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.
Kato
Y
Y
Department of Drug Delivery Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. d711@hoshi.ac.jp
Onishi
H
H
Machida
Y
Y
D000818:Animals; D019540:Area Under Curve; D002686:Chitin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D048271:Chitosan; D004337:Drug Carriers; D007275:Injections, Intravenous; D007785:Lactose / Q000493:pharmacokinetics*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016685:Mitomycin / Q000008:administration & dosage* / Q000627:therapeutic use; D009362:Neoplasm Metastasis; D014018:Tissue Distribution
D004337:Drug Carriers; C118639:N-succinyl-chitosan; D002686:Chitin; D016685:Mitomycin; D048271:Chitosan; D007785:Lactose