Elesclomol-Copper Nanoparticles Overcome Multidrug Resistance in Cancer Cells

Abstract

Elesclomol (ES), a copper-binding ionophore, forms an ES−Cu complex with copper ions (Cu(II)). ES−Cu has been proven to induce mitochondrial oxidative stress and copper-dependent cell death (cuprotosis). However, ES−Cu is poorly water-soluble, and its delivery to various cancer cells is a challenge. Herein, we designed a D-α-tocopherol polyethylene glycol 1000 succinate/chondroitin sulfate-cholic acid (TPGS/CS−CA)-based micellar nanoparticle for delivering the ES−Cu complex to various cancer cell lines to demonstrate its efficacy as an anticancer agent. The ES−Cu nanoparticles exerted high encapsulation efficiency and excellent serum stability. The anticancer efficacy of ES−Cu nanoparticles was evaluated in various drug-sensitive cell lines (DU145, PC3, and A549) and drug-resistant cell lines (DU145TXR, PC3TXR, and A549TXR). The results showed that ES−Cu nanoparticles exerted potent anticancer activities in both drug-sensitive and drugresistant cell lines. The Western blotting, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and molecular docking results suggested that ES−Cu is not a substrate for P glycoprotein (P-gp), which is an efflux transporter potentially causing multidrug resistance (MDR) in cancer cells. ES−Cu nanoparticles could bypass P-gp without compromising their activity, indicating that they may overcome MDR in cancer cells and provide a novel therapeutic strategy. Additionally, the extracellular matrix of ES−Cu nanoparticles-pretreated drug-resistant cells could polarize Raw 264.7 macrophages into the M1 phenotype. Therefore, our TPGS/CS−CA-based ES−Cu nanoparticles provide an effective method of delivering the ES−Cu complex, a promising strategy to overcome MDR in cancer therapy with potential immune response stimulation.