Lactosaminated and intact N-succinyl-chitosans as drug carriers in liver metastasis

The biodistributions of fluorescently labeled N-succinyl-chitosan (Suc-FTC) and lactosaminated N-succinyl-chitosan (Lac-Suc-FTC) after i.v. administration to mice intravenously inoculated with M5076 cells were investigated at 3 and 12 days post-inoculation. At both time points, Lac-Suc-FTC was specifically localized to the liver. However, the area under the concentration-time curve in the liver decreased gradually by progress of the liver metastasis. At 3 days post-inoculation, Suc-FTC showed good retention in the systemic circulation and was little distributed to the liver. However, at 12 days post-inoculation, Suc-FTC was eliminated relatively fast from the systemic circulation and gradually accumulated in the liver. The antitumor effects of mitomycin C (MMC), Lac-Suc-MMC conjugate (Lac-Suc-MMC) and highly succinylated Suc (Suc(II))-MMC conjugate (Suc(II)-MMC) were examined on single i.v. administration for both metastatic stages. For administration at 3 days post-inoculation, Lac-Suc-MMC alone tended to elongate significantly the lifespan at a lower dose (0.4 mg eq. MMC/kg), and MMC, Suc(II)-MMC and Lac-Suc-MMC increased significantly the lifespan at a higher dose (10 mg eq. MMC/kg). However, at 12 days post-inoculation (late stage of metastasis), neither MMC nor the conjugates were effective even at the higher dose (10 mg eq. MMC/kg). Both carriers, Suc showing systemic long-circulation and Lac-Suc with an ability of liver-specific localization, are thought to be drug carriers with potentialities for therapeutics at early stage of metastasis.