Synergistic light-activated mixed-metal targeted prodrugs for enhanced cancer therapy

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.