Targeting efficiency of galactosylated liposomes to hepatocytes in vivo: effect of lipid composition.
OBJECTIVE
To investigate the effects of the lipid composition of galactosylated liposomes on their targeted delivery to hepatocytes.


METHODS
Several types of liposomes with a particle size of about 90 nm were prepared using distearoyl-L-phosphatidylcholine (DSPC), cholesterol (Chol) and cholesten-5-yloxy-N-(4-((1-imino-2-D- thiogalactosylethyl)amino)butyl)formamide (Gal-C4-Chol), and labeled with [3H]cholesterol hexadecyl ether. Their tissue disposition was investigated in mice following intravenous injection. The binding and internalization characteristics were also studied in HepG2 cells.


RESULTS
Compared with [H]DSPC/Chol (60:40) liposomes, [3H]DSPC/Chol/Gal-C4-Chol (60:35:5) liposomes exhibit extensive hepatic uptake. Separation of the liver cells showed that galactosylated liposomes are preferentially taken up by hepatocytes, whereas those lacking Gal-C4-Chol distribute equally to hepatocytes and nonparenchymal cells (NPC). Increasing the molar ratio of DSPC to 90% resulted in enhanced NPC uptake of both liposomes, suggesting their uptake via a mechanism other than asialoglycoprotein receptors. DSPC Chol/Gal-C4-Chol (60:35:5) and DSPC/Chol/Gal-C4-Chol (90:5:5) liposomes exhibited similar binding to the surface of HepG2 cells, but the former were taken up faster by the cells.


CONCLUSIONS
The recognition of galactosylated liposomes by the asialoglycoprotein receptors is dependent on the lipid composition. Cholesterol-rich galactosylated liposomes, exhibiting less non-specific interaction and greater receptor-mediated uptake, are better for targeting drugs to hepatocytes in vivo.
Murao
Aki
A
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Nishikawa
Makiya
M
Managit
Chittima
C
Wong
Joseph
J
Kawakami
Shigeru
S
Yamashita
Fumiyoshi
F
Hashida
Mitsuru
M
D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008055:Lipids / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D008081:Liposomes / Q000008:administration & dosage / Q000378:metabolism; D008297:Male; D051379:Mice; D013862:Thiogalactosides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*
D008055:Lipids; D008081:Liposomes; D013862:Thiogalactosides