JP2021032856A - Composition for radiation dose measurement and method for producing the same, and radiation dosimeter - Google Patents

Abstract

To provide a radiation dosimeter that can measure a three-dimensional dose distribution of particle beams with higher sensitivity, and a composition for radiation dose measurement that is useful therefor and a method of producing the same.SOLUTION: A composition for radiation dose measurement 12 has water as a solvent or a dispersion medium, a compound that changes its fluorescence properties upon excitation light by a reaction with a radiation decomposition product of water, silicate, and divalent iron ions. There is also provided a radiation dosimeter 10 that has the composition for radiation dose measurement 12 as a material for radiation dose measurement.SELECTED DRAWING: Figure 7

Description

The present invention relates to a composition for measuring radiation dose, a method for producing the same, and a radiation dosimeter.

As an application of the quantum beam to radiotherapy, there is cancer treatment using heavy ion beams. In cancer treatment using heavy ion beams, there is a sharp dose peak (black peak) just before the heavy particles invade the body and stop, and by superimposing this dose peak on the tumor, conventional X-rays and γ Higher dose contrast can be obtained compared to cancer treatment using gamma rays.
In Japan, ahead of the rest of the world, in 2017, a device called a rotating gantry that can irradiate a tumor with heavy particle beams from any angle of 360 degrees and a thin beam-shaped heavy particle beam that fills the tumor. Clinical research has begun in combination with the three-dimensional scanning irradiation method, and it is expected that in the future, heavy ion beam irradiation will be performed according to the movement and deformation of the cancer in the body.

In actual radiation therapy, radiation is irradiated from multiple directions, and a three-dimensional dose distribution is planned according to the shape of the cancer in the body. The quality of the planned dose distribution is guaranteed by confirming the planned dose distribution by dosimetry under each condition before treatment.

Correspondingly, along with the improvement of the technique of concentrating the quantum beam on the affected part of the cancer, the technique of accurately measuring the quantum beam in three dimensions is required. On the other hand, it is very difficult to measure the accurate dose distribution of heavy ion beams in three dimensions, and the situation is that interpolation is used in the calculation even in the evaluation of the physical dose distribution. The reason for this is that the sensitivity characteristics of the dosimeter itself change depending on the ionization density of the quantum beam, as well as the effect of radiation on the living body.

In conventional cancer treatment using X-rays and γ-rays, in addition to pinpoint measurement using an ionization chamber, two-dimensional measurement using a film-shaped dosimeter or a dosimeter in which ionization chambers are arranged is performed. However, it has been difficult to evaluate the two-dimensional or higher dose distribution of heavy ion beams.

Under these circumstances, the present inventors independently proceeded with elucidation of radiation-induced chemical reactions and applied research to dosimeters, and developed the only three-dimensional gel dosimeter for heavy ion beams (Patent Document 1). reference).
Specifically, it reacts with both water, which is a solvent or dispersion medium, clay fine particles, any radical ionized from water when irradiated, and oxygen to change the valence. At least one of ammonium iron (II) and ferrous sulfate (II) that produces different iron (II) ions, and iron (II) ions due to oxygen that can be generated by the action of radiation, although it prevents oxygen from remaining. It loses its fluidity because it contains a radical inducer inhibitor that does not hinder the change in valence of the above, and the clay fine particles have a reaction promoting action in which iron (II) ions change the valence by oxygen. We have developed a gel dosimeter for measuring radiation doses with no residual oxygen.
According to this three-dimensional gel dosimeter, it is possible to evaluate the physical three-dimensional dose distribution in a material close to a living body.

Japanese Patent No. 6296230

However, in the above-mentioned three-dimensional gel dosimeter for heavy ion beams, the required dose is as high as 100 Gy or more, and the weight of the dosimeter near the tumor is heavier than the therapeutic dose range (several Gy) used in radiotherapy. There is a problem that the sensitivity to particle beams is low.

By the way, in actual cancer treatment, a value (organism) obtained by multiplying the physical dose obtained by repeating the ionization chamber measurement, which is a pinpoint measurement method, by a coefficient called RBE (Relative Biological Effective Effects). The treatment plan is made so that the dose) is evenly distributed at the tumor site.
The RBE is a value evaluated as a relative value of the biological effect that changes depending on the ionization density of the quantum beam. In other words, in addition to the evaluation of the physical dose distribution, the method of strictly managing the information about the dose from the particles with which energy and controlling the quality of treatment as the biological dose that reproduces the biological effect ratio. The development of is also indispensable for the treatment using the next-generation quantum beam.

Therefore, the present invention has been made in view of the above circumstances, and is a radiation dosimeter capable of measuring a three-dimensional dose distribution of a particle beam with higher sensitivity, and a radiation dose measurement composition useful for this. An object of the present invention is to provide a product and a method for producing the product.

The present invention relates to a three-dimensional gel dosimeter effective for evaluating a three-dimensional biological dose distribution planned in radiation cancer treatment. The three-dimensional gel dosimeter utilizes a radiation-induced chemical reaction, and obtains a three-dimensional dose distribution by reading the product after the reaction held in the gel after irradiation with radiation.

Conventional dosimeters evaluate the physical dose distribution. On the other hand, in the actual treatment plan, the value (biological dose) obtained by multiplying the physical dose distribution by the RBE (biological effect ratio) is used. This biological dose has so far been experimentally evaluated only by irradiating cells and counting the number of cell populations called colonies formed after several weeks of culture (cell viability curve).

