title: 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 (111)In-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 (111)In-Fuc-BSAs were mainly delivered to the liver and their hepatic uptake became saturated when the dose was increased. Of these derivatives, only (111)In-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 (111)In-Fuc41-BSA, followed by endothelial cells and hepatocytes. The hepatic uptake of (111)In-Fuc41-BSA was inhibited by co-injection of Gal42-BSA, but not by Man46-BSA. On the other hand, excess Fuc41-BSA inhibited the hepatic uptake of (111)In-Man46-BSA, while (111)In-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 (111)In-Fuc-BSA decreased with an increasing number of fucose units, and the intrinsic hepatic clearance of (111)In-Fuc25-, (111)In-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.
authors.affiliation: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.
authors.forename: P
authors.initials: P
authors.lastname: Opanasopit
authors.forename: M
authors.initials: M
authors.lastname: Nishikawa
authors.forename: F
authors.initials: F
authors.lastname: Yamashita
authors.forename: Y
authors.initials: Y
authors.lastname: Takakura
authors.forename: M
authors.initials: M
authors.lastname: Hashida
mesh_terms: D000818:Animals; D004337:Drug Carriers / Q000138:chemical synthesis / Q000493:pharmacokinetics; D005643:Fucose / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D007728:Kupffer Cells / Q000378:metabolism*; D037102:Lectins / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D051381:Rats; D012710:Serum Albumin, Bovine / Q000138:chemical synthesis / Q000493:pharmacokinetics*
chemical_list: D004337:Drug Carriers; D037102:Lectins; C053610:fucose-bovine serum albumin conjugate; D012710:Serum Albumin, Bovine; D005643:Fucose