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Features of the expression of membrane importers of 5-ALA, as well as transporters involved in the removal of photoactive precursors of protoporphyrin IX (PPIX) (uro-, copro- and protoporphyrinogens), may cause differences in the effectiveness of photodynamic therapy of malignant neoplasms using 5-aminolevulinic acid (5-ALA). Increased expression of ALA transporters is associated with an increase in the intensity of PPIX synthesis. When the expression of PPIX exporters increases, there is a decrease in PPIX concentration. The review describes the main transporters of 5-ALA, uro-, copro- and protoporphyrinogens, provides data on their expression in various tissues, and discusses the possibility of predicting the effectiveness of photodynamic therapy considering the expression of the corresponding transport proteins in malignant tissues.

Bowen’s disease is a form of non-invasive (in situ) squamous cell skin cancer localized in the non-genital area. Russian and European clinical guidelines include photodynamic therapy (PDT) in the standard of care for patients with Bowen’s disease. In the present review, the efficacy and safety profile of different PDT regimens for Bowen’s disease are analyzed according to the available literature data. PDT can be used to treat large Bowen’s disease lesions localized in areas of the body characterized by severe healing and in cases where surgery is not feasible. Analysis of the results of studies shows that PDT is superior in efficacy and cosmetic results to traditional local treatments such as 5-fluorouracil or cryotherapy. In all analyzed studies in patients with Bowen’s disease, PDT achieved a significant clinical effect. Complete regression of pathologic foci was achieved in 67-100% of patients. In studies evaluating the recurrence rate of Bowen’s disease after PDT, this value ranged from 2-28% with the range of 6-18% in most of the studies. Most often, 5-aminolevulinic acid and its methyl ester are used for PDT in Bowen’s disease. According to some researchers, aminolevulinic acid allows to achieve a more long-term positive clinical effect with a lower incidence of painful reactions during treatment

Acne is one of the most common skin conditions in the world. A number of studies have shown that photodynamic therapy (PDT) is safe and effective for both inflammatory and non-inflammatory acne and can significantly improve skin conditions in this disease. The effectiveness of PDT against acne is mainly due to a decrease in the amount of sebum produced by the sebaceous glands due to a decrease in their activity as a result of direct photodynamic damage to the sebaceous glands, eradication of Cutibacterium acnes, and a decrease in the level of hyperkeratosis. Compared with systemic drug therapy, PDT treatment of severe acne has the following advantages: fast results, high efficiency, high selectivity, no systemic adverse reactions and drug resistance, and low recurrence rate. Most often for PDT in patients with acne, drugs based on 5-aminolevulinic acid (5-ALA) and its methyl ester (ME-ALA) are used. At the moment, there are no unified recommendations on PDT regimens for the treatment of this skin pathology. Various studies demonstrate the high efficiency of PDT with a wide range of doses of 5-ALA (3-20%) and ME-ALA (4-16%), light doses (15-120 J/cm2 ), and exposure time (30-90 min). The general trend in studies by different authors is that gentle low-intensity PDT regimens for acne demonstrate the same high efficiency with a significant reduction in pain during irradiation and local skin reactions (erythrema, edema, and hyperpigmentation).

Fluorescent diagnostics is a promising method for diagnosing non-melanocytic skin tumors, which makes it possible to identify clinically undetectable skin cancer foci and clarify the margin of the tumor lesion. The main drugs for fluorescent diagnostics are drugs based on 5-aminolevulinic acid and its methyl ester. Sensitivity indicators of fluorescent diagnostics in basal cell, squamous cell carcinoma and extramammary Paget’s disease reach 79.0-100.0%, speci city – 55.6-100%. But the effectiveness of this method may be reduced due to hyperkeratinization, keratinization, and the presence of necrotic tissue on the surface of tumor foci. Comparative studies of the results of fluorescent diagnostics and histological mapping during tumor removal using Mohs micrographic surgery showed approximately equal results in the determining of the tumor edges by these methods, which indicates that safe and technically easily performed fluorescent diagnostics can serve as a good alternative to Mohs micrographic surgery, one of the most accurate, but rather labor-intensive and technically complex method for determining the margin of skin cancer foci.

