76 +/- 0.05, the mean transit time was 15.3 +/- 3.6 s, and the volume of distribution was 0.29 +/- 0.07 ml/g. Hepatic uptake was saturable and was inhibited by polyinosinic acid or polycationic liposomes but not by condensation of the DNA with polylysine. When the linear plasmid DNA was administered in vivo, plasma half-life was 3.1 +/- 0.2 min, volume of distribution was 670 +/- 85 ml/kg, and clearance was 32 +/- 4 min. Coadministration of cationic liposomes decreased the volume of distribution to 180 +/- 28 ml/kg as well as the half-life (2.6 +/- 0.2 min). By contrast, polyinosinic acid significantly increased the circulating half-life (7.7 +/- 0.5 min), decreased the volume of distribution (95 +/- 17 ml/kg), and partially inhibited DNA degradation. When administered along with the liposomes and the polyinosinic acid, the distribution of plasmid-derived radioactivity decreased in the liver and increased in most other peripheral tissues. This study shows that pharmacological manipulation of the uptake and degradation of DNA can alter its distribution and clearance in vivo. These results may be useful in optimizing gene delivery procedures for in vivo gene therapy.
Keyword Pharmacology & Pharmacy
Vivo Gene-expression
In-vivo
Scavenger Receptors
Endothelial-cells
Intravenous-injection
Rat-liver
Complexes
Disposition
Therapy
Mice
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Biomedical Sciences Publications
 
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Created: Mon, 13 Aug 2007, 22:12:40 EST