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Even though the reversal of multi-drug resistance (MDR) by numerous nanoparticles has been extensively studied, limited success has been achieved. To overcome this barrier, we report a rationally-designed pH-sensitive micelle, in which doxorubicin (Dox) and resveratrol (Res) were co-loaded. The micelle was based on methoxy poly (ethylene glycol)-poly(d,l-lactide)-poly(l-histidine) (mPEG-PLA-PHis), which integrated passive targeting, endo-lysosomal escape and pH-responsive payloads release. At a physiological pH of 7.4 (slightly alkali), Dox and Res were incorporated into the micelles core using the thin-film hydration method (pH-endoSM/Dox/Res). After cellular uptake, the micelles exhibited an enhanced dissociation in response to the acidic endosomes, triggering the release of Res and Dox. Furthermore, Res was observed to synergistically improve the cytotoxicity of Dox by down-regulating the P-glycoprotein (P-gp) expression, decreasing the membrane potential of the mitochondrial and ATP level, as well as inducing cell apoptosis mediated by mitochondria. The pH-endoSM/Dox/Res showed a prominent ability to decrease the IC 50 of Dox by a factor of 17.38 in cell cytotoxicity against the MCF-7/ADR cell line. In vivo distribution demonstrated the excellent tumor-targeting ability of the pH-endoSM/Dox/Res. All results indicated that pH-endoSM/Dox/Res held great potential for the treatment of Dox-resistance breast cancer cells.

Multi-Modulation of Doxorubicin Resistance in Breast Cancer Cells by Poly(l-histidine)-Based Multifunctional Micelles