TW201836613A - Boron neutron capture therapeutic system and applications of [alpha]-amino acid-like boron trifluoride compound in preparing drugs for tumor therapy comprising a boron neutron capture therapeutic device and an [alpha]-amino acid like boron trifluoride compound - Google Patents

Abstract

On aspect of the present invention discloses a boron neutron capture therapeutic system, which comprises: a boron neutron capture therapeutic device and an [alpha]-amino acid like boron trifluoride compound, wherein the [alpha]-amino acid like boron trifluoride compound has a structure represented by 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 a neutron beam generated by the boron neutron capture therapeutic device is reacted on the [alpha]-amino acid like boron trifluoride compound to destroy tumor cell DNAs. Another aspect of the present invention discloses applications of the [alpha]-amino acid like boron trifluoride compound in preparing drugs for tumor therapy.

Description

 Boron Neutron Capture Therapy System and Application of α-Amino Acid Boride Carbide in Preparation of Tumor Therapeutic Drugs  

One aspect of the invention relates to a radioactive beam irradiation treatment system, in particular to a boron neutron capture treatment system; another aspect of the invention relates to the field of medicine, in particular to the field of tumor-related medicine, and more particularly to an alpha-amino acid-like The use of borofluoride in the preparation of tumor therapeutic drugs.

With the development of atomic science, radiation therapy such as cobalt hexahydrate, linear accelerator, and electron beam has become one of the main methods of cancer treatment. However, traditional photon or electron therapy is limited by the physical conditions of the radiation itself. While killing the tumor cells, it also causes damage to a large number of normal tissues on the beam path. In addition, due to the sensitivity of tumor cells to radiation, traditional radiation therapy For the more radiation-resistant malignant tumors (such as: glioblastoma multiforme, melanoma), the treatment effect is often poor.

In order to reduce the radiation damage of normal tissues around the tumor, the concept of target treatment in chemotherapy has been applied to radiation therapy; and for tumor cells with high radiation resistance, it is currently actively developing with high relative biological effects (relative Biological effectiveness, RBE) radiation sources, such as proton therapy, heavy particle therapy, neutron capture therapy. Among them, neutron capture therapy combines the above two concepts, such as boron neutron capture therapy, by the specific agglomeration of boron-containing drugs in tumor cells, combined with precise neutron beam regulation, providing better radiation than traditional radiation. Cancer treatment options.

Boron Neutron Capture Therapy (BNCT) is a high-capture cross-section of thermal neutrons using boron-containing ( ¹⁰ B) drugs, produced by ¹⁰ B(n,α) ⁷ Li neutron capture and nuclear splitting reactions. ⁴ He and ⁷ Li two heavy charged particles. Refer to the following ¹⁰ B(n,α) ⁷ Li neutron capture nuclear reaction equation.

The average energy of the two charged particles is about 2.33 MeV, which has high linear transfer (LET) and short range characteristics. The linear energy transfer and range of α particles are 150 keV/μm and 8 μm, respectively, while the ⁷ Li heavy particles are 175keV/μm, 5μm, the total range of the two particles is equivalent to a cell size, so the radiation damage caused by the organism can be limited to the cell level, when the boron-containing drugs are selectively aggregated in the tumor cells, with appropriate neutrons The source can achieve the purpose of locally killing tumor cells without causing too much damage to normal tissues.

Because the effectiveness of boron neutron capture therapy depends on the concentration of boron-containing drugs in the tumor cell position and the number of thermal neutrons, it is also known as binary cancer therapy; thus, the development of boron-containing drugs and neutrons are known. Improvements in source flux and quality play an important role in the study of boron neutron capture therapy.

Tumors, especially malignant tumors, are diseases that seriously endanger human health in the world today. Their mortality rate is second only to cardiovascular diseases, ranking second in all kinds of disease mortality, and in recent years, its incidence has shown a clear upward trend. According to the current trend of cancer, the number of new cancer patients in the world will reach 15 million. Although the exact mechanism of cancer is still unclear, most cancer patients are likely to survive if they can diagnose cancer early and take surgery, radiation or chemotherapy as soon as possible (or a combination of these methods). .

One promising new form of high LET radiation cancer therapy is boron neutron capture therapy (BNCT). BNCT is a novel binary targeted radiation therapy based on the selective accumulation of stable nuclei called boron-10 or ¹⁰ B in the tumor, followed by irradiation of the tumor with thermal neutrons. Thermal energy neutrons impinge on boron-10, leading to nuclear fission (decay reaction). Nuclear fission reactions cause a high degree of local release of large amounts of energy in the form of linear energy transfer (transmission line density, LET) radiation, which kills cells more efficiently than low LET radiation such as X-rays (relative to biological effects) high).

