Targeting efficiency of galactosylated liposomes to hepatocytes in vivo: effect of lipid composition.

Purpose: 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.