CN107224675B - Boron neutron capture therapy system - Google Patents
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- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
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- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
- A61N5/1048—Monitoring, verifying, controlling systems and methods
- A61N5/1064—Monitoring, verifying, controlling systems and methods for adjusting radiation treatment in response to monitoring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
- A61N2005/1085—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy characterised by the type of particles applied to the patient
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- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
- A61N2005/1092—Details
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
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- A61N2005/1094—Shielding, protecting against radiation
Abstract
A boron neutron capture therapy system, comprising: boron neutron capture treatment device and alpha-amino acid boron trifluoride compoundThe boride has a structure as shown in formula (I):
wherein: r is hydrogen, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, hydroxymethyl, 1-hydroxyethyl, benzyl or hydroxybenzyl; m is H or a metal atom; the energy generated after the neutron beam generated by the boron neutron capture treatment device acts on the alpha-amino acid boron trifluoride compound damages the DNA of tumor cells.
Description
Technical Field
The invention relates to a radioactive ray irradiation treatment system, in particular to a boron neutron capture treatment system.
Background
With the development of atomic science, radiation therapy such as cobalt sixty, linac, electron beam, etc. has become one of the main means for cancer therapy. However, the traditional photon or electron treatment is limited by the physical condition of the radioactive rays, and a large amount of normal tissues on the beam path can be damaged while killing tumor cells; in addition, due to the different sensitivity of tumor cells to radiation, traditional radiotherapy often has poor therapeutic effects on malignant tumors with relatively high radiation resistance (such as glioblastoma multiforme (glioblastoma multiforme) and melanoma (melanoma)).
In order to reduce radiation damage to normal tissue surrounding a tumor, the concept of target treatment in chemotherapy (chemotherapy) has been applied to radiotherapy; for tumor cells with high radiation resistance, radiation sources with high relative biological effects (relative biological effectiveness, RBE) such as proton therapy, heavy particle therapy, neutron capture therapy, etc. are also actively developed. The neutron capture treatment combines the two concepts, such as boron neutron capture treatment, and provides better cancer treatment selection than the traditional radioactive rays by means of the specific aggregation of boron-containing medicaments in tumor cells and the accurate neutron beam regulation.
Boron neutron capture therapy (Boron Neutron Capture Therapy, BNCT) is carried out by using boron-containing 10 B) The medicine has the characteristic of high capture section for thermal neutrons by 10 B(n,α) 7 Li neutron capture and nuclear fission reaction generation 4 He (He) 7 Li two heavy charged particles. Reference is made to the following 10 B(n,α) 7 And a Li neutron capture nuclear reaction equation.
The average energy of the two charged particles is about 2.33MeV, the particles have high linear transfer (Linear Energy Transfer, LET) and short range characteristics, and the linear energy transfer and range of the alpha particles are 150keV/μm and 8 μm respectively 7 The Li heavy charged particles are 175 keV/mum and 5μm, the total range of the two particles is approximately equal to one cell size, so that the radiation injury caused to organisms can be limited at the cell level, and when boron-containing medicaments are selectively gathered in tumor cells, the purpose of killing the tumor cells locally can be achieved on the premise of not causing too great injury to normal tissues by matching with a proper neutron source.
The success of boron neutron capture therapy is also known as binary radiation cancer therapy (binary cancer therapy) because it depends on the concentration of boron-containing drugs and the number of thermal neutrons at the tumor cell site; therefore, the development of boron-containing medicaments and the improvement of neutron source flux and quality play an important role in the research of boron neutron capture treatment.
Disclosure of Invention
In order to achieve improvements over existing boron neutron capture therapy systems, one aspect of the present invention provides a boron neutron capture therapy system comprising: boron neutron capture treatment device and alpha-amino acid boron trifluoride compound.
The alpha-amino acid boron trifluoride compound has a structure shown as a formula (I):
wherein: r is hydrogen, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, hydroxymethyl, 1-hydroxyethyl, benzyl or hydroxybenzyl; m is H or a metal atom.
The energy generated after the neutron beam generated by the boron neutron capture treatment device acts on the alpha-amino acid boron trifluoride compound damages the DNA of tumor cells.
BNCT is an ideal tumor treatment that provides a new treatment for many tumors that cannot be treated by conventional methods.