In BNCT, when administered in a therapeutically effective amount, the boron-containing compound must be non-toxic or less toxic and capable of selectively accumulating in tumor tissue. Although BPA has the advantage of low chemical toxicity, it accumulates in critical normal tissues at a lower than desired level. In particular, the ratio of boron concentration in tumors to normal brain and tumor to blood is approximately 3:1. Such low specificity (specificity) limits the maximum dose of BPA to the tumor because the allowable dose for normal tissue is a limiting factor.

Therefore, there is a need to develop new compounds that have longer retention times in tumors and selectively target and destroy tumor cells with minimal damage to normal tissues.

Alpha-amino acids are the main components of proteins and are the most important amino acids in organisms. They play a very important role in the production and neurotransmission of ATP. In addition, alpha-amino acids are also key nutrients for the survival and proliferation of cancer cells. The -COOH in the α-amino acid is substituted by -BF ₃ to obtain a boron trifluoride compound of the α-amino acid, which is an isomer compound of the α-amino acid. Studies have shown that the pathway for the uptake of alpha-amino acid-containing boron trifluoride by cells is the same as that of alpha-amino acids, both by enzyme-mediated pathways, and both have the same transporter. The boron trifluoride-like substance of the α-amino acid has attracted much attention in the design of a novel boron carrier compound for BNCT, which has high stability, good targeting, and high enrichment in tumor cells. Compared to FDG, the absorption of this compound in the inflammatory zone is almost negligible. Further, the boron trifluoride of the α-amino acid-like substance is easily synthesized, and is usually obtained by reacting the corresponding boronic acid ester with KHF ₂ under acidic conditions.

In addition, the use of ¹⁸ F-labeled alpha-amino acid-containing boron trifluoride compounds in BNCT provides non-invasive accuracy of boron concentration and distribution in and around tumors and all tissues within the radiation therapy volume before and during irradiation. And quickly measured. This diagnostic information allows for faster, more accurate and safer boron neutron capture therapy by reducing the exposure of epithermal neutrons to areas of tissue known to contain high levels of boron.

In an effort to achieve improvements in existing boron neutron capture therapy systems, an aspect of the invention provides a boron neutron capture therapy system comprising: a boron neutron capture therapy device and an alpha-amino acid trifluoride boride.

The α-amino acid boron trifluoride 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 Metal atom.

The energy generated by the neutron beam generated by the boron neutron capture treatment device to the alpha-amino acid-containing boron trifluoride destroys the tumor cell DNA.

BNCT is an ideal tumor treatment method that provides a new treatment for many tumors that cannot be treated by conventional methods.

Further, the tumor is a malignant tumor or a metastatic tumor process, preferably a glioma, a recurrent head and neck tumor, a malignant melanoma, a breast cancer or a metastatic liver cancer. Malignant tumors are the cancers that people often say. They are the collective name for more than 100 related diseases. When a cell in a body mutates, it continually divides, is not controlled by the body, and eventually forms cancer. The cells of a malignant tumor can invade and destroy adjacent tissues and organs, and the cells can pass through the tumor and enter the blood or lymphatic system. This is how a malignant tumor forms a new tumor from the primary site to other organs. It is called the metastasis of malignant tumors.

Further, the tumor is a brain tumor or melanoma. Brain tumors are tumors that grow in the brain, including primary brain tumors that occur from the brain parenchyma and secondary brain tumors that are transferred from other parts of the body to the brain. Melanoma, also known as malignant melanoma, is a highly malignant tumor that produces melanin, which occurs mostly in the mucous membranes of the skin or near the skin, as well as in the pia mater and choroid.

Preferably, the brain tumor is a glioma. Tumors derived from the neuroepithelial neoplasms, called gliomas, account for 40-50% of brain tumors and are common intracranial malignancies.

The alpha-amino acid boron trifluoride occupies an important role in the application of the boron neutron capture therapeutic system, as will be detailed below.

Preferably, M in the alpha-amino acid boron trifluoride is potassium or sodium.

Preferably, B in the α-amino acid boron trifluoride is ¹⁰ B.

In order to further increase the content of ¹⁰ B in the boron-containing drug, the purity of ¹⁰ B in the α-amino acid boron trifluoride 95%.

At least one F of the alpha-amino acid boron trifluoride is ¹⁸ F, such that boron concentration and distribution in and around the tumor and all tissues within the radiation therapy volume can be non-invasive prior to and during the irradiation The ground is accurately and quickly measured. This diagnostic information allows for faster, more accurate and safer boron neutron capture therapy by reducing the exposure of epithermal neutrons to areas of tissue known to contain high levels of boron.

Further, the boron neutron capture treatment apparatus includes a neutron generating portion for adjusting the neutron beam energy spectrum generated by the neutron generating portion to the epithermal neutron energy region, and a beam shaping body.

