The effect of high-energy (660 MeV) proton irradiation at the phasotron accelerator in FLASH mode (80 Gy/s) compared with the standard proton exposure power of 3.0 Gy/min was studied. When irradiated in two modes at doses of 1.0 and 1.5 Gy, the induction of cytogenetic damage in bone marrow cells and the state of lymphoid organs (thymus and spleen) were evaluated; survival under total in vivo irradiation of mice was analyzed at doses of 7.0 and 8.0 Gy. The growth rate of a model tumor under ex vivo irradiation was determined at doses of 40 and 60 Gy. It has been shown that irradiation of animals in the FLASH mode at a dose of 1.5 Gy protected the proliferative activity of the spleen and also led to a decrease in cytogenetic damage in bone marrow erythrocytes according to the micronucleus test compared with the standard irradiation mode at a dose of 1.5 Gy, that is, a milder effect of the FLASH mode dose was observed. However, irradiation of mice in FLASH mode at high doses (7.0 and 8.0 Gy) led to earlier death of animals compared to the standard irradiation regime. A tumor node formed with further growth only after FLASH irradiation of a suspension of Ehrlich ascites carcinoma at a dose of 40 Gy; in all other groups a tumor was not formed.

JINR in collaboration with the St. Petersburg-based Efremov Institute of Electrophysical Apparatus (NIIEFA) is developing a superconducting isochronous cyclotron MSC230, which is intended to conduct research in radiobiology and to develop proton flash radiotherapy techniques. In relation to this, formation of a high-intensity proton beam with the energy selectable in a range of 120–230 MeV, a dose rate of 50–100 Gy/s, and homogeneous in cross section with a diameter of 13–15 cm at the new accelerator is explored. Results of modeling by the Monte Carlo method and measurements of the depth-dose distributions of a proton beam, the energy spectrum of which is modified to obtain an extended homogeneous plateau at the end of the range (spread-out Bragg peak), are presented. This is achieved by using so-called ridge filters. A method for design and manufacturing ridge filters using a 3D printer that can change the length of the plateau in a fairly wide range of values by rotating it relative to the beam axis is presented. The results of the study lend a hope that two sets, each consisting of 5–6 such filters, will be able to span the entire required range of the Bragg peak plateau, and for all values of the selected energy.

Flash irradiation is an innovative method of therapy, which ensures that the therapeutic dose is brought to the pathological focus in times of the order of several tens of milliseconds. In this mode of irradiation, the degree of damage to normal tissues surrounding the tumor that fall under the influence of radiation decreases; at the same time, the effect on cancer cells remains at almost the same level, which improves the prospect of local control of the tumor with a lower frequency of side effects. The exact radiobiological mechanisms underlying the flash effect are not completely clear. This paper presents the results of work on the formation of a high-intensity proton beam with an energy of 660 MeV from the phasotron accelerator of the Joint Institute for Nuclear Research (Dubna), designed to conduct radiobiological studies of flash irradiation therapy on cell cultures and small laboratory animals (mice and rats). The survival rate of A549 cells under proton beam irradiation in flash and standard modes was compared. A difference was found in the change in the survival rate of A549 cells irradiated in flash and standard modes. The magnitude of the flash effect was represented by the dose change factor.

