Photodynamic therapy for cancer

In recent years, in the treatment of oncological diseases, increasing attention has been paid to the development of methods such as photodynamic cancer therapy. The essence of the method lies in the selective accumulation of a photosensitizer after intravenous or local administration, followed by irradiation of the tumor with a laser or non-laser light source with a wavelength corresponding to the absorption spectrum of the sensitizer. In the presence of oxygen dissolved in tissues, a photochemical reaction occurs with the generation of singlet oxygen, which damages the membranes and organelles of tumor cells and causes their death.

Photodynamic therapy of cancer, in addition to the direct phototoxic effect on tumor cells, also disrupts the blood supply to tumor tissue due to damage to the endothelium of blood vessels in the area of light exposure, cytokine reactions caused by stimulation of the production of tumor necrosis factor, activation of macrophages, leukocytes and lymphocytes.

Photodynamic cancer therapy has an advantage over traditional treatment methods due to its selective destruction of malignant tumors, the possibility of conducting multiple courses of treatment, the absence of toxic reactions, immunosuppressive effects, local and systemic complications, and the possibility of conducting treatment on an outpatient basis.

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How is photodynamic therapy for cancer performed?

Photodynamic cancer therapy is carried out using sensitizers, which, in addition to high efficiency, also have other characteristics: a suitable spectral range and a high absorption coefficient of the sensitizer, fluorescent properties, photostability to the effects of radiation used to carry out such a treatment method as photodynamic cancer therapy.

The choice of spectral range is related to the depth of therapeutic impact on the neoplasm. The greatest depth of impact can be provided by sensitizers with a wavelength of the spectral maximum exceeding 770 nm. The fluorescent properties of the sensitizer play an important role in developing treatment tactics, assessing the biodistribution of the drug, and monitoring the results.

The main requirements for photosensitizers can be formulated as follows:

• high selectivity for cancer cells and weak retention in normal tissues;
• low toxicity and easy elimination from the body;
• weak accumulation in the skin;
• stability during storage and administration into the body;
• good luminescence for reliable tumor diagnostics;
• high quantum yield of the triplet state with an energy of at least 94 kJ/mol;
• intense absorption maximum in the region of 660 - 900 nm.

First-generation photosensitizers belonging to the hematoporphyrin class (photofrin-1, photofrin-2, photohem, etc.) are the most common drugs for PDT in oncology. In medical practice, hematoporphyrin derivatives called photofrin in the USA and Canada, photosan in Germany, NrD in China, and photohem in Russia are widely used throughout the world.

Photodynamic therapy of cancer is effective with the use of these drugs in the following nosological forms: obstructive malignant neoplasm of the esophagus, bladder tumors, early stages of lung tumor, Barrett's esophagus. Satisfactory results have been reported in the treatment of early stages of malignant neoplasms of the head and neck region, in particular, the larynx, oral and nasal cavities, and nasopharynx. However, Photofrin also has a number of disadvantages: ineffective conversion of light energy into cytotoxic products; insufficient selectivity of accumulation in tumors; light with the required wavelength does not penetrate very deeply into tissues (maximum 1 cm); cutaneous photosensitization is usually observed, which can last for several weeks.

In Russia, the first domestic sensitizer, Photohem, was developed, which underwent clinical testing between 1992 and 1995 and was approved for medical use in 1996.

Attempts to circumvent the problems that arose when using Photofrin led to the development and study of second- and third-generation photosensitizers.

One of the representatives of the second generation of photosensitizers are phthalocyanines - synthetic porphyrins with an absorption band in the range of 670 - 700 nm. They can form chelate compounds with many metals, mainly with aluminum and zinc, and these diamagnetic metals enhance phototoxicity.

Due to the very high extinction coefficient in the red spectrum, phthalocyanines appear to be highly promising photosensitizers, but significant disadvantages in their use are a long period of skin phototoxicity (up to 6 - 9 months), the need to strictly adhere to the light regime, the presence of a certain toxicity, as well as long-term complications after treatment.

In 1994, clinical trials of the drug photosens-aluminum-sulfophthalocyanine, developed by a team of authors headed by Corresponding Member of the Russian Academy of Sciences (RAS) G. N. Vorozhtsov, began. This was the first use of phthalocyanines in such treatment as photodynamic cancer therapy.

