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Hypoxic Tumour Models for Photoactivatable Ruthenium-based Chemotherapy

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A novel class of photoactivated anti-cancer drugs

Photoactivated chemotherapy (PACT) is a new treatment for cancer. PACT drugs become activated after receiving visible light irradiation of the tumour in vivo. The non-irradiated prodrug is poorly toxic, thereby limiting treatment toxicity to the area of the irradiated tumour, which unlike traditional chemotherapy prevents the spread of toxicity to healthy tissues.

Health

PACT compounds contain a light-cleavable protecting group, which prevents them from interacting with the cell environment. Once the bond gets cleaved by light, the generated product becomes toxic to cancer cells.

Designing light-cleavable anti-cancer drugs

The EU-funded HypoRuLight project set out to develop and test novel PACT compounds for anti-cancer therapy. As project coordinator Sylvestre Bonnet explains: “in contrast to photodynamic therapy (PDT) where the light-absorbing prodrug requires molecular oxygen to kill the cancer cells, PACT does not require oxygen. As a result, PACT compounds are more specifically developed to treat hypoxic tumours, where oxygen concentration is low and cancer cells are highly resistant to PDT and other therapies.″ During HypoRuLight, researchers tested the efficacy of a selection of PACT compounds in hypoxic cancer models and compared their efficacy to that in normoxic conditions. Four promising compounds were selected: one suppresses an enzyme that is overexpressed in cancer and is implicated in the biosynthesis of energy molecules , a second compound destabilises the cell cytoskeleton, and the other two are DNA-damaging drugs.

PACT compound efficacy

Addition of these PACT compounds in cancer cell monolayers in culture under hypoxic (1 % oxygen) or normoxic (21 % oxygen) conditions enabled scientists to estimate cytotoxic drug concentration. They also tested the efficacy of the compounds on 3D cancer cell spheroids in culture using imaging techniques. Furthermore, when administered in a mouse model of lung cancer, these PACT compounds exhibited cytotoxicity at low doses following green light irradiation. An overall 30 % reduction in tumour volume was seen in vivo with no adverse toxicity. However, killing hypoxic cancer cells is not as simple. Upon adapting to low-oxygen environments, cancer cells become more resistant to chemotherapy. Even if the light activation works well under hypoxia and the chemical bond is cleaved, the cytotoxicity of the generated products is not as high as in normoxic conditions. To develop PACT compounds that are more toxic in hypoxic cancer cells, Bonnet has received EUR 1.5 million via the innovational research incentives scheme called the VICI grant from the Dutch Research Council, NWO.

Future prospects

Bonnet envisages PACT compounds to have the potential to reach clinical trials in 3-5 years after acquiring the necessary pre-clinical data. This includes biodistribution, efficacy and safety in vivo, as well as mechanism delineation. Apart from non-melanoma skin cancer and head-and-neck cancer, the HypoRuLight team plan to focus on liver cancer, and eye cancer in the future for commercial exploitation of the PACT compounds. A United States (US) based company has already expressed interest in one of the compounds, which was developed in collaboration with Alexander Kornienko from Texas State University in the US, and tested in mice xenografts with Bertrand Liagre, a French phototherapy specialist. Emphasising the importance of the ERC proof-of-concept grant as a tool for bringing fundamental discoveries closer to applications, Bonnet explains: “Being trained as a chemist, I had only a very vague idea before HypoRuLight about which cancer model I should test our PACT molecules on. The ERC grant pushed me to actually implicate an oncology company to perform a market study. I have now a much better idea about these questions, which is critical for drug discovery.″

Keywords

HypoRuLight, cancer, photoactivated chemotherapy (PACT), drug, oxygen, hypoxic, photodynamic therapy (PDT), cytotoxic

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