The review highlights the current understanding of the epidemiology, etiology, pathogenesis, existing classifications of mycosis fungoides. Methods for diagnosis and treatment of the pathology are described, among which photodynamic therapy (PDT) plays an important role. The main advantages of PDT for mycosis fungoides include the absence of systemic toxicity, non-invasiveness, selectivity, absence of carcinogenic potential, the possibility of repeated courses of treatment, and good cosmetic results. This review collects and analyzes the results of clinical trials of PDT in patients with mycosis fungoides. The analysis showed high efficiency of PDT in patients with mycosis fungoides with isolated or limited spots and plaques. PDT can be considered as the therapy of choice in patients with facial lesions when a good cosmetic result is one of the main requirements, and radiation therapy, nitrogen mustard or carmustine can leave permanent and visible scars. Plaques located in the axillary or inguinal skin folds that are inaccessible to phototherapy can also be treated with PDT.

The results of a 13-year clinical observation of a patient after treatment for basal cell carcinoma of the skin of the right cheek Ist cT1N0M0 are presented. The history of the course of the disease is associated with the fact that the patient underwent radiation therapy in early childhood for hemangioma of the lower eyelid of the right eye and right cheek. In 2008, against the background of post-radiation changes in the area of the right cheek, basal cell carcinoma was diagnosed at the Moscow Oncological Research Institute. P.A. Herzen. At the Center for Laser and Photodynamic Diagnostics and Tumor Therapy, the patient underwent organ-preserving PDT treatment. A course of photodynamic therapy (PDT) with 5-aminolevulic acid was carried out. Subsequently, the patient was followed up until 2021 without relapse in the PDT area. In 2016, the patient was diagnosed with a relapse of the disease in the form of a new focus of basal cell carcinoma of the upper eyelid skin on the right Iast cT1N0M0. The patient underwent a course of PDT with a chlorin e6-based photosensitizer. Complete regression of the tumor was achieved, the period of relapse-free follow-up was 5 years.

The article presents a clinical observation. The patient, 72 years old, applied to the MNII them. P.A. Herzen with complaints about the presence of an ulcerated tumor of the left ear. After further examination, a diagnosis was made - basal cell carcinoma of the ear skin with spread to the skin of the parotid region T3N0M0. On July 9, 2021, the patient underwent a course of photodynamic therapy (PDT) using a photosensitizer based on chlorin e6 and a diode laser with a wavelength of 662 nm. After one course of PDT, complete regression of the tumor was recorded.

In the present review the authors analyzed the effectiveness of treatment of intraepithelial neoplasia I-II-III of the cervix (CIN), vulva (VIN) and vagina (VaIN) using photodynamic therapy (PDT). PDT is a method based on exposure to light after preliminary introduction of a photosensitizer into the body with the formation of singlet oxygen, which has a cytotoxic effect. The results of research on the use of PDT with various photosensitizers in the complex of therapeutic measures in patients with CIN, VIN, VaIN are presented. These data on the effectiveness and safety of PDT, ease of use allow this medical technology to be attributed to one of the most promising areas in the treatment of pathological intraepithelial changes of the cervix, vulva and vagina. The presented information allows focusing the attention on the PDT method and informing doctors and researchers about the broad prospects for applying this treatment method in clinical practice.