The tumor is malignant tumor or metastatic tumor progress, preferably brain glioma, recurrent head and neck tumor, malignant melanoma, breast cancer or metastatic hepatoma. Malignant tumors are commonly known as cancers, and are a common name for more than 100 related diseases. When a cell in the body is mutated, it will divide continuously, without being controlled by the body, and finally form cancer. Malignant cells can invade and destroy adjacent tissues and organs, and the cells can pass out of the tumor into the blood or lymphatic system, which is how the malignant tumor forms new tumors from the primary site to other organs, a process called metastasis of the malignant tumor.
The tumor of the invention is further brain tumor or melanoma. Brain tumors refer to tumors that grow intracranially, including primary brain tumors that occur from the brain parenchyma and secondary brain tumors that metastasize to the cranium from other parts of the body. Melanoma, also known as malignant melanoma, is a highly malignant tumor that produces melanin, and is found in the skin or mucous membranes close to the skin, as well as in the pia mater and choroid.
The brain tumor is further brain glioma. Tumors derived from the nerve epithelium are called brain gliomas, account for 40-50% of craniocerebral tumors, and are common intracranial malignant tumors.
The alpha-amino acid-like boron trifluoride compound plays an important role in the application of the boron neutron capture therapy system, as will be described in detail below.
Preferably, M in the alpha-amino acid boron trifluoride compound is potassium or sodium.
Preferably, B in the alpha-amino acid boron trifluoride compound is 10 B。
To further improve the boron-containing medicine 10 B content in the alpha-amino acid boron trifluoride compound 10 B (B)The purity is more than or equal to 95 percent.
At least one F in the alpha-amino acid boron trifluoride compound is 18 F, so configured, boron concentration and distribution in and around the tumor and all tissues within the radiation treatment volume can be accurately and rapidly determined non-invasively before and during irradiation. This diagnostic information allows for faster, more accurate and safer boron neutron capture treatment by reducing exposure of epithermal neutrons to areas of tissue known to contain high levels of boron.
Further, the boron neutron capture therapy device includes a neutron production section and a beam shaping body for adjusting a neutron beam energy spectrum produced by the neutron production section to an epithermal neutron energy region.
Beam shaping bodies also play an important role in improving neutron source flux and quality. The beam shaping body comprises a retarder adjacent to the neutron generating part, a reflector surrounding the retarder, a thermal neutron absorber adjacent to the retarder, a radiation shield and a beam outlet, wherein the radiation shield and the beam outlet are arranged in the beam shaping body, the neutron generating part and an incident proton beam are subjected to nuclear reaction to generate neutrons, the retarder decelerates neutrons generated by the neutron generating part to an epithermal neutron energy region, the reflector guides deviated neutrons back to improve the epithermal neutron beam intensity, the thermal neutron absorber is used for absorbing thermal neutrons to avoid excessive doses caused by shallow normal tissues during treatment, and the radiation shield is used for shielding leaked neutrons and photons to reduce the normal tissue doses of non-irradiated regions.
The boron neutron capture therapy device further includes a collimator disposed at the beam outlet for focusing the epithermal neutrons.
Drawings
FIG. 1 is a schematic plan view of an accelerator-based boron neutron capture therapy system.
FIG. 2 is a schematic plan view of a reactor-based boron neutron capture therapy system.
Detailed Description
The present invention is described in further detail below with reference to specific embodiments and figures to enable those skilled in the art to practice the invention as described in the specification. The described embodiments are only intended to illustrate and describe the best mode of the invention presently. The scope of the invention is not limited in any way by the embodiments described herein.
It will be understood that terms such as "having," "including," and "comprising," as used herein, do not preclude the presence or addition of one or more other ingredients or combinations thereof.
The fast neutrons as described herein are neutrons having an energy region greater than 40keV, an epithermal neutron energy region between 0.5eV and 40keV, and a thermal neutron energy region less than 0.5eV.
