Biodistribution characteristics of galactosylated emulsions and incorporated probucol for hepatocyte-selective targeting of lipophilic drugs in mice

Purpose. Galactosylated emulsions containing cholesten-5-yloxy-N-(4-((1-imino-2-D-thiogalactosylethyl)amino)butly)formamide (Gal-C4-Chol) as a "homing device" were developed for hepatocyte-selective drug targeting. The targeting efficiency of galactosylated emulsions was evaluated by a distribution study in mice. Methods. Soybean oil/EggPC/cholesterol (Chol) (weight ratio, 70: 25: 5) (bare) emulsions and soybean oil/EggPC/Gal-C4-Chol (weight ratio, 70: 25: 5) (Gal) emulsions were prepared and labeled with [H-3]cholesteryl hexadecyl ether (CHE). [C-14]probucol as a model lipophilic drug was incorporated in the emulsions or EggPC/Chol/Gal-C4-Chol (Gal) liposomes. Their tissue and intrahepatic distribution were evaluated following intravenous injection in mice. Results. After intravenous injection, Gal-emulsions were rapidly eliminated from the blood and accumulated in the liver, in contrast to the bare-emulsions. The liver uptake clearance of Gal-emulsions was 3.2- and 1.2-times greater than that of bare-emulsions and Gal-liposomes, respectively. The uptake ratio in liver parenchymal cells (PC) and nonparenchymal cells (NPC) of Gal-emulsions was higher than that of Gal-liposomes, being 7.4 and 3.0, suggesting that Gal-emulsions are an effective PC-selective carrier. The hepatic uptake of Gal-emulsions, but not that of bare-emulsions, was significantly inhibited by the pre-dosing of not only lactoferrin but also Gal-liposomes, suggesting asialoglycoprotein receptor-mediated endocytosis. Furthermore, [C-14]probucol incorporated in Gal-emulsions was efficiently delivered to the liver compared with Gal-liposomes. Conclusion. Gal-emulsions have been proven to be an alternative carrier for hepatocyte-selective drug targeting.