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

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 approximately 15-fold and AUC((0-infinity)) 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 (NCI-H358) 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.