Affecting intracellular iron and copper via transmetalation and study of drug delivery systems to improve the specificity of Ti(IV)-based anticancer compounds

Abstract

Cancer is the principal cause of death globally, and research and how it works have become crucial. Iron (Fe) and Copper (Cu) are essential metals present in many critical biological processes in the human body. These metals play a part in angiogenesis, metastasis, rapid growth, and cancer survival. Disrupting them can disrupt intracellular processes that could lead to cell death. In this research work, we aim to study how Titanium(IV) Deferasirox [Ti(Deferasirox)2]2-can affect both Fe and Cu and induce cell death by disrupting metals bioavailability, forming intracellular cytotoxic species, and generation an imbalance in reactive oxygen species (ROS) production. Studies in the concentration-dependent intracellular species of Cu-induced transmetalation showed that the possible intracellular products could generate cytotoxic species under physiological conditions. At the same time, Fe-induced transmetalation formed a redox active intermediate that produces a significant increase in ROS formation. The metals become unavaible for the cancer cell to perform the necessary biological processes to survive in both approaches. Nonetheless, specificity is still a field that has become important in chemotherapeutics treatments. Since patients suffer many side effects, the idea is to deliver the drug effectively to the desired target. Drug delivery systems (DDS) are being developed to reach this objective. Herein we explored three DDS types to compare their specificity against cancer cells. Interestingly, the protein-based bovine serum albumin (BSA) DDS does not show any improvement in the uptake and activity of the titanocene dichloride (Cp2TiCl2) drug. Cancer cells were treated with a high concentration of Cp2TiCl2-BSA, and no activity was observed. Results were supported by precipitation during the cell lysate experiment, where compounds interact with intracellular compounds, demonstrating that the conjugate will not survive after entering the cell. A formulate with zirconium phosphate (ZrP) was also prepared, Cp2TiCl2@ZrP, and more intracellular Ti(IV) accumulation was observed, but no improvement in specificity or activity was observed. For the [Ti(Deferasirox)2]2—Substance P (TDSP), more Ti(IV) accumulation was observed as in the formulate but again, no specificity improvement. Some researchers demonstrate that even when SP has been used as a drug carrier, this peptide can also increase viable cancer cells, playing against the compound anticancer activity. Finally, the peptide-directed DDS by the HAIPYRHK (P7) peptide seems more efficient in delivering the Ti(IV) ion and releasing it intracellularly as a still stable compound. Previous studies confirm the stability and activity of TD against cancer cells, but no selectivity was observed. The bioactive peptide TDP7 increases the intracellular Ti(IV) and improves the specificity against cancer cells. Anticancer bioinorganic research is a pretty new research field compared to the past most used chemo-agents that are mainly organic molecules. In inorganic research, these organic molecules are coordinated to a metal that often changes the drugs' biological performance. Metals can affect different biological targets depending on their properties, mainly dictated by the hard and soft acid-base (HSAB) theory. Ti(IV) drugs have been evolving, and today, there are more stable and effective compounds that can display their biological properties against cancer cells. In the past few years, inorganic research has been mainly empirical since we lack the "rules" that dictate a structure-activity relationship. Inorganic compounds often have different geometries, oxidation states, and binding properties. Changing the ligand or the metal is impactful in the compound behavior. Still, after cisplatin, many inorganic molecules had reached clinical trials and became part of the treatment for cancer patients. Now, a new horizon is explored with bimetallic complexes, with two different metals performing their activity. Ti(IV) Deferasirox has been shown to work well with other anticancer drugs such as cisplatin. Both drugs with different mechanistic pathways will generate a synergistic effect to obtain a new generation of Ti(IV)-containing drugs.