As a result of diligent studies to solve the above problems, the present inventors generally found that when two components that consume the radiolysis products of water together are used in combination in a gel, one of them is generally used. It is considered that the reaction efficiency of the components is lowered and it is difficult to obtain a combined effect on the detection sensitivity of the dose. However, in the combination of the compound (A) whose fluorescence characteristics are changed by the excitation light and the divalent iron ion, both are used. We have found that all of the components of the above components promote the oxidation reaction and synergistically increase the detection sensitivity of the dose, and in addition, the biological dosimetry gel exhibiting the same dose response characteristics as the cells can be obtained. Was completed.

The present invention provides a composition for measuring radiation dose and a method for producing the same, and a radiation dosimeter to which the composition for measuring radiation dose is applied, which are described below.

[1] Contains water as a solvent or dispersion medium, compound (A) whose fluorescence characteristics are changed by excitation light depending on the radiolysis product of water, silicate (B), and divalent iron ions. A composition for measuring radiation dose, which comprises

[2] The composition for radiation dosimetry according to the above [1], wherein the compound (A) is a cationic fluorescent probe.

[3] The composition for radiation dosimetry according to the above [1] or [2], wherein the silicate (B) is at least one selected from the group consisting of smectite, bentonite, vermiculite and mica. ..

[4] The method for producing a radiation dosimetry composition according to any one of the above [1] to [3], wherein water, the silicate (B), and the compound (A) are used. In the step of preparing the first mixed solution by mixing the above, the silicate (B) and the iron compound (C) which is ionized to generate divalent iron ions are mixed with water, and the first mixture is prepared. It is characterized by having a step of preparing a mixed solution of 2 and a step of mixing the first mixed solution and the second mixed solution while performing a degassing treatment to obtain a composition for radiation dosimetry. A method for producing a composition for measuring radiation dose.

[5] A radiation dosimeter comprising the composition for measuring radiation dose according to any one of the above [1] to [3] as a material for measuring radiation dose.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a radiation dosimeter capable of measuring a three-dimensional dose distribution of a particle beam with higher sensitivity, a composition for measuring radiation dose useful therefor, and a method for producing the same.
In addition, according to the present invention, a radiation dosimeter whose detection efficiency has been improved to the extent that it is possible to measure a biological dose that reproduces a biological effect ratio, and a radiation dose measurement composition useful for this. A product and a method for producing the product can be provided.

It is a graph which shows the relationship of the relative fluorescence intensity with respect to the depth (mm) from the irradiation surface at the time of irradiating the sample which uses the composition for radiation dose measurement of Example 1 with carbon wire 290 MeV / u. It is a graph which shows the relationship of the relative radiation dose with respect to the depth (mm) from the irradiation surface at the time of irradiating the sample which uses the composition for radiation dose measurement of Example 1 with carbon wire 290 MeV / u. Definitive when was irradiated with heavy ion ^{(56 Fe} 26+) ^{500MeV /} u to samples radiation dosimetry compositions of Examples 2 is used, the relationship of the relative fluorescence intensity versus depth (mm) from the irradiation surface It is a graph which shows. Definitive when was irradiated with heavy ion ^{(56 Fe} 26+) ^{500MeV /} u to samples radiation dosimetry compositions of Examples 2 is used, the relative radiation dose relation to the depth (mm) from the irradiation surface It is a graph which shows. Definitive when was irradiated with heavy ion ^{(56 Fe} 26+) ^{500MeV /} u to samples radiation dosimetry compositions of Examples 3 are used, the relationship of the relative fluorescence intensity versus depth (mm) from the irradiation surface It is a graph which shows. Definitive when was irradiated with heavy ion ^{(56 Fe} 26+) ^{500MeV /} u to samples radiation dosimetry compositions of Examples 3 is used, the relative radiation dose relation to the depth (mm) from the irradiation surface It is a graph which shows. Sample radiation dosimetry compositions of Examples 3 are used (heavy ion ^{(56 Fe 26+)} 500MeV / u that following 10Gy irradiation), an image captured by the two-dimensional gel scanner.

Hereinafter, embodiments for carrying out the present invention will be described in detail. Such an embodiment is an example (representative example) of an embodiment of the present invention, and the present invention is not limited thereto. Further, the present invention can be arbitrarily modified and implemented without departing from the gist thereof.

(Composition for radiation dosimetry)
The composition for radiation dosimetry of the present embodiment contains water as a solvent or dispersion medium, a compound (A) whose fluorescence characteristics are changed by excitation light depending on the radiolysis product of water, and a silicate (B). It contains a divalent iron ion, and in addition to these components, other components may be contained if necessary.

The composition for measuring radiation dose of the present embodiment can be used as a material for measuring radiation dose in a radiation dosimeter, and can be suitably applied to, for example, a material for measuring radiation dose in a gel dosimeter.
In the present embodiment, the radiation is a particle beam (proton beam, heavy particle beam (carbon beam, ⁵⁶ Fe ²⁶⁺ , neon beam, etc.)).

The composition for radiation dosimetry of the present embodiment is typically in the form of a gel (gel), but is not limited to this, and may be in the form of a sol. Preferably, the composition is preferably in a form in which at least a certain degree of shape retention (solidity) is maintained, and more preferably an object that has lost fluidity.

<Water as a solvent or dispersion medium>
In the radiation dosimetry composition of the present embodiment, water serves as a solvent or a dispersion medium. In addition, water is a component that produces radicals by the ionizing action of radiation.
As the water in the present embodiment, water from which impurities have been removed as much as possible can be adopted. Typically, in addition to ultrapure water such as RO water and ion-exchanged water, distilled water and the like can be mentioned, and it is preferable to use water having the highest possible purity.

<Compound (A) whose fluorescence characteristics are changed by excitation light depending on the radiolysis product of water>
The composition for radiation dosimetry of the present embodiment contains a compound (A) (hereinafter, also simply referred to as “compound (A)”) whose fluorescence characteristics are changed by excitation light depending on the radiolysis product of water. , The sensitivity of the radiation dosimetry equipped with the composition as a material for measuring the radiation dose can be improved.

