CN107224675A - Boron neutron capture treatment system - Google Patents
Boron neutron capture treatment system Download PDFInfo
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- CN107224675A CN107224675A CN201610180591.4A CN201610180591A CN107224675A CN 107224675 A CN107224675 A CN 107224675A CN 201610180591 A CN201610180591 A CN 201610180591A CN 107224675 A CN107224675 A CN 107224675A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
- A61N5/1048—Monitoring, verifying, controlling systems and methods
- A61N5/1064—Monitoring, verifying, controlling systems and methods for adjusting radiation treatment in response to monitoring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
- A61N2005/1085—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy characterised by the type of particles applied to the patient
- A61N2005/109—Neutrons
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
- A61N2005/1092—Details
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
- A61N2005/1092—Details
- A61N2005/1094—Shielding, protecting against radiation
Abstract
A kind of boron neutron capture treatment system, it includes：Boron neutron capture therapeutic system and class a-amino acid boron trifluoride compound, the class a-amino acid boron trifluoride compound have the structure as shown in formula (I)：Wherein：R is hydrogen, methyl, isopropyl, 1- methyl-propyls, 2- methyl-propyls, methylol, 1- hydroxyethyls, benzyl or hydroxyphenylmethyl；M is H or metallic atom；The neutron beam that the boron neutron capture therapeutic system is produced is applied to the energy damages DNA of tumor cell produced after the class a-amino acid boron trifluoride compound.
Description
Technical field
The present invention relates to a kind of radioactive ray irradiation treatment system, especially a kind of boron neutron capture treatment system.
Background technology
With the development of atomics, the radiation cure such as cobalt 60, linear accelerator, electron beam is controlled as cancer
One of Main Means for the treatment of.But conventional photonic or electronic therapy are limited by radioactive ray physical condition itself, tumour is being killed
While cell, substantial amounts of normal structure in beam approach can also be damaged；It is sensitive to radioactive ray additionally, due to tumour cell
The difference of degree, traditional radiation therapy is for relatively having the malignant tumour of radiation resistance (such as：Multirow glioblastoma
(glioblastoma multiforme), melanocytoma (melanoma)) treatment effect it is often not good.
In order to reduce the radiation injury of tumour surrounding normal tissue, the target therapy concept in chemotherapy (chemotherapy)
Just it is applied in radiation cure；And for the tumour cell of radiation resistance, also actively development has high Relative biological at present
The radiation source of effect (relative biological effectiveness, RBE), such as proton therapeutic, heavy particle therapy, neutron capture
Treatment etc..Wherein, neutron capture treatment is to combine above two concept, and such as boron neutron capture is treated, and is existed by boracic medicine
The specificity of tumour cell is gathered, and coordinating accurately neutron beam regulation and control, there is provided treatment of cancer more more preferable than conventional radiation selection.
Boron neutron capture treatment (Boron Neutron Capture Therapy, BNCT) be using boracic (10B) medicine is to hankering
Son has the characteristic of high capture cross section, by10B(n,α)7Li neutron captures and nuclear fission reaction are produced4He and7Two heavy burdens of Li
Charged particle.With reference to following10B(n,α)7Li neutron capture nuclear equation formulas.
The average energy of two charged particles is about 2.33MeV, with High Linear transfer (Linear Energy Transfer, LET), short
Range feature, linear energy transfer and the range of α particles are respectively 150keV/ μm, 8 μm, and7Li heavy burdens particle is then 175
KeV/ μm, 5 μm, the integrated range of two particle is approximately equivalent to a cell size, therefore for radiation injury energy that organism is caused
Cell level is confined to, is gathered in when boracic drug selectivity in tumour cell, appropriate neutron of arranging in pairs or groups penetrates source, just can be not
On the premise of normal tissue causes too major injury, the local purpose for killing tumour cell is reached.
Because the effect that boron neutron capture is treated depends on tumour cell position boracic drug concentration and hankers quantum count, therefore it is otherwise known as
Binary radioactive ray treatment of cancer (binary cancer therapy)；It follows that the exploitation of boracic medicine and neutron penetrate source flux with
The improvement of quality occupies key player in the research that boron neutron capture is treated.
The content of the invention
Improve existing boron neutron capture treatment system to realize, an aspect of of the present present invention is treated there is provided a kind of boron neutron capture
System, it includes：Boron neutron capture therapeutic system and class a-amino acid boron trifluoride compound.
The class a-amino acid boron trifluoride compound has the structure as shown in formula (I)：
Wherein：R is hydrogen, methyl, isopropyl, 1- methyl-propyls, 2- methyl-propyls, methylol, 1- hydroxyethyls, benzyl
Or hydroxyphenylmethyl；M is H or metallic atom.
