WO2017181790A1 - 用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统 - Google Patents

用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统 Download PDF

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WO2017181790A1
WO2017181790A1 PCT/CN2017/076935 CN2017076935W WO2017181790A1 WO 2017181790 A1 WO2017181790 A1 WO 2017181790A1 CN 2017076935 W CN2017076935 W CN 2017076935W WO 2017181790 A1 WO2017181790 A1 WO 2017181790A1
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neutron
compound
neutron capture
neutrons
plaque
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French (fr)
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陈瑞芬
何静
刘渊豪
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南京中硼联康医疗科技有限公司
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Priority to JP2018554698A priority Critical patent/JP6754846B2/ja
Priority to EP17785276.1A priority patent/EP3421089B1/en
Publication of WO2017181790A1 publication Critical patent/WO2017181790A1/zh
Priority to US16/143,891 priority patent/US20190022222A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/009—Neutron capture therapy, e.g. using uranium or non-boron material
    • A61K41/0095—Boron neutron capture therapy, i.e. BNCT, e.g. using boronated porphyrins
    • 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
    • A61N5/103—Treatment planning systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • 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
    • A61N5/1042—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy with spatial modulation of the radiation beam within the treatment head
    • 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
    • A61N5/1048—Monitoring, verifying, controlling systems and methods
    • 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
    • A61N5/1077—Beam delivery systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • 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
    • A61N2005/109—Neutrons
    • 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
    • A61N2005/1092—Details
    • A61N2005/1094—Shielding, protecting against radiation
    • 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
    • A61N2005/1092—Details
    • A61N2005/1095—Elements inserted into the radiation path within the system, e.g. filters or wedges
    • 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
    • A61N2005/1092—Details
    • A61N2005/1098—Enhancing the effect of the particle by an injected agent or implanted device

Definitions

  • the present invention relates to a neutron capture therapy system, and more particularly to a neutron capture therapy system that can be used to eliminate beta amyloid.
  • AD Alzheimer's disease
  • Mild to moderate AD treatments include the acetylcholinesterase inhibitors donepezil, rivastigmine and galantamine.
  • Donepezil is also indicated for the treatment of moderate to severe AD, either alone or in combination with the N-methyl-D-aspartate receptor antagonist memantine.
  • a ⁇ amino acid sequence from the meningeal blood vessel wall of AD patients.
  • the basic structure contains 40 or 42 amino acid polypeptides, collectively referred to as ⁇ amyloid protein, in human cerebrospinal fluid and plasma, A ⁇ 1-40.
  • a ⁇ 1-42 is more toxic than A ⁇ 1-42 , and A ⁇ 1-42 is more toxic, and it accumulates more easily, forming a core of A ⁇ precipitate, which causes neurotoxicity.
  • AD Alzheimer's disease
  • Gantenerumab is a monoclonal antibody that binds to the N-terminal epitope of A ⁇ . Gantenerumab binds to oligomeric and fibrous A[beta], resulting in microglia-mediated phagocytic clearance of plaques.
  • Previous phase III clinical trials in patients with mild to moderate AD have failed, and ongoing Phase III clinical trials are aimed at patients with AD in the early stages.
  • Recent results indicate that Gantenerumab significantly reduces the level of tau in cerebrospinal fluid, but does not significantly reduce A ⁇ levels in cerebrospinal fluid.
  • Aducanumab is a monoclonal antibody that targets only the aggregated A[beta] form. Although the ability of the antibody to cross the blood-brain barrier is poor, Aducanumab can accumulate in the brain due to its significant increase in half-life in plasma. Early data from Phase Ib trials showed that Aducanumab significantly reduced A ⁇ deposition. The latest PRIME data published at the 2015 International Conference of Alzheimer's Disease showed that Aducanumab did not significantly reduce cognitive decline after one year of intermediate dose treatment, while the side effect rate was relatively high.
  • Neutron capture therapy is a highly targeted, effective and less harmful treatment for normal tissues. No method has been found to effectively reduce or eliminate beta amyloid deposits. The study reports the application of neutron capture therapy technology to the treatment of Alzheimer's disease.
  • the present invention provides a neutron capture treatment system for eliminating beta amyloid deposition plaques, including a neutron capture therapeutic device and a compound containing 10 B, wherein the 10 B-containing compound is capable of specifically binding to the ⁇ amyloid deposition plaque, and the neutron beam generated by the neutron capture treatment device acts on the energy destruction and 10 B-containing after the 10 B-containing compound is applied The compound specifically binds to the amyloid beta deposit plaque.
  • 10 B element has a large capture cross section for thermal neutrons and constitutes the main elements of the human body.
  • C, H, O, N, P, S have small capture cross sections for thermal neutrons, and compounds containing 10 B are irradiated by thermal neutrons. Occurs as shown in Reaction Scheme I, which destroys the energy and the substance that specifically binds to the 10 B-containing compound.
  • the superheated neutron beam is slowly accelerated to thermal neutrons by human tissue and absorbed by a compound containing 10 B, and The tissue of the compound of 10 B was not damaged. Since the compound containing 10 B is capable of specifically binding and ⁇ -amyloid plaque deposition, and therefore, in their irradiation, thermal neutrons and 10 B-containing compound produced by neutron beam energy of 10 B-containing compound destruction The surrounding beta amyloid deposits the structure of the plaque to reduce or eliminate beta amyloid deposition plaques.
  • the neutron capture therapy device comprises a neutron source, a beam shaping body and a collimator, wherein the neutron source is Generating a neutron beam, the beam shaping body being located at the rear of the neutron source and adjusting the fast neutrons in the neutron beam generated by the neutron source with a broader energy spectrum into superheat
  • the collimator is used to concentrate the epithermal neutrons.
  • the neutron source comprises an accelerator neutron source or a reactor neutron source.
  • the beam shaping package a reflector, a retarding body, a thermal neutron absorber, and a radiation shield, wherein the reflector surrounds the retarding body for reflecting neutrons diffused outside the beam shaping back into the retarding body,
  • the retarding body is used to retard fast neutrons into superheated neutrons for absorbing thermal neutrons to avoid excessive doses caused by shallow normal tissue during treatment. Used to shield leaking neutrons and photons to reduce normal tissue dose in non-irradiated areas.
  • the neutron capture therapy device in the neutron capture therapy system includes a neutron source, which is used to generate neutrons, and is divided into an accelerator neutron source and a reactor neutron source according to the neutron production principle.
  • the neutron capture treatment device also includes a beam shaping body and a collimator. Since the neutron source produces a wide distribution of neutron energy spectrum, these neutrons are classified into fast neutrons, superheated neutrons, and heat according to their energy ranges.
  • the fast neutron energy region is greater than 40 keV
  • the superheated neutron energy region is between 0.5 eV and 40 keV
  • the thermal neutron energy region is less than 0.5 eV.
  • the compound containing 10 B has a large capture cross section for thermal neutrons, but in actual operation, the neutron beam will be slowed down by other substances in the process of reaching the compound containing 10 B, so it is often chosen in practical applications.
  • the epithermal neutron beam illuminates the compound containing 10 B.
  • the beam shaping body further comprises a reflector and a retarding body, wherein the slowing body functions to slow the fast neutron generated by the neutron source into a neutron of the energy spectrum in the superheat neutron energy region, and the material of the retarding body can be It is composed of one or more of Al 2 O 3 , BaF 2 , CaF 2 , CF 2 , PbF 2 , PbF 4 and D 2 O, and may also be composed of a lithium-containing substance added from the material of the retarding body. Such as LiF or Li 2 CO 3 containing 6 Li.
  • the reflector is located around the retarding body and is generally made of a material having strong neutron reflection capability, such as at least one of Pb or Ni, which acts to reflect back the neutrons that diffuse around, thereby enhancing the neutron.