The compound (A) is a compound in which water is irradiated with radiation and its fluorescence characteristics are changed by excitation light by reaction with active oxygen species such as hydroxyl radical and superoxide radical generated by the irradiation of water. A compound (A1) that emits fluorescence due to excitation light by a decomposition product (hereinafter, also simply referred to as “compound (A1)”); a compound (A2) that causes fluorescence due to excitation light to fade due to a radiolysis product of water. Hereinafter, it is also simply referred to as “compound (A2)”) and the like.
As the compound (A1), a fluorescent probe that emits fluorescence by excitation light due to a radiolysis product of water can be preferably used.
Further, as the compound (A2), a fluorescent dye can be preferably used.

Specifically, the compound (A) includes coumarin derivatives, aromatic carboxylic acid derivatives, oxazole derivatives, rhodamines, acridines, coumestrols, fluoresceins, pyrenes, stilbens, resorphins, eosin, and xanthane. , Naphthalimides, polymethines and the like. Among these, coumarin derivatives, aromatic carboxylic acid derivatives, oxazole derivatives, and rhodamines are preferable, and rhodamines are more preferable.

The coumarin derivative is not particularly limited, but is coumarin, coumarin-3-carboxylic acid, 3-aminocoumarin, umbelliferone (7-hydroxycoumarin), umbelliferone-3-carboxylic acid (7-hydroxycoumarin-3-3-). Carboxylic acid) and the like.

The aromatic carboxylic acid derivative is not particularly limited, and examples thereof include benzoic acid, terephthalic acid, pyromellitic acid, trimellitic acid, 3- (4-hydroxyphenyl) propionic acid, 1-naphthalene acid, 2-naphthalene acid and the like. Be done.

The oxazole derivative is not particularly limited, and examples thereof include 2,5-diphenyloxazole and 2- (1-naphthyl) -5-phenyloxazole.

The rhodamines are not particularly limited, and examples thereof include rhodamine B, rhodamine 6G, rhodamine 123, dihydrorhodamine 6G, and dihydrorhodamine 123.

Further, in the present embodiment, in addition to the above-exemplified compound, the following-exemplified compound widely known as compound (A) can also be used.
The following compounds also include compounds classified into any of the above-mentioned coumarin derivatives, aromatic carboxylic acid derivatives, oxazole derivatives and rodamines, which means that the compounds are the above-mentioned coumarin derivatives and the like. It does not mean that it does not correspond to.

