A method for predicting the relative biological effect of boron neutron capture therapy

Abstract

The present invention discloses a method for predicting the relative biological effect of boron neutron capture therapy, comprising the steps of: conducting an in vitro cell survival experiment to provide data support for the establishment of a relative biological effect model; establishing a relative biological effect model based on microdosimetry; and optimizing the relative biological effect model. The present invention uses the Monte Carlo method to establish a cell matrix to simulate the intracellular energy distribution of tissue cells under different types of boron drugs and different boron concentrations, taking into account the effects of different boron drugs on tissue cells, so that the simulation calculation is closer to the experimental results; fully considering the influence of biological effects, introducing saturation parameters in the biophysical model established based on microdosimetry to solve the overkill effect, introducing evaluation parameters for the dose rate effect under long-term irradiation, and fully considering the heterogeneous distribution of different boron drugs on tissue cells. Compared with the existing RBE model, the calculation accuracy of the model of the present invention is significantly improved, and it can meet the RBE prediction of different boron drugs.

Description

Technical Field

[0001] The present invention relates to the field of accelerator boron neutron capture therapy (BNCT), and in particular to a method for predicting relative biological effects of BNCT. Background Art

[0002] BNCT technology has become a new hot spot in particle therapy research and development and one of the important choices for future tumor radiotherapy because of its ability to accurately and efficiently treat cancer. In conventional photon radiotherapy, through the accumulation of a large amount of treatment experience in the past century, people have clearly mastered the prescription doses of different tumors and the dose limits of normal tissues and organs in conventional photon radiotherapy. However, China currently lacks relevant treatment experience in BNCT treatment. This means that there is no reliable tumor prescription dose and normal tissue and organ dose limit for reference in the process of using BNCT for tumor treatment. The emergence of relative biological effect (RBE) has solved this problem well. In BNCT treatment, the biological effective dose is usually used instead of the physical absorption dose to design the treatment plan. The biological effective dose is defined as the product of the physical absorption dose and RBE, while RBE is defined as the ratio of the gamma ray physical absorption dose required to achieve the same biological endpoint to the physical absorption dose of each BNCT, which can achieve the unified quantification of the dose of different radiation fields. It can be seen that the introduction of RBE reduces the complexity of the dose prescription of tumor target area and dose limit of normal tissues and organs in BNCT treatment on the one hand, and provides the possibility of drawing on the reliable experience of photon radiotherapy in BNCT treatment on the other hand. The radiation field of BNCT is a mixed radiation field, which mainly includes boron dose, nitrogen dose, hydrogen dose and photon dose. Relative biological effect (RBE) is an extremely important parameter in BNCT treatment, and accurate calculation of RBE is an important prerequisite for achieving precise BNCT treatment.

[0003] In the field of BNCT, the traditional RBE refers to the fixed values ​​corresponding to the boron dose, nitrogen dose, hydrogen dose and photon dose, which is expressed as follows: . In Japan's JCDS treatment planning software, the CBE of boron dose is set at 3.8, nitrogen dose and hydrogen dose are set at 2.5, and photon is set at 1. CBE refers to the composite biological effective factor of boron, which is affected by tissue organs and boron drug types. When calculating the BNCT biological dose, these four doses are multiplied by their corresponding RBE fixed values ​​and the sum is the final biological effective dose expression, which is generally referred to as the RBE weighted dose. The factors affecting RBE are very complex. They not only depend on biological endpoints and reference radiation, but are also affected by a series of factors such as dose, tissue material, and type and distribution of boron drugs. Therefore, it is urgent to establish an accurate biophysical model to guide RBE calculations in clinical treatment.

