Comparison of two kinds of docetaxel-vitamin E prodrugs: In vitro evaluation and in vivo antitumor activity.

To achieve optimal therapeutic index of docetaxel, we conjugated docetaxel (DTX) with vitamin E (VE) by ester bond with disulfide bond or thioether bond as spacer to produce DTX-ss-VE or DTX-s-VE. The two prodrugs were successfully loaded into liposomes. The physicochemical characterization and in vitro release profiles of the prodrug loaded liposomes were investigated. MTT assays showed that the cytotoxicity of DTX-ss-VE loaded liposomes on PC3 (IC50=27.5nM) and A549 cells (IC50=63.4nM) was comparable with the cytotoxicity of DTX-s-VE loaded liposomes (IC50=99.2 and 159.5nM, respectively). The pharmacokinetic studies demonstrated that DTX-ss-VE and DTX-s-VE loaded liposomes exhibited an extended DTX half-life (3.6±1.2 and 10.0±3.0h, respectively) as compared to DTX solutions (2.1±1.5h) and an increased AUC (30487.3±3791.6 and 20922.1±5633.3ng/L×h, respectively) compared with DTX solutions (1779.3±226.6ng/L×h). Finally, the in vivo anti-tumor studies showed that DTX-ss-VE loaded liposomes possessed similar antitumor activity compared with DTX solutions. Unexpectedly, not any tumor inhibition effect was observed in DTX-s-VE loaded liposomes group. In a conclusion, our studies suggested that simplex favorable properties of the anticancer prodrug can not ensure available good therapeutic index and the rational design of prodrug needs a comprehensive understanding of the in vitro and in vivo behavior of the prodrug.