Other examples of compound (A):
2-Hydroxybiphenyl, flulam, fluoresceinamine, anthracene, 1,2-bis (2-aminophenoxy) ethane-N, N, N', N'-tetraacetate tetraacetate, phenanthrene, anthracene-9-carboxylic acid, Phthaldialdehyde, 2', 7'-dichlorofluoresene diacetate, 1-ethylnaphthalene, 9-fluorenylmethylcarbazete, triphenylene, naphthalene, phenanthridin, dihydrofluoresene diacetate, p-terphenyl, 3- (4-Hydroxyphenyl) propionic acid, 1,2-bis (2-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid, 1-arginine-4-methyl-7-cuminylamide hydrochloride, trioxalen, p-Quarterphenyl, 5 (6) -carboxyfluorescein diacetate N-succinimidyl ester, fluorescein diacetate, 5 (6) -carboxyfluoresine diacetate, 5 (6) -carboxy-2', 7'-dichlorofluoresane Diacetate n-succinimidyl ester, 2-ethylnaphthalene, 4-nitrophenyl phosphate disodium salt, 5-methoxysolarene, 3,3-dimethyl-2- (4-dimethylaminostyryl) -1-octadecylindolium Park Lolate, 4-Methylumveriferyl Palmite, 4-Methylumveriferyl Enantate, 4-Methylumveriferyl Oleato, 4-Methylumveriferyl Acetate, 4-Methylumveriferyl Butyrate, 4 -Methylumveriferyl-n-acetyl-alpha-d-sodium neuroamic acid dihydrate, N, N'-bis (salicylidene) ethylenediamine, 4-methylumbelliferyl-beta-d-galactopyranoside, 4-Methylumveriferyl-beta-d-glucuronide trihydrate, 4-methylumbelliferyl-beta-d-glucopyranoside, 4-methylumbelliferyl-n-acetyl-beta-d-glucosaminide dihydrate , 4-Methylumveriferyl-alpha-d-glucopyranoside, 4-methylumbelliferyl-alpha-d-galactopyranoside, 8-nonanoyloxypyrrene-1,3,6-trisulfonic acid trisodium salt, 6- (p-toluidino) -2-naphthalene sulfonic acid, 6- (p-toluidino) -2-naphthalene sulfonic acid sodium salt, 4-methylumbelliferylphosphé Coumarin, 4-methylumbelliferone phosphate disodium salt, 2-naphthol, 7-hydroxy-4-methyl-2 (1H) -quinolone, salt quinine dihydrate, coumarin blue, N-succinimidyl-7-hydroxy -4-Coumarin acetate, 4-methylumbelliferyl hydrochloride-4-guanidinobenzoate monohydrate, 7-ethoxycoumarin, 4-heptadecylumbelliferone, glutalyl-1-phenylalanine-4-methyl-7- Coumarinylamide, 4- (trifluoromethyl) umbelliferone-beta-d-glucopyranoside, 4- (trifluoromethyl) umbelliferyl-beta-d-galactopyranoside, umbelliferone, 1-alanine-4-methyl -7-Coumarinylamide Trifolloaceteto, 3,4-dimethylumbelliferone, 1-leucine hydrochloride-4-methyl-7-coumarinylamide, N-succinimidyl-7-hydroxy-4-methyl-3-coumarinyl Acetate, firefly luciferone sodium salt, firefly luciferone, trans, trans-1,4-diphenyl-1,3-butadiene, 4-benzylamino-7-nitrobenzoflazan, 4-bromomethyl-7-methoxycoumarin, 1,4 -Diacetoxy-2,3-dicyanobenzene, 7-methoxy-4-methylcoumarin, 7-ethoxy-4-methylcoumarin, 3-carboxyumbelliferone-beta-d-galactopyranoside, 1-naphthol, 1, 5-Diaminonaphthalene, 4-methylumbelliferone-N, N'-diacetyl-beta-d-chitobioside monohydrate, 3-carboxyumbelliferone-beta-d-galactopyranoside N-succinimidyl ester , 3- (2-benzothiazolyl) umbelliferone, 3-phenylumbelliferyl phosphate hemipyridine salt, 7-ethoxy-4- (trifluoromethyl) coumarin, 2- (4,4,4-trifluoroacetoacetyl) Naphthalene, 7-methoxy-4- (trifluoromethyl) coumarin, 4-methylumbelliferone potassium salt, dansylcadaverine, 9,10-bis-N- (2-dimethylaminoethyl) methylaminomethylanthracembis monochloride Zinc complex, 11- (5-dimethylaminonaphthalene-1-sulfonylamino) umbelliferone, solarene, dansylhydrazine, N- (iodoacetaminoethyl) -1-naphthylami N-5-Sulfonic Acid, 4-Chloro-7-Nitrobenzoflazan, Dansyl-1-tyrosyl-1-Valyl-glycinetrifluoroacetyl, 3- (Dancilamino) Phenylboronic Acid, Bisbenzimide, 3-Phenyl Umbelliferone, 4-methylumbelliferyl-N, N'N "-triacetyl-beta-chitotrioside, bisbenzimide, 7-methoxycumarin,
1-Methylpyrene, 2-4- (iodoacetamide) phenyl-6-methylbenzothiazole, xanthoxin, 6,7-diethoxy-4-methylcoumarin, 2,3-diaminonaphthalene, 1-pyrenebutyric acid, 4,4' -Diisothiocianate stillben-2,2'-disulfonic acid disodium salt, 6- (1-pyrenyl) hexanoic acid, 1-pyrendodecanoic acid, 1-pyrendecanoic acid, 7-hydroxycoumarin-3-carboxylic acid, pyrene- 1-Carboxylic acid, 4-dimethylamino-1-naphthylisothiocianate, quinine sulfate dihydrate, 6-methoxy-1- (3-sulfopropyl) quinolinium monohydrate, pyrene-1-sulfonic acid sodium salt, Pyrene-1-carboxyaldehyde, 3-bromomethyl-7-methoxy-1,4-benzoxazine-2-one, quinine anhydride, 2-amino-5- (6-carboxyindole-2-yl) phenol-N, Potassium N, O-tetraacetate, 4- (6-methyl-2-benzothiazolyl) phenylisocyanate, 