Neutron capture therapy has been increasingly used in recent years as an effective means of treating cancer, where it is most common to supply neutrons from a boron neutron capture therapy to a nuclear reactor or accelerator. Taking accelerator boron neutron capture therapy as an example, the basic components of accelerator boron neutron capture therapy generally comprise an accelerator for accelerating charged particles (such as protons, deuterons and the like), a target and heat removal system and a beam shaping body, wherein the accelerated charged particles react with a metal target to generate neutrons, and proper nuclear reactions are selected according to the required neutron yield and energy, available energy and current of the accelerated charged particles, physicochemical properties of the metal target and the like, and the nuclear reactions often discussed are 7 Li(p,n) 7 Be and Be 9 Be(p,n) 9 And B, performing an endothermic reaction. The energy threshold values of the two nuclear reactions are respectively 1.881MeV and 2.055MeV, because the ideal neutron source for boron neutron capture treatment is epithermal neutrons with the energy level of keV, in theory, if protons with the energy only slightly higher than the threshold value are used for bombarding a metal lithium target material, relatively low-energy neutrons can Be generated, the nuclear reactions can Be clinically used without too much slowing treatment, however, the proton action cross sections of the two targets of lithium metal (Li) and beryllium metal (Be) and the threshold energy are not high, and in order to generate enough neutron flux, protons with higher energy are generally selected for initiating the nuclear reactions.
The ideal target should have the characteristics of high neutron yield, close neutron energy distribution generated to the epithermal neutron energy region (which will be described in detail later), no too much strong penetrating radiation generation, safety, low cost, easy operation, high temperature resistance, etc., but practically no nuclear reaction meeting all the requirements can be found, and the target is made of lithium metal in the embodiment of the invention. However, it is well known to those skilled in the art that the material of the target may be made of other metallic materials than those mentioned above.
The requirements for the heat removal system will vary depending on the chosen nuclear reaction, e.g 7 Li(p,n) 7 Be has lower requirements for heat removal systems due to the lower melting point and thermal conductivity of the metal target (lithium metal) 9 Be(p,n) 9 B is high. In the embodiment of the invention adopts 7 Li(p,n) 7 Nuclear reaction of Be.
Whether the neutron source of the boron neutron capture treatment is from nuclear reaction of charged particles of a nuclear reactor or an accelerator and a target, the generated mixed radiation field is that the beam contains neutrons and photons with low energy to high energy; for boron neutron capture treatment of deep tumors, the more radiation content, except for epithermal neutrons, the greater the proportion of non-selective dose deposition of normal tissue, and therefore the less radiation that will cause unnecessary doses. In addition to the air beam quality factor, in order to better understand the dose distribution of neutrons in the human body, the embodiments of the present invention use a human head tissue prosthesis for dose calculation, and use the prosthesis beam quality factor as a design reference for neutron beams, as will be described in detail below.
The international atomic energy organization (IAEA) gives five air beam quality factor suggestions for neutron sources for clinical boron neutron capture treatment, and the five suggestions can be used for comparing the advantages and disadvantages of different neutron sources and serve as reference bases for selecting neutron production paths and designing beam shaping bodies. These five suggestions are as follows:
epithermal neutron beam flux Epithermal neutron flux>1x 10 9 n/cm 2 s
Fast neutron contamination Fast neutron contamination<2x 10 -13 Gy-cm 2 /n
Photon pollution Photon contamination<2x 10 -13 Gy-cm 2 /n
The ratio thermal to epithermal neutron flux ratio of thermal neutron to epithermal neutron flux is less than 0.05
Neutron current to flux ratio epithermal neutron current to flux ratio >0.7
Note that: the epithermal neutron energy region is between 0.5eV and 40keV, the thermal neutron energy region is less than 0.5eV, and the fast neutron energy region is more than 40keV.
1. Epithermal neutron beam flux:
the neutron beam flux and the boron-containing drug concentration in the tumor together determine the clinical treatment time. If the concentration of the boron-containing medicament in the tumor is high enough, the requirement on the neutron beam flux can be reduced; conversely, if the boron-containing drug concentration in the tumor is low, a high flux epithermal neutron is required to administer a sufficient dose to the tumor. IAEA requires a epithermal neutron beam flux of greater than 10 epithermal neutrons per square centimeter per second 9 The neutron beam at this flux can generally control the treatment time to within one hour for current boron-containing drugs, and short treatment times can more effectively utilize the limited residence time of boron-containing drugs within tumors in addition to advantages for patient positioning and comfort.
