Russian scientists have proposed an innovative approach in fighting cancer, which will significantly reduce severe side effects from treatment. They have developed a promising pro-drug Riboplatin for combined chemical and photodynamic therapy based on platinum Pt (IV) and a photosensitizer (a substance that increases tissue sensitivity to light). The drug is controllably activated only in the area of malignant neoplasm under the action of blue light, without affecting unexposed tissues, thus opening up opportunities for “spot” chemotherapy. The proposed pro-drug design renders it possible to tackle the issue of toxicity and cellular resistance to conventional antitumor drugs. The research findings are published in the scientific ACS Applied Materials & Interfaces journal.
“A pro-drug is an initially pharmacologically inactive compound, which is activated in the body, releasing a therapeutic agent. In our work, the platinum (IV) pro-drug Riboplatin that constitutes a combination of clinically used cisplatin and Riboflavin, Vitamin B12 is able to be selectively activated in tumor cells under the action of blue light, with the local release of the cytotoxic agent cisplatin and the generation of reactive oxygen intermediates by Riboflavin in the process of photoactivation. The ability to localize the drug irradiation in a given area offers the possibility of combined action of chemical and photodynamic therapy and enables to increase the efficiency of treatment compared to conventional chemotherapy and to reduce the overall toxic effect on the body,” Olga Krasnovskaya, a project leader, Ph.D. (Chem.), Senior Researcher at the NUST MISIS Research Laboratory of Biophysics, explains.
Chemical therapy is a very powerful tool but often operates on all cells without distinction. In addition, where the therapy is lengthy, tumor tissues develop resistance, being the ability to undermine chemotherapeutic agents. Platinum-containing agents, such as Pt (II) cisplatin, are widespread antitumor drugs, which are used in half of all the existing chemotherapeutic regimens. However, not all platinum compounds reach the tumor. For example, 90% of administered cisplatin is deactivated in the bloodstream through irreversible binding to plasma proteins, and only 1% (or less) binds to its intended target — nuclear DNA. But the lack of selectivity to tumor cells implies that cisplatin may affect healthy cells as well, thus causing severe side effects of chemical therapy.
According to the researcher, it has been experimentally established that Riboplatin is able to be accumulated in cells 13 times more efficiently compared to free cisplatin. It means that at similar dosages Riboplatin has a stronger antitumor activity.
In photodynamic therapy (PDT), photosensitizer molecules, which are not toxic absent irradiation, transfer — when exposed to light in the visible region — the energy of light quanta to oxygen in the bloodstream, converting it into a reactive intermediate and highly active oxygen radicals that destroy cancer cells. One of the key limitations of PDT is its low efficiency in oxygen-deprived environments. For example, photodynamic therapy works poorly in hypoxic conditions that are common for tumors. Therefore, a combination of the controlled-release Pt (IV) pro-drug and a photodynamic therapy agent in a single molecule constitutes an innovative approach.
“To overcome the limitations of photodynamic therapy, we have proposed a Pt (IV) compound that contains a cytotoxic fragment of cisplatin and a photodynamic therapy agent. Therefore, in aerobic conditions, the molecule we have developed will work as a dual-action agent and will — in hypoxia under oxygen deficiency — retain the ability to release the chemotherapeutic agent cisplatin under the influence of visible light,” Daniel Spector, a co-author of the study and engineer at the NUST MISIS Research Laboratory of Biophysics, notes.
The scientists made use of tetraacetyl riboflavin (TARF) as a photosensitizer. Riboflavin is a B vitamin. In various types of cancer, it is absorbed particularly actively, so TARF-based conjugates are widely used to increase the functionality of drugs and to target cancer cells. TARF is also able to form reactive oxygen intermediates when irradiated with light, which determines its antitumor, antibacterial, antiviral properties and its prospects as a means of photodynamic therapy.
“We have repeatedly confirmed a photoactivated release of the antitumor drug cisplatin Pt (II) from the pro-drug Pt (IV), both in vitro and inside a live adenocarcinoma tumor model. It was found that riboplatin indeed releases cisplatin under the action of blue light, and the release rate may be controlled by the irradiation dose,” Olga Krasnovskaya stated.
According to the scientists, it appears to be the first confirmation of concurrent photoactivated release of the antitumor drug cisplatin Pt (II) and oxygen compounds from a dual-action pro-drug observed in real time inside a live tumor model. Similar pro-drugs constituting a combination of a photopolymer, and a cytotoxic platinum agent have been previously presented by scientists from Italy and China. The availability of unique equipment and the ability to observe the process of drug photoactivation inside a living system in real time enabled the science team to obtain truly breakthrough results, which were highly appreciated in the academic community.
“In our study, my colleagues and myself applied a unique electrochemical method to detect cisplatin inside 3D tumor models — spheroids that had been previously irradiated with visible light. Using a nanoscale sensor, we managed to penetrate to different levels inside the spheroid and demonstrate that the drug we developed not only accumulates well at the depth of the tumor model but also responds to irradiation deep inside the spheroid. We were able to detect the cytotoxic agent release from a pro-drug inside a living system in real time, which is indeed an unparalleled result,” Alexander Vaneev, an engineer at the NUST MISIS Research Laboratory of Biophysics, said.
In follow-up studies, scientists intend to examine the drug at issue on animals and to continue searching for effective photosensitizers for controlled photoactivation of Pt (IV) pro-drugs.
The project was supported by the Russian Science Foundation (No.
