RU2743417C1 - Method for determination of the absorbed dose of recoil nuclei - Google Patents

Abstract

FIELD: biotechnology

SUBSTANCE: invention relates to the field of biotechnology, namely, to the determination of the absorbed dose of recoil nuclei, as the sum of the doses of fast neutrons and thermal neutrons. The method includes irradiation of cell cultures with γ-radiation and mixed radiation (γ-radiation and neutron radiation). Next, the determination of γ-radiation D_γ dose, leading to the same magnitude of cell survival, and determination of the absorbed dose of recoil nuclei D_n from the ratio D_n=Dγ _standard –D_{γ mixed} are carried out, where D_n is absorbed dose of recoil nuclei, g eq.; D_{γ standard} is dose of γ-radiation when cells are irradiated with γ-radiation, g; D_{γ mixed} is dose of γ-radiation when cells are irradiated with mixed radiation, g.

EFFECT: invention makes it possible to measure the absorbed dose of recoil nuclei - the sum of the doses of fast neutrons and thermal neutrons - necessary for planning boron-neutron capture therapy for malignant tumors.

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Description

The invention relates to nuclear medicine, in particular to neuro-oncology, and can be used when carrying out boron neutron capture therapy (BNCT) of malignant tumors to determine the absorbed dose.

The concept of neutron capture therapy in oncology was proposed in 1936, four years after the discovery of the neutron. Its physical principle is as follows. A solution containing a stable isotope boron-10 is introduced into human blood, and after a while boron is sorbed mainly in tumor cells. Then the tumor is irradiated with a flux of epithermal neutrons with energies from 0.5 eV to 10 keV. As a result of the absorption of a neutron by a stable isotope ¹⁰ V, a nuclear reaction occurs, and the resulting energetic α-particle and ⁷ Li ion are rapidly decelerated over the length of the cell size, releasing an energy of ~ 2.3 MeV within the cell that contained the boron nucleus, and leading to her defeat. Thus, boron neutron capture therapy makes it possible to selectively damage cells of malignant tumors.

The feasibility of developing the technology of neutron capture therapy is due to its focus on the treatment of such types of malignant tumors that practically do not lend themselves to any other methods - brain glioblastomas and melanoma metastases.

Clinical trials of the BNCT technique were carried out at nuclear reactors, and positive results were obtained in the treatment of glioblastoma, melanoma, neck tumors, meningioma, pleural mesothelioma and hepatocellular carcinoma [W. Sauerwein, A. Wittig, R. Moss, Y. Nakagawa (Eds.), Neutron Capture Therapy: Principles and Applications (Springer, 2012)].

The widespread introduction of the technique into clinical practice is associated with the use of charged particle accelerators due to their safety and the possibility of forming a therapeutic neutron beam of better quality. The greatest attention is focused on two threshold reactions: ⁷ Li (p, n) ⁷ Be and ⁹ Be (p, n) ⁹ V, of which ⁷ Li (p, n) ⁷ Be is recognized as the best because of the maximum yield and minimum energy of neutrons [T. Blue, J. Yanch. Accelerator-based epilhermal neutron sources for boron neutron capture therapy of brain tumors. J. Neuro-Oncol. 62, 19 (2003)].

Several groups of researchers managed to solve the problem of creating an accelerator neutron source of the epithermal energy range, and at present the first five BNCT clinics are being built in the world everywhere by different teams with different technical solutions [S.Yu. Taskaev. Development of an accelerating source of epithermal neutrons for boron neutron capture therapy. Physics of elementary particles and atomic nucleus. 50, 657 (2019)].

One of the main problems to be solved for the introduction of BNCT into clinical practice is the measurement of the absorbed dose.

The following processes contribute to the absorbed dose.

First, the process of absorption of thermal neutrons by boron, as a result of which an energy of 2.79 MeV is released - in 6.1% of cases the energy is distributed only between lithium nuclei and an α-particle, in 93.9% of cases the lithium nucleus escapes in an excited state and emits a γ-quantum with an energy of 0.48 MeV.

Second, the capture of thermal neutrons by hydrogen, leading to the formation of deuterium and to the instantaneous emission of a γ-quantum with an energy of 2.2 MeV; capture of thermal neutrons by chlorine, leading to the instantaneous emission of a γ-quantum with an energy of 8.85 MeV; capture of thermal neutrons by nitrogen, leading to the formation of a ¹⁴ C recoil nucleus and a recoil proton with an energy release of 580 keV, and neutron capture by chlorine, leading to the formation of a ³⁵ S recoil nucleus and a recoil proton with an energy release.