[0004] Hawkins established a statistical theory of cell survival based on microscopic energy in 1994, analyzing the biological effects of cells at the micrometer scale. In 2014, the inventors tried to apply this theory to the field of BNCT research, and subsequently developed the SMK model, taking into account the dose heterogeneity, overkill effect and dose rate effect that occur during radiotherapy in BNCT. Seth Streitmatter et al. used DNA damage as the biological endpoint to study the RBE of each dose of the BNCT neutron source. By combining the RMF model to analyze the RBE parameters of DNA damage under a certain repair probability, the RBE of various secondary particles was well predicted and compared with the experimental values, and the results were in good agreement. However, the previous researchers did not consider the impact of the new boron drug in their microdosimetry research, and the RMF model did not explicitly consider the re-evaluation of its killing effect as the LET of the charged particles changes in the analysis.

[0005] BPA and BSH are two boron drugs used in boron neutron capture therapy (BNCT). They produce high-energy alpha particles and lithium-7 through nuclear reactions with neutrons to kill tumor cells. BPA is the first boron drug to be marketed. BPA can penetrate the cell membrane and enter tumor cells. The neutron capture reaction of boron-10 can directly destroy the cell nucleus. Therefore, its relative bioeffect coefficient value is much higher than that of BSH. BSH was used in clinical research in the early stage, but because BSH cannot pass through the blood-brain barrier, tumor uptake and retention are low, and there are certain toxic side effects, which limits its clinical application and popularization.

[0006] The boron drugs (BPA, BSH) currently used in clinical practice are mostly concentrated in the cytoplasm, cell membrane and extracellular regions when injected intravenously into the human body, and do not have nucleus targeting, which greatly reduces the therapeutic effect of BNCT. The research on new boron drugs with nucleus targeting has become a hot topic in BNCT research, but the RBE research on new boron drugs is still lacking. Summary of the invention

[0007] In order to overcome the shortcomings of the prior art, the present invention proposes a method for predicting the relative biological effect of boron neutron capture therapy. The technical solution of the present invention is implemented as follows:

[0008] A method for predicting the relative biological effect of boron neutron capture therapy comprises the following steps:

[0009] S1, conduct in vitro cell survival experiments to provide data support for the establishment of relative biological effect models; select Cs-137 radiation source or Co-60 radiation source to irradiate until the cell survival fraction reaches 10% as the biological endpoint, and the required photon dose is the RBE reference radiation dose; obtain the cell survival fraction and dose distribution of the same type of boron drug but different boron concentrations under the same neutron beam irradiation conditions; obtain the cell survival fraction and dose distribution after injection of different boron drugs under the same neutron beam irradiation, and study the effects of clinical boron drugs and new boron drugs on the biological effects of BNCT;

[0010] S2, based on microdosimetry, a relative biological effect model is established to obtain the line energy spectrum under corresponding experimental conditions. The relative biological effect model introduces a saturation parameter to solve the problem of the overkill effect in the high LET region where the RBE decreases with the increase of LET. A dose rate effect constant is introduced to correct the influence of the dose rate effect on the model due to the long treatment time. A cell matrix is ​​designed for Monte Carlo simulation to solve the heterogeneity of boron-10 distribution within and between cells.

[0011] S3, optimizing the relative biological effect model, including the following steps:

[0012] S31, initializing model parameters;

[0013] S32, using Monte Carlo software based on the microdosimetric doses under different experimental conditions, was substituted into the model to obtain the calculated values ​​under different experimental conditions;

[0014] S33, comparing the calculated value with the data obtained from the in vitro cell survival experiment to determine whether it is the optimal solution;

[0015] S34, if it is not the optimal solution, repeat steps S32-S33 until the optimal solution is obtained;

[0016] S35, output the optimal model parameters of the relative biological effect model, and obtain the RBE calculation model that is corrected based on microdosimetry and experimental values ​​and has the ability to predict different boron drugs and different tissue types.

[0017] Furthermore, the Monte Carlo simulation in step S2 includes the steps of:

[0018] S21, experimentally determine the proportion of different boron drugs in various regions within tissue cells;

[0019] S22, after obtaining the proportion of boron-10 content of different boron drugs in each tissue cell area, a cell matrix is ​​established and multiple Monte Carlo simulations are performed;

[0020] S23, combined with cell survival scores to evaluate the heterogeneity of B-10 distribution among cells with different boron drugs;

[0021] Furthermore, the Monte Carlo software in step S32 includes but is not limited to MCNP, PHITS, GEANT4 and FLUKA software.

