Mixed micelles of TPGS and Soluplus^® for co-delivery of paclitaxel and fenretinide: <i>in vitro</i> and <i>in vivo</i> anticancer study

Abstract

Fenretinide (4-HPR), as a semi-synthetic retinoid, has apoptosis-promoting effects as a single agent and chemotherapy synergist <i>in vitro</i>. When a human ovarian cancer cells line (A2780s) was treated with both PTX and 4-HPR, there was a synergistic anti-cancer effect demonstrated with a average combination index of 0.44. In this research, a new TPGS-Soluplus^® mixed micelles were developed which encapsulation efficiencies of paclitaxel (PTX) and fenretinide (4-HPR) were as high as 98%, and the average diameter of the micelles was 66.26 nm. Cytotoxicity of the mixed micelles co-delivered with PTX and 4-HPR reduced significantly 7.3 and 25.1 times compared with free drug respectively in A2780s cells. More importantly, <i>in vivo</i> pharmacokinetic study, the loaded drugs in mixed micelles exhibited higher AUC and t_1/2 values than free drugs. Furthermore, <i>in vivo</i> antitumor efficacy experiments demonstrated that PF-TS exhibited superior <i>in vivo</i> antitumor activity on the inhibition rate of tumor growth than other treatment groups (77.8% corresponding tumor growth inhibition in PF-TS treated group vs 19.9, 12.5, and 26.0% of tumor growth inhibition rate in Taxol^®, 4-HPR, and Taxol^®+4-HPR, respectively). Therefore, the mixed micelles of co-deliver PTX and 4-HPR successfully constructed may hopefully be applied to the cancer combination treatment with less toxic effect and more antitumor activity.