The neutron beam that the boron neutron capture therapeutic system is produced is applied to the energy produced after the class a-amino acid boron trifluoride compound
Amount destruction DNA of tumor cell.
BNCT is a kind of preferable tumor therapeuticing method, and it provides a kind of new for the tumour that many use conventional methods can not be treated
Treatment method.
Tumour of the present invention be malignant tumour or metastatic tumo(u)r process, preferably glioma, recurrent head and neck neoplasm,
Malignant mela noma, breast cancer or metastatic hepatic carcinoma knurl.Malignant tumour be exactly it has often been said that cancer, it is to plant related 100 more
The general designation of disease.After body inner cell is undergone mutation, it can constantly divide, and not by body control, eventually form cancer.
The cell of malignant tumour can be invaded, destroy neighbouring tissue and organ, and the cell can be passed from tumour, into blood or
Lymphatic system, here it is how malignant tumour is from primary position to the new tumour of other orga- nogenesis, this process is just named pernicious
The transfer of tumour.
Tumour of the present invention is further brain tumor or melanoma.Brain tumor refers to the tumour for being grown on encephalic, including by
The primary brain tumor of brain parenchym generation and the Secondary cases brain tumor that encephalic is transferred to by other positions of body.Melanoma is also known as pernicious
Melanoma, be it is a kind of can produce the high malignancy tumour of melanin, it is multiple to be born in skin or the mucous membrane close to skin, also see
Pia mater and choroid.
Brain tumor of the present invention is further glioma.Neurepithelial tumour referred to as glioma is come from, cranium brain is accounted for and swells
The 40-50% of knurl, is common intracranial malignant tumor.
The class a-amino acid boron trifluoride compound occupies important function in the application in the boron neutron capture treatment system, will be
It is detailed below.
Preferably, the M in the class a-amino acid boron trifluoride compound is potassium or sodium.
Preferably, the B in the class a-amino acid boron trifluoride compound is10B。
In order to further improve in boracic medicine10In B content, the class a-amino acid boron trifluoride compound10B purity >=95%.
At least one F in the class a-amino acid boron trifluoride compound is18F, in this way, swollen in radiotherapy volume
Knurl and institute in a organized way in and surrounding boron concentration and distribution can pre-irradiation and irradiate during non-invasively that accurately and quickly survey
It is fixed.The diagnostic message to expose in the known tissue regions containing high level of boron by reducing epithermal neutron, can faster, more
Accurate and more safely progress boron neutron capture treatment.
Further, boron neutron capture therapeutic system includes neutron generating unit and beam-shaping body, and the beam-shaping body is used for will
The neutron beam power spectrum produced by neutron generating unit is adjusted to epithermal neutron energy area.
Source flux and quality are penetrated improving neutron, beam-shaping body also occupies important function.The beam-shaping body includes being adjacent to
The slow body of the neutron generating unit, the neutron absorption for being enclosed in the slow external reflector, being abutted with the slow body
Body, the radiation shield being arranged in the beam-shaping body and beam outlet, the neutron generating unit occur with incident proton beam
Nuclear reaction to produce neutron, the slow body by the neutron degradation produced from the neutron generating unit to epithermal neutron energy area, it is described
The neutron that reflector will deviate from is led back to improve epithermal neutron intensity of beam, and the thermal neutron absorber is used to absorb thermal neutron to keep away
Multiple dose was caused when exempting from treatment with shallow-layer normal structure, the neutron and photon that the radiation shield is used to shield seepage are non-to reduce
The normal tissue dose of irradiated region.
The boron neutron capture therapeutic system further comprises being arranged on the collimater that beam exit is used to converge the epithermal neutron.
Brief description of the drawings
Fig. 1 is the floor map based on the boron neutron capture treatment system for accelerating type.
Fig. 2 is the floor map of the boron neutron capture treatment system based on reactor type.
Embodiment
With reference to specific embodiment and accompanying drawing, the present invention is described in further detail, to make those skilled in the art's reference say
Bright book word can be implemented according to this.The purpose of the embodiment is merely to illustrate and described the current optimal mode of the present invention.This hair
Bright protection domain is not limited by embodiment described herein in any way.
It should be appreciated that such as " having ", "comprising" and " comprising " term used herein be not precluded from it is one or more of the other
The presence or addition of composition or its combination.
Fast neutron as described herein is more than 40keV neutron for energy area, and epithermal neutron energy area is between 0.5eV to 40keV, heat
Neutron energy range is less than 0.5eV.
