Finetuning the Coordination Chemistry of Nontoxic Titanium(IV) for Cancer Therapy and Diagnosis

Abstract Developing effective strategies to address current cancer treatment and diagnosis challenges is imperative. Research has led to many medical breakthroughs, namely in the use of small molecules for chemotherapy as a major component of the standard of patient care. Following the serendipitous finding of cisplatin as an anticancer agent in the 1960s, titanium(IV) emerged as a metal of medicinal interest given its general nontoxicity. Many researchers have championed the potential clinical use of Ti(IV) compounds as anticancer agents given how manipulation of its coordination chemistry with the judicious selection of ligands leads to impressive cytotoxic properties with different mechanisms of action. By studying the biological speciation of the Ti(IV) compounds and their mechanism of action within cells and in vivo, much insight has been gained about the limitations posed to their therapeutic potential and about how the ligands can be finetuned to play a more active role to increase potency and specificity for cancer cells. In this review, we will take a historical tour of the evolution of titanium(IV) in its application in cancer research, dissecting the chemical properties of the metal ion that confer it with great potential for utility in different areas of cancer treatment and diagnosis. We explore the rich coordination chemistry of Ti(IV) that has led to different library of anticancer compounds and also survey efforts to use visible to activate TiO 2 nanoparticles as photosensitizers. In the latter part of the manuscript, we revisit the coordination chemistry of Ti(IV) as it illuminates ligand types that may facilitate the use of 45 Ti for PET imaging and possibly even theranostics. This work elucidates optimal approaches to bringing Ti(IV) to the anticancer market.