Elesclomol-Copper Nanoparticles Overcome Multidrug Resistance in Cancer Cells

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 drug-resistant 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.