2. Fast neutron contamination:
since fast neutrons cause unnecessary normal tissue doses, which are positively correlated with neutron energy, as a matter of pollution, the fast neutron content should be minimized in the neutron beam design. Fast neutron contamination is defined as the fast neutron dose accompanied by a unit epithermal neutron flux, with IAEA recommended for fast neutron contamination as less than 2x 10 -13 Gy-cm 2 /n。
3. Photon pollution (gamma ray pollution):
gamma rays belonging to the intense penetrating radiation can cause non-selective dose deposition of all tissues on the beam path, so reducing the gamma ray content is also an essential requirement for neutron beam design, gamma ray pollution is defined as the gamma ray dose accompanied by the unit epithermal neutron flux, and the proposal of IAEA on gamma ray pollution is less than 2x 10 -13 Gy-cm 2 /n。
4. Ratio of thermal neutron to epithermal neutron flux:
because of high thermal neutron attenuation speed and poor penetrating capacity, most of energy is deposited on skin tissues after entering a human body, and thermal neutrons are required to be used as neutron sources for boron neutron capture treatment for superficial tumors such as melanoma and the like, so that the thermal neutron content is required to be reduced for deep tumors such as brain tumors and the like. The IAEA to thermal neutron to epithermal neutron flux ratio is recommended to be less than 0.05.
5. Neutron current to flux ratio:
the ratio of neutron current to flux represents the directionality of the beam, the larger the ratio is, the better the frontage of the neutron beam is, the high frontage neutron beam can reduce the surrounding normal tissue dose caused by neutron divergence, and the treatable depth and the posture setting elasticity are improved. IAEA is recommended to have a neutron current to flux ratio greater than 0.7. The dose distribution in the tissue is obtained by using the prosthesis, and the quality factor of the prosthesis beam is deduced according to the dose-depth curve of normal tissue and tumor. The following three parameters can be used to make comparisons of the therapeutic benefits of different neutron beams.
1. Effective treatment depth:
the tumor dose is equal to the depth of the maximum dose of normal tissue, and at a position behind the depth, the tumor cells obtain a dose smaller than the maximum dose of normal tissue, i.e. the advantage of boron neutron capture is lost. This parameter represents the penetration capacity of the neutron beam, with a greater effective treatment depth indicating a deeper treatable tumor depth in cm.
2. Effective therapeutic depth dose rate:
i.e. the tumor dose rate at the effective treatment depth, is also equal to the maximum dose rate of normal tissue. Because the total dose received by normal tissues is a factor affecting the total dose size that can be given to a tumor, a larger effective treatment depth dose rate indicates a shorter irradiation time in cGy/mA-min, as the parameters affect the length of treatment time.
3. Effective therapeutic dose ratio:
the average dose ratio received from the brain surface to the effective treatment depth, tumor and normal tissue, is referred to as the effective treatment dose ratio; calculation of the average dose can be obtained from the integration of the dose-depth curve. The larger the effective therapeutic dose ratio, the better the therapeutic benefit of the neutron beam.
In order to make the beam shaping body have a comparative basis in design, besides the five IAEA suggested beam quality factors in air and the three parameters mentioned above, the following parameters for evaluating the neutron beam dose performance are also used in the embodiment of the present invention:
1. the irradiation time is less than or equal to 30min (the proton current used by the accelerator is 10 mA)
2. 30.0RBE-Gy with therapeutic depth of 7cm or more
3. The maximum tumor dose is more than or equal to 60.0RBE-Gy
4. The maximum dose of normal brain tissue is less than or equal to 12.5RBE-Gy
5. The maximum skin dose is less than or equal to 11.0RBE-Gy
Note that: RBE (Relative Biological Effectiveness) is the relative biological effect, and the above dose terms are multiplied by the relative biological effects of different tissues to obtain the equivalent dose, because the biological effects caused by photons and neutrons are different.
