n-succinyl-chitosan and Neoplasm-Metastasis

In this study,lactosaminated N-succinyl-chitosan (Lac-Suc) was investigated for its liver targeting ability in the early metastatic stage of liver cancer, and subsequently Lac-Suc-mitomycin C conjugate (Lac-Suc-MMC) and highly-succinylated N-succinyl-chitosan (Suc(II))-MMC conjugate (Suc(II)-MMC) were examined for efficacy against the liver metastasis. Mice into which M5076 cells were inoculated intravenously were used as liver metastatic models. Fluorescently labelled Lac-Suc (Lac-Suc-FTC) was intravenously administered at a daily dose of 0.2 mg/mouse for 4 days or at a single dose of 0.8 mg/mouse at 3 days post-inoculation. At a dose of 0.2 mg/mouse for 4 days, liver accumulation of Lac-Suc-FTC was increased after all except the fourth injection, indicating that the capacity of accumulation might be limited to around 110 microg per mouse with repeated daily administration at 0.2 mg/mouse. As to the efficacy of intravenous administration at 7 days post-inoculation, Lac-Suc-MMC was less effective at a dose of 1 mg kg(-1) for 4 days than a single dose of 4 mg kg(-1). This result was not in accordance with that expected from the biodistribution study. On the other hand, with intravenous administration at 3 days post-inoculation, Suc(II)-MMC was more effective on repeated administration, and it showed higher efficacy than Lac-Suc-MMC at both 1 mg kg(-1) for 4 days and 4 mg kg(-1) as a single dose. Further, with intravenous administration at 3 days post-inoculation, Suc(II)-MMC exhibited a much higher survival effect at a dose of 4 mg kg(-1) for 4 days.

Topics: Amino Sugars; Animals; Area Under Curve; Chitin; Chitosan; Drug Administration Schedule; Fluorescein-5-isothiocyanate; Humans; Injections, Intravenous; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Mitomycin; Neoplasm Metastasis; Tissue Distribution; Treatment Outcome; Tumor Cells, Cultured

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.

Topics: Animals; Area Under Curve; Chitin; Chitosan; Drug Carriers; Injections, Intravenous; Lactose; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Mitomycin; Neoplasm Metastasis; Tissue Distribution