[0022] The beneficial effect of the present invention lies in that, compared with the prior art, the present invention uses the Monte Carlo method to establish a cell matrix to simulate the intracellular energy distribution of tissue cells under different types of boron drugs and different boron concentrations, taking into account the influence of different boron drugs on tissue cells, so that the simulation calculation is closer to the experimental results; fully considering the influence of biological effects, introducing saturation parameters in the biophysical model established based on microdosimetry to solve the overkill effect, introducing evaluation parameters of the dose rate effect under long-term irradiation, and fully considering the heterogeneous distribution of different boron drugs on tissue cells. In addition, compared with the existing RBE model, the calculation accuracy of the model of the present invention is significantly improved, and can meet the RBE prediction of different boron drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is a flow chart of a method for predicting relative biological effects of boron neutron capture therapy according to the present invention;

[0024] Figure 2 It is a flow chart of the method for optimizing the relative biological effect model in the present invention. DETAILED DESCRIPTION

[0025] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0026] See also Figure 1 , a method for predicting the relative biological effect of boron neutron capture therapy, comprising the steps of:

[0027] S1, conduct in vitro cell survival experiments to provide data support for the establishment of relative biological effect models; select Cs-137 radiation source or Co-60 radiation source to irradiate until the cell survival fraction reaches 10% as the biological endpoint, and the required photon dose is the RBE reference radiation dose; obtain the cell survival fraction and dose distribution of the same type of boron drug irradiated with the same neutron beam but with different boron concentrations; obtain the cell survival fraction and dose distribution after injection of different boron drugs under the same neutron beam irradiation, and study the effects of clinical boron drugs and new boron drugs on the biological effects of BNCT;

[0028] S2, based on microdosimetry, a relative biological effect model is established to obtain the line energy spectrum under corresponding experimental conditions. The relative biological effect model introduces a saturation parameter to solve the problem of the overkill effect in the high LET region where the RBE decreases with the increase of LET. A dose rate effect constant is introduced to correct the influence of the dose rate effect on the model due to the long treatment time. A cell matrix is ​​designed for Monte Carlo simulation to solve the heterogeneity of boron-10 distribution within and between cells.

[0029] The superkill effect refers to the phenomenon that when the dose rate or linear energy transfer (LET) of radiation is too high, the killing effect on cancer cells is reduced. This is because the energy of radiation is too high, resulting in excessive free radicals in cancer cells, which activates the antioxidant system in the cells and enhances the cell's repair ability and radiation resistance. Another explanation is that the energy of radiation is too high, resulting in cancer cells being killed at once, rather than producing repairable sublethal damage, thereby reducing the total killing effect of radiation on cancer cells. The dose rate effect refers to the effect of the ratio of radiation dose to radiation time on the organism. Generally speaking, under the same radiation dose, the shorter the radiation time, the higher the dose rate, and the greater the damage to the organism; conversely, the longer the radiation time, the lower the dose rate, and the less damage to the organism. This is because the organism has a certain repair ability. If the radiation time is long, the organism can be repaired to a certain extent during the radiation process; if the radiation time is short, the organism will be fatally damaged before it has time to repair.

[0030] Boron-10 distribution heterogeneity refers to the phenomenon that the boron drug is unevenly distributed in tumor tissue and normal tissue during BNCT treatment, whether outside or inside the tissue cells. This heterogeneity will affect the therapeutic effect and safety of BNCT, because the distribution of the boron drug determines the location and intensity of the neutron capture reaction, thereby affecting the killing effect of radiation on cancer cells and normal cells.

