Analysis of hepatic disposition of galactosylated cationic liposome/plasmid DNA complexes in perfused rat liver.
OBJECTIVE
To determine the intrahepatic disposition characteristics of galactosylated liposome/plasmid DNA (pDNA) complexes in perfused rat liver.


METHODS
Galactosylated liposomes containing N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA), cholesterol (Chol), and cholesten-5-yloxy-N-14-[(1-imino-2-D-thiogalactosylethyl)amino]butyl] formamide (Gal-C4-Chol) were prepared. The liposome/[32P]-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.


CONCLUSIONS
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 (approximately 150 nm), however, penetration across the fenestrated sinusoidal endothelium appears to be limited.
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Shintaro
S
Fumoto
Fumi
F
Nakadori
Shigeru
S
Kawakami
Makiya
M
Nishikawa
Fumiyoshi
F
Yamashita
Mitsuru
M
Hashida
D000818:Animals; D002412:Cations; D002784:Cholesterol / Q000031:analogs & derivatives / Q000737:chemistry; D004247:DNA / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D005690:Galactose / Q000031:analogs & derivatives* / Q000737:chemistry*; D018014:Gene Transfer Techniques; D066298:In Vitro Techniques; D008081:Liposomes; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D008954:Models, Biological; D010477:Perfusion; D010957:Plasmids; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D002412:Cations; D008081:Liposomes; D000644:Quaternary Ammonium Compounds; C054005:N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium; D004247:DNA; D002784:Cholesterol; D005690:Galactose