  • the intensity of the beam is located at the rear of the retarding body, and the collimator is used to concentrate the neutron beam to make the treatment more precise.
  • the structural formula of the 10 B-containing compound is:
  • R is a phenylboronic acid group and boron in the phenylboronic acid group is 10 B.
  • the 10 B-containing compound as shown in Structural Formula I is capable of specifically binding to the beta amyloid deposition plaque, and the compound class is able to cross the blood brain barrier.
  • the R group in the structural formula I is divided into R 1 and R 2 according to the substitution position of the boronic acid group, wherein R 1 The group is:
  • the R 2 group is:
  • the 10 B-containing compound is Compound I: when the substituent R in the 10 B-containing compound is R 2 , The compound containing 10 B is the compound II.
  • the beta amyloid deposition plaque comprises A[beta] 42 .
  • the ⁇ -amyloid-deposited plaque is mainly accumulated by the highly accumulating A ⁇ 42.
  • the ⁇ -amyloid-deposited plaque can cause neurotoxicity, resulting in decreased cognitive ability and symptoms of Alzheimer's disease.
  • a neutron source in the neutron capture treatment device is used to generate a beam shaping body in a neutron capture treatment device.
  • the neutron beam with a wide spectrum can be adjusted to a neutron beam that can be captured by a 10 B element with a larger cross section.
  • the collimator in the neutron capture therapy device is used to concentrate the neutron beam to improve the precision of the illumination.
  • the neutron beam emerging from the collimator is irradiated onto a compound that has been specifically bound to the beta amyloid-containing 10 B element, and the energy produced by the reaction of the neutron and the 10 B element destroys the amyloid beta deposit plaque.
  • the capture cross section of 10 B element for thermal neutrons is more than one hundred times larger than the capture cross section of the basic elements of the human body to thermal neutrons.
  • thermal neutrons are specific to 10 B elements, while compounds containing 10 B can
  • the neutron capture therapeutic system for eliminating beta amyloid deposition plaques provided by the present invention is capable of specifically reducing or eliminating beta amyloid deposition plaques.
  • Figure 1 is a schematic plan view of a neutron capture treatment system for eliminating beta amyloid deposits.
  • Alzheimer's disease is a central nervous system degenerative disease characterized by progressive cognitive dysfunction and behavioral damage in the elderly and early senile.
  • the senile plaque is an important pathological feature of Alzheimer's disease.
  • a ⁇ beta amyloid
  • a ⁇ 42 in ⁇ amyloid deposits has a high degree of aggregation. After being secreted by neurons, it will rapidly aggregate to form soluble oligomers, and then further aggregate to form A ⁇ plaques and deposit in the brain.
  • the internal amyloid beta deposit plaque is the main cause of axonal and inflammatory responses. Therefore, how to reduce beta amyloid deposition plaque in the brain becomes an important strategy for the prevention or treatment of Alzheimer's disease.
  • neutron capture therapy has been widely studied as a treatment with strong targeting, good therapeutic effect and little damage to normal tissues, but the application of this technology is concentrated in the treatment of cancer. This technique of high precision and high therapeutic effect has not been found to be used in the treatment of Alzheimer's disease.
  • Neutron capture therapy has been increasingly used as an effective means of treating 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.
  • 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 proton bombardment with energy only slightly higher than the threshold is used.
  • a metallic lithium target that produces relatively low-energy neutrons that can be used clinically without too much slow processing.
  • proton interaction cross sections for lithium metal (Li) and base metal (Be) targets and threshold energy 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 a 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 inexpensive to operate, and high temperature resistance.
  • a target made of lithium metal is used in the embodiment of the present invention.
  • 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.
  • 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.
  • the nuclear reaction of the charged particles from the nuclear reactor or the accelerator produces a mixed radiation field, that is, the beam contains low-energy to high-energy neutrons and photons; for deep tumors in boron
  • Sub-capture treatment in addition to super-thermal neutrons, the more radiation content, the greater the proportion of non-selective dose deposition in normal tissue, so these will cause unnecessary doses of radiation should be minimized.
  • 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 has given five air beam quality factor recommendations for clinical neutron sources for clinical boron neutron capture therapy. These five recommendations can be used to compare the pros and cons of different neutron sources and provide The reference basis for selecting the neutron generation route and designing the beam shaping body.
  • the five recommendations are as follows:
  • Epithermal neutron beam flux Epithermal neutron flux>1x10 9 n/cm 2 s
  • 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.
  • 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's requirement for the epithermal neutron beam flux is that the number of epithermal neutrons per square centimeter per second is greater than 10 9 .
  • the neutron beam at this flux can roughly control the treatment of current boron-containing drugs. In one hour, short treatment time, in addition to the advantages of patient positioning and comfort, can also make more effective use of boron-containing drugs in the tumor for a limited residence time.
  • Fast neutron contamination is defined as the fast neutron dose accompanying the unit's superheated neutron flux, and the IAEA's recommendation for fast neutron contamination is less than 2x10 -13 Gy-cm 2 /n.
  • ⁇ -rays are strong radiation, which will non-selectively cause dose deposition of all tissues in the beam path. Therefore, reducing ⁇ -ray content is also a necessary requirement for neutron beam design.
  • ⁇ -ray pollution is defined as the unit of superheated neutron flux.
  • the gamma dose, IAEA's recommendation for gamma ray contamination is less than 2x10 -13 Gy-cm 2 /n.
  • thermal neutrons Due to the fast decay rate and poor penetrability of thermal neutrons, most of the energy is deposited on the skin tissue after entering the human body. In addition to melanoma and other epidermal tumors, thermal neutrons are needed as the neutron source for boron neutron capture therapy. Deep tumors such as 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.
  • 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 elasticity of the treatment depth and 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.
  • 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.
  • 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.
  • the effective therapeutic 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 following embodiments are also used in the present invention to evaluate the neutron beam dose performance. Good and bad parameters:
  • Irradiation time ⁇ 30min (the proton current used by the accelerator is 10mA)
  • RBE Relative Biological Effectiveness
  • the neutron capture therapy system 1 comprises a neutron capture therapy apparatus 100 and 200 containing 10 B compound, wherein the neutron capture neutron source 110, the beam shaping member 120 and the collimator 100 includes a therapy device 130 .
  • the neutron source 110 is classified into an accelerator-type neutron source and a reactor-type neutron source according to the mechanism of neutron production.
  • the accelerator neutron source is widely used, and the accelerator neutron source is charged by the charged particle accelerated by the accelerator.
  • the target nucleus T generates neutrons through a nuclear reaction.
  • the material currently used as the target nucleus T is a substance containing 7 Li or 9 Be.
  • the neutron source of neutron capture therapy comes from the nuclear reaction of nuclear reactors or accelerator charged particles with the target, producing a mixed radiation field, ie the beam contains low-energy to high-energy neutrons; these neutrons are classified according to their energy For fast neutrons, superheated neutrons and thermal neutrons, for neutron capture therapy, in addition to superheated neutrons, the more radiation content, the greater the proportion of non-selective dose deposition in normal tissues, so these Radiation that would cause unnecessary doses should be minimized.
  • the beam shaping body acts to reduce unnecessary doses and enhance the epithermal neutron beam.
  • the beam shaping body 120 includes a retarding body 122, a reflector 121 surrounding the retarding body 122, and a thermal neutron absorber 123 adjacent to the retarding body 122.
  • the retarding body 122 will mix the fast neutrons in the radiation field.