Referring to fig. 1, there is shown a schematic plan view of an accelerator-based boron neutron capture therapy system including an accelerator 10, a beam expanding device 20, a charged particle beam inlet for passing a charged particle beam P, a neutron generating section T for generating a neutron beam N by nuclear reaction with the charged particle beam P, a beam shaping body 30 for adjusting the flux and quality of the neutron beam generated by the neutron generating section T, a collimator 40 adjacent to the beam shaping body 30, and an alpha-amino acid boron trifluoride 50 irradiated with the beam exiting through the collimator 40. The accelerator 10 is used to accelerate the charged particle beam P, and may be a cyclotron or a linear accelerator, which is suitable for an accelerator type neutron capture therapy system; the charged particle beam P here is preferably a proton beam; the beam expander 20 is provided between the accelerator 10 and the neutron generator T; the charged particle beam entrance is housed in the beam shaping body 30 in close proximity to the neutron generator T, and three arrows between the neutron generator T and the beam expander 20 serve as charged particle beam entrances; the neutron generator T is preferably lithium metal, and is accommodated in the beam shaping body 30; the beam shaping body 30 comprises a reflector 31, a retarder 32 surrounded by the reflector 31 and abutting the neutron generating part T, a thermal neutron absorber 33 abutting the retarder 32, a radiation shield 34 arranged in the beam shaping body 30, the neutron generating part T and a charged particle beam P incident from a charged particle beam inlet are subjected to nuclear reaction to generate a neutron beam N, the retarder 32 retards neutrons generated by the neutron generating part T to an epithermal neutron energy region, the reflector 31 guides the deviated neutrons back to improve the epithermal neutron beam intensity, the thermal neutron absorber 33 is used for absorbing thermal neutrons to avoid excessive dose caused by shallow normal tissues during treatment, the radiation shield 34 is used for shielding leaked neutrons and photons to reduce normal tissue dose of a non-irradiated region, and the collimator 40 is used for focusing the neutron beam; the energy generated by the neutron beam emitted from the collimator 40 acting on the alpha-amino acid boron trifluoride 50 destroys the tumor cell DNA.
Referring to fig. 2, a schematic plan view of a reactor-based boron neutron capture therapy system is disclosed, the boron neutron capture therapy system including a reactor 100 (a neutron beam is generated within the reactor and may also be referred to as a neutron generating section), a beam expanding device 200, a neutron beam inlet, a beam shaping body 300 for adjusting the flux and quality of the neutron beam generated by the neutron generating section, a collimator 400 adjacent to the beam shaping body 300, and an alpha-amino acid boron trifluoride 500 irradiated by the beam exiting through the collimator 400. Wherein the reactor 100 may be subjected to a nuclear reaction associated with neutrons capable of generating the required energy, such as fast neutrons released when uranium-235 or plutonium-239 produce a fission reaction, as is well known to those skilled in the art; the beam expanding device 200 is disposed between the reactor 100 and the neutron beam inlet; three arrows after the beam expanding device 200 serve as neutron beam inlets; the beam shaping body 300 comprises a reflector 310, a retarder 320 surrounded by the reflector 310, a thermal neutron absorber 330 adjacent to the retarder 320, a radiation shield 340 disposed within the beam shaping body 300, the retarder 320 retarding neutrons generated from the neutron generating section 100 to an epithermal neutron energy region, the reflector 310 guiding the deflected neutrons back to increase the epithermal neutron beam intensity, the thermal neutron absorber 330 for absorbing thermal neutrons to avoid excessive dose with shallow normal tissue during treatment, the radiation shield 340 for shielding leaking neutrons and photons to reduce normal tissue dose in non-irradiated regions, and the collimator 400 for focusing the neutron beam; the energy generated by the neutron beam emitted from the collimator 400 acting on the alpha-amino acid boron trifluoride 500 damages the DNA of tumor cells.
The beam shaping body 30, 300 can retard neutrons to the epithermal neutron energy region and reduce thermal and fast neutron content. The reflector 31, 310 is made of a material having a strong neutron reflecting ability, and as a preferred embodiment, the reflector 31, 310 is made of at least one of Pb or Ni. The retarder 32, 320 is made of a material having a large fast neutron action cross section and a small epithermal neutron action cross section, and as a preferred embodiment the retarder 32, 320 is made of D 2 O、AlF 3 、Fluental TM 、CaF 2 、Li 2 CO 3 、MgF 2 And Al 2 O 3 At least one of them. The thermal neutron absorber 33, 330 is made of a material having a large cross section for acting with thermal neutrons, and as a preferred embodiment, the thermal neutron absorber 33, 330 is made of 6 Li. The radiation shield 34, 340 includes a photon shield and a neutron shield, and as a preferred embodiment, the radiation shield 34, 340 includes a photon shield made of lead (Pb) and a neutron shield made of Polyethylene (PE). The collimator 40, 400 is made of a material having a high convergence of the medium, and as a preferred embodiment, the collimator 40, 400 is made of at least one of graphite and lead.
It is well known to those skilled in the art that other neutron production methods, such as D-D neutron generators, D-T neutron generators, etc., may be used in addition to the accelerator type and reactor type neutron production methods described above, and the materials, structures, and compositions of the beam shaping bodies may be adjusted accordingly as desired.