Introduction: Radioprotectors help to protect the body or at least minimize the negative consequences of radiation exposure. The present study aimed to assess the radioprotective potential of Helianthus tuberosus L. polysaccharide (HTLP) in vitality and micronuclei tests. To assess the cytotoxic effects of HTLP, both vitality and MTT reductase assays were conducted. Materials and methods: RAW 264.7 cells viability was assessed 24 h after adding 200 mu g/ml HTLP solution by staining cell cultures with propidium iodide and bis-benzimide to detect the nuclei of dead cells and the total number of cells in culture. To assess cell viability via cellular metabolic activity MTT test was used. In this work outbred 24-30 g 5-months old SHK mice have been used. Irradiation was provided with proton beams with an energy of 660 MeV at a dose rate of 80 Gy with doses 1.5 Gy for micronuclei test and 8.5 Gy for survival test. Whole body X-ray irradiation was conducted using the RUT-15 therapeutic X-ray unit with doses of 1.5 Gy for MN test and 6.5 Gy for survival. The HTLP sterile solution in dose 100 mu g/animal was injected into the tail vein 15 min before X-ray or proton irradiation. Results and conclusion: s: Vitality test showed no significant differences between the control group and cells treated with 200 mu l of 200 mu g/ml HTLP solution, though a greater variability was noted. In contrast, the MTT assay indicated enhanced cell viability in the HTLP-treated cells. HTLP does not exert any toxic effects in cell culture. Moreover, results of MTT reductase assay shows, that HTLP may enhance the cells' metabolic activity. Animals pre-treated with HTLP displayed a significant reduction in micronuclei formation, showing five times fewer micronuclei in bone marrow cells compared to the non-treated group. This comparison highlights HTLP's potential protective effect against radiation-induced chromosomal damage. HTLP treatment demonstrates a significant reduction in hazard compared to the control, indicating its protective effects against irradiation. Thus, it can be concluded that the use of HTLP increases the likelihood of animal survival under the ionizing effects of X-rays and protons. The survival analysis reveals that the HTLP-treated groups exhibit a higher survival rate compared to both the control and Cysteamine-treated groups, suggesting a significant protective effect of HTLP against irradiation, regardless of the type of irradiation (proton or X-ray) with p < 0.0001.

FLASH radiotherapy is the innovative radiotherapy technique in which the short treatment times, few tens of milliseconds, are used to deliver a therapeutic dose of radiation to the tumor. This novel approach reduces damage and minimizes the dose to normal tissues surrounding the tumor and to tissues that are affected by radiation, whilst maintaining the treatment effect on cancer cells. This regimen may improve the level of local control of the tumor and lower the occurrence of side effects. To date, the exact radiobiological mechanisms underpinning the FLASH effect are not completely understood. The paper presents the results on the delivery of a high-intensity proton beam at an energy of 660 MeV produced by Phasotron, a proton accelerator at the Joint Institute for Nuclear Research, Dubna. This proton beam has been created to perform radiobiological studies involving cell cultures and small laboratory animals (mice, rats) using FLASH radiation. Also, the survival rates were compared between A549 cells irradiated at extremely high dose rates (FLASH technique) and those exposed to conventional irradiation with the lower dose rate. It was found that there is a difference between these groups of A549 cells in the survival rates. The magnitude of the FLASH effect is represented by a factor of different dose rates.

The FLASH effect of high-energy (660 MeV) proton irradiation using the Phasotron accelerator with the capacity of delivering dose rates of 80 Gy/s has been studied and compared to the effect after exposure to proton radiation at a conventional dose rate of 3 Gy/min. After FLASH and conventional dose-rate irradiation with doses of 1.0 and 1.5 Gy, the induction of cytogenetic damage to bone marrow cells and the state of lymphoid organs (thymus and spleen) were estimated; at doses of 7.0 and 8.0 Gy, the survival rate after total irradiation of mice in vivo was analyzed; and at doses of 40 and 60 Gy, the tumor growth rate was determined after irradiation ex vivo. It has been shown that irradiation of animals using the FLASH mode at a dose of 1.5 Gy protects the proliferative activity of the spleen and also leads to a decrease in cytogenetic injuries in bone marrow erythrocytes, based on the micronucleus test, as compared to the conventional irradiation at a dose of 1.5 Gy; thus, the FLASH effect has lower toxicity compared to conventional radiation. However, irradiation of mice, the FLASH effect which delivers high doses (7.0 and 8.0 Gy) of radiation, leads to earlier death of animals compared to those exposed to conventional radiation. Only after FLASH irradiation of a suspension of Ehrlich ascites carcinoma at a dose of 40 Gy, a tumor node with further growth was formed; no tumors were formed in all other groups.