In improving the flux and quality of neutron emitters, beam shaping bodies also play an important role. The beam shaping body includes a retarding body adjacent to the neutron generating portion, a reflector surrounding the retarding body, and a thermal neutron absorber adjacent to the retarding body, and the beam is disposed on the beam a radiation shield and a beam exit in the shaping body, the neutron generating portion reacting with the incident proton beam to generate a neutron, the retarding body decelerating the neutron generated from the neutron generating portion to the superheat neutron In the energy region, the reflector directs the deviated neutrons to increase the intensity of the epithermal neutron beam, the thermal neutron absorbers being used to absorb thermal neutrons to avoid excessive doses associated with shallow normal tissue during treatment. The neutrons and photons used to shield the leak are shielded to reduce the normal tissue dose in the non-irradiated area.

The boron neutron capture treatment device further includes a collimator disposed at the beam exit for converging the epithermal neutrons.

Another aspect of the present invention is to provide a novel use of an α-amino acid-containing boron trifluoride, and more particularly to the use of an α-amino acid-containing boron trifluoride in the preparation of a therapeutic drug for tumors.

The tumor treatment refers to a boron neutron capture treatment of a tumor. Boron neutron capture therapy (BNCT) is a new binary targeted radiotherapy, by boron ⁽¹⁰ B) within the tumor cells to destroy the cancer cells nuclear fission reaction. First, oral or intravenous injection of a boron carrier with strong affinity for tumor cells. After the drug is enriched in tumor cells, it is irradiated with neutrons, and ¹⁰ B atoms undergo nuclear fission reaction to generate high radiant energy and small radiation range. The alpha and ⁷ Li particles, in turn, selectively kill the tumor cells in which they are located. BNCT is an ideal tumor treatment method that provides a new treatment for many tumors that cannot be treated by conventional methods.

Further, the tumor is a malignant tumor or a metastatic tumor process, preferably a glioma, a recurrent head and neck tumor, a malignant melanoma, a breast cancer or a metastatic liver cancer. Malignant tumors are the cancers that people often say. They are the collective name for more than 100 related diseases. When a cell in a body mutates, it continually divides, is not controlled by the body, and eventually forms cancer. The cells of a malignant tumor can invade and destroy adjacent tissues and organs, and the cells can pass through the tumor and enter the blood or lymphatic system. This is how a malignant tumor forms a new tumor from the primary site to other organs. It is called the metastasis of malignant tumors.

Further, the tumor is a brain tumor or melanoma. Brain tumors are tumors that grow in the brain, including primary brain tumors that occur from the brain parenchyma and secondary brain tumors that are transferred from other parts of the body to the brain. Melanoma, also known as malignant melanoma, is a highly malignant tumor that produces melanin, which occurs mostly in the mucous membranes of the skin or near the skin, as well as in the pia mater and choroid.

Preferably, the brain tumor is a glioma. Tumors derived from the neuroepithelial neoplasms, called gliomas, account for 40-50% of brain tumors and are common intracranial malignancies.

The α-amino acid boron trifluoride has a structure as shown in formula (I):

Wherein: R is hydrogen, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, hydroxymethyl, 1-hydroxyethyl, benzyl or hydroxybenzyl.

The compound according to formula (I) can be achieved by the following preparation method, and the preparation route is as follows:

10,100‧‧‧Accelerator

20,200‧‧‧Expansion device

30,300‧‧‧beam shaping

31,310‧‧‧ reflector

32,320‧‧‧Speed body

33,330‧‧‧ Thermal neutron absorber

34,340‧‧‧radiation shielding

40,400‧‧ ‧collimator

50,500‧‧‧α-amino acid trifluoride boride

P‧‧‧ charged particle beam

N‧‧‧neutron beam

T‧‧‧neutron production department

1 is a schematic plan view of an accelerator-based boron neutron capture treatment system.

2 is a schematic plan view of a reactor-based boron neutron capture treatment system.

The present invention will be further described in detail below in conjunction with the specific embodiments and the accompanying drawings. The embodiments are only intended to illustrate and describe the present best mode of the invention. The scope of the invention is not limited in any way by the embodiments described herein.

It is to be understood that the terms "comprising", "comprising" and "comprising" or "comprising" or "comprising" does not exclude the presence or addition of one or more other components or combinations thereof.

The fast neutrons described herein are neutrons with an energy region greater than 40 keV, the superheated neutron energy region is between 0.5 eV and 40 keV, and the thermal neutron energy region is less than 0.5 eV.

