Cancer diseases of more than 100 different kinds represent a major cause of human deaths worldwide, with more than 10 million new cases diagnosed each year. Since the historical mentions of cancer conditions back in 500 BC, significant progress was achieved in recent years with better understanding of malignancy and novel therapeutic methodologies, such as immunotherapy and precision (personalized) medicine. Nevertheless, such approaches are applicable only for specific cases and are very limited to particular cancer types and populations. The vast majority of cancer cases thus still relies on chemotherapy for attempted treatment, and will surely continue to do so for many years to come. As the main limitation of classical chemotherapy is the severe side effects accompanying drug efficacy, developing highly potent chemotherapy of reduced/negligible side effects, effective toward a wide range of cancer types, is of incredible merit.
Cisplatin as a pioneering metal-based anticancer drug represents a landmark in cancer chemotherapy. It is a highly effective drug used in the clinic toward certain types of cancers, including testicular, ovarian, lung, and more. Nevertheless, cisplatin, along with its Pt-based derivatives, suffer from two main limitations: development of resistance in some cancer types, and most severely – acute side effects in the treated patients, imposing irreversible critical damages to vital organs. These features damage the patient's quality of life during treatment and risk the patient’s health after treatment termination – thus limiting the tolerated dose and by that – the drug efficacy and chances for cure.
The titanium(IV) metal is known to be a biologically friendly metal. The compound titanium dioxide is widely used in food products, cosmetics, and drugs. It is completely safe, with no side effects or any dietary restrictions. The titanium metal of different forms is used in medicine for transplants and various devices.
In the quest toward alternative anti-cancer metallodrugs, titanium(IV) complexes were previously investigated, and demonstrated high antitumor efficacy with no reports on titanium resistance in treated cells/tumours to date. Importantly, in accordance with the biocompatibility of the titanium metal, markedly reduced toxicity was detected in mice treated with the titanium(IV) compounds, where the minor toxicity was mostly reversible. These features reflect the high advantage in the use of titanium(IV) in anticancer chemotherapy.
The past titanium(IV) complexes did not proceed beyond phase II clinical trials due to their limiting feature – hydrolytic instability. This feature also hampered mechanistic investigations of the past compounds. Nevertheless, the hydrolysis to form the final safe product titanium dioxide, which can leave the human body without harm, is a big advantage for the use of titanium(IV) complexes as drugs. Thus, to utilize the titanium(IV) potential, more stable titanium(IV) complexes were needed.
We have introduced advanced titanium(IV) anticancer complexes that are based on strongly binding ligands, decelerating hydrolysis. Through the current ERC-CoG, we synthesize various derivatives and analyze their anticancer and hydrolytic reactivities. Our objectives include: (a) synthesizing optimal derivatives with high activity and slow hydrolysis, and establish the role of symmetry and geometry; (b) determining the mechanism of operation of these drugs and cellular pathways affected by the treatment; and (c) developing particular drug delivery systems based on tailored architectures for selective transport to cancer tissue. These studies should substantially promote the development of safe and effective anticancer chemotherapy.