  • the material of the retarding body 122 is made of at least one material containing LiF, Li 2 CO 3 , Al 2 O 3 , AlF 3 , CaF 2 or MgF 2 , wherein the retarding body
  • the material of 122 is changed into a block from the powder or powder compact by a powder sintering process through a powder sintering process, and the reflector 121 is guided back to the neutrons deviating from the periphery to increase the intensity of the epithermal neutron beam, and the thermal neutron absorber 123 is used.
  • the thermal neutron absorber 123 is used to absorb thermal neutrons to avoid excessive doses with shallow normal tissue during treatment.
  • the collimator 130 is located at the rear of the retarding body 122 for concentrating the neutron beam to provide precise directivity of the neutron beam during the treatment.
  • a radiation shield 124 is located at the rear of the retarding body 122 for shielding leaking neutrons and photons to reduce the normal tissue dose in the non-irradiated area.
  • the 10 B-containing compound 200 binds to the amyloid beta deposition plaque 300 and is emitted by the neutron capture treatment device 100 when the concentration of the 10 B-containing compound on the beta amyloid deposition plaque 300 is greatest.
  • the neutron beam N is irradiated, and a suitable slow-moving body 122 is selected according to the position of the beta amyloid deposition plaque 300 so as to reach the 10 B-containing compound 200 that specifically binds to the amyloid-deposited plaque 300 Where the energy of the sub-beam is in the hyperthermal neutron energy region.
  • Epithermal neutrons to the energy range between 0.5eV 40keV, epithermal neutron beam energy is retarder element 10 B and the thermal neutron beam generation reaction of destructuring ⁇ -amyloid deposition in plaques.
  • the 10 B-containing compound described in the examples of the present invention is classified into Compound I and Compound II according to the difference of the substituent group R group.
  • Step 1 90 mmol of 2-acetylfuran was dissolved in 40 mL of dimethylformamide (DMF), and then 108 mmol of N-bromosuccinimide (NBS) was added thereto at 0 ° C to mix the solution. After stirring at room temperature overnight, the reaction mixture contained 1-(5-bromo-2-furanyl)ethanone.
  • DMF dimethylformamide
  • NBS N-bromosuccinimide
  • Step 2 To a mixed solution of 10 mL of 2M sodium carbonate and 10 mL of dimethyl ether (DME), 5.3 mmol of 1-(5-bromo-2-furanyl)ethanone and 5.3 mmol of 4-(two) were added. Methylamino)benzeneboronic acid, and then added tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ) at 0 ° C, and the reaction solution was reacted at 80 ° C for 24 h to obtain a reaction mixture containing 1 -(5-(4-dimethylaminophenyl)-2-furanyl)ethanone;
  • Step 3 To a solution of 2.1 mmol of 1-(5-(4-dimethylaminophenyl)-2-furanyl)ethanone and 2.1 mmol of benzaldehyde derivative in dimethylformamide (DMF) (50 mL) In 1:1), a concentration of 5 M NaOH was added under the condition of 0 ° C, and the reaction mixture solution was stirred at room temperature for 8 hours, and the obtained mixed solution contained Compound I and Compound II.
  • DMF dimethylformamide
  • the blood-brain barrier Due to the presence of the blood-brain barrier (BBB), most compounds are difficult to enter the brain via blood flow. For many drugs, they cannot pass the blood-brain barrier and cannot exert their effects. In general, water-soluble drugs are difficult to pass the blood-brain barrier, while fat-soluble drugs have better permeability than water-soluble drugs.
  • the dissolution, absorption, distribution and transport of drugs in the body are related to the water solubility and fat solubility of the drug, ie the oil-water partition coefficient (logP).
  • the oil-water partition coefficient is the logarithm of the ratio of the partition coefficient of the drug in n-octanol and the water phase. The larger the logP value, the more oleophilic the substance is, and the more soluble the water.
  • the oil-water partition coefficient (logP) of the substance is preferably between 1 and 3.
  • the lipid-water partition coefficient of the compound containing 10 B according to the embodiment of the present invention is 2.97. Therefore, the 10 B-containing compound has a good blood-brain barrier penetration as a drug for preparing a drug for eliminating beta amyloid deposition plaque.
  • the affinity of the 10 B-containing compound and the ⁇ amyloid protein is evaluated by the equilibrium dissociation constant K D value, and K D can indicate the degree of dissociation of the two substances in the equilibrium state, and the larger the K D value is The more dissociation, the weaker the affinity between the two substances. The smaller the K D value, the less dissociation, the stronger the affinity between the two substances.
  • a ⁇ amyloid solution with a concentration of 10 ⁇ M was prepared and mixed with Compound I or Compound II at different concentrations (concentration ranging from 0.1 to 10 ⁇ M), and allowed to stand at room temperature for 20 min, and then the equilibrium dissociation constant K was measured and calculated.
  • the equilibrium dissociation constant K D was also measured and calculated, wherein Compound I The equilibrium dissociation constant is 0.79, the equilibrium dissociation constant of compound II is 0.9, and the equilibrium dissociation constant of the control is 1.59, which indicates that compound I and compound II and compounds known to specifically bind to amyloid ⁇ It has a stronger affinity than beta amyloid.
  • the medicament prepared by the 10 B-containing compound of the present invention needs to specifically bind to and be applied to the neutron capture therapeutic system through the blood brain barrier and amyloid beta to further eliminate the beta amyloid. It can be seen from this example that a compound containing 10 B can be used to prepare a drug that specifically binds to amyloid beta and allows the drug to eliminate beta amyloid in a neutron capture therapeutic system.
  • boric acid H 3 10 BO 3
  • the compound containing 10 B including compound I and compound II
  • the boron element in boric acid (H 3 10 BO 3 ) is 10 B
  • bovine serum albumin is used.
  • BSA bovine serum albumin to simulate ⁇ -amyloid
  • a mixed solution of boric acid and bovine serum albumin was placed in a neutron capture treatment device to generate a neutron beam environment, and neutrons were analyzed by SDS-PAGE gel electrophoresis for bovine serum albumin. The role of neutron beam on bovine serum albumin in the presence of H 3 10 BO 3 .
  • the BSA solution with a concentration of 0.01% (w/w) was placed in ultrapure water.
  • the prepared solution was stored at 4 ° C and experimentally operated.
  • 1 mL of BSA solution was placed on the center line of the collimator outlet of the neutron capture treatment device. Wherein the solution is 2 cm from the collimator exit distance, and the neutron capture treatment device is arranged such that the neutron intensity at the outlet of the collimator is 2.4 ⁇ 10 11 /s, and the BSA solution is in the neutron environment Irradiation for 2 h; another 1 mL of BSA solution was used as a control solution without neutron irradiation.
  • the BSA solution and the control solution which were irradiated with neutrons for 2 hours were stained with Coomassie brilliant blue and subjected to SDS-PAGE gel electrophoresis.
  • the color of the protein bands in the electrophoresis patterns of the above sample solution and the control solution were quantified by Image J software.
  • the value is used to indicate the relative content of the protein, wherein the BSA content in the control solution is defined as 1.
  • the content of BSA after neutron irradiation for 2 hours is 0.8, and its content is about 20%. The reduction, as can be seen, the radiation containing the neutron beam can affect the protein content.
  • a solution of BSA and H 3 10 BO 3 was prepared with ultrapure water, wherein the concentration of BSA in the solution was 0.01% (w/w), and the concentration of H 3 10 BO 3 was 0.18 M;
  • Store at 4 ° C and experimental operation take 8 parts from the solution (numbered A, B, C, D, E, F, G, H), and each 1 mL solution is treated with a neutron capture treatment device. Irradiation, respectively, 8 solutions were placed on the center line of the collimator outlet of the neutron capture treatment device, the distance of the solution A from the exit of the collimator was 2 cm, and the solution B was 4 cm from the outlet of the collimator.
  • the outlet of the straightener is 6cm, and so on.