4-methylumbelliferyl-alpha-d-mannopyranoside, 3- (2-benzoxazolyl) umbelliferyl octa Noate, 2- (2-amino-5-methylphenoxy) methyl-6-methoxy-8-aminoquinolin-N, N, N', N'-tetrax (acetoxymethyl ester), cholesterylpyrene-l- Carboxylic acid, 1,6-diphenyl-1,3,5-hexatriene-4'-propionic acid, 6,7-dimethoxy-4- (trifluoromethyl) coumarin, 3- (2-benzoxazolyl) un Veriferyl acetylene, n-hexadecylpyrene-1-sulfonamide, 1,6-diphenyl-1,3,5-hexatriene, 7-amino-4-methyl-3-cuminylacetic acid, pyrene, phthalocyanine, 7 −Amino-4-methylcoumarin, 4-bromomethyl-6,7-dimethoxycoumarin, dihydroethidium, 1- (ethoxycarbonylmethyl) -6-methoxyquinolinium bromide, 1,6-diphenyl-1,3,5- Hexatriene-4'-trimethylammonium tosylate, 5-dimethylaminonaphthalene-1-sulfonylfluoride, 1,8-diaminonaphthalene, 8-aminonaphthalene-1,3,6-trisulfonic acid disodium salt, 1, 4-Bis (5-phenyl-2-oxazolyl) benzene, N-succinimidyl-7-methoxy Kumarin-3-carboxylate, 7-hydroxy-n-octadesilkmarin-3-carboxamide, 4- (4-dimethylaminostyryl) -1-octadecilpyridinium percolate, 4-chloro-7-sulfobenzoflazanammonium salt, 3-Octadecanoyl umveriferone, 7-methoxykumarin-3-carboxylic acid, 7-hydroxy-4-methyl-3-cuminylacetic acid, 6,7-dihydroxy-4-methylcoumarin, anthrace-9-carbonylcyanide , Hydroxystilvamidin-bis-methanesulfonate, N, N-dimethyl-6-propionyl-2-naphthylamine, hula-2, N, N-dimethyl-6-dodecanoyl-2-naphthylamine, 6,8-diacetoxy Pyrene-1,3-disulfonic acid disodium salt, 2- (4-dimethylaminostyryl) -3-octadecylbenzothiazolium perchlorate, 7-hydroxy-4-cummarinyl acetate, 6,7-dihydroxy-4- ( Trifluoromethyl) coumarin, 8-hexadecanoyloxypyrene-1,3,6-trisulfonic acid trisodium salt, 8-dodecanoyloxypyrene-1,3,6-trisulfonic acid trisodium salt, cholesterylanthracen- 9-carboxylate, 5,6-benzocoumarin-3-carbonyl chloride, 3-acetylumbelliferone, 5-dimethylaminonaphthalene-1-sulfonyl chloride, 8-anilinonaphthalene-1-sulfonate ammonium salt, 4- Methylumveriferone (beta), 11- (pyrene-1-sulfonylamino) undecanoic acid, 3,3'-diethylthiacarbocyanine iodide, monochromobiman, trans-4'-hydrazino-2-stilbazoledihydro Chloride, 3,6,8-tris (dimethylaminosulfonyl) -1-pyrenyl phosphate pyridine salt, 1- (4-methoxyphenyl) -6-phenylhexatriene, 9,10-anthracendiyl-bis- (methylene) -Dimalonic acid, 12- (anthracene-9-carbonyloxy) stearate, 8-oleoyloxypyrrene-1, 3, 6-trisulphonic acid trisodium salt, 8-octanoyloxypyrrene-1,3,6- Tri-Sulfonic Acid Trisodium Salt, 8-Butylyloxypyrene-1,3,6-Trisulphonic Acid Trisodium Salt, 8-Butylyloxy-N, N, N', N', N ", N" -Hexamethylpyrene -1,3,6-trisulfonamide, 12-oxo-12- (1-pyrenyl) dodecanoic acid, 4- (trifluoromethyl) umveriferone, 6,7-dihydroxy-4-cumulinylacetic acid, 3,3 '-Dioctyl thiacarbocyanine iodide, 7-octadecyloxy-3-3- (3-sulfopropyl) -2-benzothiazoliliocoumarin, 3- (2-benzothiazolyl) -7-octadecyloxycoumarin, 3-methyl -2-7-Octadecyloxy-3-cuminylbenzothiazolium metosulfate, 8-tetradecyloxypyrene-1,3,6-trisulfonic acid trisodium salt, dibromobiman, 8-acetoxy-N, N, N ', N', N', N'-Hexamethylpyrene-1,3,6-trisulfonamide, n- (7-dimethylamino-4-methyl-3-cuminyl) maleimide, 7- (diethylamino) coumarin- 3,4-Dicarboxylic acid, monobromobiman, N- (l-leucyl) -2-aminoacridone, N- (s-benzyl-l-cystinyl) -2-aminoacridone, n- (n-succinyl-) 1-phenylalanyl) -2-aminoacridone, n- (n-glutaryl-1-phenylalanyl) -2-aminoacridone, n- (n-tosyl-l-phenylalanyl) -2-amino Acridone, benzofluorantene, perylene, octadecyl-7-hydroxycoumarin-3-carboxylate, 8-hexadecyloxypyrene-1,3,6-trisulfonic acid trisodium salt, 8-dodecyloxypyrene-1, 3,6-Trisulfonic acid trisodium salt, 8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt, 7-acetoxy-1-methylquinolinium iodide, 8-octadecyloxypyrene-1, 3,6-Trisulfonic acid trisodium salt, 8-decyloxypyrene-1,3,6-trisulfonic acid trisodium salt, 8-methoxypyrene-1,3,6-trisulfonic acid trisodium salt, 1- (4-Nitrophenyl) -6-phenylhexatriene, 6,8-dihydroxypyrene-1,3-disulfonic acid disodium salt, 7-hydroxy-1-methylquinolinium iodide, protoporphyrin, protoporphyrin-dimethyl Estel, 7- (diethylamino) coumarin-3-carboxylic acid, N-succinimidyl-3- (2-benzothiazolyl) umveriferone-4-carboxylate, 3- (5-Chloro-2-benzoxazolyl) -4-cyanoumbelliferyl phosphate pyridine salt, thioflavin, 10- (3-sulfopropyl) acridinium betaine, 10- (3-sulfopropyl) acridinium betaine , 3- (5-Chloro-2-benzoxazolyl) -4-cyanoumbelliferone, N-succinimidyl-7-hydroxycoumarin-3-carboxylate, 