Synthesis, characterization and antitumor evaluation of CMCS-DTX conjugates as novel delivery platform for docetaxel.

The purpose of this study is to synthesis and evaluate the antitumor efficacy of a novel carboxymethyl chitosan-docetaxel (CMCS-DTX) conjugates and the availability of CMCS as the polymer material in polymer-drug conjugates development. Docetaxel (DTX) was attached to carboxymethyl chitosan (CMCS) via biodegradable linker for the first time and the weight percentage of DTX in the CMCS-DTX conjugates was up to 20%. The resulting CMCS-DTX conjugates could spontaneously self-assemble into nanoparticles in aqueous buffer, with uniform size of 127.2±3.58 nm and zeta potential of -25.65 mV. The stability test result showed that only 12.46% of DTX was released after incubation in plasma for 48 h, indicating good stability of CMCS-DTX conjugates in plasma. The results of in vitro cytotoxicity and Hoechst staining indicated that CMCS-DTX conjugates exhibited significant cytotoxicity against B16 and HepG2 cells. CMCS-DTX conjugates also displayed better antitumor effect than Duopafei® by inhibiting tumor growth and prolonging the survival time of B16 melanoma bearing mice more effectively (the median survival time was >30 days for CMCS-DTX conjugates versus 24 days for the Duopafei®). Besides, CMCS-DTX conjugates demonstrated an excellent safety profile with a maximum tolerated dose (MTD) of >250 mg/kg in mice, which was more than 4 fold higher than that of Duopafei® (50 mg/kg). CMCS-DTX conjugates could be exploited as a promising platform for the effective delivery of DTX and CMCS was a favorable choice as the polymer material in polymer-drug conjugates development.