Title: Synergistic light-activated mixed-metal targeted prodrugs for enhanced cancer therapy
Funder: The Academy of Medical Sciences

Abstract: Cancer is one of the deadliest threats to human health. Platinum-based drugs are currently used in about 50% of all chemotherapy treatments for cancer. However, the emergence of chemo-resistance together with side-effects has stimulated the demand for new generations of metallodrug. Among the many factors inducing chemo-resistance, the array of nuclear DNA repair mechanisms pose a primary obstacle for Pt-based drugs. Mitochondria are defective in cancer cells with mutated less protected mtDNA that prompts tumorigenesis, and mitochondrial metabolism that is reprogrammed for adaptation to hypoxia in cancer cells. Mitochondria are therefore an attractive target for therapy. Hence, directing drugs to mitochondria can not only bypass the extensive DNA repair issue, but also generate potent anti-proliferative effects on resistant cancers by handicapping mitochondrial function. I will design and investigate the molecular mechanism of action of a novel series of ruthenium(II)-rhenium(I) mixed-metal complexes as imaging-guided mitochondria-targeted phototherapeutic prodrugs to combat chemo-resistance in lung cancers. In the bimetallic prodrug system, Ru(II) is responsible for interfering with mtDNA, and Re(I) for the navigation to mitochondria and generation of Reactive Oxygen Species (ROS). The photophysical and biological activities of Ru(II) and Re(I) will be mutually quenched by conjugation with a monodentate bridging ligand. Such a strategy will reduce detoxification by endogenous thiols in the dark, as well as reducing off-target side effects. After the translocation to mitochondria, the prodrug will be activated by photo-irradiation, whereby efficient energy transfer from Re(I) to Ru(II) will uncouple the bimetallic system and unleash anticancer potency specifically in the mitochondria of the irradiated cancer cells. Meanwhile, the activation of the prodrug will be monitored by the recovery of Re(I) phosphorescence. I will investigate the molecular mechanism of action of these prodrugs with cutting-edge techniques. The mitochondrial localization will be confirmed by multiple new methods. Mitochondrial dysfunction will be characterized by the loss of membrane potential, change in mtDNA copy number, identification of mtDNA binding sites, mtDNA fragmentation, protein oxidation, disturbance of mitochondrial metabolism, cytochrome c efflux, and overall inhibition of metabolic pathways. The reactions of key proteins that contribute to cancer resistance will be studied by comparison of the prodrugs with the clinical drug cisplatin.

Lay abstract: Mitochondria are the energy powerhouses in cells- working overtime in cancer cells because they divide rapidly. Mitochondria are already malfunctioning in cancer cells because of mutations in their special DNA, and are therefore vulnerable to attack. Platinum therapy is now the major form of cancer chemotherapy– used in about 50% of all cases. However, resistance to platinum therapy has become a major clinical problem– meaning that cancer cells that were destroyed initially with platinum drugs cease to be sensitive to platinum after several rounds of treatment. The second problem is that current platinum drugs often give rise to unwanted side effects- e.g. nausea. vomiting, damage to the nervous system. A third problem is that not all cancers are equally sensitive to platinum treatment, and in particular lung cancer (which is prevalent in China and other countries) is usually not curable with existing drugs. The research to be carried out here will aim to generate novel relatively non-toxic anticancer prodrugs containing coupled precious metals ruthenium and rhenium that have little effect on either cancer cells or normal cells in the dark, but are activated specifically in tumours using directed light. This will not only reduce side effects, but also kill cells by a totally new mechanism, and even platinum-resistant cells will not be able to survive. Moreover my new compounds are designed to be ‘smart’ prodrugs in which the success in activating the prodrug in tumours can be monitored (imaged) by the emission of light once the prodrug has been photoactivated.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS