Chemotherapy is one of the leading forms of therapy to treat cancer. During this procedure, the patient is administered a cytotoxic agent that (preferably) accumulates in the tumorous tissue and is able to eradicate cancer cells. To date, platinum complexes are among the most frequently applied chemotherapeutic agents in the world. Despite their enormous clinical success, the application of these compounds is limited due to severe side effects (e.g., kidney damage, nausea, vomiting, and bone marrow suppression), low cancer cell selectivity, and, more worryingly, an increasing number of platinum-resistant tumors. Capitalizing on this, researchers are working on the development of new compounds with new mechanisms of action.

In our research group, research efforts are devoted to the design, synthesis, and biological evaluation of Cu(II) complexes as anticancer agents. Cu(II) complexes generally have redox properties within the biological window, allowing for redox cycling in cancer cells, and therefore the catalytic generation of cytotoxic species. Importantly, several Cu(II) Casiopeinas complexes are currently studied in clinical trials in Mexico as chemotherapeutic agents. Despite their promising therapeutic effects, recent studies have indicated the poor stability of Cu(II) Casiopeinas complexes under physiological conditions, resulting in the speciation of the compound and ultimately causing severe side effects. To overcome this limitation, in our group, Cu(II) complexes with multidentate, strongly binding ligands are designed and evaluated (exemplary compound: Figure 1).

Figure 1. Structure of redox-active Cu(II) complex as a chemotherapeutic agent.

The biological evaluation of this metal complex revealed that the compound primarily accmulated in the cytoplasm of cancerous cells where it was able to catalytically generate reactive oxygen species. Based on the high reactivity of these species, various biomolecules could be readily oxidized, ultimately causing cell death. In-depth studies revealed that this compound was able to trigger cell death by autophagy-dependent apoptosis, a rarely described form of cell death. Capitalizing on this distinctive mechanism from traditional chemotherapeutic agents, the compound was found to be therapeutically highly active towards multidrug-resitant cancer cells.

Figure 2. Morphological changes of multidrug-resistant colon cancer cells upon treatment with the Cu(II) complex. During the treatment, the formation of vacuoles (membrane-bound inclusions) is observed.

Despite the strong anticancer effect, the Cu(II) complex was found not to differentiate between cancerous and healthy cells, causing a cytotoxic effect towards any kind of human cells. To overcome this limitation and generate a tumor-selective treatment, the metal complex was encapsulated with the naturally occurring metal storage protein Apoferritin. Due to the high demand for nutrition during tumor growth as well as the overexpression of ferritin receptors on the surface of tumor cells, apoferritin could be utilized as a cancer tumor-targeting drug delivery system. The nanoparticles were found with a highly cytotoxic effect against a variety of colon cancer cells. The generated nanoparticles were found with good biocompatibility and high stability under physiological conditions (Figure 3).

Figure 3. Transmission electron microscopy images of the Cu(II) complex encapsulated with Apoferritin.

Future studies will focus on the development of Cu(II) complexes as anticancer drug candidates with improved pharmacological properties and high tumor selectivity for a tumor-selective chemotherapeutic treatment.

Key References