Periodic Reporting for period 4 - TiDrugArchitectures (Highly Competent and Safe Titanium(IV) Therapeutic Frameworks that are Cancer Targeted based on Complex 1, 2, and 3D Chemical Architectures)
Période du rapport: 2020-12-01 au 2022-05-31
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.
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.
The project has yielded advanced families of titanium-based anticancer chemotherapy. Currently employed metal-based chemotherapy includes mainly platinum-based compounds. Due to the inert nature of the platinum metal, platinum compounds are highly toxic, and therefore their use is mostly accompanied by severe side effects and damages to the kidneys, liver and brain among others. We have turned to the titanium metal as it is a by far more biologically friendly metal: the product of all titanium complexes of organic ligands in water environment is titanium dioxide, which is a safe material with no known side effects. This metal is therefore highly attractive for use in drugs; nevertheless, its rapid decomposition in water has inhibited its use. We have analyzed the structural parameters that affect the anticancer activity of the titanium-based compounds and their and hydrolytic stability – an essential feature for biologically active titanium(IV) compounds. We were able to eventually achieve complexes that are stable for weeks in water solutions, and profound mechanistic investigations have confirmed that the lead complexes maintain their original structure in the cell. We also have developed complexes with enhanced stability and bioavailability, and have fine-tuned the synthetic pathway to enable development of asymmetric derivatives that are valuable for combination therapy and drug delivery and targeting.
Our mechanistic studies have tracked the titanium-based drug in the cellular and sub-cellular organelles, and genome analyses point to endoplasmic-reticulum-stress as a main cellular pathway involved. We have also revealed that the titanium-base complexes operate via protein-binding and not through binding to DNA. We have also detected some serum protein binding with ligand binding intact, and correlation to ROS formation. The lead complex has shown high efficacy toward several murine models, efficacy also upon oral administration and in combination with known drug. The complex does not show any indications of toxicity in various assays applied. Treated mice did not reveal any grooming, hair loss, weight loss or any behavioral changes, with no impact on kidney function, unlike those treated with platinum-based positive controls.
Our work has been disseminated in various conferences and meetings with students at all levels, including High-School students. Additionally, the work was reported in the public media.
Our mechanistic studies have tracked the titanium-based drug in the cellular and sub-cellular organelles, and genome analyses point to endoplasmic-reticulum-stress as a main cellular pathway involved. We have also revealed that the titanium-base complexes operate via protein-binding and not through binding to DNA. We have also detected some serum protein binding with ligand binding intact, and correlation to ROS formation. The lead complex has shown high efficacy toward several murine models, efficacy also upon oral administration and in combination with known drug. The complex does not show any indications of toxicity in various assays applied. Treated mice did not reveal any grooming, hair loss, weight loss or any behavioral changes, with no impact on kidney function, unlike those treated with platinum-based positive controls.
Our work has been disseminated in various conferences and meetings with students at all levels, including High-School students. Additionally, the work was reported in the public media.
We consider the development of our advanced drug, combined with mechanistic elucidation and adaption to tumor targeting – a breakthrough in the field. It is normally accepted that in within the spectrum of possible anticancer treatments – on one edge – treatments that are highly effective and of wide possible application such as chemotherapy are normally aggressive and therefore of low selectivity and high toxicity and side effects; on the other edge, treatments that are more selective (targeted therapy, precision medicine) are often of a narrow possible application as they are highly condition- and population-specific. The ability to produce treatment that is highly and widely effective on one hand, as characteristic of chemotherapy, and yet with no detected side effects whatsoever in all measurements thus far, is incredible. As most cancer cases still rely nowadays on chemotherapy as a main treatment, our findings open new horizons for more tolerable treatments for numerous conditions and patients.