7- (diethylamino) coumarin-3-carbohydrazide, 8 -(Beta-d-galactopyranosyloxy) -N, N, N', N', N ", N" -hexamethylpyrene-1,3,6-trisulfonamide, actinomycin, 2- (4) −Dimethylaminostyryl) -3-methylbenzoazolium perchlorate, 8-aminopyrene-1,3,6-trisulfonic acid trisodium salt, 2-aminoacrydone, phenazine, lucifer yellow dipotassium salt, lucifer yellow dilithium salt , N-Succinimidyl-7- (diethylamino) coumarin-3-carboxylate, 7- (diethylamino) coumarin-3-carbonyl azide, 8-isothiocyanate pyrene-1,3,6-trisulfonic acid disodium salt, 9- (2-Carboxy-2-cyanvinyl) -durolysin-N-succinimidyl ester, 9- (2,2-dicyanvinyl) -durolysin, 9- (2-carboxy-2-cyanvinyl) -durolysin, 4-nitro -4'-(octadecylamino) stelvene, 4- (dioctadecylamino) -4'-nitrostylben, proflavin hemisulfate dihydrate, 3- (2-benzothiazolyl) -7- (diethylamino) coumarin-4- Carboxylic acid, benzonin hydrin monohydrate, 8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt, N, N'-dimethyl-9,9'-biacridinium dinitrate, N, N'-Dimethyl-9,9'-biacridinium dinitrate, tris (4,7-diphenylphenanthroline) ruthenium (ii) bis-complex, 3- (2-benzothiazolyl) -7- (diethylamino) coumarin, 2- (4) -Dimethylaminostyryl) -1-methylquinolinium iodide, 11- (7-nitrobenzoflazan-4-ylamino) undecanoic acid, 6- (7-nitrobenzoflazan-4-ylamino) hexanoic acid, 12 -(7-Nitrobenzoflazan-4-ylamino) dodecanoic acid , Resolvin-beta-d-galactopyranoside,
Fluorescein phosphate pyridine salt, fluorescein-beta-d-glucopyranoside, 4-fluoro-7-nitrobenzoflazan, 1,3'-diethyl-4,2'-quinolylthiocyanin iodide, doxorubicin hydrochloride, 4-( 4-Dipentadecylaminostyryl) -1-methylpyridinium iodide, 2- (4-diethylaminostyryl) -1-methylpyridinium iodide, dimidium bromide, ethidium bromide solution, ethidium bromide, fluorescein-5 (6)- Carboxamide caproic acid, 2', 7'-bis (2-carboxyethyl) -5 (6) -carboxyfluorescein, flopidium iodide, 2- (4-dimethylaminostyryl) -1-methylpyridinium iodide, 3, 3'-diheptyl oxacarbosianin iodide, 3,3'-diethyloxacarbocyanin iodide, 3,3'-dipropyl oxacarbosianin iodide, 3,3'-dipentyloxacarbosianin iodide, 3, 3'-dioctadecyloxacarbosianin percolate, 3,3'-dihexyloxacarbosianin iodide, 3,3'-dibutyloxacarbosianin iodide, 4- (4-diethylaminostyryl) -1-methylpyridinium iodide , Fluorescein isothiocyanate dextran, 5 (6) -carboxyfluorescein, sodium fluorescein, fluorescein (free acid), fluorescein-5 (6) -carboxamide caproic acid n-succinimidyl ester, 5-carboxy-fluorescein n-succinimidi Ruester, 5-carboxy-fluorescein, 6-carboxyfluorescein, 6-carboxy-fluorescein N-succinimidyl ester, fluorescein-5-thiosemicarbazide, 5- (iodoacetamide) fluorescein, ethidium homodimer, 10-dodecylacridin orange bromide, 10-Octadecylacridin orange bromide, calcein disodium salt, 10-nonylacridin orange bromide, fluorescein mercuric acetate, rhodamine 110 chloride, N'-octadecylfluorescein-5-thiourea, fluorescein 3,5 (6) -carboxy- 2', 7'-dichlorofluorescein, 3- (2-benzoxazolyl) -4-cyanoumbelliferone, 9- (2-carboxyphenyl) -6-dimethylamino-3-xante Non-sulfate, Rhodamine 16 percolate, Rhodamine 640 percolate, Rhodamine 590 chloride, eosin, Rhodamine 5-3 (4)-(aminocarbonyl) -4 (3) -carboxybenzenesulfonyl fluoride, Rhodamine B 5-3 (4) )-(Aminocarbonyl) -4 (3) -carboxybenzenesulfonyl fluoride, eosin yellowish, 5,10,15,20-tetrakis (1-methyl-4-pyridinio) porphyrintetra (toluene-4-sulfonate), Eosin 5-Isothiocyanate, Rhodamine 19 Parklolate, Rhodamine 123, DihydroRhodamine 123, Rhodamine 6G, DihydroRhodamine 6G, Rhodamine 6G Tetrafluoroborate, Rhodamine 800, 3,3'-Dioctadecylthia carbocyanine perchlorate, Resolvin Butyrate, Resolvin Acetate, 5 (6) -carboxytetramethylrhodamine, Tetramethylrhodamine B isothiocyanate, Rhodamine B isothiocyanate, 6-carboxy-tetramethylrhodamine N-succinimidyl ester, 5-carboxy-tetra Methyl Rhodamine N-Succinimidyl Ester, 6-carboxy-Tetramethyl Rhodamine, 5-carboxy-Tetramethyl Rhodamine, n-Octadecanoyl-Nile Blue, Streptavidin-B-Phycoerythrin, Biotin-B-Phycoerythrin, 1,1 '-Dioctyl-3,3,3', 3'-Tetramethyl indocarbocyanine iodide, 3,3'-dihexylthia carbocyanin iodide, 1,1'-dihexyl-3,3,3', 3' -Tetramethyl indocarbocyanine iodide, Bengal Rose b, Tetramethyl Rhodamine Methyl Esterparklorate, 1,1'-Dipropyl-3,3,3', 3'-Tetramethyl Rhodamine Carbocyanin Iodide, 1,1'-Dipentyl-3,3,3',3'-Tetramethyl indocarbocyanine iodide, 1,1'-dibutyl-3,3,3', 3'-Tetramethyl