Neutron capture treatment gradually increases as a kind of application of means of effective treating cancer in recent years, wherein being caught with boron neutron
Obtain and treat most commonly seen, the neutron of supply boron neutron capture treatment can be supplied by nuclear reactor or accelerator.The implementation of the present invention
Example is by taking the treatment of accelerator boron neutron capture as an example, and the basic module of accelerator boron neutron capture treatment generally includes to be used for band electrochondria
Accelerator, target and hot removal system and beam-shaping body that sub (such as proton, deuteron) is accelerated, wherein accelerating powered
The effect of particle and metal targets produces neutron, according to required neutron yield rate and energy, available acceleration charged particle energy with
The characteristics such as size of current, the materialization of metal targets select suitable nuclear reaction, and the nuclear reaction often come into question has7Li(p,n)7Be
And9Be(p,n)9B, both reactions are all the endothermic reaction.The energy threshold of two kinds of nuclear reactions be respectively 1.881MeV and
2.055MeV, due to the epithermal neutron that the preferable neutron source that boron neutron capture is treated is keV energy grades, if in theory using energy
Amount is only slightly taller than the proton bombardment lithium metal target of threshold values, can produce the neutron of relative low energy, be not necessary to too many slow processing and just may be used
For clinic, but the proton-effect section of two kinds of targets of lithium metal (Li) and beryllium metal (Be) and threshold values energy is not high, is
Sufficiently large neutron flux is produced, generally triggers nuclear reaction from the proton of higher-energy.
Preferable target should possess high neutron yield rate, the neutron energy produced distribution (will in detail below close to epithermal neutron energy area
Description), without it is too many wear by force radiation produce, the characteristic such as cheap easily operated and high temperature resistant of safety, but actually and can not find and meet
The target being made in the nuclear reaction required, embodiments of the invention of lithium metal.But it is well known to those skilled in the art,
The material of target can also be made up of other metal materials in addition to the above-mentioned metal material talked about.
Requirement for hot removal system is then different according to the nuclear reaction of selection, such as7Li(p,n)7Be is because of metal targets (lithium metal)
Fusing point and thermal conductivity coefficient it is poor, requirement to hot removal system just compared with9Be(p,n)9B is high.Used in embodiments of the invention7Li(p,n)7Be nuclear reaction.
No matter boron neutron capture treatment nuclear reaction of the neutron source from nuclear reactor or accelerator charged particle and target, generation
It is all mixed radiation field, i.e., beam contains neutron, photon of the low energy to high energy；For the boron neutron capture treatment of deep tumor,
In addition to epithermal neutron, remaining radiation content is more, causes the ratio of the non-selective dosage deposition of normal structure bigger, because
This these the radiation of unnecessary dosage can be caused to try one's best reduction.Except air beam quality factor, to know more about neutron in human body
In the dosage distribution that causes, carry out Rapid Dose Calculation using human body head tissue prosthese in embodiments of the invention, and with prosthese beam
Quality factor is used as the design reference of neutron beam, will be described in more detail below.
International Atomic Energy Agency (IAEA) is directed to the neutron source of clinical boron neutron capture treatment, given five air beam product
Quality factor advises that this five suggestions can be used for the quality of relatively different neutron sources, and is provided with as selecting neutron the way of production, set
Count reference frame during beam-shaping body.This five suggestion difference are as follows：
Epithermal neutron beam flux Epithermal neutron flux>1x 109n/cm2s
Fast neutron pollution Fast neutron contamination<2x 10-13Gy-cm2/n
Photon contamination Photon contamination<2x 10-13Gy-cm2/n
Thermal and epithermal neutron flux ratio thermal to epithermal neutron flux ratio<0.05
Middle electron current and flux ratio epithermal neutron current to flux ratio>0.7
Note：Subzone is hankered less than 0.5eV, fast-neutron range is more than 40keV in epithermal neutron energy area between 0.5eV to 40keV.
1st, epithermal neutron beam flux：
Boracic drug concentration has together decided on the clinical treatment time in neutron beam flux and tumour.If tumour boracic medicine is dense
The enough height of degree, the requirement for neutron beam flux just can be reduced；If conversely, boracic drug concentration is low in tumour, needing height
Flux epithermal neutron gives the dosage that tumour is enough.IAEA is every square per second for the requirement of epithermal neutron beam flux
Centimetre epithermal neutron number be more than 109, the neutron beam under this flux can control substantially for current boracic medicine
Treatment time, short treatment time in addition to advantageous to patient's positioning and comfort level, also can more effectively utilize in one hour
Boracic medicine is in the intra-tumor limited holdup time.
