Pluronic micelles with suppressing doxorubicin efflux and detoxification for efficiently reversing breast cancer resistance

Abstract

The antitumor activity of doxorubicin (DOX) is often limited owing to the occurrence of multidrug resistance (MDR) during treatment. Herein, we developed hybrid polymeric micelles, which consisted of pluronic F127 as long-circulating helper in blood, and phenylboronic ester-grafted pluronic P123 (PHE) as efflux and detoxification regulator to efficiently deliver DOX and reverse MDR in vivo. Hybrid F127/PHE micelles exhibited higher stability and drug encapsulation (~80%) than simple F127/P123 micelles due to its lower CMC, and displayed in vitro drug release in a hydrogen peroxide (H2O2)-sensitive manner. Besides, DOX-loaded hybrid micelles (F127/PHE-DOX) possessed higher cell-killing ability and induce more apoptotic in MDR-cells than other groups, which was probably because it not only could greatly increase intracellular drug concentration by inhibiting P-gp mediated drug efflux, but also promote reactive oxygen species (ROS) generation by decreasing glutathione (GSH) levels. Besides, in vivo evaluation indicated that F127/PHE-DOX could well accumulate at tumor regions and exhibit the strongest tumor growth inhibition (TGI 87.87%) accompanied with low side effects. As a result, F127/PHE micelles had great potentials as a platform for anticancer drugs delivery and tumor MDR reversal in clinical application.