indocarbocyanine iodide, Tetramethylrhodamine ethyl Esterparkrolate, 2- (4-dimethylaminostyryl) -1-octadecylpyridinium perchlorate, 1,1'-dioctadecyl-3,3,3', 3'-tetramethylindocarbocyanine perchlorate, Rhodamine B, Rhodamine B Octade Sylester perchlorate, merocyanine 540, 3,3'-dipropylthiacarbocyanine iodide, sulforhodamine b5-acid fluoride, 3,3'-dipentylthiacarbocyanine iodide, 1,1'-diethyl-3,3 , 3', 3'-Tetramethyl indocarbocyanine iodide, 3,3'-dibutylthiacarbosianin iodide, sulforhodamine B 2-acid fluoride, 3,3'-diheptylthiacarbosianin iodide, sulforhodamine B Acid Chloride, Rhodamine B Monosodium Salt, Rhodamine 101, 5 (6) -carboxy-x-Rhodamine, Rhodamine Q 5-Rhodamine, 6-Rhodamine-Rhodamine-N-Succinimidyl Estel, 5- Carboxyx-Rhodamine-n-Succinimidyl ester, 5-carboxy-X-Rhodamine (5-ROX), 6-carboxy-X-Rhodamine (6-Rox), 5 (6) -carboxy-X-Rhodamine N -Succinimidyl ester, 3,3'-diethyloxadicarbocyanine iodide, sulforhodamine Q 2-acid fluoride, sulforhodamine 101 acid chloride, sulforhodamine 101 free acid, naphthofluoresane, biotin-c-phycocyanine, cresyl Violet Park Rhodamine, 5 (6) -carboxynaphthofluoresane N-succinimidyl ester, octaethylporphine, azul A, fluorescent red 646, 1,1'-dioctadecyl-3,3,3', 3'- Tetramethylindodicarbocyanine perchlorate, mesotetraphenylporphyrin, azur B, 3,3'-diflopirthia dicarbocyanine iodide,
3,3'-diethylthiadicarbocyanine iodide, 4,5-benzo-5'-(n-succinimidyluoxycarbonyl-methyl) -1'-ethyl-3,3,3', 3'- Tetramethyl-1- (4-sulfobutyl) indodicarbocyanine, 4,5-benzo-5'-(indoacetaminomethyl) -1'3,3,3', 3'-pentamethyl-l- (4-) Sulfobutyl) indodicarbocyanine, 1,1'-bis (4-sulfobutyl) -11- (4-isothiocyanate phenylthio) -3,3,3', 3'-tetramethyl-10,12-trimethylene India Tricarbocyanine monosodium salt, 3,3'-diethyloxatricarbocyanine iodide, 3,3'-diethylthia tricarbocyanine iodide, 1,1'-diethyl-4,4'-carbocyanine iodide, 2,5-bis (4-biphenylyl) -1,3,4-oxadiazole, 1-naphthylacetic anhydride, 5-dimethylaminonaphthalene-1-sulfonamide, diphenylmaleic anhydride, carbazole-9-carbonyl chloride, n- (3-Fluoranchile) maleimide, n-4- (2-benzimidazolyl) phenylmaleimide, 6-hydroxy-2-naphthyldisulfide, 2- (2-amino-5-methylphenoxy) methyl-6-methoxy-8 -Aminoquinolin-N, N, N', N'-Tetrapotassium tetraacetate, 1,2-phenylenediamine dihydrochloride, 1,2-phenylenediamine, 2- (4-maleimidephenyl) -6-methylbenzothiazole , Meso-1,2-bis (4-methoxyphenyl) ethylenediamine, N- (l-pyrenyl) maleimide, 1,2-diacetylbenzene, 4', 6-diamidino-2-phenylindole dihydrochloride, 4-methylun Veriferyl-alpha-1-fucopyranoside, isonicotin hydrazide, 4-hydroxybenzhydrazide, 9-chloromethyl-anthracene, 4-methylumbelliferyl-beta-d-lactoside, diphenylporin anhydride, 4,5-methylenedi Oxy-1,2-phenylenediamine dihydrochloride, malonamide, Z-glycyl-l-florin-4-methyl-7-cuminylamide, 1,3-cyclohexanedione, 8-ethoxy-N, N, N', N', N ", N" -hexamethylpyrene-1,3,6-trisulfonamide, 4- (trifluoromethyl) umbe Riferyl phosphate disodium salt, 4- (trifluoromethyl) umveriferyl enantate, 4- (trifluoromethyl) umberiferryl oleate, 7-fluorobenzoflazan-4-sulfonate ammonium salt, 4-( Trifluoromethyl) umveriferyl butyrate, 2-methoxy-2,4-diphenyl-3 (2H) -furanone, 4- (trifluoromethyl) umberiferryl acetate, 8-methoxy-N, N, N', N', N ", N" -hexamethylpyrene-1,3,6-trisulfonamide, 8-acetooxypyrene-1,3,6-trisulfonic acid trisodium salt, 4-hydrazino-7-nitrobenzo Frazan, 5 (6) -carboxy-2', 7'-dichlorofluoresane diacetate, 4', 5'-bis N, N-di (carboxymethyl) aminomethylfluoresane, 2', 7'-bis (2', 7'-bis (2) -Carboxyethyl) -5 (6) -Carboxyfluorecein tetrakis (acetmethyl) ester, fluorescein dilaurate, fluorescein dibutyrate, fluorescein diacetate-5-isothiocyanate, 5 (6) -carboxyeosindiacetate, 5-maleimide-eosin Naftfluolecein diacetate, 5 (6) -carboxynaphthofluorethane diacetate N-succinimidyl ester, 4-dimethylamino-4'-nitrostylben, 1,4-bis (2-methylstyryl) benzene, 1,4- Bis (4-methyl-5-phenyl-2-oxazolyl) benzene, 2- (4-biphenylyl) -5-phenyl-1,3,4-oxadiazole, 2- (4-tert-butylphenyl) -5 -(4-Biphenylyl) -1,3,4-oxadiazole, 2- (p-tolyl) benzoxazole, 2- (4-biphenylyl) -6-phenylbenzoxazole, 4-hydroxycoumarin, 2,5- Diphenyl-1,3,4-oxadiazole, 1,4-bis-2- (5-phenyloxazolyl) benzene, 1,4-bis-2- (4-methyl-5-phenyloxazolyl) Benzene, Auramine O, Safranin, Basic Bull-12, Crystal Violet, 3,6-Acrydindiamine, 7-diethylamino-4-methylcoumarin

