Copper(II) complexes with plumbagin and bipyridines target mitochondria for enhanced chemodynamic cancer therapy

The combination of mitochondrial targeting and chemodynamic therapy is a promising anti-cancer strategy. Three mitochondria targeting copper(II) complexes (Cu1-Cu3) with plumbagin and bipyridine ligands for enhanced chemodynamic therapy were synthesized and characterized. Their anti-proliferative activity to HeLa cells was higher than that of cisplatin, and their toxicity to normal cells was low. Cellular uptake and distribution studies indicated that Cu1 and Cu3 were mainly accumulated in mitochondria. The mechanism studies showed that Cu1 and Cu3 converted intracellular H₂O₂ into toxic hydroxyl radicals by consuming glutathione, leading to mitochondrial dysfunction. Treatment with the copper complex caused ER stress and cell arrest in the S phase which resulted in apoptosis. In vivo, Cu1 and Cu3 effectively inhibited the growth of HeLa xenograft tumors without obvious toxic and side effects.