Photodynamic therapy (PDT) is a type of cancer treatment based on a photochemical reaction catalyzed by oxygen, which is activated by a photosensitizer (PS) under the influence of laser radiation. The classical definition of PDT was given by E.F. Stranadko [1], who viewed PDT as a method of locally activating a photosensitizer accumulated in the tumor using visible red light, which, in the presence of tissue oxygen, triggers a photochemical reaction that destroys tumor cells.
The photodynamic effect was first described by O. Raab in the laboratory of H. von Tappeiner at the University of Munich in 1900 [2]. It was proven that when exposed to sunlight in the presence of acridine and some other dyes, paramecia died, whereas when exposed to light without the dye or with the dye in the dark, the paramecia survived. The term "photodynamic reaction" was introduced by H. von Tappeiner in 1904 to describe the specific photochemical reaction that leads to the destruction of biological systems in the presence of light, a dye that absorbs light radiation, and oxygen [3].
The use of the photodynamic effect in oncology began with the work of A. Policard [4], in which it was shown that some malignant human tumors fluoresce in the orange-red region of the spectrum when exposed to ultraviolet radiation. This phenomenon was explained by the presence of endogenous porphyrins in the tumors. Later, this was confirmed in experimental tumors, which began to fluoresce in the red region of the spectrum when animals were pre-injected with hematoporphyrin [5].
The modern era of PDT in oncology began with the publications of R. Lipson in the 1960s, which demonstrated that after the intravenous injection of a mixture of hematoporphyrin derivatives (HpD), malignant tumors could be visualized due to the characteristic fluorescent radiation of selectively accumulated porphyrins [6, 7]. In 1966, fluorescent detection and the first PDT treatment of a patient with breast cancer were conducted [8]. In 1976 HpD was first successfully used in the United States for treating bladder cancer. As a result of PDT, conducted 48 hours after intravenous administration of a hematoporphyrin derivative, researchers observed selective necrosis of a recurrent papillary bladder tumor, while the normal mucosa was not damaged [9].
In 1978, T.J. Dougherty et al. [10] described the development of partial or complete necrosis in 111 cases during the treatment of 113 skin and subcutaneous malignant tumors with PDT. While a lamp light source with a filter system was used in this study, laser radiation with a wavelength of 630 nm was first used in 1980 [11].
From the early 1980s, PDT began to be used for the treatment of endobronchial cancer [12], head and neck tumors [13], esophageal cancer [14–16]. J. Mc Caughan et al. were the first to use PDT for the destruction of choroidal melanoma [16, 17].
In 1984, T.J. Dougherty et al. [18] conducted studies to isolate the active fraction of HpD. A purified mixture of monomers, dimers, and oligomers of hematoporphyrin, after partial removal of the monomers, received the commercial name PhotoCure. This drug became the first and most widely used photosensitizer for PDT of malignant tumors.
In 1993, PhotoCure was approved for clinical use in treating bladder cancer in Canada in 1997 [19, 20] it was approved in the Netherlands and France for obstructive esophageal and lung tumors, in Germany and Japan for the treatment of lung, esophageal, stomach cancer, and cervical cancer, and in the USA for esophageal cancer. In 1998, PhotoCure was approved in the United States for PDT of lung cancer.
In Russia, the domestic counterpart of PhotoCure is the drug Photogem, developed by the Mendeleev Russian Chemical Technology University. Clinical trials, started in 1992, demonstrated its high efficiency.
PhotoCure (USA), Photogem (Russia), and the similar drug Photosan (Germany) belong to the first-generation photosensitizers. For PDT with hematoporphyrin derivative-based drugs, laser radiation with a wavelength of 628–632 nm is used. The depth of photo-induced necrosis does not exceed 1 cm. Light energy doses vary significantly, depending on the tumor size and location, ranging from 50 to 500 J/cm².
