Hypoxia-sensitive copper(II) nanoparticles achieve broad-spectrum anticancer therapy through synergistic cuproptosis, ferroptosis, and apoptosis

The discovery of cuproptosis provides a new perspective for copper overload treatment of cancer. However, the existing copper ion carriers only show oversimplified copper consignment and limited anti-tumor effect, which limits their further clinical application. Herein, we first design and synthesize two copper (II) complexes Py-Cu and TPE-Cu for synergistic cuproptosis, ferroptosis, and apoptosis anticancer therapy. In vitro , Py-Cu and TPE-Cu could induce dihydrolipoamide S -acetyltransferase (DLAT) aggregation, leading to cellular cuproptosis in PC-3 and CT-26 cells. Meanwhile, Py-Cu and TPE-Cu can amplify cellular oxidative stress by simultaneously boosting reactive oxygen species (ROS) production and depleting reduced glutathione (GSH), causing down-regulation of glutathione peroxides 4 (GPX4) expression and inducing ferroptosis. Moreover, Py-Cu and TPE-Cu could induce efficient apoptosis in vitro . To specifically release drugs at the tumor site, Py-Cu and TPE-Cu were co -assembled with hypoxia-responsive polymer PAL into nanoparticles, named NanoPy-Cu and NanoTPE-Cu, respectively. In vivo , NanoPy-Cu and NanoTPE-Cu showed superior tumor suppression effect both in the CT-26 tumor-bearing BALB/c mice model and ovarian (OV) cancer PDX-bearing BALB/c nude mice model. Here, we first reported two copper (II) complexes with unexpected broad anti-tumor activity, which synergized with cuproptosis, ferroptosis, and apoptosis to kill tumor cells.