Biological characteristics of lactosaminated N-succinyl-chitosan as a liver-specific drug carrier in mice.
Lactosaminated N-succinyl-chitosan (Lac-Suc) was prepared by reductive amination of N-succinyl-chitosan (Suc) and lactose using sodium cyanoborohydride. Six-day reaction using lactose (12.8-fold (w/w)) yielded Lac-Suc with lactosamination degree of 30% (mol/sugar unit). Fluorescein thiocarbamyl-Lac-Suc (Lac-Suc-FTC) was prepared by labeling Lac-Suc with fluorescein isothiocyanate. Lac-Suc-FTC was injected intravenously at a dose of either 1 (high dose) or 0.2 (low dose) mg/mouse. At both doses, Lac-Suc-FTC initially underwent fast hepatic clearance, showed maximum liver localization at 8 h, and the amounts localized there were maintained even at 48 h post-injection. Very slow excretion into feces and urine was observed. The ratio of liver AUC(0--48 h) to plasma AUC(0--48 h) at low dose was three times higher than that at high dose. On the other hand, the Suc derivative, Gal-Suc, obtained by reductive amination of Suc/galactose showed very little distribution to the liver similarly to Suc itself. Further, since the liver uptake of Lac-Suc-FTC was inhibited by asialofetuin, it was suggested that the liver distribution of Lac-Suc should be concerned with asialoglycoprotein receptor. Thus, Lac-Suc was found available as a carrier exhibiting a high affinity to and long retention in the liver.
Kato
Y
Y
Department of Drug Delivery Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, 142-8501, Tokyo, Japan
Onishi
H
H
Machida
Y
Y
D000606:Amino Sugars / Q000493:pharmacokinetics; D000818:Animals; D037263:Asialoglycoprotein Receptor; D001667:Binding, Competitive; D002686:Chitin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D048271:Chitosan; D004337:Drug Carriers; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011956:Receptors, Cell Surface / Q000378:metabolism; D014018:Tissue Distribution
D000606:Amino Sugars; D037263:Asialoglycoprotein Receptor; D004337:Drug Carriers; C118639:N-succinyl-chitosan; D011956:Receptors, Cell Surface; C032233:lactosamine; D002686:Chitin; D048271:Chitosan; D016650:Fluorescein-5-isothiocyanate