Third, the radiative capture of neutrons by sodium, chlorine, potassium and manganese, leading to their activation with the subsequent emission of γ-quanta. The table shows the characteristics of these stable nuclei and radioactive nuclei formed by the absorption of neutrons.

Fourth, the appearance of recoil nuclei during elastic scattering of neutrons, mainly fast ones, from the nuclei of matter, mainly hydrogen.

Fifth, the flux of γ-quanta from the accelerator, target, neutron beam formation system and from the irradiated object (patient). A charged particle accelerator is a source of bremsstrahlung due to the inevitably present high-energy electron fluxes. The lithium neutron-generating target is a source of γ-quanta with an energy of 478 keV, emitted as a result of inelastic scattering of protons on atomic nuclei of lithium in the reaction ⁷ Li (p, p'γ) ⁷ Li and emitted as a result of the decay of the radioactive isotope beryllium-7, formed in the reaction generation of neutrons ⁷ Li (p, n) ⁷ Be. The source of γ-quanta with an energy of 2.2 MeV is water cooling the target due to absorption of neutrons by hydrogen in the reaction ¹ H (n, γ) ² H. Some structural materials of the neutron beam formation system are activated by neutrons and are sources of γ- radiation, usually much less intense than the radiation intensity of the accelerator and the target. Internal sources of γ-radiation are nuclear reactions of absorption of neutrons by hydrogen and chlorine, leading to the instantaneous emission of γ-quanta, and nuclear reactions of radiative capture of neutrons by sodium, chlorine, potassium and manganese, leading to their activation followed by the emission of γ-quanta.

In BNCT, it is customary to distinguish four components of the absorbed dose:

1) Boron dose due to α-particles and atomic nuclei of lithium - products of the nuclear reaction ¹⁰ B (n, αγ) ⁷ Li. Due to the small path length of particles, this dose is released in a small volume - in the volume of the cell containing the boron nucleus. In the BNCT technique, when boron is accumulated mainly in tumor cells, the boron dose is therapeutic; they strive to make it as large as possible.

2) The dose of γ-radiation due to the ionization of atoms of a substance under the influence of γ-radiation. The sources of γ-quanta are a charged particle accelerator, a neutron-generating target, a neutron beam formation system, and an irradiated object (patient).

3) The dose of fast neutrons due to recoil nuclei in the elastic scattering of neutrons, mainly fast, on the nuclei of matter, mainly hydrogen.

4) The dose of thermal neutrons due to recoil nuclei, mainly protons, of the nuclear reaction of neutron absorption by the atomic nucleus of chlorine ³⁵ Cl (n, p) ³⁵ S and nitrogen ^l4 N (n, p) ^l4 C. The main contribution to the dose is made by the reaction ¹⁴ N ( n, p) ^l4 C due to the larger cross section and higher nitrogen concentration in the human body. For this reason, this dose from thermal neutrons is sometimes referred to as the "nitrogen" dose.

Although it is customary to separate the dose of fast neutrons and the dose of thermal neutrons separately, in both cases the ionization of matter is carried out by recoil nuclei - the products of elastic scattering of fast neutrons by the atomic nuclei of matter and the products of the nuclear reaction of absorption of thermal neutrons by atomic nuclei of chlorine and nitrogen. On the basis of the ionization of matter by recoil nuclei, let us combine the dose of fast neutrons and the dose of thermal neutrons in the dose of recoil nuclei.

In the course of therapy, each of these components makes its own contribution to the absorbed dose, some of them - a determining contribution. Thus, the boron dose is decisive in the irradiation of tumor cells in which boron is accumulated. The dose of fast neutrons is significant for the skin, through the surface of which a neutron flux is directed to the tumor. The dose of thermal neutrons is decisive in the dose received by cells of healthy organs, for example, brain cells in the treatment of glioblastoma.

Measurement of dose components is an important task during BNCT.

A method that directly allows you to measure the boron dose in a tumor is γ-spectroscopy, based on the registration of a γ-quantum with an energy of 478 keV, emitted during the instantaneous decay of a boron nucleus after absorbing a neutron by it [T. Kobayashi, K. Kanda. Microanalysis system of ppm order В-10 concentrations in tissue for neutron capture therapy by prompt gamma-ray spectrometry. Nucl. Instrum. Methods Phys. Res. 204 (1983) 525-531].