In BNCT, the boron-containing compound must be non-toxic or low toxic when administered in a therapeutically effective amount, and capable of selectively accumulating in tumor tissue. Although BPA has the advantage of low chemical toxicity, it accumulates in critical normal tissues at lower than desired levels. In particular, the ratio of boron concentration in the tumor relative to normal brain and tumor relative to blood is about 3:1. Such low specificity limits the maximum dose of BPA to tumors, as the allowable dose for normal tissue is a limiting factor.
Thus, there is a need to develop new compounds that have a longer retention time in tumors and selectively target and destroy tumor cells with minimal damage to normal tissue.
Alpha-amino acids are the main components of proteins, the most important amino acids in organisms, and play a very important role in ATP production and neurotransmission. Furthermore, α -amino acids are also key nutrients for cancer cell survival and proliferation. -COOH-b-BF in alpha-amino acids 3 The substitution is carried out to obtain the boron trifluoride compound of alpha-amino acid, which is an isoelectric compound of alpha-amino acid. It has been shown that the cellular uptake of boron trifluoride complexes of alpha-amino acids is identical to that of alpha-amino acids, both via enzyme-mediated pathways and both have identical transporters. Boron trifluoride compound of alpha-amino acid is attracting attention in the design of novel boron carrier compound for BNCT, and the compound has high stability, good targeting property and high enrichment degree in tumor cells. Compared to FDG, the inflammatory region has almost negligible absorption of the compound. Furthermore, boron trifluoride complexes of alpha-amino acids are easy to synthesize, usually from the corresponding borates with KHF under acidic conditions 2 And (3) reacting to obtain the product.
Furthermore, use is made in BNCT 18 Boron trifluoride complexes of F-labeled alpha-amino acids, boron concentration and distribution in and around tumors and all tissues within the radiation treatment volume can be determined non-invasively, accurately and rapidly, both before and during irradiation. This diagnostic information allows for faster, more accurate and safer boron neutron capture therapies by reducing exposure of epithermal neutrons to areas of tissue known to contain high levels of boron.
The boron trifluoride compound of the alpha-amino acid is described in detail below with reference to specific examples.
Example 1Phe-BF 3 Preparation
Reaction route
Benzyl borate (15 mg,0.05 mmol), KF (0.15 mmol,0.05 mL) solution, HCl (0.2 mmol,0.03 mL) solution, 0.1mLMeCN solution were added to a 1.5mL microreactor and reacted at room temperature for 2 hours to give Phe-BF 3 Crude product. Further purifying the crude product by HPLC to obtain Phe-BF 3 。 1 H NMR(300MHz，MeOD)：δppm 7.30(m,5H)，3.04(d,J＝9.8Hz,1H)，2.67(t,J＝9.8Hz,1H)，2.42(brs,1H)；[M-H] - 188.0901,Found:188.0589。
In vitro studies of the Compounds according to the invention
For the purification material of this example 1 (hereinafter referred to as Phe-BF 3 ) Four different tumor cell lines U343mga derived from human, liver cancer cell line Hep3B, breast cancer cell line MCF7 and sarcoma cell line 4SS were used for the in vitro experiments. Cells were plated on uncoated tissue culture dishes and incubated at 37℃with 5% CO 2 The culture was performed in an equilibrated humid-air incubator (10% FCS and PEST (penicillin 100IU/mL and streptomycin 100 mg/mL) were added to the medium). For cell passage, cells were trypsinized with trypsin-EDTA (phosphate buffered saline (PBS) with 0.25% trypsin and 0.02% EDTA, without calcium and magnesium).
Example 2Phe-BF 3 Is to be taken up by cells
U343mga cells were plated at 75% cell density on Petri dishes and used with 1, 4-dihydroxyborophenylalanine (BPA) or Phe-BF in tissue culture medium 3 Incubation was carried out for 6 hours. Both boron-containing compounds were used in a ratio to boron content (5X 10 -4 mol/L boron) is added and dissolved in tissue culture medium. By removing the boron-containing tissue culture medium and adding cold phosphate buffer for washing excess medium from the cellsThe incubation was ended with saline solution (PBS buffer). Cells were harvested immediately by scooping off the petri dish using a rubber wiper, they were collected in cold PBS and formed into pellets by centrifugation.