The NICA accelerator complex includes beam transfer lines and stations for applied research. The first commissioning of the Station of Chip Irradiation (SOCHI) was performed at the end of 2021with С4+ heavy ions extracted from the linear accelerator (HILAC) at an energy of 3.2 MeV/n. The new SOCHI beam transfer line is integrated in the existing HILAC-Booster beamline. The Irradiation Setup for Components of Radioelectronic Apparatus (ISCRA) with ion energy ranging from 150 to 500 MeV/n and the Setup for Investigation of Medical Biological Objects (SIMBO) with the ion energy ranging from 400 to1100 MeV/n are based on the beams extracted from Nuclotron. The equipment of ISCRA and SIMBO stations has been manufactured and is planned to mount in the end of 2022. The beamlines are being designed now. The technical parameters of the beamlines and stations and the results of the first run of the SOCHI station are presented in this study.

Flash-therapy is a rapidly developing field of radiology that has the potential to revolutionize future cancer treatment techniques. The method involves delivery the therapeutic radiation dose to the tumor volume at an ultra-high dose rate in the beam, several orders of magnitude higher than that usually used in conventional radiotherapy. In this mode of irradiation, the degree of damage to normal tissues surrounding the tumor and falling under the influence of radiation decreases, at the same time, the effect on cancer cells remains at the same level, which preserves the prospect of local control of the tumor with a lower frequency of side effects. The paper presents the results on the delivery of a high-intensity proton beam with an energy of 660 MeV from the Phasotron of the Joint Institute for Nuclear Research, Dubna, designed for radiobiological studies under flash therapy irradiation of cell cultures and small laboratory animals (mice, rats). In addition, the main design features and parameters of the created detectors for measuring the characteristics of this beam are presented.

Purpose: To study was to study the effect of GNP nanoparticles on tumor cells of human lung carcinoma A 549 when irradiated with protons. Materials and methods: Cell culture: Human lung carcinoma cells A 549. Gold nanoparticles Au/PEG 6000/W 200/30 nm: A colloidal solution of gold nanoparticles purchased from the firm M 9 Nanomaterials & Technologies was used in the work. Proton irradiation: The irradiation of cells was carried out on a therapeutic proton beam in the Medical and Technical Complex of the Laboratory of Nuclear Problems Joint Institute for Nuclear Research. Determination of radiosensitivity of cells: By determining the clonogenic survival of cells. Determination of the genotoxic activity of nanoparticles under the action of proton irradiation: investigated using a micronucleus test with blocking cytokinesis. The genotoxicity of gold nanoparticles was estimated by the number of micronuclei per 1000 binuclear cells. Micronucleus were counted only in binuclear cells. At least 1000 binuclear cells were calculated for each dose, experiments were carried out in three repeats. Results: The frequency of micronucleus formation indicates an increase in the genotoxic effect of nanoparticles when irradiated with protons at a dose of 2 Gy. Proton irradiation caused an increase in the frequency of micronucleus formation depending on the concentration of nanoparticles. When irradiated with protons at a dose of 2 Gy in the presence and absence of nanoparticles, the difference in the frequency of micronucleus formation for the concentration of nanoparticles was 2.5 mg/ml – 1.1; for 5 mg/ml and 10 mg/ml – 1.2; for 15 mg/ml – 1.3 and for 30 mg/ml –1.5. Cell survival curves reflect a decrease in their survival rate when metal nanoparticles with high Z are added, which reflects the occurrence of radiosensitization effects. The gain for 10 % and 50 % survival rates is 1.4 and 2.5, respectively. Conclusions: Under the influence of proton irradiation, the genotoxic activity of gold nanoparticles in human lung carcinoma cells A 549 increases, depending on their concentration. The survival rate of human lung carcinoma A 549 cells irradiated with protons in the presence of gold nanoparticles decreases.