2nd, fast neutron pollutes：
Because fast neutron can cause unnecessary normal tissue dose, therefore it is regarded as pollution, this dosage size and neutron energy
Amount is proportionate, thus neutron beam design on should try one's best reduction fast neutron content.Fast neutron pollution definition is unit
The adjoint fast neutron dosage of epithermal neutron flux, the suggestion that IAEA pollutes to fast neutron is less than 2x 10-13Gy-cm2/n。
3rd, photon contamination (gamma-ray contamination)：
Gamma-rays belongs to wears radiation by force, can non-selectively cause the organized dosage deposition of institute on course of the beam, therefore drop
Low gamma-rays content is also the exclusive requirement of neutron beam design, and gamma-ray contamination is defined as the adjoint γ of unit epithermal neutron flux
Roentgen dose X, suggestions of the IAEA to gamma-ray contamination is less than 2x 10-13Gy-cm2/n。
4th, thermal and epithermal neutron flux ratio：
Because thermal neutron decay speed is fast, penetration capacity is poor, into human body after most of energy be deposited on skin histology, remove
Outside the neutron source that the Several Epidermal Tumors such as melanocytoma need to be treated as boron neutron capture with thermal neutron, for deep layers such as brain tumors
Tumour should reduce thermal neutron content.IAEA is less than 0.05 to the suggestion of thermal and epithermal neutron flux ratio.
5th, middle electron current and flux ratio：
Middle electron current represents the directionality of beam with flux ratio, and ratio is bigger to represent that tropism is good before neutron beam, Gao Qian
The neutron beam of tropism can reduce because neutron dissipate caused by normal surrounding tissue dosage, also improve in addition can treat depth and
Put pose gesture elasticity.IAEA centerings electron current is more than 0.7 with flux ratio suggestion.
The dosage distribution in tissue is obtained using prosthese, according to the dose versus depth curve of normal structure and tumour, prosthese beam is pushed away to obtain
Quality factor.Following three parameter can be used for carrying out the comparison that different neutron beams treat benefit.
1st, effective therapeutic depth：
Tumor dose is equal to the depth of normal structure maximum dose, the position after this depth, the dosage that tumour cell is obtained
Less than normal structure maximum dose, that is, lose the advantage of boron neutron capture.This parameter represents the penetration capacity of neutron beam,
Effective therapeutic depth is bigger to represent that medicable tumor depth is deeper, and unit is cm.
2nd, effective therapeutic depth close rate：
That is the tumor dose rate of effective therapeutic depth, also equal to the maximum dose rate of normal structure.Because normal structure receives total agent
The factor of tumour accumulated dose size can be given for influence by measuring, therefore parameter influences the length for the treatment of time, effective therapeutic depth
Irradiation time needed for tumour doses are given in the bigger expression of close rate is shorter, and unit is cGy/mA-min.
3rd, dose therapeutically effective ratio：
From brain surface to effective therapeutic depth, the mean dose ratio that tumour and normal structure are received is referred to as effectively treatment
Dose ratio；The calculating of mean dose, can be obtained by dose versus depth curve integration.Dose therapeutically effective ratio is bigger, represents
The treatment benefit of the neutron beam is better.
In order that beam-shaping body has in design compares foundation, except beam quality factor in the air of five IAEA suggestions and
Also the following parameter for being used to assess neutron beam dosage performance quality is utilized in three above-mentioned parameters, the embodiment of the present invention：
1st, irradiation time≤30min (proton current that accelerator is used is 10mA)
2nd, 30.0RBE-Gy can treat depth >=7cm
3rd, tumour maximum dose >=60.0RBE-Gy
4th, normal cerebral tissue's maximum dose≤12.5RBE-Gy
5th, skin maximum dose≤11.0RBE-Gy
Note：RBE (Relative Biological Effectiveness) is relative biological effect, because photon, neutron can be caused
Biological effect is different, so dosage as above is respectively multiplied by the relative biological effect of different tissues in the hope of dose,equivalent.
Fig. 1 is referred to, there is disclosed a kind of floor map based on the boron neutron capture treatment system for accelerating type, boron neutron
Capture treatment system includes accelerator 10, expands device 20, for the charged particle beam entrance by charged particle beam P, powered
Particle beams P, through with charged particle beam P occur nuclear reaction so as to produce neutron beam N neutron generating unit T, for adjust warp in
The neutron beam flux of sub- generating unit T generations and the beam-shaping body 30 of quality, the collimater 40 for being adjacent to beam-shaping body 30
With the class a-amino acid boron trifluoride compound 50 of the beam exposure come out at collimator 40.Wherein, accelerator 10 is used for giving
Charged particle beam P accelerates, and can be suited to speed up type neutron capture treatment system for cyclotron or linear accelerator etc.