Neutron capture therapy has been increasingly used as an effective treatment for cancer in recent years, with boron neutron capture therapy being the most common, and neutrons supplying boron neutron capture therapy can be supplied by nuclear reactors or accelerators. Embodiments of the invention take the accelerator boron neutron capture treatment as an example. The basic components of the accelerator boron neutron capture treatment typically include an accelerator, target and heat removal for accelerating charged particles (eg, protons, deuterons, etc.). Systems and beam shaping bodies in which accelerated charged particles interact with metal targets to produce neutrons, depending on the desired neutron yield and energy, the energy and current of the accelerated charged particles, and the physicochemical properties of the metal target. To select a suitable nuclear reaction, the nuclear reactions that are often discussed are ⁷ Li(p,n) ⁷ Be and ⁹ Be(p,n) ⁹ B, both of which are endothermic. The energy thresholds of the two nuclear reactions are 1.881 MeV and 2.055 MeV, respectively. Since the ideal neutron source for boron neutron capture therapy is the superheated neutron of the keV energy level, theoretically, if the proton bombardment metal with energy slightly higher than the threshold is used, Lithium target, which can produce relatively low-energy neutrons, can be used in clinical without too much slow processing. However, the proton interaction cross section of lithium metal (Li) and base metal (Be) targets and threshold energy is not High, in order to generate a sufficiently large neutron flux, a higher energy proton is usually used to initiate the nuclear reaction.

The ideal target should have high neutron yield, produce a neutron energy distribution close to the epithermal neutron energy zone (described in detail below), no excessively strong radiation generation, safe and cheap to operate, and high temperature resistance, but In fact, it is not possible to find a nuclear reaction that meets all the requirements, and a target made of lithium metal is used in the embodiment of the present invention. However, it is well known to those skilled in the art that the material of the target can also be made of other metallic materials than the metal materials discussed above.

The requirements for the heat removal system vary depending on the selected nuclear reaction. For example, ⁷ Li(p,n) ⁷ Be has a lower melting point and thermal conductivity coefficient of the metal target (lithium metal), and the requirements for the heat removal system are higher. ⁹ Be(p,n) ⁹ B is high. A nuclear reaction of ⁷ Li(p,n) ⁷ Be is employed in an embodiment of the invention.

Regardless of the neutron source of boron neutron capture treatment, the nuclear reaction of the nuclear reactor or accelerator charged particles with the target produces a mixed radiation field, ie the beam contains low-energy to high-energy neutrons, photons; boron for deep tumors In the neutron capture treatment, in addition to the superheated neutrons, the more the radiation content, the greater the proportion of non-selective dose deposition in normal tissues, so these radiations that cause unnecessary doses should be minimized. In addition to the air beam quality factor, in order to better understand the dose distribution caused by neutrons in the human body, the human head tissue prosthesis is used for dose calculation in the embodiment of the present invention, and the prosthetic beam quality factor is used as the neutron shot. The design reference for the bundle will be described in detail below.

The International Atomic Energy Agency (IAEA) has given five air beam quality factor recommendations for clinical neutron sources for boron neutron capture therapy. These five recommendations can be used to compare the advantages and disadvantages of different neutron sources and provide them for selection. Reference basis for neutron generation and design of beam shaping. The five recommendations are as follows: Epithermal neutron flux >1 x 10 ⁹ n/cm ² s

Fast neutron contamination Fast neutron contamination<2 x 10 ^-13 Gy-cm ² /n

Photon contamination Photon contamination<2 x 10 ^-13 Gy-cm ² /n

Thermal neutron flux ratio to thermal neutron flux ratio<0.05

Neutron current to flux ratio epithermal neutron cuirent to flux ratio>0.7

Note: The superheated 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 greater than 40keV.

1. Superheated neutron beam flux:

The neutron beam flux and the concentration of boron-containing drugs in the tumor determine the clinical treatment time. If the concentration of the boron-containing drug in the tumor is high enough, the requirement for the flux of the neutron beam can be reduced; conversely, if the concentration of the boron-containing drug in the tumor is low, a high-flux superheated neutron is required to give the tumor a sufficient dose. The IAEA requires a superheated neutron beam flux of more than 10 ⁹ per square centimeter of epithermal neutrons. The neutron beam at this flux can roughly control the treatment time for current boron-containing drugs. Within one hour, in addition to the advantages of patient positioning and comfort, short treatment time can also effectively utilize the limited residence time of boron-containing drugs in the tumor.

2. Fast neutron pollution:

Since fast neutrons cause unnecessary normal tissue doses, they are considered as contamination, and this dose size is positively correlated with neutron energy, so the neutron beam design should minimize the fast neutron content. Fast neutron contamination is defined as the fast neutron dose accompanying the unit's superheated neutron flux. The IAEA's recommendation for fast neutron contamination is less than 2 x 10 ^-13 Gy-cm ² /n.

3. Photon pollution (gamma ray pollution):

Gamma ray is a strong radiation that non-selectively causes dose deposition of all tissues in the beam path. Therefore, reducing gamma ray content is also a necessary requirement for neutron beam design. γ ray pollution is defined as the unit of superheated neutron flux. The gamma dose, IAEA's recommendation for gamma ray contamination is less than 2 x 10 ^-13 Gy-cm ² /n.