  • the beam at the exit of the collimator includes gamma rays and other radiation in addition to the neutron rays.
  • the neutron rays are mainly used to destroy the protein.
  • the neutrons in the beam are used.
  • the intensity of the beam is described in terms of intensity, wherein the neutron neutron intensity used in this embodiment is 2.4 ⁇ 10 11 /s, 8 solutions are irradiated in the neutron environment for 2 h; and from the BSA and H 1 mL of 3 10 BO 3 solution was used as a control solution, and the control solution was not irradiated with neutrons.
  • control solution and the 8 doses of the radiation irradiated by the neutron capture treatment device were stained with Coomassie brilliant blue and subjected to SDS-PAGE gel electrophoresis.
  • Figure 2 shows the control solution and 8 parts of the solution SDS- PAGE electrophoresis map.
  • the first two protein bands in Figure 2 are BSA in the control solution, and the rest are BSA after irradiation with the radiation, and 8 solutions are placed on the center line of the collimator exit, due to the center line
  • the solution contains H 3 10 BO 3
  • the 10 B element has a large capture cross section for the thermal neutrons, so the neutrons in the radiation from the exit of the collimator pass through the solution containing H 3 10 BO 3
  • the sub-dose is drastically reduced, and the farther away from the collimator outlet, the less radiation dose the BSA receives.
  • the color of the protein bands irradiated by the eight neutron-irradiated solutions is shallower to varying degrees compared with the control, and the closer to the outlet of the collimator, the solution is in the solution.
  • the lighter the color of the protein band the more the protein content is reduced, and the closer the outlet is to the collimator, the larger the neutron radiation dose of the solution, further indicating that the size of the neutron dose affects the BSA content in the solution.
  • the stronger the neutron dose the less the BSA content in the solution after the neutron irradiation.
  • the color of the BSA protein band in the electrophoresis pattern corresponding to the control solution and the 8 parts solution was quantified by Image J software, and the value was used to indicate the relative content of the protein, wherein the BSA content in the control solution was defined as 1.
  • the content of BSA after neutron irradiation for 2 hours under the above neutron irradiation experimental conditions is shown in Table 1.
  • the compound I and the compound II provided by the present invention both carry the nuclide 10 B having a large thermal neutron capture cross section like H 3 10 BO 3 , and the compound is capable of specifically binding to amyloid ⁇ , and the compound is placed.
  • the compound forms a higher concentration around the amyloid beta, and the neutron beam emitted by the neutron capture treatment device illuminates the region where the compound accumulates, which is released. Energy can destroy the structure of amyloid beta.
  • the 10 B-containing compound of the present invention is also fluorescent due to the nature of the molecule itself, so that the 10 B -containing compound can be used in addition to the ⁇ -amyloid-deposited plaque in the neutron capture treatment system.
  • the optimal timing of irradiation with a boron neutron capture treatment device can be determined by measuring its fluorescence intensity.
  • the compounds having a 10 B containing BBB penetration properties and capable of ⁇ -amyloid deposition and specifically binds to plaques and since the compound containing the element 10 B 10 B has a high among the The thermal neutron captures the cross section, so the 10 B containing compound is provided for elimination of beta amyloid deposition plaques in a neutron capture therapy system.
