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Chemotherapy without side effects? It’s possible, with light

Nausea, neurologic pain and hair loss: some of the severe side effects of chemotherapy. Not necessary, biochemist Liyan Zhang showed. Together with Leiden biologists and others, she achieved great results with a drug that is only active in combination with light. Zhang will defend her PhD on 4 July.

Chemotherapy is effective and dreaded at the same time. The patient is injected drugs consisting of toxic molecules, some of which often contain a metal, for example platinum. Having molecules that are toxic to the tumour cells is great, but it is not great to also kill healthy cells in the patient. 'The drug is also active in healthy tissues and that often causes serious side effects,' says Liyan Zhang who did her PhD research at the Leiden Institute of Chemistry (LIC).

Drug with a light switch

Zhang and her supervisor, chemistry professor Sylvestre Bonnet, developed a chemotherapy that only works when you shine visible light on it. The molecule contains a metal component based on ruthenium that gives the molecule light-switching properties. If proven to work and safe, this family of molecules could replace current chemotherapies by safer alternatives. 

Zhang: 'You administer the drug, and then you wait for the drug to reach the tumour. Then you shine light on the tumour using a laser. Of course it is easier at the surface of the body. The skin, the lungs, or the bladder are easily accessible to light irradiation. However, with optical fibre technology we can also bring the light deeper into the body, for example in the brain or liver.'

portrait Liyan Zhang

Safe in the dark, toxic by light

Zhang showed that when green light is applied onto the tumor, the drug becomes highly toxic to cancer cells in petri dishes, but also in mice and zebrafish models of real tumors. 'I felt great when I saw the trace of the drug in the cancer cells or in a transparent zebrafish by microscope, when I could see that something that we expected was happening. We showed that our drugs were very safe in the dark at certain doses, while activation with light made the drug active. Very importantly, the active part of the drug can efficiently accumulate in the tumour area, even if it must cross the blood-brain barrier to reach a brain tumour.'

The research in mice took place with the help of colleagues in China. For the research in zebrafish embryos, Zhang only needed to step a few meters to her colleagues from the Faculty of Science of Leiden University. 'I told my fellow PhD student Gangyin Zhao who works at the Institute of Biology Leiden that I wanted to test my drug in an animal model. He works with zebrafish embryo tumor models and he was happy to help. We and our promoters had a very pleasant collaboration and interesting conversations about that project.' 

When will people benefit from this drug?

Supervisor Sylvestre Bonnet is of course very pleased with the results his PhD student managed to achieve. What remains to be done before the new drug can cure people of cancer? Bonnet: ‘The first step is probably to obtain activation with red light. Green light is currently being tested clinically for bladder cancer in Canada, but it is does not penetrate very deep in biological tissues. Mice and zebrafish tumor models are small so their tumor are small as well, but in humans it is another dimension. Ideally we would need red or near-infrared light activation of this kind of drugs. There is also a range of experiments to be performed to demonstrate safety of the prodrug for the brain.

Thesis cover Liyan Zhang

Successful despite corona pandemic 

Although this article reads like one big success story, the research certainly did not always go smoothly, says Zhang. 'I had a lot of frustrations, I think a PhD research can really train your brain to handle adversity better.' Bonnet admires her. 'Liyan is very thorough and systematic in her work and very courageous. She was also very resilient in spite of the way covid-19 struck our society. During her research, she could not see her family for several years due to the pandemic, and in spite of this, she succeeded very well. I am very proud of her work.

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