Despite their high therapeutic activity, these drugs have several significant drawbacks, the most notable being pronounced phototoxic effects. U.O. Nseyo et al., when analyzing 1009 clinical cases using PhotoCure, noted changes in skin color, such as greenish-yellow-brown or reddish-brown tones. With exposure to sunlight, hyperpigmentation occurred, which persisted for several months. In patients who had recently undergone chemotherapy with doxorubicin, the skin turned gray-blue. With rare exceptions, when the skin reaction lasted up to 6 months, most patients only required avoiding sunlight for a month to prevent phototoxic reactions. However, as many authors emphasize, the discomfort caused by temporary skin photosensitivity is incomparable to the side effects of chemotherapy and radiation therapy.
Photosensitizers accumulate not only in tumor and skin tissues but also in the cells of the reticuloendothelial system, liver, kidneys, spleen, and inflammatory tissues.
Over the past 10–15 years, many second-generation photosensitizers have undergone clinical trials. These compounds mostly belong to the classes of chlorins, bacteriochlorins, phthalocyanines, etc.
Chlorins: Purlytin (SnET2, USA) is a selenium-based etiopurpurin, approved in the United States for the treatment of skin metastases from breast cancer and Kaposi’s sarcoma in HIV-infected patients. Lutex (Lu-tex, lutecephyrin, USA) is used for the treatment of malignant skin lesions, such as metastases of breast cancer, melanoma, Kaposi’s sarcoma, basal cell carcinoma, and squamous cell carcinoma of the skin. A distinctive feature of the Lutex drug is its high selectivity in accumulating in tumors.
Foscan (Germany) is a drug approved in Europe for treating head and neck tumors. Currently, it is the most potent photosensitizer among those described in the literature. For PDT with Foscan, minimal doses (0.1–0.15 mg/kg body weight) and light energy doses (10–20 J/cm² at a wavelength of 652 nm) are required. It should be noted that the use of Foscan has been associated with cases of tracheal and bronchial stenosis, esophagotracheal fistulas, and esophageal perforations. At the same time, the drug is rapidly eliminated from the body, with skin toxicity persisting for only 1 week.
Phthalocyanines: In 1994, the Moscow Institute of Oncology and Chemotherapy developed and clinically tested a new-generation photosensitizer, Photosens, which is a sulfonated aluminum phthalocyanine, used for treating malignant tumors of various localizations. This drug is highly active and induces significant tumor destruction when exposed to laser radiation at wavelengths of 670–675 nm. Photosens has a prolonged retention time in tissues, allowing the development of a method for prolonged photodynamic therapy.
It should be noted that the mentioned photosensitizers do not fully meet the requirements for this group of drugs. The "ideal" photosensitizer should be rapidly excreted from the body, have high absorption in the infrared spectrum range (700–900 nm), a homogeneous chemical composition, and high selectivity in tumor tissue accumulation. The drug should also not be phototoxic at therapeutic doses.
One photosensitizer that meets these requirements is Photoditazin. It is made from the microalgae Spirulina platensis and is based on derivatives of chlorophyll "A." This drug has powerful absorption in the long-wavelength red region of the spectrum (λ max 662 nm), where biological tissues have high transmission and fluorescence in the 660–680 nm range. Photoditazin dissolves well in water without forming aggregated forms, which is typical of hematoporphyrin derivatives. The drug's ability to bind to tumor cell membranes results in its high photodynamic activity. When injected into the body, the maximum accumulation in the tumor occurs within 1.5–2 hours, with a contrast index to surrounding normal tissue greater than 10 and almost complete elimination from the body within 28 hours.
Unfortunately, the mechanisms underlying the selective accumulation of photosensitizers in tumors are not fully understood. After the administration of a photosensitizer, it accumulates in all tissues of the body. However, tumor tissues exhibit a greater affinity for the drug. This is due to the higher number of receptors sensitive to low-molecular-weight proteins in tumors. The lower pH compared to normal tissues and other features of the tumor stroma, such as a larger volume of interstitial space, increased vascular permeability, impaired lymphatic drainage, and a high amount of newly synthesized collagen that binds to porphyrins, contribute to the accumulation of photosensitizers in tumor tissues. Additionally, lipophilic photosensitizers tend to accumulate more in tumors due to the high lipid content of tumor cells. The higher hydrophobicity of the molecule increases its tropism to neoplastic tissues.