Cell samples were subjected to total protein analysis according to Bradford standard procedure. The precipitated cells were subjected to boron analysis by direct current plasma atomic emission spectroscopy (DCP-AES). The sample (50-130 mg) was digested with sulfuric acid/nitric acid (1/1) at 60 ℃. Triton X-100 and water were added to give concentrations of 50mg tissue/mL, 15% total acid v/v and 5% Triton X-100 v/v. The boron concentration is based on known control samples. The results are shown in Table 1 below. As can be seen from Table 1, phe-BF 3 Is superior to uptake of boron as Boron Phenylalanine (BPA).
Table 1: cellular uptake of different boron compounds
For the different boron compounds in the two parallel experiments (experiments 1 and 2), the boron content was expressed as a function of total cellular protein in U343mga cells (μg boron/g cellular protein) (7.2 and 7.7 μg boron/mL medium in experiment 1 and experiment 2, respectively).
Example 3 different tumor cells against Phe-BF 3 Is (are) taken in
Four different tumor cell lines derived from humans were used: u343mga, hep3B, MCF7 and 4SS were plated on Petri dishes at 40-50% (low) and 90-100% (high) cell densities, and Phe-BF dissolved in tissue culture medium was used as described above 3 Incubation was carried out for 6 hours. The incubation was ended by removing the boron-containing medium and adding cold PBS buffer in order to wash out excess medium from the cells. Cells were harvested immediately by scooping off the petri dish using a rubber wiper, they were collected in cold PBS and formed into pellets by centrifugation. Cell samples were subjected to total protein analysis (as above) according to Bradford standard procedure. The results are shown in Table 2 below. Pairs of tumor cell lines (glioblastoma (U343 mga), liver cancer (Hep 3B), breast cancer (MCF 7), sarcoma (4 SS)) for all four humans tested at low and high cell densitiesIn the ratio, phe-BF was found 3 Is a high-efficiency boron carrier.
Table 2: phe-BF 3 Is a cell uptake of (a). Boron content is expressed as a function of total cellular protein (μg boron/g cellular protein).
Example 4Phe-BF 3 Is retained in the cell
U343mga cells were plated at 75% cell density on Petri dishes and used for 1, 4-dihydroxyborophenylalanine (BPA) or Phe-BF in tissue culture medium 3 Incubation was carried out for 18 hours. Both boron compounds were used in a ratio to the boron content (5X 10 -4 mol/L boron) is added to the tissue culture medium. The incubation was ended by replacing the boron-containing medium with a medium without boron. Cell samples were taken at time points 0, 2 and 7 hours, respectively, wherein time point 0 represents just 18 hours of incubation with boron compound.
Cells were washed with cold PBS and immediately harvested by scooping them off the petri dish using a rubber wiper, they were collected in cold PBS and formed into a pellet by centrifugation. The cell pellet was analyzed for total protein and boron content in the same manner as described above. The results are shown in Table 3 below. With intracellular uptake, the compound of formula (I) remains in the tumor cells at 7h after complete depletion of Ia in the medium at 50% of the total uptake.
Table 3: boron content (μg boron/g cell pellet) in U343mga cells at 0, 2 and 7h after removal of the boron-containing medium.
In summary, as shown in examples 2-4, the compound Phe-BF 3 Expected results have been shown in vitro assays that are superior to BPA in terms of tumor cell uptake, accumulation and retention.
Example 5Phe-BF 3 CellsToxicity study test
The cell culture solution containing the peptide bovine serum was incubated at 37℃for 24 hours. The subcultured mouse fibroblast L-929 cells were prepared into a cell suspension of 1X 105 cells/mL with a cell culture solution, and the cell suspension was inoculated into a 96-well cell culture plate (100. Mu.l/well) and cultured in a carbon dioxide incubator at 37℃for 24 hours. After the cell attachment growth, the supernatant was removed, a control solution (without compound Ia) was added, and the test group (Phe-BF 3 The concentration of the culture solution is 5 mmol/L), and the culture is continuously carried out in a carbon dioxide incubator at 37 ℃. After 2 days, the cells were taken out, and the culture was continued for 4 hours by adding MTT solution. The stock solution was removed by pipetting, DMSO was added and shaking was performed for 10min. The absorbance was measured at a wavelength of 630nm using an enzyme-linked immunosorbent assay, and the relative proliferation degree (RGR) of the cells was calculated according to the formula based on the absorbance. The results are shown in Table 4 below.
