Novel prodrug strategy for personalised therapy of cancer developed by UNN researchers

Lobachevsky University scientists have succeeded in combining several active molecules within a single drug, which makes it possible to perform combined photodynamic therapy (PDT) and chemotherapy in treating cancerous tumours. The new compound may be particularly effective in the therapy of bladder, skin and other cancers where PDT is used.

The combination of a photosensitizer and a chemopreventive agent will potentially enable the treatment of metastatic tumours. High selectivity of the developed molecule's action is achieved through the use of a special linker, which breaks up in tumour tissues.

"It is difficult to bring new drugs for photodynamic therapy into the market due to the large number of expert examinations and trials required. We have created a conjugate based on already known and proven components: a photosensitizer produced from blue-green algae, an analogue of photoditazine, and the modern chemopreventive drug cabozantinib. The study has shown that they complemented each other and were more effective against the tumour. In the process of developing the combined drug, the most modern approaches of medicinal chemistry were used," said Vasily Otvagin, the author of the study, Associate Professor at the UNN Department of Organic Chemistry.

The linker is sensitive to the enzyme glucoronidase. Its concentration is particularly high in tumours. Due to this, once reaching the cancer cell, the drug breaks down into its components. At this point, under the influence of irradiation, the photosensitizer is activated and destroys the tumour, while the chemopreventive agent eliminates the surviving tumour tissues that PDT failed to cope with.

Experiments on cell cultures have shown that under the influence of the drug the tumour stops growing and eventually dies off. The combined therapy is effective both during irradiation with visible light and in the dark.

It should be added that specially for this study artificial tumours were created at the Department of Biophysics of the UNN Institute of Biology and Biomedicine (IBBM). According to scientists, in view of the trend to abandon experiments with animals, this is now a popular substitute for murine models.

"We have combined in a single molecule two therapeutic agents that target different molecular pathways in the tumour cell. The efficacy of PDT is complemented by the precision of targeted chemotherapy. Studies have shown that the combination of anti-tumour agents significantly improve the efficiency of treatment. In addition, the use of such a compound will reduce the drug load on the patient and reduce the risk of drug resistance in the tumour," explained study co-author Lubov Krylova, a researcher at the UNN Department of Biophysics.

Starting materials for producing photosensitisers were obtained with the participation of scientists from Ivanovo State University of Chemistry and Technology.

The project was supported by a grant from the Russian Science Foundation. The results were published in the  European Journal of Medicinal Chemistry in 2024.