Traditional anti-cancer chemotherapy often has toxic and side effects [[1], [2], [3]]. Therefore, the development of novel anticancer strategies with high efficiency and low toxicity has attracted increasing attention. Chemodynamic therapy (CDT) is a promising anticancer strategy. CDT converts hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals (·OH, a type of ROS) through Fenton or Fenton-like reactions [[4], [5], [6], [7], [8]], thereby inducing apoptosis of tumor cells. It is important that H2O2 is mainly enriched in the tumor microenvironment rather than normal tissues, avoiding the production of ·OH in normal tissue cells and reducing the damage to normal cells [[9], [10], [11]]. Glutathione (GSH) level is also high in the tumor microenvironment. Because GSH has a significant scavenging effect on ROS, it is necessary to reduce GSH and enhance the efficacy of CDT. Cu(II) complexes with redox activity can convert intracellular GSH into Cu(I) species and oxidized glutathione (GSSG), which catalyze H2O2 to produce ·OH [[12], [13], [14], [15]]. In addition, copper is a cofactor of many enzymes [16,17]. Therefore, the copper complexes are considered as potential anticancer agents.

Mitochondria are rich in H2O2 [18], therefore CDT molecules targeting mitochondria may enhance the efficiency of Fenton or Fenton-like reaction in cancer cells, thereby improving the therapeutic effect of CDT. In addition, lipophilic compounds with positive charges can selectively penetrate inner mitochondrial membrane and accumulate in mitochondria [19], exhibiting mitochondrial targeting properties [[20], [21], [22], [23]]. Recently, Chen's group reported a group of mitochondria-targeted platinum complexes, which are mainly distributed in the mitochondria of cancer cells, thereby enhancing the anti-tumor efficacy [24]. In addition, Ru-complexes and Iridium(III) complexes have been reported as mitochondria-targeting antitumor agents [25,26]. At the same time, ROS is also mainly enriched in mitochondria, excessive ROS can induce mitochondrial dysfunction, which causes apoptosis [[27], [28], [29]]. Therefore, the accumulation of copper complexes in mitochondria may lead to the continuous generation of ROS and apoptosis. Based on these findings, the design of copper complex with mitochondria targeting properties is expected to improve CDT effect.

Plumbagin (PLB, 5-hydroxy-2-methyl-1,4-naphthoquinone) is a natural ligand with antitumor activity [30]. In recent years, five lanthanide(III)-PLB complexes and two copper(II) complexes of PLB have been reported, which showed strong inhibitory effects on tumor cells [[31], [32], [33]]. Li et al. reported four Ru(II) polypyridyl PLB complexes (Ru1–Ru4) that induced apoptosis by inducing GADD45A-mediated cell cycle arrest and inhibiting energy metabolism [34]. However, PLB metal complexes with enhanced CDT effect have not been reported. It is worth noting that introduction of nitrogen-containing ligand (such as bipyridine) as auxiliary ligand in metal complexes is an effective strategy to improve activity [[35], [36], [37]].

He et al. reported nanomaterials that combine mitochondria targeting to enhance CDT [18,29,38]. However, no mitochondria targeting metal complexes for CDT have been reported. Development of mitochondria targeting metal complexes is a new strategy for enhancing CDT. We selected copper as the metal, PLB as the first ligand, and bipyridine as the second ligand to synthesize a series of copper complexes for targeting mitochondria to improve CDT. The in vitro and in vivo anticancer activities of these Cu(II) PLB complexes were investigated.