In vivo antitumor effects of chitosan-conjugated docetaxel after oral administration

摘要

The purpose of this study is to evaluate in vivo antitumor efficacy and subacute toxicity of docetaxel (DTX)prodrug comprising a conjugate between DTX and low molecular weight chitosan (LMWC) after oral administration. DTX was covalently attached to LMWC via a cleavable linker so as to be released from LMWC-DTX conjugate in body. In vitro cytotoxicity of LMWC-DTX conjugate was evaluated by MTT assay against two human cancer cell lines, showing similar IC_(50) values to the parent DTX. The pharmacokinetic data of the conjugate after oral administration revealed that half-life in blood circulation was increased by ~15-fold and AUC(0–∞) was 3.8–6.2 times higher in comparison with the intravenously injected DTX (i.v.).In vivo antitumor efficacy was evaluated in nude mice bearing human non-small cell lung carcinoma (NCIH358)and glioblastoma (U87MG), respectively. The orally administered LMWC-DTX conjugate (10 mg DTX equivalent/kg) showed comparable antitumor efficacy to the same dose of DTX (i.v.) for both NCI-H358 and U87MG models, but revealed much lower subacute toxicity as seen in body weight loss and hematological toxicity.