Controlled biodistribution of galactosylated liposomes and incorporated probucol in hepatocyte-selective drug targeting.

Two types of galactosylated liposomes containing cholesten-5-yloxy-N-(4-((1-imino-2-beta-D-thiogalactosyle thyl)amino)b utyl)formamide (Gal-C4-Chol) as a homing device were prepared to study the biodistribution of liposomal carriers and the incorporated drug. Distearoylphosphatidylcholine (DSPC)/cholesterol (Chol)/Gal-C4-Chol (60:35:5) (Gal DSPC), DSPC/Chol (60:40) (DSPC), egg yolk phosphatidylcholine (eggPC)/Chol/Gal-C4-Chol (60:35:5) (Gal eggPC), and eggPC/Chol (60:40) (eggPC) liposomes labeled with [(3)H]cholesteryl hexadecyl ether (CHE) were tested and [(14)C]probucol, with a partition coefficient between octanol and water (PC(oct)) of 10(10.8), was selected as a model drug with lipophilicity suitable for liposomal incorporation. After intravenous injection of the combination of [(14)C]probucol and [(3)H]liposomes, the liver uptake of [(3)H]CHE was the highest in Gal DSPC liposomes, followed by Gal egg PC liposomes, egg PC liposomes, and DSPC liposomes in that order. [(14)C]Probucol incorporated in Gal DSPC liposomes exhibited lower liver uptake than [(3)H]CHE, suggesting that substantial release from liposomes had taken place. In contrast, [(14)C]probucol incorporated in Gal eggPC liposomes was more stably incorporated under in vivo conditions. Co-administration with galactosylated bovine serum albumin significantly inhibited the liver uptake of [(14)C]probucol in both types of galactosylated liposomes, suggesting that the hepatic uptake of liposomes should be mediated by asialoglycoprotein receptors being [(14)C]probucol incorporated in them.