The review is dedicated to the analysis of the effectiveness of the treatment of erythroplasia of Queyrat (EQ) using photodynamic therapy (PDT). Particular attention is paid to the relationship between EQ and human papillomavirus (HPV) infection. The data of various researchers are presented, confirming the correlation between the development of the EQ and the HPV infection, however, it is noted that due to the small number of studies it is difficult to draw reliable conclusions on the presence and strength of this connection. The mechanisms of PDT involved in the implementation of both the antitumor effect in the treatment of EQ and the antiviral effect against HPV are considered. The data of 12 clinical studies and observations of the results of PDT of the EQ conducted in recent years are analyzed. An analysis of literature data showed that in the treatment of EQ, one of the two photosensitizers is usually used locally: 5-aminolevulinic acid or 5-aminolevulinic acid methyl ester. The treatment parameters in all the analyzed studies were similar: exposure to the ointment for 3–5 hours followed by irradiation with a light dose of 37–105 J/cm2. The number of PDT courses in different studies varied from 1 to 19. The effectiveness of treatment varied widely in different studies and clinical observations. Most studies have demonstrated high efficacy of PDT with complete regression in 36–83% (100% in one study) and a relapse-free follow-up period of up to 51 months. However, there were also individual clinical observations of patients in whom the treatment with the method of PDT was ineffective. It is possible that the described results were associated with improperly selected regimes of PDT or a large lesion area. Most authors especially note a very good cosmetic effect and a complete absence of scars after the treatment. Thus, PDT is an effective and promising method for the treatment of EQ that requires, however, a more thorough development of the application regimen and a deeper study of the antitumor and antiviral components of the mechanism of action.

This article presents the results of a clinical study that examined the diagnostic efficacy of fluorescent diagnostics (FD) of non-muscularinvasive bladder cancer using a photosensitizer of FD of malignant neoplasms – 5-aminolevulinic acid hexyl ester (5-ALA HE) compared with standard cystoscopy. The study involved 110 patients. The study began with intravesical administration of 50 ml of 0.2% solution of 5-ALA HE, the exposure time was 1 hour, after which the drug was removed from the organ. During the next hour, the mucous membranes were examined in two cystoscopy modes, followed by a standard transurethral resection of all urothelium sites with suspicion for tumor lesion based on white light and visible red fluorescence, and a control blind biopsy from the visually unchanged and non-fluorescent mucous tissue in each patient. The results of the study indicate the high effectiveness of the developed FD methodology with 5-ALA HE in detecting non-muscularinvasive bladder cancer during intravesical administration of the drug, due to selective accumulation of hexasens-induced PPIX in the tumor tissue compared with healthy mucosa. Compared with the results of standard cystoscopy, fluorescence diagnostics significantly increased diagnostic sensitivity by 24.4% (from 75.1% to 99.5%), diagnostic accuracy – by 15.8% (from 82.4% to 98.2%) and a negative predictive value – by 33.2% (from 65.8% to 99%) (p≤0.05). Additionally, a total of 37 (33.6%) patients was found to have 63 foci of fluorescence with a diameter of 2.5 to 3.0 mm. 59 of these were morphologically confirmed to contain cancer cells.

A comparative experimental study of the specific activity of drugs based on 5-aminolevulinic acid (5-ALA) and its hexyl ester (5-ALA HE) was carried out. Their ability to induce the synthesis of photoactive protoporphyrin IX in the healthy tissues of the rabbit bladder when instilling the drug solutions at various concentrations has been estimated. It was shown that 5-ALA HE results in the induction and accumulation of PPIX in the rabbit bladder epithelium at much lower concentrations than 5-ALA. Thus, a significant increase in the fluorescence intensity in comparison with the control was achieved by instillation of 5-ALA HE solution in the rabbit’ bladder at a concentration of only 0.0001% (fluorescence intensity 2.20±0.60 a.u.), and for 5-ALA – only when using a solution at a concentration of 0.3% (fluorescence intensity 2.60±1.02 a.u.).

The results of multicenter trial for efficacy of fluorescence diagnosis for bladder cancer with agent hexasens (SSC Scientific Research Institute Organic Intermediates and Dyes, Russia) based on hexyl ester of 5-aminolevulinic acid compared with routine cystoscopy are represented in the article. The study included 124 patients. All patients had intravesical instillation of 50 ml of 0,2% hexasens. The exposure time accounted for 1-2 h. After removal of the drug from bladder standard cystoscopy followed by fluorescence diagnosis was performed in every patient. During the local fluorescence spectroscopy the intravesical instillation of the agent hexasens was shown to induce selective accumulation of photoactive protoporphyrin IX in tumor cells comparing with intact bladder mucosa. During 1 h after intravesical instillation of hexasens solution the level of fluorescence of hexasens-induced protoporphyrin IX in the tumor was higher than that in surrounding intact mucosa at average in 5.8 fold. As compared with results of standard cystoscopy, fluorescence diagnosis improved the sensitivity of the method by 24.4% (from 75.6% to 100%), the accuracy – by 15.2% (from 83.3% to 98.5%) and negative predictive value – by 33.5% (from 66.5% to 100%). Fluorescence diagnosis gave an opportunity to detect additional tumor foci, which were invisible in white light, in 27.4% of patients. For fluorescence diagnosis in 4.0% of patients false-positive fluorescence of bladder mucosa was detected that was probably due to inflammation. None of patients received active dose of the drug hexasens had adverse reactions, changes in general well-being and blood and urine parameters. According to the results of the study fluorescence diagnosis with hexasens for bladder cancer is recommended for use in clinical practice.

