Pharmacokinetic Analysis of Lectin-dependent Biodistribution of Fucosylated Bovine Serum Albumin: A Possible Carrier for Kupffer Cells

Abstract

To examine the potential utility of fucosylation of drug carriers for targeted drug delivery to Kupffer cells, the pharmacokinetics of 111In-labeled fucosylated bovine serum albumin (Fuc-BSA) with different numbers of fucose residues (11, 16, 25, 31 or 41) was studied. After intravenous injection in mice, all 111In-Fuc-BSAs were mainly delivered to the liver and their hepatic uptake became saturated when the dose was increased. Of these derivatives, only 111In-Fuc41-BSA showed a slow plasma elimination at low doses, suggesting an interaction with blood components. Examination of binding conditions as well as electrophoretic analysis of the binding components indicated that the serum-type mannan binding protein (MBP) is responsible. Kupffer cells, which possess fucose receptors, showed the highest uptake of 111In-Fuc41-BSA, followed by endothelial cells and hepatocytes. The hepatic uptake of 111In-Fuc41-BSA was inhibited by co-injection of Gal42-BSA, but not by Man46-BSA. On the other hand, excess Fuc41BSA inhibited the hepatic uptake of 111In-Man46-BSA, while 111In-Gal42-BSA did not: These findings suggest that not only the fucose receptors on Kupffer cells but also other lectins are involved in the biodistribution of Fuc-BSAs. To understand how the degree of fucose modification affects the binding affinity of Fuc-BSA with hepatic lectins and serum MBP, a pharmacokinetic analysis was performed based on a physiological model. The Michaelis constant of the hepatic uptake of 111in-Fuc-BSA decreased with an increasing number of fucose units, and the intrinsic hepatic clearance of 111In-Fuc25-, 111In-Fuc31- and 111 In-Fuc41-BSAs was close to, or much greater than, the hepatic plasma flow rate, indicating efficient hepatic uptake of these derivatives. These results suggest that fucosylation is a potentially useful method making drug carriers selective for Kupffer cells, although extensive modification might result in retarded delivery due to binding to other lectins like MBP.