The second method, which directly allows measuring the boron dose in the tumor, is the method protected by the patent [S.Yu. Taskaev, A.A. Fence. A method for measuring the absorbed dose in boron neutron capture therapy of malignant tumors. Patent for invention No. 2606337 dated 01/10/2017]. In this method, a boron targeted delivery preparation is additionally labeled with a stable atomic nucleus activated by neutrons. Measurement of the induced activity with a γ-spectrometer after irradiation makes it possible to reconstruct the spatial distribution of the absorbed dose.

It is possible to measure the boron dose in a phantom with a neutron detector with a boron-enriched scintillator, for example, with a small-sized cast polystyrene scintillator specially designed for use in BNCT [T. Bykov, D. Kasatov, A. Koshkarev, A. Makarov, V. Porosev, G. Savinov, I. Shchudlo, S. Taskaev. A multichannel neutron flux monitoring system for a boron neutron capture therapy facility. JINST 14 (2019) P12002]. Since the size of the developed scintillator is small - 1 mm in diameter and 1 mm in length, it can be used during therapy, placing it next to the tumor.

Thus, there are several ways to measure boron dose.

To measure the dose of γ-radiation, Geiger-Muller counters are widely used, for example, the γ-radiation dosimeter DBG-S11D (OOO Doza, Dubna, Russia); scintillation detectors, for example, scintillation detectors with a NaI (Tl) or CaF ₂ crystal (Azimut Photonics LLC, Moscow, Russia); semiconductor detectors, for example, a γ-ray spectrometer based on a semiconductor PPD detector made of ultrapure germanium type SEG-1KP-IFTP (Institute of Physical and Technical Problems, Dubna, Russia); thermoluminescent, for example, dosimeters DTL-02 or TLD-3 (LLC NPP Doza, Zelenograd, Russia), etc. Thus, there are many devices γ-radiation dose measurement.

To measure the dose of fast neutrons, fission ionization chambers or thermal neutron detectors with a moderator are used. However, their use during BNCT is impossible. Thus, fission ionization chambers with a ²³⁸ U radiator (NIITFA JSC, Moscow) are sensitive to neutrons with energies above 1 MeV, while neutrons with energies above 1 MeV are completely absent in the generated therapeutic neutron beam for BNCT. the so-called dose of fast neutrons can also be produced by neutrons of the epithermal energy range, of course smaller, but significant for the planning of BNCT. Widely used dosimeters of mixed radiation DVGN-01 based on thermoluminescent detectors with ⁷ Li and ⁶ Li (IHEP, Moscow) or any other dosimeters with a moderator are albedo-type dosimeters, i.e. their readings significantly depend on the neutron spectrum.Neutrons for BNCT are characterized by a noticeably softer spectrum compared to the neutron spectrum of calibration sources, and therefore these dosimeters will give overestimated readings. there are no fast neutrons for BNCT. When planning BNCT, the results of numerical simulation of neutron transport.

There are no methods for measuring the dose of thermal neutrons as a result of their capture by atomic nuclei of nitrogen and chlorine. Of course, there are many detectors that are sensitive to thermal neutrons, but BNCT is characterized by a situation when the thermal neutron flux is minimized in the therapeutic neutron beam. Neutrons become thermal already in the process of their inhibition in the patient's body. The probability of their absorption by atomic nuclei of nitrogen and chlorine depends on the spectrum of neutrons and the spatial distribution of the concentration of atomic nuclei of matter, not only nitrogen and chlorine. Since the products of nuclear reactions ³⁵ Cl (n, p) ³⁵ S and ¹⁴ N (n, p) ¹⁴ C are charged particles with a short path, there is no direct method for their measurement, similar to instant γ-spectroscopy when measuring boron dose. Thus, there are no methods for measuring the thermal neutron dose for BNCT. When planning BNCT, they are limited to the results of numerical simulation of neutron transport.

The proposed invention is aimed at creating a method that makes it possible to determine the absorbed dose of recoil nuclei - the sum of doses of fast neutrons and thermal neutrons that provide ionization of matter by recoil nuclei, which is extremely important for planning BNCT.

The present invention has no close analogue-prototype. At the same time, the analogue of the methodological approach can be considered the one that is implemented in determining the relative biological effectiveness (RBE) of ionizing radiation. RBE is assessed by comparing the dose of radiation that causes a certain biological effect with the dose of standard radiation that causes the same effect. As a standard radiation, γ-radiation is taken, which is widely used in radiation therapy of tumors and for which quantitative data are known on the relationship with the dose of various damage effects. RBE value is calculated by the formula: RBE = D _γ / D _x , where D _γ - dose of γ-radiation, Gy; D _x is the dose of the studied radiation, Gy; the effect is compared for the same indicator.

