Photodynamic therapy of cancer

In recent years, in the treatment of cancer, more attention has been paid to developing methods such as photodynamic therapy for cancer. The essence of the method consists in the selective accumulation of a photosensitizer after intravenous or topical administration followed by irradiation of the tumor with a laser or non-laser light source with a wavelength corresponding to the spectrum of sensitizer uptake. 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 direct phototoxic effects on tumor cells, also disrupts the blood supply of tumor tissue due to damage to the endothelium of blood vessels in the light exposure zone, cytokine reactions caused by stimulation of production of neoplastic necrosis factor, activation of macrophages, leukocytes and lymphocytes.

Photodynamic therapy of cancer favorably differs from traditional methods of treatment by the selectivity of the defeat of malignant tumors, the possibility of multi-course treatment, the absence of toxic reactions, immunosuppressive action, local and systemic complications, the ability to perform treatment in outpatient settings.

[1], [2], [3], [4], [5], [6], [7], [8], [9], [10]

How is photodynamic therapy performed?

Photodynamic therapy of cancer is carried out with the use of sensitizers, which along with high efficiency have other characteristics: an appropriate spectral range and high absorption coefficient of the sensitizer, fluorescent properties, photo-resistance to the radiation used for the treatment such as photodynamic therapy of cancer.

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

The main requirements for photosensitizers can be formulated as follows:

• high selectivity to cancer cells and a weak delay in normal tissues;
• low toxicity and easy elimination from the body;
• poor accumulation in the skin;
• stability during storage and introduction into the body;
• good luminescence for reliable tumor diagnosis;
• high quantum yield of a triplet state with an energy of not less than 94 kJ / mol;
• an intense absorption maximum in the region of 660 ± 900 nm.

Photosensitizers of the first generation, belonging to the class of hematoporphyrins (photophryn-1, photophryn-2, photohem, etc.), are the most common preparations for PDT in oncology. In medical practice, hematoporphyrin derivatives are widely used throughout the world under the name of photophryin in the USA and Canada, photos in Germany, NDD in China and photograms in Russia.

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 the lung tumor, esophagitis Barrett. The results of treatment of early stages of malignant neoplasms of the head and neck region, in particular, the larynx, oral and nasal cavity, and also the nasopharynx have been reported. However, photophryn has a number of disadvantages: it is ineffective to convert light energy into cytotoxic products; insufficient selectivity of accumulation in tumors; light with the required wavelength does not penetrate deeply into the tissue (maximum 1 cm); skin photosensitivity is usually observed, which can last several weeks.

In Russia, the first domestic photoship sensitizer was developed, which during the period from 1992 to 1995 was clinically tested and, since 1996, allowed for medical use.

Attempts to bypass the problems manifested by the use of photofrin led to the emergence and study of photosensitizers of the second and third generations.

One of the second generation photosensitizers is phthalocyanines - synthetic porphyrins with an absorption band in the range 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 are highly promising photosensitizers, but significant shortcomings in their use are the long period of cutaneous phototoxicity (up to 6 to 9 months), the need for strict adherence to the light regime, the presence of certain toxicity, and long-term complications after treatment.

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

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

Photodynamic therapy of cancer is carried out using several chlorins. A new photosensitizer is a derivative of these derivatives. It contains a complex of trinatrium salts of chlorin E-6 and its derivatives with low molecular weight medical polyvinylpyrrolidone. The photon selectively accumulates in malignant tumors and under the local action of monochromatic light with a wavelength of 666 - 670 nm provides a photosepsibilizing effect, leading to damage to the tumor tissue.

The photon is also a highly informative diagnostic tool in the spectro fluorescence study.

Bacteriochlorophyllide-serine, a third generation sensitizer, is one of the few known water-soluble sensitizers with a working 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 due to the accumulation of a photosensitizer (in addition to the tumor) in the skin, which, under the influence of daylight, causes a pathological reaction. Therefore, patients after PDT must comply with the light regime (goggles, clothing that protects the exposed parts of the body). The duration of the light regime depends on the type of photosensitizer. When using the first generation photosensitizer (hematoporphyrin derivatives), this period can be up to one month, with the use of a photosensitizer of the second generation of phthalocyanines - up to six months, chlorines - up to several days.

In addition to 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 (interstitial) method of introducing a sensitizer into the tumor tissue. It excludes accumulation of the drug in organs with high metabolic activity, allows to increase the concentration of the photosensitizer and relieves patients from the need to observe the light regime. With the local administration of the photosensitizer, the consumption of the drug and the cost of treatment are reduced.

Perspectives of application

Currently, photodynamic therapy of cancer is widely used in oncology practice. There are reports in the scientific literature when photodynamic cancer therapy was used in Barrett's disease and other precancerous processes of the gastrointestinal mucosa. According to endoscopic studies, in all patients with epithelial dysplasia of the esophagus mucosa and Barrett's disease after PDT, no residual changes were noted on the mucosa and in the underlying tissues. Complete ablation of the tumor in all patients receiving PDT was observed with restriction of tumor growth within the gastric mucosa. In this case, the effective treatment of superficial tumors by the method of PDT allowed to optimize the laser technology of palliative treatment of obstructive processes of the esophagus, biliary tract, and colorectal pathology, as well as the subsequent stent placement of this category of patients.

The scientific literature describes the positive results after PDT with the use of a new photosensitizer photoditazine. With lung tumors, photodynamic therapy of cancer can be a method of choice for bilateral lesions of the bronchial tree in those cases when performing a surgical operation on the opposite lung is impossible. Studies are conducted on the use of PDT in malignant tumors of the skin, soft tissues, gastrointestinal tract, metastases of malignant tumors of the breast, etc. The results of intraoperative application of PDT for neoplasms of the abdominal cavity are encouraging.

Since the amplification of apoptosis of transformed cells in PDT in combination with hyperthermia, hyperglycemia, biotherapy or chemotherapy is found, the wider application of such combined approaches in clinical oncology seems justified.

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

Improvement of laser medical technology due to the development of new photosensitizers and means of transport of light fluxes, optimization of techniques will improve the results of PDT tumors of various localizations.