Table 4: results of relative proliferation (RGR) of cells measured by MTT colorimetry
Note that:
the toxic response of cells was assessed in terms of their relative proliferation, see table 5 below.
Table 5: assessment of cytotoxicity response
Conclusion: as can be seen from Table 5, phe-BF 3 No signs of toxicity were observed.
The boron neutron capture therapy system disclosed in the present invention is not limited to the structures described in the above embodiments and shown in the drawings. Obvious changes, substitutions, or modifications to the materials, shapes, and positions of the components therein are made on the basis of the present invention, and are within the scope of the present invention as claimed.
Claims (7)
1. A boron neutron capture therapy system, comprising: boron neutron capture therapeutic device and alpha-amino acid boron trifluoride compound,
the alpha-amino acid boron trifluoride compound has a structure shown as a formula (I):
wherein: r is hydrogen, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, hydroxymethyl, 1-hydroxyethyl, benzyl or hydroxybenzyl; m is H or a metal atom; b is 10 B；
The energy generated after the neutron beam generated by the boron neutron capture treatment device acts on the alpha-amino acid boron trifluoride compound damages the DNA of tumor cells.
2. The boron neutron capture therapy system of claim 1, wherein the boron neutron capture therapy device includes a neutron production section and a beam shaping body for adjusting a neutron beam energy spectrum produced by the neutron production section to an epithermal neutron energy region.
3. The boron neutron capture therapy system of claim 2, wherein the beam shaper includes a moderator adjacent to the neutron generator, a reflector surrounding the moderator, a thermal neutron absorber adjacent to the moderator, and a radiation shield disposed within the beam shaper, the neutron generator nuclear reacting with the incident proton beam to produce neutrons, the moderator moderating neutrons produced from the neutron generator to an epithermal neutron energy region, the reflector directing stray neutrons back to increase the epithermal neutron beam intensity, the thermal neutron absorber to absorb thermal neutrons to avoid excessive doses with shallow normal tissue during therapy, the radiation shield to shield leaking neutrons and photons to reduce normal tissue doses in non-irradiated regions.
4. The boron neutron capture therapy system of claim 3, wherein the boron neutron capture therapy device further comprises a collimator disposed at the beam outlet for focusing the epithermal neutrons.
5. The boron neutron capture therapy system of claim 1, wherein M is potassium or sodium.
6. The boron neutron capture therapy system of claim 1, wherein in the alpha-amino acid boron trifluoride-like compound 10 The purity of B is more than or equal to 95 percent.
7. The boron neutron capture therapy system of claim 1, wherein at least one F is 18 F。
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| CN201610180591.4A CN107224675B (en) | 2016-03-25 | 2016-03-25 | Boron neutron capture therapy system |
| EP17769370.2A EP3424561B1 (en) | 2016-03-25 | 2017-03-16 | Boron neutron capture treating system and alpha-amino acid-like boron trifluoride compounds for use in treating tumors |
| PCT/CN2017/076946 WO2017162093A1 (en) | 2016-03-25 | 2017-03-16 | Boron neutron capture treatingsystem and application of α-amino acid-like boron trifluoride inmanufacturing medicament for treating tumors |
| JP2018549835A JP6649504B2 (en) | 2016-03-25 | 2017-03-16 | Application of α-amino acid-like boron trifluoride compounds in the preparation of boron neutron capture therapy system and tumor therapeutics |
| US16/134,018 US20190054319A1 (en) | 2016-03-25 | 2018-09-18 | Boron neutron capture therapy system and use of α-amino acid-like boron trifluoride compound in preparation of medicament for tumor therapy |
| US16/459,908 US20190381337A1 (en) | 2016-03-25 | 2019-07-02 | Boron neutron capture therapy system |
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| CN109192273B (en) * | 2018-09-10 | 2021-09-28 | 东莞东阳光高能医疗设备有限公司 | Beam evaluation method, device and equipment for boron neutron capture therapy and storage medium |
| TWI816951B (en) * | 2018-12-11 | 2023-10-01 | 日商Ｊ Ｂｅａｍ股份有限公司 | Neutron diagnostic equipment |
| CN111888664A (en) * | 2020-08-05 | 2020-11-06 | 合肥中科离子医学技术装备有限公司 | Neutron capture treatment system based on superconducting cyclotron |
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