The applied stations: ISCRA (energy range of 150–500 MeV/n), SOCHI (ion energy up to 3.2 MeV/n), and SIMBO (energy range 500–1000 MeV/n) are under construction as a part of the NICA accelerator complex. These stations will be used for single event effects testing of as capsulated, so decapsulated microchips, and for radiobiological research and modelling of influence of heavy charged particles on cognitive functions of animal's brain, respectively. This paper presents the applied stations description. Mounting and commissioning of the SOCHI station are completed. The ISCRA and SIMBO stations mounting is planned in early 2022. Beam runs at the SOCHI were performed in December 2021, at the ISCRA and SIMBO are planned in fall 2022.

New beam channels and stations for applied research at the NICA complex are currently under construction at JINR. They are intended for radiobiological studies and investigation into electronics irradiation by high-energy and low-energy ion beams. A detailed technical design of the magnet and the vacuum systems is ready. Construction of these systems is started. Installation and commissioning are planned for summer 2022 followed by the first beam run in autumn 2022. The project status overview is given, and practical technical highlights are presented.

Studies at the Medical Technical Complex (MTC) of the Joint Institute for Nuclear Research (Dubna) developed an automatic multileaf collimator (MLC) under the working name Aura for forming therapeutic proton beam of defined cross-sectional shape (aperture) for use in a passive 3D conformal radiotherapy in the treatment of oncological disease of the head and neck. A prototype collimator was constructed using four pairs of leaves and was subjected to a series of experimental tests whose results satisfied the requirements. A full-scale MLC will be used as one of the main devices in the new dynamic irradiation system for deep-seated targets of complex shape.

Nowadays space exploration has faced the issue of radiation risk to microelectronics and biological objects. The new beamlines and irradiation stations of the Nuclotron-based Ion Collider fAcility (NICA) at JINR are currently under construction to study this issue. The beamline parameters, different methods for homogeneous irradiation of targets such as scanning, and beam profile shaping by octupole magnets are discussed. A short description of the building infrastructure, magnet elements, and detectors for these beamlines is also given.

Within the framework of the NICA project an Innovation Block is being constructed. It includes an applied research station for microchips with a package for Single Event Effects (SEE) testing (energy range of 150-500 MeV/n, the SODIT station), an applied research station for testing of decapsulated microchips (ion energy up to 3,2 MeV/n, the SOCIT station), and an applied research station for space radiobiological research and modelling of influence of heavy charged particles on cognitive functions of the brain of small laboratory animals and primates (energy range 500-1000 MeV/n, the SODIB station). The systems for diagnostics and control of the beam characteristics during the certification and adjustment as well as the systems for online diagnostics and control of the beam characteristics of the SOCIT, SODIT and SODIB applied research stations are described.

A new technique for dynamic irradiation of deep–seated targets of complex shape has been developed at the Medical–Technical Complex of the Joint Institute of Nuclear Research (Dubna). The technique is implemented using a variable–thickness automated range shifter and a multileaf collimator. The devices were constructed taking cognizance of the characteristics of the existing system for forming radiotherapy proton beams. Preliminary results of dosimetry measurements demonstrated better irradiation field conformity compared to the standard technique of 3D passive conformal proton radiotherapy.

Applied research at the NICA accelerator complex include the following areas that are under construction: single event effects testing on capsulated microchips (energy range of 150-500 MeV/n) at the Irradiation Setup for Components of Radioelectronic Apparature (ISCRA) and on decapsulated microchips (ion energy up to 3,2 MeV/n) at the Station of CHip Irradiation (SOCHI), space radiobiological research and modelling of influence of heavy charged particles on cognitive functions of the brain of small laboratory animals and primates (ener-gy range 500-1000 MeV/n) at the Setup for Investigation of Medical Biological Objects (SIMBO). Description of main systems and beam parameters at the ISCRA, SOCHI and SIMBO applied research stations is presented. The new beam transfer lines from the Nuclotron to ISCRA and SIMBO stations, and from HILAC to SOCHI station are being constructed. Description of the transfer lines layout, the magnets and diagnostic detectors, results of the beam dynamics simulations are described given.