Ultimately, the increased accumulation of the photosensitizer means that tumor cells absorb more light energy than normal tissues.
The mechanism of photodynamic therapy (PDT) is complex and not fully understood. Analyzing the literature on the mechanisms of PDT, one can conditionally distinguish between the process of the photodynamic effect or photodynamic reaction and the processes occurring in the tumor after the completion of the photodynamic reaction, i.e., the process of direct tumor tissue destruction.
It is known that the main role in PDT is played by what is called singlet or active oxygen, which is formed in the molecules of lipids and proteins of cell membranes and intracellular organelles when exposed to a quantum of light. Singlet oxygen breaks atomic bonds with other atoms that are part of the molecule and begins to move in a linear direction, advancing about 50 Å within approximately 1 μs. This process results in the breaking of the molecular chain, its destruction, the formation of free radicals, and the damage to cell membranes, occurring within a few minutes after the onset of laser irradiation.
When the photosensitizer molecule absorbs a quantum of light, it also transitions to a singlet state and a more long-lived triplet state. This creates resonance, enhancing the photodynamic reaction, or the photosensitizer molecule in the triplet state transfers energy to the oxygen molecule, converting it into a singlet state. The excited molecules of oxygen and photosensitizer return to their ground state and are capable of undergoing chemical reactions. This entire cycle can be restarted after the arrival of another quantum of light energy. After several cycles, the photosensitizer may photodegrade – "burn out," i.e., lose its ability to participate in the photodynamic reaction. This effect is called photobleaching.
After the destruction of tumor cells due to the photodynamic reaction, all the processes accompanying cell death, regardless of the cause that led to it, occur in the tissue. The specific feature of PDT can be partially attributed to the formation of atomic oxygen and free radicals, which partly engage in chemical reactions with other substances and cause biochemical reactions between newly formed free radicals.
The remaining free radicals and cell debris are removed through venous and lymphatic capillaries, according to the theory of E.H. Starling. Phagocytosis is also activated.
An important role in tumor destruction as a result of PDT is played by the so-called vascular component. Damage to blood vessels during PDT was first discovered by B.W. Henderson (1985), who considered it to be the main mechanism of tumor destruction. The result of the photodynamic reaction is the destruction of the endothelium of blood vessels, platelet activation with the release of thromboxane, and platelet aggregation, leading to the formation of mural and occlusive clots, capillary compression due to interstitial edema. All of this disrupts blood flow to the tumor tissue, even to the point of complete cessation of blood supply, resulting in necrosis.
In recent years, studies have emerged suggesting that one of the mechanisms of PDT is apoptosis. Apoptosis induced by photooxidative distress as a result of photodynamic effects was described by N.L. Oleinick et al. Research results indicate the role of apoptosis in cell death when photosensitizers are localized in mitochondria. However, the role of apoptosis in the mechanisms of PDT remains unresolved and requires further study.
Even less understood is the influence of the immune system on photodynamic therapy. It is known that humoral and cellular immunity is reduced in patients with malignant tumors. However, G. Canti et al. observed an increase in both humoral and cellular immunity in oncological patients undergoing PDT.
J. Nieva et al. believe that all immunoglobulins play a role in the body's defense against malignant tumors as effector participants in the immune system. Regardless of their antigenic specificity, they can catalyze a reaction between singlet oxygen and water, forming H₂O₂, which opens the pathway for antitumor protection in the body during photodynamic therapy.
In reviewing the literature on the mechanisms of PDT, conflicting data are often found, and unfortunately, there are no works that systematize the processes occurring as a result of photodynamic therapy. The presented review is an attempt to formulate a working hypothesis describing the processes that occur in tissues during PDT.*
Get ready to dive into the fascinating world of the development of Photodynamic Therapy and Diagnostics!
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