4. The ratio of thermal neutron to superheated neutron flux:

Due to the fast decay rate and poor penetrability of thermal neutrons, most of the energy deposited in the human body after deposition into the human body, in addition to melanoma and other epidermal tumors need to use thermal neutrons as a neutron source for boron neutron capture therapy, for brain tumors, etc. Deep tumors should reduce the thermal neutron content. The IAEA's ratio of thermal neutron to superheated neutron flux 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, the better the forward neutron beam, and the high forward neutron beam can reduce the surrounding normal tissue dose caused by neutron divergence. It also increases the depth of treatment and the flexibility of the positional posture. The IAEA's ratio of neutron current to flux is recommended to be greater than 0.7.

The prosthesis was used to obtain the dose distribution in the tissue, and the prosthetic beam quality factor was derived according to the dose-depth curve of normal tissues and tumors. The following three parameters can be used to compare the benefits of different neutron beam treatments.

1. Effective treatment depth:

The tumor dose is equal to the depth of the maximum dose of normal tissue. At this post-depth, the tumor cells receive a dose that is less than the maximum dose of normal tissue, ie, the advantage of boron neutron capture is lost. This parameter represents the penetrating ability of the neutron beam. The greater the effective treatment depth, the deeper the tumor depth that can be treated, in cm.

2. Effective treatment of deep dose rate:

That is, the effective dose rate of the tumor is also equal to the maximum dose rate of normal tissues. Because the total dose received by normal tissues is a factor that affects the total dose of tumor, the parameters affect the length of treatment. The greater the effective dose rate, the shorter the irradiation time required to give a tumor dose, the unit is cGy/mA. -min.

3. Effective therapeutic dose ratio:

From the surface of the brain to the effective depth of treatment, the average dose ratio received by the tumor and normal tissue is called the effective therapeutic dose ratio; the calculation of the average dose can be obtained by integrating the dose-depth curve. The greater 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 design, in addition to the five IAEA recommended airborne beam quality factors and the above three parameters, the following embodiments are also used in the present invention to evaluate the neutron beam dose performance. Good and bad parameters:

1, irradiation time 30min (the proton current used by the accelerator is 10mA)

2, 30.0RBE-Gy can treat depth 7cm

3, the maximum dose of tumor 60.0RBE-Gy

4, the maximum dose of normal brain tissue 12.5RBE-Gy

5, the maximum dose of skin 11.0RBE-Gy

Note: RBE (Relative Biological Effectiveness) is a relative biological effect. Because the biological effects caused by photons and neutrons are different, the above dose terms are multiplied by the relative biological effects of different tissues to obtain the equivalent dose.

Referring to FIG. 1, there is disclosed a schematic plan view of an accelerator-based boron neutron capture treatment system including an accelerator 10, a beam expander 20, and a charged particle beam inlet for passing a charged particle beam P. a charged particle beam P, a neutron generating portion T that undergoes a nuclear reaction with the charged particle beam P to generate a neutron beam N, and beam shaping for adjusting the neutron beam flux and quality generated by the neutron generating portion T The body 30, the collimator 40 adjacent to the beam shaping body 30, and the alpha-amino acid boron trifluoride 50 irradiated by the beam exiting the collimator 40. Wherein, the accelerator 10 is used to accelerate the charged particle beam P, and may be an accelerator suitable for an accelerator type neutron capture treatment system such as a cyclotron or a linear accelerator; the charged particle beam P here is preferably a proton beam; the beam expanding device 20 is disposed at Between the accelerator 10 and the neutron generating portion T; the charged particle beam inlet is adjacent to the neutron generating portion T and housed in the beam shaping body 30, and three arrows between the neutron generating portion T and the beam expanding device 20 are charged. The particle beam inlet; the neutron generating portion T is housed in the beam shaping body 30, where the neutron generating portion T is preferably lithium metal; the beam shaping body 30 includes the reflector 31, surrounded by the reflector 31 and adjacent to the neutron The retarding body 32 of the generating portion T, the thermal neutron absorber 33 adjacent to the retarding body 32, the radiation shield 34 provided in the beam shaping body 30, the neutron generating portion T and the charged particles incident from the entrance of the charged particle beam The beam P undergoes a nuclear reaction to generate a neutron beam N, and the retarding body 32 decelerates the neutron generated from the neutron generating portion T to the epithermal neutron energy region, and the reflector 31 conducts the deviated neutrons back to enhance the superheated neutron emission. Beam strength, thermal neutron absorber 33 For absorbing thermal neutrons to avoid excessive doses with shallow normal tissue during treatment, radiation shields 34 are used to shield leaking neutrons and photons to reduce normal tissue dose in non-irradiated areas, and collimator 40 is used to neutrons Beam aggregation; the energy generated by the neutron beam emitted by the collimator 40 after acting on the alpha-amino acid boron trifluoride 50 destroys the tumor cell DNA.

