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Titolo:
Pharmacokinetic analysis of lectin-dependent biodistribution of fucosylated bovine serum albumin: A possible carrier for Kupffer cells
Autore:
Opanasopit, P; Nishikawa, M; Yamashita, F; Takakura, Y; Hashida, N;
Indirizzi:
Kyoto Univ, Grad Sch Pharmaceut Sci, Dept Drug Delivery Res, Sakyo Ku, Kyoto 6068501, Japan Kyoto Univ Kyoto Japan 6068501 ivery Res, Sakyo Ku, Kyoto 6068501, Japan
Titolo Testata:
JOURNAL OF DRUG TARGETING
fascicolo: 5, volume: 9, anno: 2001,
pagine: 341 - 351
SICI:
1061-186X(2001)9:5<341:PAOLBO>2.0.ZU;2-N
Fonte:
ISI
Lingua:
ENG
Soggetto:
FUCOSE-CONTAINING GLYCOPROTEINS; MACROPHAGE MANNOSE RECEPTOR; MEDIATED GENE-TRANSFER; HIGH-AFFINITY BINDING; RAT-LIVER; HEPATIC LECTINS; DRUG-DELIVERY; IN-VIVO; EXPRESSION; PROTEINS;
Keywords:
biodistribution; cell-specific drug targeting; fucose; lectins; pharmacokinetics;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
45
Recensione:
Indirizzi per estratti:
Indirizzo: Hashida, N Kyoto Univ, Grad Sch Pharmaceut Sci, Dept Drug Delivery Res, Sakyo Ku, Kyoto 6068501, Japan Kyoto Univ Kyoto Japan 6068501 Sakyo Ku, Kyoto 6068501, Japan
Citazione:
P. Opanasopit et al., "Pharmacokinetic analysis of lectin-dependent biodistribution of fucosylated bovine serum albumin: A possible carrier for Kupffer cells", J DRUG TAR, 9(5), 2001, pp. 341-351

Abstract

To examine the potential utility of fucosylation of drug carriers for targeted drug delivery to Kupffer cells, the pharmacokinetics of In-111-labeledfucosylated 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 In-111-Fuc-BSAs were mainly delivered to the liver and their hepatic uptake became saturated when the dose was increased. Of these derivatives, only In-111-Fuc(41)-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 In-111-Fuc(41)-BSA, followed by endothelial cells and hepatocytes. The hepatic uptake of (111)InFuc(41)-BSA was inhibited by co-injection of Gal(42)-BSA, but not by Man(46)-BSA. On the other hand, excess Fuc(41)-BSA inhibited the hepatic uptake of In-111-Man(46)-BSA, while In-111-Gal(42)-BSA did not:These findings suggest that not only the fucose receptors on Kupffer cellsbut also other lectins are involved in the biodistribution of Fuc-BSAs. Tounderstand 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 In-111-Fuc-BSA decreased with an increasing number offucose units, and the intrinsic hepatic clearance of In-111-Fuc(25)-, In-111-Fuc(31)- and In-111-Fuc(41)-BSAs was close to, or much greater than, thehepatic 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 Re MBP.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 20/01/20 alle ore 21:59:46