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.