The original method of intraoperative photodynamic therapy for multimodality treatment of primary and recurrent breast cancer for devitalization of malifnant cells at wound surface and for prevention of further cancer dissemination was developed in P.A. Herzen Moscow Cancer Research Institute. The developed method was approved in 79 patients with locally advanced breast cancer stage IIB and IIIA,B,C with poor prognostic factors. For photodynamic therapy the photosensitizer photosens (30 min intravenous infusion at dose of 0.3 mg/kg of body weight 2 h before surgery) was used in 56 patients; alasens (solution in 100 ml of still drinking water, orally at dose of 30 mg/kg of body weight 2 h before general anesthesia) — in 23 patients. The surgical field was irradiated on a single occasion: the dose of laser irradiation on the bed of removed primary or recurrent tumor was 20–30 J/cm2, in the removed regional lymph nodes area – 50 J/cm2. Long-term results of the treatment were assessed in 34 patients: there were no disease progression in 50% of patients, 14.7% of patients had locoregional recurrence, distant metastases were in 35.3% of patients. The level of photosensitizer accumulation in tissue was additionally analyzed in 26 patients by fluorescence intensity in tumor and in normal breast tissue. After injection of alasens the increase in level of alasens-induced protoporphyrin IX fluorescence was recorded in tumor (the average diagnostic parameter was 6.5 a.u.) and in intact breast tissue (an average of 0.47 a.u.), tumor/normal tissue fluorescence contrast varied from 3 to 33. The level of protoporphyrin IX accumulation was noticed to be lower in tumors with pathomorphological response after neoadjuvant therapy. For photosens value of the average diagnostic parameter in normal breast tissue was 5.6 a.u., in tumor – 34.3 a.u., tumor/normal tissue fluorescence contrast – from 2 to 9.

The results of clinical study for efficacy of photodynamic therapy (PDT) with radachlorine in patients with pre-cancer and cancer of cervix are represented. The study enrolled 30 patients including 4 patients with cervical erosion, 5 patients with cervical intraepithelial neoplasia II, 13 patients with cervical intraepithelial neoplasia III, 4 patients with carcinoma in situ and 4 patients with cervical cancer stage Ia. Radachlorine was administrated as single 30 minute intravenous injection at dose of 1,0 mg/kg of body weight 3 h before irradiation (wavelength of 662 nm, light dose of 300–350 J/cm2). The results of treatment in 26 (86,7%) patients was assessed as complete tumor regression and in 4 (13,3%) patients — as partial regression. In cervical erosion, intraepithelial neoplasia II and carcinoma in situ groups total regression was in all cases. In the cervical intraepithelial neoplasia III group total regression after first course of PDT was achieved in 77% of patients, in cervical cancer stage Ia group – in 75% of patients. From 3 to 6 months after first course of treatment all patients with partial tumor regression underwent the second course of PDT with complete regression. There were no side-effects due to radachorine or PDT in the course of treatment and during follow-up. Thus, PDT with Russian photosensitizer radachlorine showed high efficiency for treatment of pre-cancer and cancer of cervix.

