Employees of the laboratory "Chemoinformatics and Molecular Modeling" of the Institute of Intelligent Cybernetic Systems of MEPhI Alexander Shtil and Alina Markova, together with colleagues from other institutes, conducted a study during which a new emulsion was obtained that allows treating cancer with an oxygen-dependent method even in an oxygen-free environment.
One of the most "gentle" methods of cancer treatment — photodynamic therapy — allows you to destroy the tumor by converting oxygen molecules into an active form destructive to cells with the help of light and a special activator molecule. However, in particularly aggressive neoplasms, oxygen-free conditions may occur, where such an approach will be ineffective. Scientists have come up with a special emulsion that simultaneously serves as a source of both molecular oxygen and its activating substance. As a result, it allows the use of photodynamic therapy to combat complex tumors in the late stages. The work supported by a grant from the Russian Science Foundation (RNF) can be found on the pages of the International Journal of Molecular Sciences.
In tumors, especially in the late stages, unique conditions arise that not only contribute to the progression of the neoplasm, but also allow it to resist traditional therapy. For example, due to active division, hypoxic zones appear in the tumor, in which there is practically no oxygen. As a result, cancer cells begin to actively mutate in order to adapt to hypoxia: some of them rebuild their metabolism to an oxygen-free regime, becoming resistant to various influences widely used in oncology (including chemotherapeutic drugs), other cells emit special "SOS signals" that cause blood vessels to actively germinate into the tumor and supply it is all necessary, which leads to further growth of the tumor.
At the same time, due to lack of oxygen, immune cells that come to the tumor in large quantities lose their activity — in particular, they cannot convert oxygen into active forms, and this is exactly what serves as one of the ways to fight cancer. A doctor will face the same problem if he tries to prescribe photodynamic therapy for such a tumor — it simply will not work. The essence of this treatment is to introduce a photosensitizer substance into the neoplasm, which, when irradiated, converts molecular oxygen into reactive oxygen species that damage the tumor.
Scientists belonging to the interinstitutional scientific group forced photodynamic therapy to work even in such conditions when, by definition, it cannot be effective. To do this, they proposed to bring oxygen to the tumor as part of a special emulsion — hydrophobic nanodrops in water, which were created by ultrasonic treatment of an initially immiscible mixture. The droplets were formed by hydrophobic perfluorocarbons, which, compared with water, can dissolve up to 20-40 times more oxygen, and still retain its active form in working condition 7000 times longer. They are inert, that is, they will not react with the environment and turn into substances dangerous to the body. And in order to kill cancer cells, the authors synthesized new photosensitizers — fluorinated derivatives of chloride. They are a rigid cyclic skeleton of carbon and nitrogen atoms; the skeleton absorbs light well in the red region, in which the tissues of the body are optically transparent, which means that even fairly deep tumors can be treated. In order for photosensitizers to be dissolved in hydrophobic liquids, additional fluorine—containing cycles were hung on the chloride - they form a hydrophobic "coat", which also helped the substance penetrate through cell membranes and destroy them from the inside. Experiments have shown that the emulsion remained stable at 4 °C and -20°C — that is, when stored in a conventional refrigerator and freezer, respectively — for at least 30 days, which means that in the future hospitals will not have to prepare a new solution for the patient every time.
Since perfluorocarbons in the composition of the emulsion, providing its oxygen capacity, are superhydrophobic, standard protocols for the analysis of dead cells and their components are not always applicable. To study the mechanism of action of the emulsion, scientists need to destroy dead cells, but the accumulated emulsion is destroyed along with them - this is how superhydrophobic perfluorocarbons are released from their bioavailable formation and interfere with working with solutions and sediments of cellular structures. To overcome this methodological difficulty, the staff of the laboratory "Chemoinformatics and Molecular Modeling" of NRU MEPhI modified algorithms for conducting experiments with an emulsion in aqueous cellular media and organic solvents. The experimental methods described in the article can also be used for other new biologically promising therapeutic compositions based on perfluorocarbons.
The researchers tested the development on cells of a model line of human colon carcinoma, which anatomically allows photodynamic therapy, but which is characterized by hypoxia at late stages. They grew a culture of tumor cells in oxygen-free conditions and added an emulsion to the nutrient medium. In the dark, no uncontrolled effect was observed, but red laser illumination quickly triggered cell death: generation of reactive oxygen species and peroxide damage to membranes and mitochondria (cellular power plants) occurred. The massive "bombardment" of cells by the products of launched photochemical reactions does not allow the tumor to recover, and it literally bursts from the inside (this is called photonecrosis).
"Our approach will both significantly improve the effectiveness of photodynamic cancer treatment and expand its applicability to cases of hypoxic malignant tumors that are aggressive and often do not respond to conventional therapies. We have described in detail the technology of obtaining a therapeutic emulsion and described step by step the mechanism of its action on tumor cells. Our results allow us to proceed to studies on mice, developing the idea of photodynamic therapy in hypoxia, as well as to investigate the applicability of this emulsion for other oxygen-dependent methods of antitumor therapy. We have found conditions under which the emulsion brings oxygen to hypoxic cells and allows it to be "activated" — this is important for the development of approaches to chemotherapy and radiation therapy in complex cases when oxygen is needed during treatment, but it is not in the tissues," said an employee of the laboratory "Chemoinformatics and Molecular Modeling" of the MEPhI Research Institute Alina Markova.
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