Accelerator；Here charged particle beam P is preferably proton beam；Expand device 20 and be arranged on accelerator 10 and neutron generating unit
Between T；Charged particle beam entrance is close to neutron generating unit T and is contained in beam-shaping body 30, in neutron generating unit T and expansion
Three arrows between bundle device 20 are used as charged particle beam entrance；Neutron generating unit T is contained in beam-shaping body 30, this
In neutron generating unit T be preferably lithium metal；Beam-shaping body 30 includes reflector 31, is surrounded and be adjacent to by reflector 31
Neutron generating unit T slow body 32, with slow body 32 abut thermal neutron absorber 33, be arranged in beam-shaping body 30
Radiation shield 34, neutron generating unit T from the incident charged particle beam P generation nuclear reactions of charged particle beam entrance with producing neutron
Beam N, slow body 32 by the neutron degradation produced from neutron generating unit T to epithermal neutron energy area, during reflector 31 will deviate from
Son is led back to improve epithermal neutron intensity of beam, and thermal neutron absorber 33 is normal with shallow-layer when being used to absorb thermal neutron to avoid treating
Tissue caused multiple dose, and radiation shield 34 is used for the neutron and photon that shield seepage to reduce the normal tissue dose in non-irradiated area,
Collimater 40 is used to assemble neutron beam；The neutron beam that collimator 40 is projected is applied to class a-amino acid boron trifluoride compound 50
The energy damages DNA of tumor cell produced afterwards.
Fig. 2 is referred to, there is disclosed a kind of floor map of the boron neutron capture treatment system based on reactor type, boron neutron
Capture treatment system include reactor 100 (neutron beam is produced in the reactor, therefore also referred to as neutron generating unit),
Expand device 200, neutron beam entrance, the beam-shaping for adjusting the neutron beam flux produced through neutron generating unit and quality
Class α-ammonia of body 300, the beam exposure for being adjacent to the collimater 400 of beam-shaping body 300 and being come out at collimator 400
Base acid boron trifluoride compound 500.Wherein, reactor 100 can know ground by those skilled in the art can produce the energy of needs
The related nuclear reaction of the neutron of amount, such as uranium -235 or plutonium -239 produce the fast neutron released during fission reaction；Expand device 200
It is arranged between reactor 100 and neutron beam entrance；Three arrows after device 200 is expanded are used as neutron beam entrance；Penetrate
The thermal neutron that beam shaping body 300 is abutted including reflector 310, the slow body 320 surrounded by reflector 310, with slow body 320
Absorber 330, the radiation shield 340 being arranged in beam-shaping body 300, slow body 320 will be produced from neutron generating unit 100
Neutron degradation to epithermal neutron energy area, the neutron that reflector 310 will deviate from leads back to improve epithermal neutron intensity of beam, hankered
Multiple dose was caused with shallow-layer normal structure when sub- absorber 330 is used to absorb thermal neutron to avoid treating, radiation shield 340 is used
In the neutron and photon of shielding seepage to reduce the normal tissue dose in non-irradiated area, collimater 400 is used to assemble neutron beam；
The neutron beam that collimator 400 is projected is applied to the energy damages tumour cell produced after class a-amino acid boron trifluoride compound 500
DNA。
Beam-shaping body 30,300 can be slow to epithermal neutron energy area by neutron, and reduces thermal neutron and fast neutron content.Reflection
Body 31,310 with the strong material of neutron reflection ability by being made, and as a kind of preferred embodiment, reflector 31,310 is by Pb
Or at least one of Ni is made.Slow body 32,320 is by with fast neutron action section is big, epithermal neutron action section is small
Material is made, and as a kind of preferred embodiment, slow body 32,320 is by D2O、AlF3、FluentalTM、CaF2、Li2CO3、
MgF2And Al2O3At least one of be made.Thermal neutron absorber 33,330 is made up of the material big with thermal neutron action section,
As a kind of preferred embodiment, thermal neutron absorber 33,330 by6Li is made.Radiation shield 34,340 is shielded including photon
And neutron shield, as a kind of preferred embodiment, radiation shield 34,340 include the photon shielding being made up of lead (Pb) and by
The neutron shield that polyethylene (PE) is made.Collimater 40,400 is made up of the material strong to neutron aggregate capabilities, is used as one kind
Preferred embodiment, collimater 40,400 is made up of at least one of graphite, lead.