Для облучения новообразований, расположенных вблизи жизненно важных радиочувствительных структур и органов необходимо обеспечить точное пространственное совмещение пучка с мишенью в сеансах протонной терапии. Целью работы является сравнение и анализ распределений доз, полученных в программе планирования протонного пучка и измеренных в результате эксперимента с применением радиохромных пленок в Медико-техническом комплексе (МТК) Лаборатории ядерных проблем (ЛЯП) Объединенного института ядерных исследований (ОИЯИ). На первом этапе измерений было определено соответствие степени потемнения пленки от дозы облучения. Для этого из одного листа пленки были вырезаны тринадцать кусочков размером 20×20 мм, которые затем облучали дозами (0; 0.25; 0.5; до 3 Гр). На их основе построена калибровочная кривая и рассчитано уравнение аппроксимации, которое использовано для перевода значений матрицы потемнения облученных пленок в значения поглощенной дозы. Продольный и поперечный спад дозы от уровня 80% до уровня 20% происходит соответственно на глубине 9.2±0.3 мм и на ширине 9.0±0.3 мм.

Для облучения новообразований, расположенных вблизи жизненно важных радиочувствительных структур и органов, разработана методика трехмерной конформной протонной лучевой терапии в Медико-техническом комплексе Лаборатории ядерных проблем Объединенного института ядерных исследований (Дубна), при которой максимум сформированного дозного распределения наиболее точно совпадает с формой мишени. При этом доза резко спадает за границами мишени, что позволяет проводить облучение ранее не доступных для лучевой терапии локализаций. В настоящей работе приводятся основные технологические этапы предлучевой подготовки и проведения облучения по разработанной методике.

First experiments on using proton beams for radiotherapy of malignant tumours at the 680 MeV proton synchrocyclotron of the V.P. Dzhelepov Laboratory of Nuclear Problems of the Joint Institute for Nuclear Research (DLNP JINR) have been initiated by Prof. V.P. Dzhelepov and were started in 1967. 28 patients with different types of superficially located malignancies, such as skin melanomas, metastases of cancer to peripheral nodes, larynx cancers and so on, were treated during the period of 1967–1971. Then the method of scanning rotation irradiation of deep-seated tumours was developed and started to use at DLNP JINR. 50 patients with esophagus cancer, larynx cancer and metastases of malignant tumors were treated with that technique. During the period of 1974–1984 the synchrocyclotron was modified to the Phasotron with the increase of output current. At the same time, a multi-room Medico-technical complex for hadron radiotherapy of cancer patients was constructed. It allows tumour treatment with wide and narrow horizontal beams of protons (70–660 MeV), negative pions (30–80 MeV), high-energy neutrons (mean energy 350 MeV), and with their combinations. The complex includes also the standard gamma-therapy unite Rokus-M with 60Co source for external irradiation. The unique equipment has been developed and constructed, including full-scale PET, X-ray CT for topometry of patients in sitting position, and proton CT. A new round of the development started in December 1999 when a specialized radiological department of patient capacity of 25 beds was opened in Dubna. Since 2000 regular sessions have been conducted in research of proton therapy efficiency in irradiation of patients with neoplasms located in the head, neck and other parts of the body. 1283 patients have received courses of radiotherapy at the Phasotron beams by the end of 2018. The technique of 3D conformal proton radiotherapy in which the maximum of the formed dose distribution conforms most accurately to the shape of the irradiated target has been realized and put into operation. In this way, the maximum sparing effect is achieved in normal tissues and organs surrounding the tumor. The statistical analysis of the proton treatment results of two classes of neoplasms treated with the JINR proton beam (arteriovenous malformation) of the brain and the skull base chordomas and chondrosarcomas) are presented. A new project of the development and construction of a modern superconducting cyclotron SC202 dedicated for proton radiotherapy was prepared recently by the staff of the DLNP JINR and Institute of Plasma Physics Chinese Academy of Sciences (Hefei, China). It is supposed that the accelerator will become the base of a new Proton Therapy Centre in Dubna. It will consist of two treatment rooms: the first one will be equipped with static wide horizontal proton beam and a therapeutic chair, and the second one is planned to provide with gantry for a pencil proton beam dynamic scanning and a positioner for supine patient position during irradiation.