Referring to FIG. 2, there is disclosed a schematic plan view of a reactor-based boron neutron capture treatment system including a reactor 100 (a neutron beam is generated from the reactor, and thus may also be referred to as Sub-generation unit), beam expander 200, neutron beam inlet, beam shaping body 300 for adjusting neutron beam flux and quality generated by neutron generation unit, and collimation adjacent to beam shaping body 300 The device 400 and the alpha-amino acid boron trifluoride 500 that is illuminated by the beam exiting the collimator 400. Wherein, the reactor 100 may be associated with a nuclear reaction capable of generating neutrons of a desired energy, such as neutrons emitted by uranium-235 or strontium-239 during fission reaction; the beam expanding device 200 is disposed in the reactor 100. And between the neutron beam entrances; three arrows after the beam expanding device 200 serve as neutron beam inlets; the beam shaping body 300 includes a reflector 310, a retarding body 320 surrounded by the reflector 310, and the retarding body 320. The adjacent thermal neutron absorber 330, the radiation shield 340 disposed in the beam shaping body 300, the retarding body 320 decelerates the neutron generated from the neutron generating portion 100 to the epithermal neutron energy region, and the reflector 310 will deviate. The neutrons are led back to increase the intensity of the epithermal neutron beam, the thermal neutron absorber 330 is used to absorb the thermal neutrons to avoid excessive doses to the shallow normal tissue during treatment, and the radiation shield 340 is used to shield the leaking neutrons and photons. Reducing the normal tissue dose in the non-irradiated area, the collimator 400 is used to concentrate the neutron beam; the energy generated by the neutron beam emitted by the collimator 400 after acting on the alpha-amino acid boron trifluoride 500 destroys the tumor cells DNA.

The beam shaping bodies 30, 300 can slow the neutrons to the superheated neutron energy zone and reduce the thermal neutron and fast neutron content. The reflectors 31, 310 are made of a material having a strong neutron reflection ability. As a preferred embodiment, the reflectors 31, 310 are made of at least one of Pb or Ni. The retarding bodies 32, 320 are made of a material having a large fast neutron action cross section and a superheated neutron action cross section. As a preferred embodiment, the retarding bodies 32, 320 are composed of D ₂ O, AlF ₃ , Fluental ^TM , CaF. _2. Made of at least one of Li ₂ CO ₃ , MgF ₂ and Al ₂ O ₃ . The thermal neutron absorbers 33, 330 are made of a material having a large cross section with thermal neutrons. As a preferred embodiment, the thermal neutron absorbers 33, 330 are made of ⁶ Li. The radiation shields 34, 340 include photonic shields and neutron shields. As a preferred embodiment, the radiation shields 34, 340 include photonic shields made of lead (Pb) and neutron shields made of polyethylene (PE). The collimators 40, 400 are made of a material having a strong neutron convergence ability. As a preferred embodiment, the collimators 40, 400 are made of at least one of graphite and lead.

It is well known to those skilled in the art that other neutron generation methods, such as a DD neutron generator, a DT neutron generator, etc., may be used in addition to the neutron generation mode of the accelerator type and the reactor type described above, or may be based on actual needs. The material, structure and composition of the beam shaping body are adjusted accordingly.

In BNCT, when administered in a therapeutically effective amount, the boron-containing compound must be non-toxic or less toxic and capable of selectively accumulating in tumor tissue. Although BPA has the advantage of low chemical toxicity, it accumulates in critical normal tissues at a lower than desired level. In particular, the ratio of boron concentration in tumors to normal brain and tumor to blood is approximately 3:1. Such low specificity (specificity) limits the maximum dose of BPA to the tumor because the allowable dose for normal tissue is a limiting factor.

Therefore, there is a need to develop new compounds that have longer retention times in tumors and selectively target and destroy tumor cells with minimal damage to normal tissues.

Alpha-amino acids are the main components of proteins and are the most important amino acids in organisms. They play a very important role in the production and neurotransmission of ATP. In addition, alpha-amino acids are also key nutrients for the survival and proliferation of cancer cells. The -COOH in the α-amino acid is substituted by -BF ₃ to obtain a boron trifluoride compound of the α-amino acid, which is an isomer compound of the α-amino acid. Studies have shown that the pathway for the uptake of alpha-amino acid-containing boron trifluoride by cells is the same as that of alpha-amino acids, both by enzyme-mediated pathways, and both have the same transporter. The boron trifluoride-like substance of the α-amino acid has attracted much attention in the design of a novel boron carrier compound for BNCT, which has high stability, good targeting, and high enrichment in tumor cells. Compared to FDG, the absorption of this compound in the inflammatory zone is almost negligible. Further, the boron trifluoride of the α-amino acid-like substance is easily synthesized, and is usually obtained by reacting the corresponding boronic acid ester with KHF ₂ under acidic conditions.

