Biodistribution characteristics of mannosylated, fucosylated, and galactosylated liposomes in mice

The in vivo disposition behavior and pharmacokinetic characteristics of gal actosylated (Gal), mannosylated (Man) and fucosylated (Fuc) liposomes were compared in this study. For the preparation of the glycosylated liposomes, cholesten-5-yloxy-N-(4-((1-imino-2-beta -D-thiogalactosylethyl)amino)alkyl) formamide (Gal-C4-Chol) (Kawakami et al., Biochem. Biophys. Res. Commun. 25 2 (1998) 78-83) and its mannosylated and fucosylated derivatives (Man-C4-Ch ol and Fuc-C4-Chol, respectively) were synthesized. The glycosylated liposo mes are composed of distearoylphosphatidylcholine (DSPC), cholesterol (Chol ), and Gal-C4-Chol (or Man-C4-Chol or Fuc-C4-Chol) with the molar ratio of 60:35:5. After intravenous injection in mice, these three types of [H-3]cho lesteryl hexadecyl ether-labeled glycosylated liposomes were rapidly elimin ated from the circulating blood and preferentially recovered in the liver. In contrast, DSPC/Chol (60:40) liposomes without glycosylation were retaine d for a long time in the circulating blood. The uptake ratios by parenchyma l cells (PC) and nonparenchymal cells (NPC) (PC/NPC ratios) for 0.5% Gal, M an and Fuc liposomes were found to be 15.1, 0.6 and 0.2, respectively. The effect of predosing glycosylated proteins and liposomes on the hepatic upta ke of 0.5% H-3-labeled Gal, Man, and Fuc liposomes was investigated and the results support the conclusion that Gal, Man, and Fuc liposomes are taken up by the liver via asialoglycoprotein receptors in PC, mannose receptors i n NPC, and fucose receptors in NPC, respectively. Interestingly, Gal liposo mes were taken up by NPC rather than by PC at a high dose (5%). Together wi th the finding that 5% Gal liposomes inhibit the hepatic uptake of H-3-labe led Fuc liposomes, this suggests that Gal-liposomes administered at a high dose will also be taken up by fucose receptors in NPC, that are considered to act as galactose particle receptors. (C) 2000 Elsevier Science B.V. All rights reserved.