  • the neutron capture treatment system for eliminating beta amyloid deposition plaque disclosed by the present invention is not limited to the contents described in the above embodiments and the structures represented by 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.

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Abstract

一种用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统，包括中子捕获治疗装置和能够和β淀粉样蛋白沉积斑块特异性结合的含 10B的化合物，中子捕获治疗装置产生的中子射束照射在 10B元素上时产生的能量能够破坏β淀粉样蛋白沉积斑块的结构，其有益效果是有针对性的高效的破坏β淀粉样蛋白沉积斑块。

Description

用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统 技术领域
本发明涉及一种中子捕获治疗系统，尤其是一种能够用于消除β淀粉样蛋白的中子捕获治疗系统。
背景技术
阿尔兹海默症(AD)是一种潜伏、渐进性和不可逆的脑部疾病，以65岁以上人群高发。目前AD的治疗目标是，在减缓或延迟症状的同时维持身体功能和能力。轻度至中度AD治疗药物包括乙酰胆碱酯酶抑制剂多奈哌齐、利凡斯的明和加兰他敏。多奈哌齐也用于治疗中度至重度AD，单独或与N-甲基-D-天冬氨酸受体拮抗剂美金刚组合使用。这些神经递质调节药物可暂时改善症状，但患者仍会遭遇认知能力逐渐恶化，以及精神疾病、躁动、抑郁和睡眠障碍。
1984年科学家首次从AD患者脑膜血管壁中纯化并测得了Aβ氨基酸顺序，其基本结构中都含40或42个氨基酸多肽，统称为β淀粉样蛋白，在人脑脊液和血浆中，Aβ1-40分别比Aβ1-42的含量水平高10倍和1.5倍，Aβ1-42具有更强的毒性，且更容易聚积，从而形成Aβ沉淀的核心，引发神经毒性作用。Aβ级联学说认为，AD患者可能是由于APP和PS基因的突变产生过多的Aβ或高集聚能力的Aβ1-42在脑组织内沉积，对周围的突触和神经元具有毒性作用，最终引起神经元细胞死亡，因为Aβ异常分泌和产生过多会导致AD的其他病理变化，所以它是AD发病的核心环节。
目前AD治疗新药开发的主要热点是Aβ聚集抑制和Aβ清除。Gantenerumab是一种结合在Aβ的N-末端表位的单克隆抗体。Gantenerumab可结合低聚和纤维状Aβ，从而导致小胶质细胞介导的吞噬细胞清除斑块。此前一项治疗轻度至中度AD患者的Ⅲ期临床试验遭遇失败，目前正在进行的Ⅲ期临床试验针对早期阶段AD患者。最新结果表明，Gantenerumab显著降低脑脊液中tau蛋白的水平，但没有显著减少脑脊液Aβ水平。
Aducanumab是一种仅靶向于聚集Aβ形式的单克隆抗体。尽管该抗体穿过血脑屏障的能力差，但由于其在血浆中的半衰期显著延长，Aducanumab可以在脑中累积。Ib期试验早期数据显示，Aducanumab可以显著减少Aβ沉积。在2015年阿尔茨海默病协会国际会议公布的最新PRIME数据显示，Aducanumab中间剂量治疗一年后并没有显著减少认知功能减退，而副作用率相对较高。
中子捕获治疗技术是一种针对性强，效果好并且对正常组织伤害较小的治疗技术，目前尚未发现一种能有效的减少或消除β淀粉样蛋白沉积斑块的方法，也尚未发现有研究报道将中子捕获治疗技术应用与阿尔兹海默症的治疗过程中。
发明内容
为了有效的减少或消除β淀粉样蛋白沉积斑块，本发明提供了一种用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统，包括中子捕获治疗装置以及含10B的化合物，其中，含10B的化合物能够和β淀粉样蛋白沉积斑块特异性结合，并且所述中子捕获治疗装置产生的中子束作用到含10B的化合物后产生的能量破坏和含10B的化合物特异性结合的β淀粉样蛋白沉积斑块。
10B元素对热中子具有较大的捕获截面并且构成人体的主要元素C、H、O、N、P、S对热中子的捕获截面小，含10B的化合物被热中子照射后发生如反应式I所示，其产生的能量破坏和含10B的化合物特异性结合的物质。
Figure PCTCN2017076935-appb-000001
根据这一性质，服用含10B的化合物的人体在进行中子射束照射时，超热中子射束经人体组织缓速为热中子并被含有10B的化合物吸收，而对不含10B的化合物的组织没有损伤。由于含10B的化合物能够和β淀粉样蛋白沉积斑块特异性结合，因此，在用中子射束对其照射时，热中子和含10B的化合物产生的能量破坏含10B的化合物周围的β淀粉样蛋白沉积斑块的结构，以减少或消除β淀粉样蛋白沉积斑块。
优选的是，用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统中，所述中子捕获治疗装置包括中子源、射束整形体和准直器，其中所述中子源用于产生中子射束，所述射束整形体位于所述中子源后部并将所述中子源产生的具有较宽能谱的中子射束中的快中子调整为超热中子，所述准直器用于汇聚所述超热中子。
优选的是，用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统中，所述中子源包括加速器中子源或反应堆中子源。
优选的是，用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统中，所述射束整形体包 括反射体、缓速体、热中子吸收体和辐射屏蔽，其中所述反射体包围所述缓速体，用于将向射束整形体外扩散的中子反射回所述缓速体中，所述缓速体用于将快中子缓速为超热中子，所述热中子吸收体用于吸收热中子以避免治疗时与浅层正常组织造成过多剂量，所述辐射屏蔽用于屏蔽渗漏的中子和光子以减少非照射区的正常组织剂量。
中子捕获治疗系统中的中子捕获治疗装置包括中子源，中子源用于产生中子，根据中子产生原理不同分为加速器中子源和反应堆中子源。中子捕获治疗装置还包括射束整形体和准直器，由于中子源产生中子能谱分布很广，这些中子根据其能量范围不同分为快中子、超热中子和热中子，其中快中子能区大于40keV，超热中子能区在0.5eV到40keV之间，热中子能区小于0.5eV。含10B的化合物是对热中子的捕获截面较大，但是在实际操作过程中，中子射束到达含10B的化合物的过程中会被其他物质缓速，因此在实际应用中往往选择超热中子射束对含10B的化合物进行照射。射束整形体又包括反射体和缓速体，其中缓速体的作用为将中子源产生的快中子缓速为能谱在超热中子能区的中子，缓速体的材料可以由Al2O3、BaF2、CaF2、CF2、PbF2、PbF4以及D2O中的一种或者几种结合而成，也可以由上述缓速体的材料添加含锂物质后组成，如含有6Li的LiF或Li2CO3。反射体位于缓速体的周围，一般由具有中子反射能力强的材料制成，如Pb或Ni中的至少一种材料，其作用是将向四周扩散的中子反射回来，从而增强中子射束的强度。准直器位于所述缓速体的后部，所述准直器用于汇聚所述中子射束以使治疗更有精准性。
优选的是，用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统中，所述含10B的化合物的结构通式为：
Figure PCTCN2017076935-appb-000002
其中，R为苯硼酸基团，且所述苯硼酸基团中的硼为10B。
如结构式I所示的含10B的化合物能够和β淀粉样蛋白沉积斑块特异性结合，并且该化合 物类别能够透过血脑屏障。
优选的是，用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统中，所述结构式I中的R基根据硼酸基团的取代位置不同分为R1和R2，其中，R1基团为：
Figure PCTCN2017076935-appb-000003
R2基团为：
Figure PCTCN2017076935-appb-000004
当所述含10B的化合物中的取代基团R为R1时，所述含10B的化合物为化合物I：当所述含10B的化合物中的取代基团R为R2时，所述含10B的化合物为化合物II。
