PH-sensitive micelles for the intracellular co-delivery of curcumin and Pluronic L61 unimers for synergistic reversal effect of multidrug resistance

Zehui Zhang,Lingying Dong,Chunpeng Zhao,Fucheng Xie,Wenting Yang,Wei Hong,Mingxi Qiao,Hong Shi,Li Kang

doi:10.1038/srep42465

Abstract

Pluronic L61 unimers, which are biomacromolecular modulators, and curcumin, a small-molecule modulator, were co-formulated into pH-sensitive micelles to reveal the full synergistic potential of combination drug treatments to reverse multidrug resistance (MDR). Compared to monotherapy, combined therapy significantly improved the cytotoxicity, cellular uptake and apoptotic effects of doxorubicin (DOX) against MCF-7/ADR cells. In mechanistic studies, both L61 and curcumin enhanced the cytotoxic effect by acting on mitochondrial signalling pathways. The compounds selectively accumulated in the mitochondria and disabled the mitochondria by dissipating the mitochondrial membrane potential, decreasing the ATP levels, and releasing cytochrome c, which initiated a cascade of caspase-9 and caspase-3 reactions. Furthermore, both curcumin and L61 down-regulated the expression and function of P-gp in response to drug efflux from the MCF-7/ADR cells. In the MCF-7/ADR tumour-bearing mouse model, intravenous administration of the combined therapy directly targeted the tumour, as revealed by the accumulation of DiR in the tumour site, which led to a significant inhibition of tumour growth without measurable side effects. In conclusion, co-formulation consisting of L61 and curcumin in pH-sensitive micelles induced significant synergistic effects on the reversal of MDR. Therefore, the intracellular co-delivery of various MDR modulators has great potential to reverse MDR in tumours.

Highlights

Multidrug resistance (MDR) has become a major obstacle to the successful treatment of cancer
For the intracellular co-delivery of Pluronic L61 unimers and curcumin in multidrug resistance (MDR) cells, endosomal pH-sensitive micelles conjugated with folate (F-pHSM) were constructed using a copolymer composed of PHis-PLA-polyethylene glycol (PEG)-PLA-PHis and Pluronic F127
The optimal curcumin loading content in the tested micelles was set to 1 × 10−2 wt% using the MTT method, and the details are provided in the Supplementary Information

Summary

Introduction

Multidrug resistance (MDR) has become a major obstacle to the successful treatment of cancer. Curcumin can induce the translocation of mitochondrial permeability transition pores (PTPs), resulting in the release of cytochrome c from the mitochondria into the cytoplasm, the dissipation of the mitochondrial membrane potential (∆Ψ), the impairment of respiration, the inhibition of ATP synthesis and the activation of the apoptotic protein enzyme caspase-9, which triggers the activation of the downstream caspase-3 protein. Pluronics have been identified as the most promising MDR reversal agents due to their effects on reversing several distinct drug resistance mechanisms, including blocking drug efflux transporters[23,24,25], changing the microviscosity of cell membranes[26], reducing the ATP levels in MDR cells[27], inhibiting the glutathione (GSH)/glutathione (GST) detoxification system[28], inducing the release of cytochrome c and increasing the reactive oxygen species (ROS) levels in the cytoplasm[29]. Considering the complexity of MDR, the combination of two MDR modulators could hold great promise for synergistically reversing MDR40–42

Methods

Results

Conclusion