Efficacy of lactosaminated and intact N-succinylchitosan-mitomycin C conjugates against M5076 liver metastatic cancer.
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.
Kato
Yoshinori
Y
Department of Drug Delivery Research, Hoshi University, Tokyo, Japan. yk-no.1@jcom.home.ne.jp
Onishi
Hiraku
H
Machida
Yoshiharu
Y
D000606:Amino Sugars / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000818:Animals; D019540:Area Under Curve; D002686:Chitin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D048271:Chitosan; D004334:Drug Administration Schedule; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016685:Mitomycin / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D014018:Tissue Distribution; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D000606:Amino Sugars; C118639:N-succinyl-chitosan; C032233:lactosamine; D002686:Chitin; D016685:Mitomycin; D048271:Chitosan; D016650:Fluorescein-5-isothiocyanate