The essence of the invention is as follows.

Cell cultures are irradiated with γ-radiation and mixed radiation (neutron and γ-radiation), measuring the dose of γ-radiation. Doses of γ-radiation are compared for the same effect, for example, survival. The value of the absorbed dose of recoil nuclei is calculated by the formula: D _n = D _{γ standard} -D _{γ mixed} , where D _n is the absorbed dose of recoil nuclei, Gy eq .; D _{γ standard} - dose of γ-radiation when cells are irradiated with γ-radiation, Gy; D _{γ mixed} - dose of γ-radiation during irradiation of cells with mixed radiation, Gy.

The proposed method for determining the absorbed dose of recoil nuclei for BNCT planning can be implemented in practice as follows.

Take a cell culture, for example, human glioma cells, human glioblastoma cells, Chinese hamster ovary cells, Chinese hamster lung fibroblasts, or the like. Of the four cultures given, the first two are relevant for BNCT, and the last two were widely used in studying the effect of X-ray and γ-radiation. When carrying out measurements, cells are used that have not been incubated in a medium with boron, i.e. they do not contain boron and there is no boron dose.

The cell culture is irradiated with γ-radiation in several doses, controlling the dose with a γ-radiation dosimeter. Irradiation can be carried out at the accelerator neutron source of the Institute of Nuclear Physics SB RAS [S.Yu. Taskaev. Accelerating source of epithermal neutrons. Physics of elementary particles and atomic nucleus. Volume 46, No. 6 (2015) pp. 1770-1830] at proton energies below the threshold of the reaction ⁷ Li (p, n) ⁷ Be, for example, 1.85 MeV - in this case only γ quanta with an energy of 478 keV are emitted in as a result of inelastic scattering of protons by atomic nuclei of lithium. After irradiation, cell viability is determined, for example, using the colony-forming method. Build a graph of the dependence of cell survival on the dose of γ-radiation and draw a line of approximation. Curve 1 in FIG. 1 shows a possible dose-dependent cell survival.

Then, the cell culture is irradiated with mixed radiation, in which fluxes of neutrons and γ-quanta are present, controlling the γ-radiation dose with a γ-radiation dosimeter. Irradiation can be carried out at the same accelerator neutron source of the Institute of Nuclear Physics SB RAS at proton energies above the ⁷ Li (p, n) ⁷ Be reaction threshold, for example, 2 MeV - in this case, a wide neutron flux is added to γ-quanta with an energy of 478 keV. energy spectrum, from thermal to fast. After irradiation, cell viability is determined, for example, using the colony-forming method. Build a curve of dependence of cell survival on the dose of γ-radiation and draw a line of approximation. Curve 2 in FIG. 1 shows a possible dependence of cell survival on the dose of γ-radiation when they are irradiated with mixed radiation.

Next, the doses of γ-radiation are determined upon irradiation with γ-radiation and mixed radiation, leading to the same effect, for example, to 10% cell survival. From FIG. 1 shows that irradiation with γ-quanta dose D _{γ standard} = 1.5 Gy leads to 10% cell survival (point A in Fig. 1). When irradiated with mixed radiation, 10% cell survival is achieved at a dose of γ-radiation D _{γ mixed} = 1.2 Gy (point B in Fig. 1).

Applying the formula D _n = D _{γ standard} -D _{γ mixed} , we obtain that the absorbed dose of recoil nuclei D _n = 0.3 Gy eq. Dividing D _n by D _{γ standard} , we obtain that fast and thermal neutrons, due to recoil nuclei, contribute to the absorbed dose equal to 25% of the γ-radiation dose, which can be used when planning BNCT.

The technical result of the proposed invention is to measure the absorbed dose of recoil nuclei, which is the sum of doses of fast neutrons and thermal neutrons, necessary for planning BNCT.

Claims (3)

A method for determining the absorbed dose of recoil nuclei as the sum of doses of fast neutrons and thermal neutrons, including irradiation of cell cultures with γ-radiation and mixed radiation (γ-radiation and neutron), determining the dose of γ-radiation D _γ , leading to the same value of cell survival, and determination of the absorbed dose of recoil nuclei D _n from the relation D _n = D _{γ standard} -D _{γ mixed} , where D _n is the absorbed dose of recoil nuclei, Gy eq .; D _{γ standard} - dose of γ-radiation when cells are irradiated with γ-radiation, Gy; D _{γ mixed} - dose of γ-radiation during irradiation of cells with mixed radiation, Gy.

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