Preparation and evaluation of poly(L-histidine) based pH-sensitive micelles for intracellular delivery of doxorubicin against MCF-7/ADR cells

In this study, a pH-sensitive micelle self-assembled from poly((L)-histidine) based triblock co-polymers of poly( ethylene glycol)-poly((D,L)-lactide)-poly((L)-histidine) (mPEG-PLA-PHis) was prepared and used as the intracellular doxorubicin (Dox) delivery for cancer chemotherapy. Dox was loaded into the micelles by thin-film hydration method and a Box-Behnken design for three factors at three levels was used to optimize the preparations. The optimized mPEG-PLA-Phis/Dox micelles exhibited good encapsulation efficiency of 91.12%, a mean diameter of 45 nm and narrow size distribution with polydispersity index of 0.256. In vitro drug release studies demonstrated that Dox was released from the micelles in a pH-dependent manner. Furthermore, the cellular evaluation of Dox loaded micelles displayed that the micelles possessed high antitumor activity in vitro with an IC50 of 35.30 mu g/ml against MCF-7/ADR cells. The confocal microscopy and flow cytometry experiments indicated that mPEG-PLA-Phis micelles mediated efficient cytoplasmic delivery of Dox with the aid of poly(L-histidine) mediated endosomal escape. In addition, blank mPEG-PLA-Phis micelles were shown to be nontoxic to MCF-7/ADR cells even at a high concentration of 200 mu g/ml. The pH-sensitive mPEG-PLA-PHis micelles have been demonstrated to be a promising nanosystem for the intracellular delivery of Dox for MDR reversal. (C) 2017 Shenyang Pharmaceutical University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license