NITI MISiS: Riboplatin (Drug for combined chemotherapy and photodynamic therapy)

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• Cancer treatment
• Drugs to treat cancer

2023: Announcement of the drug for combined chemotherapy and photodynamic therapy

Russian scientists have proposed an innovative approach in the fight against cancer, which will reduce severe side effects from treatment. They developed the prodrug Riboplatin for combination chemotherapy and photodynamic therapy based on Pt (IV) platinum and a photosensitizer (substances that increase the sensitivity of tissues to light exposure). The drug is controllably activated only in the malignant neoplasm zone under the influence of blue light, without affecting irradiated tissues, opening up opportunities for "point" chemical therapy. The design of the proposed prodrug solves the problem of toxicity and cellular resistance to traditional antitumor drugs. The research results are published in the scientific journal ACS Applied Materials & Interfaces. This was announced on April 25, 2023 by representatives of NUST MISIS.

A prodrug is an initially pharmacologically inactive compound that is activated in the body, releasing a therapeutic agent. In our work, platinum (IV) prodrug Riboplatin, which is a combination of clinically used cisplatin and Riboflavin, Vitamin V12, can be selectively activated in tumor cells under the influence of blue light, while local release of the cytotoxic agent cisplatin occurs in the process of photoactivation, as well as generation of reactive oxygen species by Riboflavin. The possibility of localizing the irradiation of the drug in a given area opens up the possibility of combined action of chemotherapy and photodynamic therapy, increase the effectiveness of treatment compared to conventional chemotherapy, as well as reduce the general toxic effect on the body. explained Olga Krasnovskaya, Project Manager, Ph.D., Senior Researcher, Research Laboratory of Biophysics, NUST MISIS

In the photo: from left to right: Engineer of the Research Laboratory of Biophysics NUST MISIS Alexander Vaneev
Head of the Department of Biophysics MISIS Alexander Erofeev
Project Manager, Ph.D., Senior Researcher, Research Laboratory of Biophysics NUST MISIS Olga Krasnovskaya

Chemotherapy is a very powerful tool, but it often acts indiscriminately on all cells. In addition, with long-term therapy, tumor tissues produce resistance, that is, the ability to reduce the effectiveness of chemotherapeutic agents. Platinum-containing agents, for example, such as cisplatin Pt (II), are widely used antitumor drugs, they are used in half of all existing chemotherapy regimens. However, not all platinum compounds reach the tumor. For example, 90% of the administered cisplatin is deactivated in the bloodstream by irreversible binding to plasma proteins, and only 1% (or less) binds to the intended target, nuclear DNA. However, the lack of selectivity to tumor cells means that cisplatin can also affect healthy cells, which is the cause of severe side effects of chemotherapy.

According to the researcher, it was experimentally established that Riboplatin is capable of accumulating 13 times more efficiently in cells compared to free cisplatin. This means that at similar dosages Riboplatin has a higher antitumor activity.

In photodynamic therapy (PDT), molecules of photosensitizers that are not toxic in the absence of radiation, under the influence of light in the visible region, transmit the energy of light quanta to oxygen existing in the bloodstream, converting it into an active form and highly active oxygen-containing radicals that destroy cancer cells. One of the key limitations of the use of PTC is its low efficiency in conditions of lack of oxygen. For example, in hypoxic conditions characteristic of tumors, where the content is significantly reduced, photodynamic therapy is ineffective. Therefore, the combination of a controlled-release prodrug Pt (IV) and a photodynamic therapy agent in one molecule represents a modern approach.

To overcome the limitations of photodynamic therapy, we have proposed the compound Pt (IV), which contains a cytotoxic fragment of cisplatin, as well as an agent of photodynamic therapy. Thus, under aerobic conditions, the molecule we developed will work as a double-acting agent, and in hypoxia, in case of lack of oxygen, it will retain the ability to release the chemotherapeutic agent cisplatin under the action of visible light. noted Daniil Spector, co-author of the study, engineer of the research laboratory of biophysics NUST MISIS

Riboplatin

Scientists used tetraacetyl riboflavin (TRAP) as a photosensitizer. Riboflavin is vitamin B. In various cancers, it is taken up particularly actively, so TARF-based conjugates are widely used to enhance drug functionality and to target cancer cells. Also, TARF is able to form reactive oxygen species when irradiated with light, which causes its antitumor, antibacterial, antiviral properties and its prospects as a means of photodynamic therapy.

We have already received repeated confirmation of photoactivated release of the antitumor drug cisplatin Pt (II) from the prodrug Pt (IV), both "in tubes" and within the adenocarcinoma living tumor model. It has been found that riboplatin actually releases cisplatin by the action of blue light, and the release rate can be controlled by the radiation dose. stated Olga Krasnovskaya

According to the scientists, this appears to confirm the simultaneous photoactivated release of the anticancer drug cisplatin Pt (II) and oxygen compounds from a dual-acting prodrug observed in real time inside a living tumor model. Similar prodrugs, which are a combination of a photopolymer, and a cytotoxic platinum agent, have previously been represented by scientists from Italy and China. However, thanks to the presence of equipment, and the ability to observe the process of photoactivation of the drug inside the living system in real time, provided the scientific group with results that were evaluated in the scientific community.

In my study, my colleagues and I applied an electrochemical method to detect cisplatin inside 3D tumor models - spheroids that were previously irradiated with visible light. With the help of a nanoscale sensor, we were able to penetrate different levels inside the spheroid and show that the drug we developed not only accumulates well at the depth of the tumor model, but also responds to radiation in the depth of the spheroid. We were able to detect in real time the release of a cytotoxic agent from a prodrug within a living system. told Alexander Vaneev, engineer of the research laboratory of biophysics NUST MISIS

In further studies, the scientists plan to study the developed drug in animals, as well as continue to search for effective photosensitizers for the controlled photoactivation of Pt (IV) prodrugs. The project was supported by the Russian Science Foundation (No. 22-15-00182).