优选的是，用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统中，所述β淀粉样蛋白沉积斑块包括Aβ42。β淀粉样蛋白沉积斑块主要是由容易聚积的Aβ42高度聚积而成，β淀粉样蛋白沉积斑块会引发神经毒性作用，导致认知能力下降，表现出阿尔兹海默症的症状。
本发明提供的用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统中，由所述中子捕获治疗装置中的中子源产生中子，中子捕获治疗装置中的射束整形体将能谱较广的中子射束调整到能被10B元素以较大截面捕获的中子射束，中子捕获治疗装置中的准直器用以将中子射束汇聚以提高照射的精准度，从准直器出来的中子射束照射在已经和β淀粉样蛋白特异性结合含10B元素的化合物上，中子和10B元素反应产生的能量破坏β淀粉样蛋白沉积斑块。10B元素对热中子的捕获截面是人体基本元素对热中子的捕获截面的一百倍以上，换句话说，热中子对10B元素具有特异性，而含10B的化合物又能和β淀粉样蛋白沉积斑块特异性结合，因此本发明提供的用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统能够有效地特异性地减少或消除β淀粉样蛋白沉积斑块。
附图说明
图1是用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统的平面示意图。
图2是牛血清白蛋白和H3 10BO3的混合溶液分别在距离准直器出口不同位置处经辐射线照射后的SDS-PAGE电泳图谱。
具体实施方式
下面结合附图对本发明做进一步的详细说明，以令本领域技术人员参照说明书文字能够据以实施。
应当理解，本文所使用的诸如“具有”、“包含”以及“包括”术语并不排除一个或多个其它成分或其组合的存在或添加。
阿尔兹海默症是发生于老年和老年前期，以进行性认知功能障碍和行为损害为特征的中枢神经系统退行性疾病，老年斑是阿尔兹海默症的重要病理特征，老年斑的主要组成物质是β淀粉样蛋白(Aβ)，当前研究明确Aβ是阿尔兹海默症的致病物质，Aβ在脑内过度产生和沉积会引起神经元突触功能障碍。
β淀粉样蛋白沉积斑块中的Aβ42具有高度聚集能力，经神经元产生分泌后，会迅速聚集，形成可溶状态的寡聚体，然后进一步聚集形成Aβ斑块而沉积在脑内，脑内的β淀粉样蛋白沉积斑块是引起神经轴突变性和炎性反应的主要原因。因此如何降低脑内β淀粉样蛋白沉积斑块成为防治或治疗阿尔兹海默症的重要策略。
随着技术的进步，中子捕获治疗作为一种靶向性强，治疗效果好并且对正常组织损伤小的治疗方法得到广泛的研究，但是这种技术的应用集中在癌症的治疗过程中，目前尚未发现将这种精准度高治疗效果好的技术用于阿尔兹海默症的治疗技术中。
中子捕获治疗作为一种有效的治疗癌症的手段近年来的应用逐渐增加，其中以硼中子捕获治疗最为常见，供应硼中子捕获治疗的中子可以由核反应堆或加速器供应。本发明的实施例以加速器硼中子捕获治疗为例，加速器硼中子捕获治疗的基本组件通常包括用于对带电粒子(如质子、氘核等)进行加速的加速器、靶材与热移除系统和射束整形体，其中加速带电粒子与金属靶材作用产生中子，依据所需的中子产率与能量、可提供的加速带电粒子能量与电流大小、金属靶材的物化性等特性来挑选合适的核反应，常被讨论的核反应有7Li(p,n)7Be及9Be(p,n)9B，这两种反应皆为吸热反应。两种核反应的能量阀值分别为1.881MeV和2.055MeV，由于硼中子捕获治疗的理想中子源为keV能量等级的超热中子，理论上若使用能量仅稍高于阀值的质子轰击金属锂靶材，可产生相对低能的中子，不须太多的缓速处理便可用于临床，然而锂金属(Li)和铍金属(Be)两种靶材与阀值能量的质子作用截面不高，为产生足够大的中子通量，通常选用较高能量的质子来引发核反应。
理想的靶材应具备高中子产率、产生的中子能量分布接近超热中子能区(将在下文详细描述)、无太多强穿辐射产生、安全便宜易于操作且耐高温等特性，但实际上并无法找到符合所有要求的核反应，本发明的实施例中采用锂金属制成的靶材。但是本领域技术人员熟知的，靶材的材料也可以由其他除了上述谈论到的金属材料之外的金属材料制成。
针对热移除系统的要求则根据选择的核反应而异，如7Li(p,n)7Be因金属靶材(锂金属)的熔点及热导系数差，对热移除系统的要求便较9Be(p,n)9B高。本发明的实施例中采用7Li(p,n)7Be的核反应。
无论硼中子捕获治疗的中子源来自核反应堆或加速器带电粒子与靶材的核反应，产生的皆为混合辐射场，即射束包含了低能至高能的中子、光子；对于深部肿瘤的硼中子捕获治疗，除了超热中子外，其余的辐射线含量越多，造成正常组织非选择性剂量沉积的比例越大，因此这些会造成不必要剂量的辐射应尽量降低。除了空气射束品质因素，为更了解中子在人体中造成的剂量分布，本发明的实施例中使用人体头部组织假体进行剂量计算，并以假体射束品质因素来作为中子射束的设计参考，将在下文详细描述。
国际原子能机构(IAEA)针对临床硼中子捕获治疗用的中子源，给定了五项空气射束品质因素建议，此五项建议可用于比较不同中子源的优劣，并供以作为挑选中子产生途径、设计射束整形体时的参考依据。这五项建议分别如下：
超热中子射束通量Epithermal neutron flux>1x109n/cm2s
快中子污染Fast neutron contamination<2x10-13Gy-cm2/n
光子污染Photon contamination<2x10-13Gy-cm2/n
热中子与超热中子通量比值thermal to epithermal neutron flux ratio<0.05
中子电流与通量比值epithermal neutron current to flux ratio>0.7
注：超热中子能区在0.5eV到40keV之间，热中子能区小于0.5eV，快中子能区大于40keV。
1、超热中子射束通量：
中子射束通量和肿瘤中含硼药物浓度共同决定了临床治疗时间。若肿瘤含硼药物浓度够高，对于中子射束通量的要求便可降低；反之，若肿瘤中含硼药物浓度低，则需高通量超热中子来给予肿瘤足够的剂量。IAEA对于超热中子射束通量的要求为每秒每平方厘米的超热中子个数大于109，此通量下的中子射束对于目前的含硼药物而言可大致控制治疗时间在一小时内，短治疗时间除了对病人定位和舒适度有优势外，也可较有效利用含硼药物在肿瘤内有限的滞留时间。
2、快中子污染：
由于快中子会造成不必要的正常组织剂量，因此视之为污染，此剂量大小和中子能量呈正相关，因此在中子射束设计上应尽量减少快中子的含量。快中子污染定义为单位超热中子通量伴随的快中子剂量，IAEA对快中子污染的建议为小于2x10-13Gy-cm2/n。
3、光子污染(γ射线污染)：
γ射线属于强穿辐射，会非选择性地造成射束路径上所有组织的剂量沉积，因此降低γ射线含量也是中子束设计的必要要求，γ射线污染定义为单位超热中子通量伴随的γ射线剂量，IAEA对γ射线污染的建议为小于2x10-13Gy-cm2/n。
4、热中子与超热中子通量比值：
由于热中子衰减速度快、穿透能力差，进入人体后大部分能量沉积在皮肤组织，除黑色素细胞瘤等表皮肿瘤需用热中子作为硼中子捕获治疗的中子源外，针对脑瘤等深层肿瘤应降低热中子含量。IAEA对热中子与超热中子通量比值建议为小于0.05。
5、中子电流与通量比值：
中子电流与通量比值代表了射束的方向性，比值越大表示中子射束前向性佳，高前向性的中子束可减少因中子发散造成的周围正常组织剂量，另外也提高了可治疗深度及摆位姿势弹性。IAEA对中子电流与通量比值建议为大于0.7。
利用假体得到组织内的剂量分布，根据正常组织及肿瘤的剂量-深度曲线，推得假体射束品质因素。如下三个参数可用于进行不同中子射束治疗效益的比较。
1、有效治疗深度：
肿瘤剂量等于正常组织最大剂量的深度，在此深度之后的位置，肿瘤细胞得到的剂量小于正常组织最大剂量，即失去了硼中子捕获的优势。此参数代表中子射束的穿透能力，有效治疗深度越大表示可治疗的肿瘤深度越深，单位为cm。
2、有效治疗深度剂量率：
即有效治疗深度的肿瘤剂量率，亦等于正常组织的最大剂量率。因正常组织接收总剂量为影响可给予肿瘤总剂量大小的因素，因此参数影响治疗时间的长短，有效治疗深度剂量率越大表示给予肿瘤一定剂量所需的照射时间越短，单位为cGy/mA-min。
3、有效治疗剂量比：
从大脑表面到有效治疗深度，肿瘤和正常组织接收的平均剂量比值，称之为有效治疗剂量比；平均剂量的计算，可由剂量-深度曲线积分得到。有效治疗剂量比值越大，代表该中子 射束的治疗效益越好。
为了使射束整形体在设计上有比较依据，除了五项IAEA建议的空气中射束品质因素和上述的三个参数，本发明实施例中也利用如下的用于评估中子射束剂量表现优劣的参数：