In addition, the use of ¹⁸ F-labeled alpha-amino acid-containing boron trifluoride compounds in BNCT provides non-invasive accuracy of boron concentration and distribution in and around tumors and all tissues within the radiation therapy volume before and during irradiation. And quickly measured. This diagnostic information allows for faster, more accurate and safer boron neutron capture therapy by reducing the exposure of epithermal neutrons to areas of tissue known to contain high levels of boron.

The boron trifluoride compound of the α-amino acid type will be described in detail below in conjunction with specific examples.

Example 1 Phe-BF ₃ preparation

Reaction route

Add benzyl borate (15 mg, 0.05 mmol), KF (0.15 mmol, 0.05 mL) solution, HCl (0.2 mmol, 0.03 mL) solution, 0.1 mL of MeCN solution in a 1.5 mL microreactor, and react at room temperature for 2 h. , obtained crude Phe-BF ₃ . The crude product was further purified by HPLC, to give 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); [MH ] ^- 188.0901, Found: 188.0589.

In vitro studies of compounds according to the invention

The in vitro assay of the purified material of Example 1 (hereinafter referred to as Phe-BF ₃ ) used four different human-derived tumor cell lines U343mga, human liver cancer cell line Hep3B, human breast cancer cell line MCF7, and human Sarcoma cell line 4SS. Cells were plated on uncoated tissue culture dishes and incubated at 37 ° C in an incubator with humidified air equilibrated with 5% CO ₂ (10% FCS and PEST (penicillin) added to the medium 100 IU/mL and streptomycin 100 mg/mL)). For cell passage, cells were trypsinized with trypsin-EDTA (0.25% trypsin and 0.02% EDTA, phosphate buffered saline (PBS) without calcium and magnesium).

Example 2 Phe-BF ₃ Cellular uptake

The U343mga cells at a cell density of 75% of the tile in the Petri dish, and the tissue culture medium with soluble boron 1,4-dihydroxy-phenylalanine (BPA) or Phe-BF ₃ were incubated for 6 hours. Both boron-containing compounds were added in an equimolar concentration relative to the boron content (5 x 10 ^-4 mol/L boron) and dissolved in the tissue culture medium. The incubation was terminated by removing the boron-containing tissue culture medium and adding cold phosphate buffered saline (PBS buffer) to wash away excess medium from the cells. The cells were harvested immediately by scooping down from the culture dish using a rubber lake, they were collected in cold PBS and precipitated by centrifugation.

Total protein analysis was performed on cell samples according to Bradford's standard program. The precipitated cells were subjected to boron analysis by direct current atomic emission spectrometry (DCP-AES). The sample (50-130 mg) was digested with sulfuric acid/nitric acid (1/1) at 60 °C. Triton X-100 and water were added to give a concentration of 50 mg 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 the 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 (Runs 1 and 2), the boron content is expressed as a function of total cellular protein in U343mga cells (μg boron/g cellular protein) (in Tests 1 and 2, respectively). 7.2 and 7.7 μg boron/mL medium).

Example 3 Different tumor cells to Phe-BF ₃ Ingestion

Four different human tumor cell lines derived from human: U343mga, Hep3B, MCF7 and 4SS were plated on Petri dishes at 40-50% (low) and 90-100% (high) cell density, and dissolved as described above. Phe-BF ₃ in tissue culture medium was incubated for 6 hours. The incubation was terminated by removing the boron-containing medium and adding cold PBS buffer to wash away excess medium from the cells. The cells were harvested immediately by scooping down from the culture dish using a rubber lake, they were collected in cold PBS and precipitated by centrifugation. Total protein analysis of cell samples was performed according to Bradford's standard program (above). The results are shown in Table 2 below. Phe-BF _{3 was} found in comparison of all four human tumor cell lines (glioblastoma (U343mga), liver cancer (Hep3B), breast cancer (MCF7), sarcoma (4SS)) tested at low and high cell densities. It is a highly efficient boron carrier.

Table 2: Phe-BF ₃ cell uptake. Boron content is expressed as a function of total cellular protein (μg boron/g cellular protein)

Example 4 Phe-BF ₃ Intracellular retention

The U343mga cells at a cell density of 75% of the tile in the Petri dish, and boron for 1,4-dihydroxy phenylalanine (BPA) in tissue culture or Phe-BF ₃ was incubated for 18 hours. Both boron compounds were added to the tissue culture medium at equimolar concentrations relative to the boron content (5 x 10 ^-4 mol/L boron). The incubation was terminated by replacing the boron-containing medium with a medium without boron. Cell samples were sampled at time points 0, 2, and 7 hours, respectively, with time 0 representing incubation with boron compounds for 18 hours.