[0031] There are three main steps in Monte Carlo simulation:

[0032] S21, the reaction of boron-10 with neutrons produces 1.47 MeV alpha particles and 0.84 MeV neutrons in 93.7% of cases. 7 Li particles, 1.78 MeV alpha particles and 1.01 MeV 7 Li particles are uniformly set in the nucleus, cytoplasm, cell membrane or extracellular region as source items;

[0033] S22, Monte Carlo simulation was used to explore the changes in the energy spectrum of the cell nucleus caused by different regions;

[0034] S23, based on the boron-10 content ratio of each cell region, weighted summation is performed on the line energy spectra caused by different regions to obtain the final line energy spectrum parameters.

[0035] S3, optimizing the relative biological effect model, including the following steps:

[0036] S31, initializing model parameters;

[0037] S32, using Monte Carlo software based on the microdosimetric doses under different experimental conditions, was substituted into the model to obtain the calculated values ​​under different experimental conditions;

[0038] S33, comparing the calculated value with the data obtained from the in vitro cell survival experiment to determine whether it is the optimal solution;

[0039] S34, if it is not the optimal solution, repeat steps S32-S33 until the optimal solution is obtained;

[0040] S35, output the optimal model parameters of the relative biological effect model, and obtain the RBE calculation model that is corrected based on microdosimetry and experimental values ​​and has the function of predicting different boron drugs and tissue types.

[0041] At this point, a RBE computational model that can predict different boron drugs and tissue types can be obtained based on microdosimetry and experimental values.

[0042] The above is a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several improvements and modifications without departing from the principle of the present invention. These improvements and modifications are also considered to be within the scope of protection of the present invention.

Claims

1. A method for predicting the relative biological effect of boron neutron capture therapy, characterized in that: Includes steps: S1, conduct in vitro cell survival experiments to provide data support for the establishment of relative biological effect models; select Cs-137 radiation source or Co-60 radiation source to irradiate until the cell survival fraction reaches 10% as the biological endpoint, and the required photon dose is the reference radiation dose for relative biological effect; obtain the cell survival fraction and dose distribution of cells injected with the same type of boron drugs but with different boron concentrations under the same neutron beam irradiation conditions; obtain the cell survival fraction and dose distribution after injection of different boron drugs under the same neutron beam irradiation, and study the effects of clinical boron drugs and new boron drugs on the biological effects of boron neutron capture therapy; S2, based on microdosimetry, a relative biological effect model is established to obtain the linear energy spectrum under corresponding experimental conditions. The relative biological effect model introduces a saturation parameter to solve the problem of the overkill effect in which the relative biological effect in the high linear energy transfer region decreases with the increase of linear energy transfer. A dose rate effect constant is introduced to correct the influence of the dose rate effect on the model due to the long treatment time. A cell matrix is ​​designed for Monte Carlo simulation to solve the heterogeneity of boron-10 distribution within and between cells, including the following steps: S21, the reaction of boron-10 with neutrons produces 93.7% of the alpha particles of 1.47 MeV and 0.84 MeV. 7 Li particles, 1.78 MeV alpha particles and 1.01 MeV 7 Li particles are uniformly set in the nucleus, cytoplasm, cell membrane or extracellular region as source items; S22, Monte Carlo simulation was used to explore the changes in the energy spectrum of the cell nucleus caused by different regions; S23, based on the boron-10 content ratio of each cell region, weighted summation of the line energy spectra caused by different regions is performed to obtain the final line energy spectrum parameters; S3, optimizing the relative biological effect model, including the following steps: S31, initializing model parameters; S32, using Monte Carlo software based on the microdosimetric doses under different experimental conditions, was substituted into the model to obtain the calculated values ​​under different experimental conditions; S33, comparing the calculated value with the data obtained from the in vitro cell survival experiment to determine whether it is the optimal solution; S34, if it is not the optimal solution, repeat steps S32-S33 until the optimal solution is obtained; S35, outputting the optimal model parameters of the relative biological effect model, and obtaining a calculation model that is corrected based on microdosimetry and experimental values ​​and can predict the relative biological effects of different boron drugs and different tissue types.

2. The method for predicting the relative biological effect of boron neutron capture therapy according to claim 1, characterized in that: The Monte Carlo software in step S32 includes but is not limited to MCNP, PHITS, GEANT4 and FLUKA software.

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