Those skilled in the art know ground, except the neutron producing method of above-mentioned acceleration type and reactor type, can also use it
His neutron producing method, such as D-D accelerators for neutron production, D-T accelerators for neutron production etc., can also be whole to beam according to actual needs
Material, structure and the composition of body are adjusted correspondingly.
In BNCT, when being given with therapeutically effective amount, the compound of boracic must be nontoxic or hypotoxicity, with
And optionally can accumulate in tumor tissues.Although BPA has the advantage of low chemical toxicity, it is with less than desired
Level is accumulated in critical normal structure.Especially, the boron concentration in tumour relative to normal brain activity and tumour relative to blood
Ratio is about 3:1.So low specificity (selectivity) limits maximum doses of the BPA to tumour, because being used for
The admissible dosage of normal structure is restrictive factor.
Accordingly, it would be desirable to develop new compound, it has longer retention time in tumour, and is selectively targeting and destroys
Tumour cell and normal tissue have minimum damage.
A-amino acid is the key component of protein, is most important amino acid in organism, generation and neurotransmission in ATP
During play very important effect.In addition, the critical nutrients of a-amino acid or cancer cell existence and propagation.α-ammonia
- COOH in base acid is by-BF3Substitution obtains the boron trifluoride compound of class a-amino acid, and it is the isoelectronic species of a-amino acid
Compound.There are some researches show the approach of the boron trifluoride compound of cellular uptake class a-amino acid is identical with a-amino acid, is all logical
Enzyme mediated pathways are crossed, and both have identical transport protein.The boron trifluoride compound of class a-amino acid is for the new of BNCT
Cause our strong concerns in the design of type boron carrier compound, the compound stability is high, and targeting is good, in tumour cell
Interior enrichment is high.Compared FDG, and absorption of the areas of inflammation to the compound is almost negligible to be disregarded.In addition, class a-amino acid
Boron trifluoride compound be readily synthesized, generally by corresponding borate in acid condition with KHF2Reaction is made.
In addition, being utilized in BNCT18The boron trifluoride compounds of the class a-amino acid of F marks, in radiotherapy volume
Tumour and institute in a organized way in and the boron concentration of surrounding and distribution can be in pre-irradiation and during irradiating non-invasively that accurately and quickly
Determine.The diagnostic message to expose in known tissue regions containing high level of boron by reducing epithermal neutron, can faster,
It is more accurate and more safely carry out boron neutron capture therapy.
The boron trifluoride compounds of class a-amino acid are explained in detail below in conjunction with specific embodiment.
Embodiment 1Phe-BF3Prepare
Reaction scheme
Benzyl boric acid ester (15mg, 0.05mmol) is added in 1.5mL microscale reactors, KF (0.15mmol, 0.05mL) is molten
2h is reacted under liquid, HCl (0.2mmol, 0.03mL) solution, 0.1mLMeCN solution, room temperature condition, Phe-BF is obtained3Slightly
Product.Crude product is further purified through HPLC, obtains Phe-BF3。1H NMR (300MHz, MeOD)：δ ppm 7.30 (m, 5H),
3.04 (d, J=9.8Hz, 1H), 2.67 (t, J=9.8Hz, 1H), 2.42 (brs, 1H)；[M-H]-188.0901,Found:188.0589。
According to the in vitro study of the compound of the present invention
To purified material (the hereinafter referred to as Phe-BF of the present embodiment 13) in vitro test that carries out different derives from people using four kinds
Tumor cell line U343mga, the hepatoma cell strain Hep3B of people, the breast carcinoma cell strain MCF7 and the sarcoma cell of people of people
Strain 4SS.By plating cells on uncoated tissue culture dishes, and with using 5%CO at 37 DEG C2The moistening of balance is empty
Cultivated in the incubator of gas and (10% FCS and PEST (penicillin 100IU/mL and chain is with the addition of in the culture medium
Mycin 100mg/mL)).For passing through for cell, by cell with trypsase-EDTA (have 0.25% trypsase and
The phosphate buffered saline (PBS) (PBS) of 0.02% EDTA, not calcic and magnesium) carry out trypsinized.
Embodiment 2Phe-BF3Cellular uptake
U343mga cells are laid on Petri culture dishes with 75% cell density, and be dissolved in the Isosorbide-5-Nitrae of tissue culture medium (TCM)-
Dihydroxy boron phenylalanine (BPA) or Phe-BF3Incubate 6 hours.Two kinds of boron-containing compounds are with relative to Boron contents
(5×10-4Mol/L boron) equimolar concentration add and be dissolved in tissue culture medium (TCM).By remove boracic tissue culture medium (TCM) and
Cold phosphate buffered saline solution (PBS) is added in order to wash away excessive culture medium from cell to terminate to incubate.Pass through
Shoveled using rubber policeman from culture dish and harvesting at once, they collect in cold PBS and formed by centrifuging
Precipitation.
