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Analysis of Hepatic Disposition of Galactosylated Cationic Liposome/Plasmid DNA Complexes in Perfused Rat Liver.
- Source :
- Pharmaceutical Research; Sep2003, Vol. 20 Issue 9, p1452-1459, 8p
- Publication Year :
- 2003
-
Abstract
- Purpose. To determine the intrahepatic disposition characteristics of galactosylated liposome/plasmid DNA (pDNA) complexes in perfused rat liver. Methods. Galactosylated liposomes containing N-[1-(2,3dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA), cholesterol (Chol), and cholesten-5-yloxy-N-{4-[(1-imino-2-D-thiogalactosylethyl)amino]butyl} formamide (Gal-C4-Chol) were prepared. The liposome/[[sup32]p]-labeled pDNA complexes were administered to perfused liver, and the venous outflow patterns were analyzed based on a two-compartment dispersion model. Results. The single-pass hepatic extraction of pDNA complexed with DOTMA/Chol/Gal-C4-Chol liposomes was greater than that with control DOTMA/Chol liposomes. A two-compartment dispersion model revealed that both the tissue binding and cellular internalization rate were higher for the DOTMA/Chol/Gal-C4-Chol liposome complexes compared with the control liposome complexes. The tissue binding was significantly reduced by the presence of 20 mM galactose. When their cellular localization in the perfused liver at 30 min postinjection was investigated, it was found that the parenchymal uptake of the DOTMA/Chol/Gal-C4-Chol liposome complexes was greater than that of the control liposome complexes. The parenchymal cell/ nonparenchymal cell uptake ratio was as high as unity. Conclusion. Galactosylation of the liposome/pDNA complexes increases the tissue binding and internalization rate via an asialoglycoprotein receptor-mediated process. Because of the large particle size of the complexes (∼150 nm), however, penetration across the fenestrated sinusoidal endothelium appears to be limited. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 07248741
- Volume :
- 20
- Issue :
- 9
- Database :
- Complementary Index
- Journal :
- Pharmaceutical Research
- Publication Type :
- Academic Journal
- Accession number :
- 10875652