1、照射时间≤30min(加速器使用的质子电流为10mA)
2、30.0RBE-Gy可治疗深度≥7cm
3、肿瘤最大剂量≥60.0RBE-Gy
4、正常脑组织最大剂量≤12.5RBE-Gy
5、皮肤最大剂量≤11.0RBE-Gy
注：RBE(Relative Biological Effectiveness)为相对生物效应，由于光子、中子会造成的生物效应不同，所以如上的剂量项均分别乘上不同组织的相对生物效应以求得等效剂量。
如图1所示，中子捕获治疗系统包括中子捕获治疗装置100和含10B的化合物200，其中，中子捕获治疗装置100包括中子源110、射束整形体120和准直器130。中子源110根据中子产生的机理不同分为加速器式中子源和反应堆式中子源，应用较广的是加速器式中子源，加速器中子源是利用加速器加速的带电粒子轰击适当的靶核T，通过核反应产生中子，目前常用的作为靶核T的材料为含7Li或9Be的物质。
无论中子捕获治疗的中子源来自核反应堆或加速器带电粒子与靶材的核反应，产生的皆为混合辐射场，即射束包含了低能至高能的中子；这些中子根据其能量的不同分为快中子、超热中子和热中子，对于中子捕获治疗，除了超热中子外，其余的辐射线含量越多，造成正常组织非选择性剂量沉积的比例越大，因此这些会造成不必要剂量的辐射应尽量降低。射束整形体起到降低不必要剂量，增强超热中子射束的作用。
射束整形体120包括缓速体122、包围在缓速体122外的反射体121、与缓速体122邻接的热中子吸收体123，缓速体122将混合辐射场中的快中子减速至超热中子能区，缓速体122的材料由含有LiF、Li2CO3、Al2O3、AlF3、CaF2或MgF2中的至少一种材料制成，其中缓速体122的材料经粉末烧结设备通过粉末烧结工艺由粉末或粉末压坯变成块，反射体121将向四周偏离的中子导回以提高超热中子射束强度，热中子吸收体123用于吸收热中子以避免治疗时与浅层正常组织造成过多剂量。准直器130位于缓速体122的后部，用以汇聚中子射束以使中子射束在治疗过程中具有精准的指向性。辐射屏蔽124位于缓速体122的后部，用于屏蔽渗漏的中子和光子以减少非照射区的正常组织剂量。
发明内容所述的含10B的化合物200与β淀粉样蛋白沉积斑块300结合，在β淀粉样蛋白沉积斑块300上的含10B的化合物浓度最大时用中子捕获治疗装置100发射的中子射束N 对其进行照射，根据β淀粉样蛋白沉积斑块300所在位置选择合适缓速体122以使到达特异性结合在β淀粉样蛋白沉积斑块300的含10B的化合物200时，其中子射束的能量处于超热中子能区。超热中子能区在0.5eV到40keV之间，超热中子射束被缓速为热中子射束后和10B元素反应产生的能量破坏β淀粉样蛋白沉积斑块的结构。本发明实施例中所述的含10B的化合物根据其取代基团R基的不同分为化合物I和化合物II。
下面通过实施例进一步说明本发明的技术方案。
<实施例1>含10B的化合物的制备方法
本发明所述的含10B的化合物的制备步骤如下：
步骤一：90mmol的2-乙酰基呋喃溶于40mL的二甲基甲酰胺(DMF)中，再在0℃条件下向其中加入108mmol的N-溴代琥珀酰亚胺(NBS)，将混合液于室温条件下搅拌过夜，反应混合液里含有1-(5-溴-2-呋喃基)乙酮。
用乙酸乙酯稀释步骤一中所述的反应混合液，并过滤，滤液中的有机相用饱和氯化钠水溶液洗涤，并依次经无水硫酸钠干燥、浓缩，再用色谱进行分离得到1-(5-溴-2-呋喃基)乙酮。
1H NMR(500MHz,CDCl3,δ,ppm):2.46(3H.s),6.49(1H,d,J＝3.4Hz),7.12(1H,d,J＝3.4Hz).MS m/z 188(M+H)+。
步骤二：向10mL浓度为2M的碳酸钠和10mL的二甲醚(DME)的混合溶液中加入5.3mmol的1-(5-溴-2-呋喃基)乙酮和5.3mmol的4-(二甲氨基)苯硼酸，再在0℃的条件下加入四(三苯基膦)钯(Pd(PPh3)4)，反应溶液在80℃的条件下反应24h，得到的反应混合液里含有1-(5-(4-二甲氨基苯)-2-呋喃基)乙酮；
其中所述4-(二甲氨基)苯硼酸中的硼为10B。
用乙酸乙酯稀释步骤二中所述的反应混合液，并过滤，滤液中的有机相用饱和氯化钠水溶液洗涤，并依次经无水硫酸钠干燥、浓缩，再用色谱进行分离得到1-(5-(4-二甲氨基苯)-2-呋喃基)乙酮。
1H NMR(500MHz,CDCl3,δ,ppm):2.49(3H.s),3.02(6H.s),6.56(1H,d,J＝3.7Hz),6.72(2H,d,J＝9.1Hz),7.25(1H,d,J＝3.7Hz),7.67(2H,d,J＝9.1Hz).MS m/z 230(M+H)+.
步骤三：向溶解有2.1mmol的1-(5-(4-二甲氨基苯)-2-呋喃基)乙酮和2.1mmol的苯甲醛衍生物的二甲基甲酰胺(DMF)溶液(50mL，1:1)中在0℃的条件下加入浓度为5M的NaOH，反应混合溶液在室温条件下搅拌8h，所得的混合溶液里含有化合物I和化合物II。
将含有化合物I和化合物II的混合溶液用浓度为1M的HCl调整pH至6，过滤并将过滤所得的固体物质用色谱进行分离得到化合物I：
1H NMR(500MHz,DMSO-d6,δ,ppm):2.96(6H.s),6.78(2H,d,J＝8.8Hz),6.97(1H,d,J＝3.7Hz),7.67-7.71(4H,m),7.78(2H,d,J＝8Hz),7.82(2H,d,J＝8Hz),7.89(1H,d,J＝3.7Hz).MS m/z 362(M+H)+.
和化合物II：
1H NMR(500MHz,DMSO-d6,δ,ppm):2.93(6H.s),6.76(2H,d,J＝9.2Hz),6.92(1H,d,J＝3.8Hz),7.41(1H,t,J＝7.6Hz),7.63-7.69(4H,m),7.79-7.82(2H,m),7.85(1H,d,J＝7.6Hz).MS m/z 362(M+H)+.
制备含10B的化合物的反应过程如反应式II所示：
Figure PCTCN2017076935-appb-000005
<实施例2>含10B的化合物在制备和β淀粉样蛋白特异性结合药物中的应用
由于血脑屏障(BBB)的存在，大部分化合物很难经由血液流进入大脑，对于很多药物来说，不能穿过血脑屏障就不能发挥药效。一般情况下，水溶性药物难以通过血脑屏障，而脂溶性的药物相对于水溶性药物有较好的渗透性。药物在体内的溶解、吸收、分布、转运与药物的水溶性和脂溶性有关，即油水分配系数(logP)。油水分配系数为药物在正辛醇和水相中的分配系数比值的对数值，logP值越大，说明该物质越亲油，反之则越易溶于水。
有研究报道物质的油水分配系数(logP)的值在1～3之间较好，根据所述报道中的实验计算得出本发明实施例所述含10B的化合物的脂水分配系数为2.97，因此所述含10B的化合物在作为制备消除β淀粉样蛋白沉积斑块的药物的应用时有良好的血脑屏障穿透性。
本发明实施例用平衡解离常数KD值来评价含10B的化合物和β淀粉样蛋白的亲和力，KD可以表示出处于平衡状态时两种物质的解离程度，KD值越大说明解离越多，表示两种物 质之间的亲和力越弱，KD值越小说明解离越少，代表两种物质间的亲和力越强。
配制浓度为10μM的β淀粉样蛋白溶液，并将其分别与不同浓度(浓度范围在0.1～10μM)的化合物I或化合物II混合，室温静置20min后，通过测量并计算其平衡解离常数KD；另外根据已知的能够和β淀粉样蛋白特异性结合的化合物作为对照样和浓度为10μM的混合并在室温静置20min，同样测量并计算其平衡解离常数KD，其中化合物I的平衡解离常数为0.79，化合物II的平衡解离常数为0.9，对照样的平衡解离常数为1.59，由此可说明化合物I和化合物II和已知能够和β淀粉样蛋白特异性结合的化合物相比和β淀粉样蛋白具有更强的亲和力。
其中对照样中的能够和β淀粉样蛋白特异性结合的化合物具有如下结构式：
Figure PCTCN2017076935-appb-000006
本发明所述的含10B的化合物制备的药物需要透过血脑屏障和β淀粉样蛋白特异性结合并应用到所述中子捕获治疗系统中以进一步消除所述β淀粉样蛋白。通过本实施例可以看出含10B的化合物能够用来制备和β淀粉样蛋白特异性结合的药物并使所述药物在中子捕获治疗系统中消除β淀粉样蛋白。
<实施例3>中子捕获治疗系统消除β淀粉样蛋白沉积斑块的模拟试验
本实施例用硼酸(H3 10BO3)来代替含10B的化合物(包括化合物I和化合物II)，其中硼酸(H3 10BO3)中的硼元素为10B，用牛血清白蛋白(BSA)来模拟β淀粉样蛋白，将硼酸和牛血清白蛋白构成的混合溶液置于中子捕获治疗装置产生中子射束环境中，通过SDS-PAGE凝胶电泳分析中子对牛血清白蛋白的作用以及在H3 10BO3存在的条件下，中子射束对牛血清白蛋白的作用。