Total protein analysis is carried out to cell sample according to Bradford standardization programs.Pass through direct current plasm atomic emission spectrum
(DCP-AES) boron analysis is carried out to sedimentation cell.Sample (50-130mg) is disappeared with sulfuric acid/nitric acid (1/1) at 60 DEG C
Change.Add Triton X-100 and water so as to obtain 50mg tissues/mL, 15% total acid v/v and 5%Triton X-100v/v it is dense
Degree.Boron concentration is based on known control sample.As a result it see the table below 1.As can be seen from Table 1, Phe-BF3Better than to being used as boron
The intake of the boron of phenylalanine (BPA).
Table 1：The cellular uptake of different boron compounds
For the different boron compounds in two parallel tests (experiment 1 and 2), it is thin that Boron contents are expressed as U343mga
The function (μ g boron/g cell proteins) of total cell protein (is respectively 7.2 and 7.7 μ g boron/mL in experiment 1 and experiment 2 in born of the same parents
Culture medium).
The different tumour cells of embodiment 3 are to Phe-BF3Intake
By four kinds of different tumor cell lines from people：U343mga, Hep3B, MCF7 and 4SS are with 40-50% (low)
And 90-100% (height) cell density is laid on Petri culture dishes, and as described above with the Phe-BF for being dissolved in tissue culture medium (TCM)3
Incubate 6 hours.By removing boracic culture medium and cold PBS bufferings being added to wash away excessive culture medium from cell
Liquid come terminate incubate.Shoveled by using rubber policeman from culture dish and harvesting at once, they are received in cold PBS
Collect and form precipitation by centrifuging.Total protein analysis (as above) is carried out to cell sample according to Bradford standardization programs.As a result
It see the table below 2.For all four people for being tested with low and high-cell density tumor cell line (glioblastoma (U343mga),
Liver cancer (Hep3B), breast cancer (MCF7), sarcoma (4SS)) contrast in, find Phe-BF3It is a kind of efficient boron carrier.
Table 2：Phe-BF3Cellular uptake.Boron contents are expressed as the function (μ g boron/g cell proteins) of total cell protein.
Embodiment 4Phe-BF3Intracellular reservation
U343mga cells are laid on Petri culture dishes with 75% cell density, and the Isosorbide-5-Nitrae being used in tissue culture medium (TCM)-
Dihydroxy boron phenylalanine (BPA) or Phe-BF3Incubate 18 hours.Two kinds of boron compounds are with relative to Boron contents
(5×10-4Mol/L boron) equimolar concentration add tissue culture medium (TCM) in.Boracic culture is replaced by using the culture medium without boron
Base and terminate incubate.Cell sample is sampled time point 0,2 and 7 hours respectively, wherein 0 time point, which represented, just uses boron
Compound incubation 18 hours.
Cell is washed with cold PBS, and is shoveled and harvested at once from culture dish by using rubber policeman, they
Collected in cold PBS and form precipitation by centrifuging.The analysis of total protein and Boron contents is carried out to cell precipitation with aforesaid operations.
As a result 3 be see the table below.With intracellular intake, during the completely depleted rear 7h of I a in the medium, it is retained in tumour cell
Formula (I) compound be always absorb 50%.
Table 3：(μ g boron/g cells sink Boron contents in 0,2 and 7h after removing boracic culture medium in U343mga cells
Form sediment).
In summary, as shown in embodiment 2-4, compound Phe-BF3Expected knot is shown in testing in vitro
Really, its better than BPA in terms of tumour cell intake, accumulation and reservation.
Embodiment 5Phe-BF3Study of cytotoxicity is tested
The cell culture fluid of the cow's serum containing peptide is placed in 37 DEG C of culture 24h.By the mouse fibroblast L-929 cells of Secondary Culture,
1 × 105/mL cell suspension is made of cell culture fluid, by the cell suspension inoculation in 96 porocyte culture plates (100 μ l/
Hole), put in 37 DEG C of CO2gas incubators and cultivate 24h.After cell attachment growth, supernatant is removed, comparison liquid is added (no
The a) containing chemical compounds I, test group (Phe-BF3Concentration be 5mmol/L) nutrient solution swap, put 37 DEG C of carbon dioxide
Continue to cultivate in incubator.In being taken out after 2 days, add MTT liquid and continue to cultivate 4h.Stoste is absorbed, DMSO is added, shakes
Swing 10min.Its absorbance is determined in the case where wavelength is 630nm with enzyme-linked immunosorbent assay instrument, and according to its absorbance based on formula
Calculate the relative propagation degree (RGR) of cell.As a result 4 be see the table below.
