Журнал "Макрогетероциклы"

A. Tsyb Medical Radiological Research Center – branch of the Federal State Budgetary Institution “National Medical Research Radiological Center” of the Ministry of Health of the Russian Federation, 249036 Obninsk, Russia

^@Corresponding author E-mail: olyabramova@gmail.com

 

DOI: 10.6060/mhc224208a
Macroheterocycles 2021 14(4) 312-316

 

Photodynamic therapy (PDT) is a modern treatment method based on the synergistic interaction of a non-toxic photosensitizer (PS), low-energy and non-thermal visible light and tissue oxygen for destruction of target cells and tissues by producing singlet oxygen and its other reactive forms. At present, three main mechanisms of the antitumor effect of PDT have been studied: a direct damaging effect on tumor cells, disruption of the tumor blood supply due to vascular damage, and elimination of malignant cells due to the cytotoxic effect of immune system cells due to the development of acute inflammation. A certain sequence of photochemical and photobiological reactions causes irreversible damage to tumor tissues, a cascade of photochemical reactions occurs with the formation of reactive oxygen species, which have a strong cytotoxic effect, causing damage to the membranes and organelles of pathological cells. Significant changes in the endothelial cells of the tumor vessels, after photodynamic therapy, lead to the activation of circulating platelets and polymorphonuclear leukocytes and, as a result, to a thrombogenic effect and impaired microcirculation. The biological consequences of PDT-initiated radical-mediated photooxidation can cause autophagic, apoptotic, or necrotic cell death, depending on the energy density (J/cm²) and power density (W/cm²) of light and the concentration of the photosensitizer. Sublethal damage initiated by cytotoxic products of photochemical reactions can lead to apoptosis of tumor cells. Also, the response of tissues to photodynamic therapy is vasoconstriction of arterioles and thrombosis of venules, metabolic changes and subsequent necrosis of endothelial cells, which leads to their separation, increased permeability of the vascular wall and necrosis of most of the tumor tissue.^[1–4]

Natural chlorins and their derivatives are widely used in photodynamic therapy as photosensitizers. The development of photodynamic therapy involves the search for new photosensitizers with a chemical modification of natural pigments from chlorophyll a, combining optimal photophysical properties and targeted delivery of drugs to specific cellular targets. In this work, we studied the effectiveness of PDT of experimental tumors: Ehrlich carcinoma of mice and M-1 sarcoma of rats with a new photosensitizer Heliochlorin. Heliochlorin – a derivative of chlorin e₆ for PDT – was developed and created by Professor Ponomarev G.V. with co-authors.^[12] Manufacturer – Limited Liability Company “HELIOCHLORIN” (RU). The drug is produced in a freeze-dried form, including trismeglumine salt of chlorin e₆ and, as a cryostabilizer, meglumine in a ratio of 1:0.1–0.2 wt.h. Heliochlorin is a PS based on highly purified chlorin e₆ from methylpheophorbide a, with a high content of the main substance in the sample up to 93–98 %.

We studied the kinetics of PS accumulation in tumors and surrounding tissues of the thigh of two types of laboratory animals to determine the optimal time for laser irradiation. To assess the antitumor efficacy of PDT, the following indicators were used: tumor volume, absolute growth rate in animals with neoplasia growth, inhibition of tumor growth, their complete regression, and an increase in the lifespan of individuals in the experimental groups compared with the control (tumor-bearing animals without exposure). The criterion for cure was considered complete regression of tumors and the absence of recurrence within 90 days after therapy. Carrying out treatment at the optimal time after PS administration with certain parameters of laser exposure made it possible to achieve the maximum inhibitory effect on malignant neoplasms (Ehrlich’s carcinoma and M-1 sarcoma) in 100 % of animals up to 90 days after PDT.