Simultaneous Activation of Cuproptosis/Ferroptosis/Apoptosis Cell Death by Copper (II) Terpyridine Complexes for Cancer Therapy
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 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.