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 (IC 50   =   27.5   nM) and A549 cells (IC 50   =   63.4   nM) was comparable with the cytotoxicity of DTX-s-VE loaded liposomes (IC 50   =   99.2 and 159.5   nM, 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   ±   3.0   h, respectively) as compared to DTX solutions (2.1   ±   1.5   h) and an increased AUC (30487.3   ±   3791.6 and 20922.1   ±   5633.3   ng/L   ×   h, respectively) compared with DTX solutions (1779.3   ±   226.6   ng/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.