Building of CuO2@Cu-TA@DSF/DHA Nanoparticle Targets MAPK Pathway to Achieve Synergetic Chemotherapy and Chemodynamic for Pancreatic Cancer Cells

<b>Background/Objectives:</b> With the increase of reactive oxygen species (ROS) production, cancer cells can avoid cell death and damage by up-regulating antioxidant programs. Therefore, it will be more effective to induce cell death by using targeted strategies to further improve ROS levels and drugs that inhibit antioxidant programs. <b>Methods:</b> Considering that dihydroartemisinin (DHA) can cause oxidative damage to protein, DNA, or lipids by producing excessive ROS, while, disulfiram (DSF) can inhibit glutathione (GSH) levels and achieve the therapeutic effect by inhibiting antioxidant system and amplifying oxidative stress, they were co-loaded onto the copper peroxide nanoparticles (CuO₂) coated with copper tannic acid (Cu-TA), to build a drug delivery system of CuO₂@Cu-TA@DSF/DHA nanoparticles (CCTDD NPs). In response to the tumor microenvironment, DHA interacts with copper ion (Cu²⁺) to produce ROS, and a double (diethylthiocarbamate)-copper (II) (CuET) is generated by the complexation of DSF and Cu²⁺, which consumes GSH and inhibits antioxidant system. Meanwhile, utilizing the Fenton-like effect induced by the multi-copper mode can achieve ROS storm, activate the MAPK pathway, and achieve chemotherapy (CT) and chemodynamic (CDT). <b>Results:</b> Taking pancreatic cancer cell lines PANC-1 and BxPC-3 as the research objects, cell line experiments in vitro proved that CCTDD NPs exhibit efficient cytotoxicity on cancer cells. <b>Conclusions:</b> The CCTDD NPs show great potential in resisting pancreatic cancer cells and provides a simple strategy for designing powerful metal matrix composites.