Representatives of the second generation of sensitizers are also chlorins and chlorin-like sensitizers. Structurally, chlorin is a porphyrin, but has one less double bond. This leads to significantly greater absorption at wavelengths shifted further into the red spectrum compared to porphyrins, which to a certain extent increases the depth of light penetration into tissue.

Photodynamic therapy of cancer is carried out using several chlorins. Their derivatives include a new sensitizer photolon. It contains a complex of trisodium salts of chlorin E-6 and its derivatives with low-molecular medical polyvinylpyrrolidone. Photolon selectively accumulates in malignant tumors and, when locally exposed to monochromatic light with a wavelength of 666 - 670 nm, provides a photosepsibilizing effect, leading to damage to tumor tissue.

Photolon is also a highly informative diagnostic tool for spectrofluorescence research.

Bacteriochlorophyllide serine is a third-generation sensitizer, one of the few known water-soluble sensitizers with an operating wavelength exceeding 770 nm. Bacteriochlorophyllide serine provides a sufficiently high quantum yield of singlet oxygen and has an acceptable quantum yield of fluorescence in the near infrared range. Using this substance, successful photodynamic treatment of melanoma and some other neoplasms was carried out on experimental animals.

What are the complications of photodynamic therapy for cancer?

Photodynamic therapy of cancer is often complicated by photodermatoses. Their development is caused by the accumulation of the photosensitizer (in addition to the tumor) in the skin, which leads to a pathological reaction under the influence of daylight. Therefore, patients after PDT must adhere to the light regime (protective glasses, clothing that protects open parts of the body). The duration of the light regime depends on the type of photosensitizer. When using a first-generation photosensitizer (hematoporphyrin derivatives), this period can be up to one month, when using a second-generation photosensitizer of phthalocyanines - up to six months, chlorines - up to several days.

In addition to the skin and mucous membranes, the sensitizer can accumulate in organs with high metabolic activity, in particular in the kidneys and liver, with a violation of the functional capacity of these organs. This problem can be solved by using a local (intra-tissue) method of introducing the sensitizer into the tumor tissue. It eliminates the accumulation of the drug in organs with high metabolic activity, allows increasing the concentration of the photosensitizer and relieves patients from the need to comply with the light regime. With local administration of the photosensitizer, the consumption of the drug and the cost of treatment are reduced.

Application Prospects

Currently, photodynamic therapy of cancer is widely used in oncological practice. There are reports in the scientific literature when photodynamic therapy of cancer was used for Barrett's disease and other precancerous processes of the gastrointestinal mucosa. According to the endoscopic studies, no residual changes in the mucosa and underlying tissues were observed in all patients with epithelial dysplasia of the esophageal mucosa and Barrett's disease after PDT. Complete ablation of the tumor in all patients receiving PDT was observed with tumor growth limited to the gastric mucosa. At the same time, effective treatment of superficial tumors by PDT allowed optimizing laser technology for palliative treatment of obstructive processes in the esophagus, biliary tract, and colorectal pathology, as well as subsequent stent installation in this category of patients.

The scientific literature describes positive results after PDT using the new photosensitizer photoditazine. In lung tumors, photodynamic therapy of cancer can become the method of choice in case of bilateral bronchial tree damage in cases where surgical operation on the opposite lung is impossible. Studies are being conducted on the use of PDT in malignant neoplasms of the skin, soft tissues, gastrointestinal tract, metastases of malignant neoplasms of the mammary gland, etc. Encouraging results have been obtained from the intraoperative use of PDT for neoplasms of the abdominal cavity.

Since an increase in apoptosis of transformed cells was found during PDT in combination with hyperthermia, hyperglycemia, biotherapy or chemotherapy, a wider use of such combined approaches in clinical oncology seems justified.

Photodynamic therapy of cancer can be the method of choice in the treatment of patients with severe concomitant pathology, functional unresectability of tumors with multiple lesions, ineffectiveness of treatment with traditional methods, and palliative interventions.

Improvement of laser medical technology through the development of new photosensitizers and means of transporting light fluxes, optimization of methods will improve the results of PDT of tumors of various localizations.