Table 4：Cell relative growth rate (RGR) result that MTT colorimetric methods are measured
Note：
The toxic reaction of cell is evaluated according to cell relative growth rate, 5 are see the table below.
Table 5：Cell-cytotoxic reaction is evaluated
Conclusion：As can be seen from Table 5, Phe-BF3The sign of any toxicity is not occurred.
The boron neutron capture treatment system that the present invention is disclosed is not limited to represented by content and accompanying drawing described in above example
Structure.The apparently change made on the basis of the present invention to the material of wherein component, shape and position, substitute or
Modification, all within the scope of protection of present invention.
Claims (8)
1. a kind of boron neutron capture treatment system, it is characterised in that including：Boron neutron capture therapeutic system and class a-amino acid trifluoro
Change boride,
The class a-amino acid boron trifluoride compound has the structure as shown in formula (I)：
Wherein：R is hydrogen, methyl, isopropyl, 1- methyl-propyls, 2- methyl-propyls, methylol, 1- hydroxyethyls, benzyl
Or hydroxyphenylmethyl；M is H or metallic atom；
The neutron beam that the boron neutron capture therapeutic system is produced is applied to the energy produced after the class a-amino acid boron trifluoride compound
Amount destruction DNA of tumor cell.
2. boron neutron capture treatment system according to claim 1, it is characterised in that the boron neutron capture therapeutic system includes
Neutron generating unit and beam-shaping body, the beam-shaping body are used to the neutron beam power spectrum produced by neutron generating unit being adjusted to super
Hanker subzone.
3. boron neutron capture treatment system according to claim 2, it is characterised in that the beam-shaping body includes being adjacent to institute
State the slow body of neutron generating unit, be enclosed in the slow external reflector, the thermal neutron absorber with the slow body adjoining
With the radiation shield being arranged in the beam-shaping body, with incident proton beam nuclear reaction to occur for the neutron generating unit produce
Neutron, the slow body is by the neutron degradation produced from the neutron generating unit to epithermal neutron energy area, and the reflector will deviate from
Neutron lead back to improve epithermal neutron intensity of beam, the thermal neutron absorber be used to absorbing thermal neutron with avoid during treatment with it is shallow
Layer normal structure caused multiple dose, and the radiation shield is used to shield the neutron and photon of seepage to reduce the normal of non-irradiated area
Tissue dose.
4. boron neutron capture treatment system according to claim 3, it is characterised in that the boron neutron capture therapeutic system enters one
Step includes being arranged on the collimater that beam exit is used to converge the epithermal neutron.
5. the boron neutron capture treatment system according to any one of claim 1-4, it is characterised in that the M is potassium or sodium.
6. the boron neutron capture treatment system according to any one of claim 1-4, it is characterised in that B is10B。
7. boron neutron capture treatment system according to claim 6, it is characterised in that the class a-amino acid boron trifluoride compound
In10B purity >=95%.
8. the boron neutron capture treatment system according to any one of claim 1-4, it is characterised in that at least one F is18F。
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
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| CN201610180591.4A CN107224675B (en) | 2016-03-25 | 2016-03-25 | Boron neutron capture therapy system |
| PCT/CN2017/076946 WO2017162093A1 (en) | 2016-03-25 | 2017-03-16 | Boron neutron capture treatingsystem and application of α-amino acid-like boron trifluoride inmanufacturing medicament for treating tumors |
| JP2018549835A JP6649504B2 (en) | 2016-03-25 | 2017-03-16 | Application of α-amino acid-like boron trifluoride compounds in the preparation of boron neutron capture therapy system and tumor therapeutics |
| EP17769370.2A EP3424561B1 (en) | 2016-03-25 | 2017-03-16 | Boron neutron capture treating system and alpha-amino acid-like boron trifluoride compounds for use in treating tumors |
| US16/134,018 US20190054319A1 (en) | 2016-03-25 | 2018-09-18 | Boron neutron capture therapy system and use of α-amino acid-like boron trifluoride compound in preparation of medicament for tumor therapy |
| US16/459,908 US20190381337A1 (en) | 2016-03-25 | 2019-07-02 | Boron neutron capture therapy system |
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| CN111888664A (en) * | 2020-08-05 | 2020-11-06 | 合肥中科离子医学技术装备有限公司 | Neutron capture treatment system based on superconducting cyclotron |
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