(一)、中子对牛血清白蛋白的作用
用超纯水配置浓度为0.01％(w/w)的BSA溶液，配置的溶液在4℃条件下保存及实验操作，取1mLBSA溶液置于中子捕获治疗装置的准直器出口的中心线上，其中所述溶液距离准直器出口距离为2cm，设置中子捕获治疗装置以使准直器出口处的中子强度为2.4×1011个/s，所述BSA溶液在该中子环境中照射2h；另取1mLBSA溶液作为对照液不进行中子照射。
将用中子照射2h的BSA溶液和对照液分别用考马斯亮蓝染色并做SDS-PAGE凝胶电泳，用Image J软件分别将上述样品液和对照液的电泳图谱中蛋白条带的颜色进行量化，其数值用来表示蛋白质的相对含量，其中定义对照液中的BSA含量为1，在上述中子照射实验条件下，经中子照射2h后的BSA的含量为0.8，其含量约有20％的减少，由此可见，包含有中子射束的辐射线能够影响蛋白质的含量。
(二)、在H3 10BO3存在的条件下，中子对牛血清白蛋白的作用
用超纯水配置BSA和H3 10BO3的溶液，其中，在所述溶液中，BSA的浓度为0.01％(w/w)，H3 10BO3的浓度为0.18M；配置的溶液均在4℃保存及实验操作，从所述溶液中分别取8份(编号分别为A、B、C、D、E、F、G、H)，每份1mL的溶液用中子捕获治疗装置进行照射，分别将8份溶液置于中子捕获治疗装置准直器出口的中心线上，溶液A距离准直器出口的距离为2cm，溶液B距离准直器的出口为4cm，溶液C距离准直器的出口为6cm，并以此类推。准直器出口处的射束中除了包括中子射线，还包括伽马射线及其他辐射线，在实际对蛋白质起到破坏作用的主要是中子射线，本实施例用射束中的中子强度来描述所述射束的强度，其中，本实施例采用的中子中子强度为2.4×1011个/s，8份溶液在该中子环境中照射2h；另从所述BSA和H3 10BO3溶液中取1mL作为对照液，该对照液不经中子照射。
将对照液和经中子捕获治疗装置放射的辐射线照射过的的8份溶液分别用考马斯亮蓝染色并做SDS-PAGE凝胶电泳，图2所示为对照液和8份溶液的SDS-PAGE电泳图谱。
图2中前两个蛋白条带为对照液中的BSA，其余分别为经过所述辐射线照射后的BSA，8份溶液均置于准直器出口中心线上，由于在所述中心线上的溶液中均含有H3 10BO3，而10B元素对热中子有较大的捕获截面，因此从准直器出口出来的辐射线中的中子经过含有H3 10BO3的溶液后，其中子剂量大幅度下降，离准直器出口越远的溶液，其BSA接受到的辐射剂量越少。
从图2可以看出，8个经中子照射过的溶液相比于对照样，其蛋白条带的颜色均有不同程度的变浅，并且，离准直器出口越近，其溶液内的蛋白条带的颜色越浅，说明蛋白含量减少的越多，而离准直器出口越近，溶液受到的中子辐射剂量越大，进一步说明，中子剂量的大小影响溶液中BSA的含量，中子剂量越强，经所述中子照射后的溶液中BSA的含量越少。
用Image J软件分别将对照液和8份溶液对应的电泳图谱中的BSA蛋白条带的颜色进行量化，其数值用来表示蛋白的相对含量，其中，定义对照液中的BSA含量为1，在上述中子照射实验条件下，经中子照射2h后的BSA的含量如表1所示。
由表1可以看出，经中子照射的溶液中BSA含量均有不同程度的降低，距离准直器出口 2cm的溶液经中子强度为2.4×1011个/s的中子照射2h后，其BSA含量仅剩5.3％，说明在H3 10BO3存在的条件下，中子能大幅度破坏BSA结构，降低BSA的含量；并且在实验误差允许的范围内，8个溶液随着溶液距离准直器出口的距离越远，其BSA含量整体呈减少的趋势，进一步说明中子剂量的大小对影响BSA的含量。
表1，在H3 10BO3存在条件下，中子对牛血清白蛋白的作用
溶液编号 BSA含量(％)
对照液 100
A 5.3
B 2.6
C 18.9
D 14.0
E 22.9
F 35.1
G 49.6
H 60.7
本发明提供的化合物I及化合物II均和H3 10BO3一样携带有热中子捕获截面大的核素10B，并且该化合物能够和β淀粉样蛋白特异性结合，将所述化合物置于含有β淀粉样蛋白的环境中，所述化合物会在β淀粉样蛋白的周围形成较高的浓度，再用中子捕获治疗装置发射的中子射束照射所述化合物聚积的区域，其释放的能量能破坏β淀粉样蛋白的结构。本发明所述的含10B的化合物由于其分子本身的性质还具有荧光性，因此所述含10B的化合物除了用于中子捕获治疗系统中消除β淀粉样蛋白沉积斑块以外，还可以用于检测或定位体内的β淀粉样蛋白沉积斑块。由于所述含10B的化合物具有荧光性，在用于消除β淀粉样蛋白沉积斑块的过程中，可以通过测量其荧光强度以确定用硼中子捕获治疗装置照射的最佳时机。
综上所述，含10B的化合物具有血脑屏障穿透力强并且能够和β淀粉样蛋白沉积斑块特异性结合的性质，并且由于含10B的化合物当中的10B元素具有很高的热中子捕获截面，因此所述含10B的化合物具备用于中子捕获治疗系统中消除β淀粉样蛋白沉积斑块。
本发明揭示的用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统并不局限于以上实施例所述的内容以及附图所表示的结构。在本发明的基础上对其中构件的材料、形状及位置所做的显而易见地改变、替代或者修改，都在本发明要求保护的范围之内。
本发明揭示的含10B的化合物在制备和β淀粉样蛋白特异性结合药物中的应用并不局限 于以上实施例所述的内容以及附图所表示的结构，任何含10B的化合物并且能够和β淀粉样蛋白特异性结合的物质均在本发明保护的范围之内。在本发明的基础上对其中构件的材料、形状及位置所做的显而易见地改变、替代或者修改，都在本发明要求保护的范围之内。

Claims (7)

  1. 一种用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统，其特征在于，包括中子捕获治疗装置以及含10B的化合物，其中，含10B的化合物能够和β淀粉样蛋白沉积斑块特异性结合，并且所述中子捕获治疗装置产生的中子束作用到含10B的化合物后产生的能量破坏和含10B的化合物特异性结合的β淀粉样蛋白沉积斑块。
  2. 如权利要求1所述的用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统，其特征在于，所述中子捕获治疗装置包括中子源、射束整形体和准直器，其中所述中子源用于产生中子射束，所述射束整形体位于所述中子源后部并将所述中子源产生的具有较宽能谱的中子射束中的快中子调整为超热中子，所述准直器用于汇聚所述超热中子。
  3. 如权利要求2所述的用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统，其特征在于，所述中子源包括加速器中子源或反应堆中子源。
  4. 如权利要求2所述的用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统，其特征在于，所述射束整形体包括反射体、缓速体、热中子吸收体和辐射屏蔽，其中所述反射体包围所述缓速体，用于将向射束整形体外扩散的中子反射回所述缓速体中，所述缓速体用于将快中子缓速为超热中子，所述热中子吸收体用于吸收热中子以避免治疗时与浅层正常组织造成过多剂量，所述辐射屏蔽用于屏蔽渗漏的中子和光子以减少非照射区的正常组织剂量。
  5. 如权利要求1所述的用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统，其特征在于，所述含10B的化合物具有如结构式I所示的结构：
    Figure PCTCN2017076935-appb-100001
    其中，R为苯硼酸基团，且所述苯硼酸基团中的硼为10B。
  6. 如权利要求5所述的用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统，其特征在于，所述结构式I中的R基根据硼酸基团的取代位置不同分为R1和R2，其中，R1基团为：
    Figure PCTCN2017076935-appb-100002
    R2基团为：
    Figure PCTCN2017076935-appb-100003
    当所述含10B的化合物中的取代基团R为R1时，所述含10B的化合物为化合物I；当所述含10B的化合物中的取代基团R为R2时，所述含10B的化合物为化合物II。
  7. 如权利要求1所述的用于消除β淀粉样蛋白沉积斑块的中子捕获治疗系统，其特征在于，所述β淀粉样蛋白沉积斑块包括Aβ42。
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