The results of multicenter prospective trial for efficacy of combined modality treatment: transurethral resection (TUR) + photodynamic therapy (PDT) with alasens for bladder cancer are represented in the article. Trials were organized by Research Institute of Organic Intermediates and Dyes and conducted according to clinical protocol approved by Ministry of Health of Russia, at the sites of leading Russian cancer clinical centers. The trial included 45 subjects with verified diagnosis of non-muscle-invasive bladder cancer. Patients underwent TUR of bladder with simultaneous PDT as anti-relapse treatment. Alasens was administered to patients as intravesicular instillation of 3% solution in volume of 50 ml with 1.5–2h exposure (prior to TUR). TUR was performed after instillation. PDT session was conducted immediately after the completion of TUR on a single occasion by means of combined local irradiation on tumor bed with diffuse irradiation on whole urinary bladder mucosa (light dose of local irradiation – 100 J/cm2, diffuse irradiation – 20 J/cm2). Good tolerance of the treatment was noticed, there were no complications. Among 45 patients included in the trial, 35 (78%) completed 12 month protocol follow-up without relapse. The recurrence of bladder tumor was registered in 10 (22%) cases 6–12 months after TUR+PDT including 3 patients with recurrence 6 months after treatment, 3–9 months and 4–12 months. These patients underwent repeated TUR, whereafter their follow-up in the settings of the clinical trial was disposed. Thus, PDT with alasens after TUR allowed to decrease the recurrence rate of non-muscle-invasive bladder cancer for 1st year after treatment to 22% versus 40–80% for TUR as monotherapy according to literature data. The obtained results were comparable by efficiency with TUR combined with methods of adjuvant treatment for bladder tumors (the recurrence rates for 1-year follow-up after TUR+chemotherapy – 36–44%, after TUR+BCG – 20–59%).

The case of successful intraoperative fluorescence diagnosis (IOFD) for removal of cervical and thoracic ependymoma performed in P.A. Herzen MCRI is reported. For FD we used the Alasens (Research Institute of Organic Semi-Finished Products and Dyes). The drug solution was given per os at a dose of 20 mg/kg body weight 2.5 h before surgery. IOFD was per-formed 3 h after intake of photosensitizer. For fluorescence diagnosis there was average in-tensity of fluorescence in tumor and no fluorescence in normal spinal tissues. The extent of surgery was determined according to results of IOFD. The control MRI of cervical and supeior thoracic spine with contrast enhancement and follow-up confirmed definitive removal of tumor and showed no postoperative complications.

The review of available theories explaining mechanisms of photosensitizer selective accumulation in tumor tissue is represented in the article. Variants associated with both targeted delivery of compounds with different chemical structure to tumor and low elimination rate of photosensitizers in the tumor are described. Details of tumor cell up-take of photosensitizer bounded with lipoproteins due to increased expression of low solidity lipoproteins receptors comparing with normal cells; mechanisms of photosensitizer accumulation in tumor tissue due to phagocytosis by macrophages localized in this area; mechanisms of binding of porphyrin-based photosensitizer by collagen fibers, production of which is increased in tumor cells, and other mechanisms are reviewed. Perspectives of practical application of knowledge about mechanisms of selective accumulation for induced increase in selectiveness of photosensitizer accumulation in tumor through targeted delivery of agent to pathological tissues are shown. Analysis of world trends in the search of transport systems for photosensitizers is performed.

The results of investigation for photodynamic activity of new tetraazachlorin derivate – tetramethyltribenzotetraazachlorin, synthesized in Research Institute of Organic Intermediates and Dyes. The study was performed on female mice of СВА line. The tumor model was transferred solid ascetic sarcoma S-37. The samples of photosensitizer, previously solubilized in 10% aqueou s solution ofCremophor EL, injected to mice intravenously on the 7th day of tumor growth in dose of 1–2 mg/kg. Two hours later the irradiation of sensitized tumor using light emitting diode device in a maximal wavelength of 755 nm (light power density – 50 mW/cm2, maximal total light dose – 300 J/cm2) was performed. The efficacy of photodynamic therapy was assessed by growth inhibition rates in the study group comparing with control group. The study showed that photodynamic therapy with investigated sample in dose of 2 mg/kg and light dose of 300 J/cm2 significantly inhibited the tumor growth (inhibition rate of 70–80% within 20 days), indicating prospectivity of subsequent investigations of tetraazachlorin as photosensitizer for photodynamic therapy of malignant tumors.