The cells were washed with cold PBS and harvested immediately by scooping them off from the culture dishes using a rubber bottle, they were collected in cold PBS and precipitated by centrifugation. The cell pellet was analyzed for total protein and boron content as described above. The results are shown in Table 3 below. With intracellular uptake, the compound of formula (I) remaining in tumor cells was 50% of total uptake 7 h after complete depletion of Ia in the medium.

Table 3: Boron content in U343mga cells at 0, 2 and 7 h after removal of boron-containing medium (μg boron/g cell pellet)

Taken together, as shown in Examples 2-4, the compound Phe-BF ₃ has been shown to have the expected results in in vitro assays, which are superior to BPA in tumor cell uptake, accumulation and retention.

Example 5 Phe-BF ₃ Cytotoxicity study

The cell culture medium containing the peptide bovine serum was incubated at 37 ° C for 24 h. The subcultured mouse fibroblast L-929 cells were prepared into a cell suspension of 1×10 5 cells/mL with a cell culture solution, and the cell suspension was seeded in a 96-well cell culture plate (100 μl/well). Incubate in a 37 ° C carbon dioxide incubator for 24 h. After the cells adhered to the wall, the supernatant was removed, the control solution (without compound Ia) was added, and the culture solution of the test group (Phe-BF ₃ concentration: 5 mmol/L) was exchanged, and the mixture was kept at 37 ° C in a carbon dioxide incubator. to cultivate. After 2 days, it was taken out, and MTT solution was added to continue the culture for 4 hours. The stock solution was aspirated, DMSO was added, and the mixture was shaken for 10 min. The absorbance value was measured by an enzyme-linked immunosorbent assay at a wavelength of 630 nm, and the relative proliferation (RGR) of the cells was calculated according to the formula according to the absorbance. The results are shown in Table 4 below.

Table 4: Cell Relative Proliferation (RGR) Results by MTT Colorimetry

The toxicity of the cells was evaluated based on the relative proliferation of the cells, as shown in Table 5 below.

Table 5: Assessment of cytotoxicity

Conclusion: As can be seen from Table 5, Phe-BF ₃ did not show any signs of toxicity.

The boron neutron capture treatment system disclosed in the present invention is not limited to the contents described in the above embodiments and the structures represented in the drawings. Obvious modifications, substitutions, or alterations of the materials, shapes and positions of the components in the present invention are within the scope of the invention as claimed.

Claims (15)

A boron neutron capture therapeutic system comprising: a boron neutron capture therapeutic device and an alpha-amino acid trifluoride boride having 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 by the neutron beam generated by the boron neutron capture treatment device to the alpha-amino acid-containing boron trifluoride destroys tumor cell DNA.  The boron neutron capture treatment system of claim 1, wherein the boron neutron capture treatment device comprises a neutron generator and a beam shaping body, the beam shaping body being used for generation by neutrons The neutron beam energy spectrum produced by the part is adjusted to the superheated neutron energy region.    The boron neutron capture treatment system according to claim 2, wherein the beam shaping body includes a retarding body adjacent to the neutron generating portion, a reflector surrounding the retarding body, a thermal neutron absorber adjacent to the retarding body and a radiation shield disposed within the beam shaping body, the neutron generating portion undergoes a nuclear reaction with the incident proton beam to generate neutrons, and the retarding body will The neutrons generated by the neutron generating portion are decelerated to an epithermal neutron energy region, the reflector directing the deviated neutrons to increase the intensity of the epithermal neutron beam, the thermal neutron absorber being used to absorb the thermal neutrons Avoiding excessive doses with shallow normal tissue during treatment, the radiation shield is used to shield leaking neutrons and photons to reduce normal tissue dose in the non-irradiated area.    The boron neutron capture treatment system of claim 3, wherein the boron neutron capture treatment device further comprises a collimator disposed at the beam exit for converging the epithermal neutrons.    The boron neutron capture treatment system according to any one of claims 1 to 4, wherein the M is potassium or sodium.   The boron neutron capture treatment system according to any one of claims 1 to 4, wherein B is ¹⁰ B. The boron neutron capture therapeutic system according to claim 6, wherein the purity of ¹⁰ B in the α-amino acid boron trifluoride compound 95%. The boron neutron capture treatment system according to any one of claims 1 to 4, wherein at least one F is ¹⁸ F.  The use of an α-amino acid boron trifluoride in the preparation of a medicament for tumor therapy.   The application of claim 9, wherein the α-amino acid boron trifluoride 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 Metal atom.  The application of claim 10, wherein the M is potassium or sodium.    The use according to any one of claims 9 to 11, wherein the tumor treatment refers to a boron neutron capture treatment of a tumor.    The application of claim 12, wherein the tumor is a malignant tumor or a metastatic tumor process.    The application of claim 12, wherein the tumor is a glioma, a recurrent head and neck tumor, a malignant melanoma, a breast cancer or a metastatic liver cancer.    The application of claim 14, wherein the tumor is a glioma or a malignant melanoma.