The compound (A) in the composition for measuring radiation dose of the present embodiment can be used alone or in combination of two or more.
Among the above, the compound (A1) is preferably the compound (A1) that emits fluorescence by excitation light due to the radiolysis product of water because the sensitivity can be more easily increased. Among the compounds (A1), a fluorescent probe is more preferable, and a cationic fluorescent probe is further preferable.

The content of the compound (A) in the composition for measuring radiation dose of the present embodiment is preferably 0.1 to 1000 μM, more preferably 1 to 500 μM, and even more preferably 10 to 200 μM.
In the case of compound (A1), 1 to 500 μM is preferable, 5 to 200 μM is more preferable, and 10 to 100 μM is even more preferable.
In the case of compound (A2), 0.1 to 500 μM is preferable, 0.5 to 200 μM is more preferable, and 1 to 100 μM is even more preferable.

<Silicate (B)>
The composition for radiation dosimetry of the present embodiment contains a silicate (B).
Examples of the silicate (B) include water-swellable silicate particles such as smectite, bentonite, vermiculite, and mica. Among these, those that form a colloid using water or a hydrous liquid as a dispersion medium are preferable.

Smectite is a general term for clay minerals having swelling properties such as montmorillonite, bidelite, hectorite, saponite, and stebunsite.

Examples of the shape of the primary particles of the silicate particles include a disk shape, a plate shape, a spherical shape, a granular shape, a cubic shape, a needle shape, a rod shape, an amorphous shape, and the like, for example, a disc shape or a plate shape having a diameter of 5 nm or more and 1000 nm or less. Those are preferable.

Preferred silicates (B) include layered silicates, and examples of readily available commercially available products are LAPONITE® XLG (synthetic hectorite) and XLS (synthetic synthetic) manufactured by BYK. Hectorite, containing sodium pyrophosphate as a dispersant), XL21 (sodium magnesium fluorosilicate), RD (synthetic hectorite), RDS (synthetic hectorite, containing inorganic polyphosphate as a dispersant) and S482 (synthetic hectorite) , Dispersant included); Lucentite (registered trademark) SWN (synthetic smectite), SWF (synthetic smectite), micromica (synthetic mica) and saponite (synthetic mica) manufactured by Katakura Corp. Agri Co., Ltd .; manufactured by Kunimine Kogyo Co., Ltd. Examples thereof include Kunipia (montmorillonite) and smecton SA (synthetic saponite); Bengel (natural bentonite refined product) manufactured by Hojun Co., Ltd.

The silicate (B) in the composition for measuring radiation dose of the present embodiment can be used alone or in combination of two or more.
Among the above, it is preferable to use at least one silicate (B) selected from the group consisting of smectite, bentonite, vermiculite and mica because of its good gel-forming property or sol-forming property. It is more preferable to use smectite.
The content of the silicate (B) in the radiation dosimetry composition of the present embodiment is preferably 0.01 to 20% by mass, preferably 0.1 to 10% by mass, based on 100% by mass of the composition. More preferably, 0.5 to 5% by mass is further preferable.

<Divalent iron ion>
The composition for radiation dosimetry of the present embodiment contains divalent iron ions (iron (II) ions, Fe ²⁺ ).
In the composition, divalent iron ions are oxidized to trivalent iron ions (iron (III) ion, Fe ^{3+) by irradiation.} Along with this, the reaction between the compound (A) and the reactive oxygen species is promoted, and the sensitivity to the dose is increased.

The composition contains divalent iron ions, for example, by using an iron compound (C) that is ionized to generate divalent iron ions (hereinafter, also simply referred to as "iron compound (C)"). Can be done.
The iron compound (C) is not particularly limited as long as it is a compound that can be ionized to generate divalent iron ions when made into an aqueous solution, and is, for example, ferrous sulfate (II) and iron ammonium sulfate (II). ), and the like of iron (II) sulfate ammonium hexahydrate _{((NH 4) 2 SO 4} · FeSO 4 · 6H 2 O) it is.

The content of divalent iron ions in the composition for measuring radiation dose of the present embodiment is preferably 0.05 to 5 mM, more preferably 0.1 to 2 mM, and even more preferably 0.2 to 1 mM.

In the radiation dosimetry composition of the present embodiment, the ratio of the compound (A) to the divalent iron ion is 0.001 or more as the molar ratio represented by the divalent iron ion / compound (A). It is preferably 0.01 to 100, more preferably 0.1 to 10, and even more preferably 0.1 to 10.
When the molar ratio represented by the compound (A) / divalent iron ion is equal to or higher than the lower limit of the above-mentioned preferable range, the detection efficiency with respect to the dose is further enhanced, and the biological dose distribution that reproduces the biological effect ratio is reproduced. Can be measured.
On the other hand, if it is not more than the upper limit of the above-mentioned preferable range, only the compound (A) reacts selectively, so that the LET (Linear Energy Transfer) is increased as in the conventional dosimeter. It is easy to lead to a decrease in detection efficiency. That is, the molar ratio represented by the divalent iron ion / compound (A) depends on the reactivity of the compound (A) with the radiolytic radical.

<Other ingredients>
The composition for radiation dosimetry of the present embodiment contains water as a solvent or a dispersion medium, compound (A), silicate (B), and divalent iron ions, as well as other components as necessary. You may.
The other components here are not particularly limited, and examples thereof include a silicate dispersant, an oxygen scavenger, a pH adjuster such as glucono-δ-lactone, perchloric acid, sulfuric acid, or salt.

(Manufacturing method of composition for radiation dosimetry)
The method for producing the composition for radiation dosimetry according to the above-described embodiment is not particularly limited, and for example, water, the compound (A), and the silicate (B) are ionized to form a divalent iron ion. Examples thereof include a method of gelling by mixing the iron compound (C) that produces the above-mentioned iron compound (C) with other components that may be contained if necessary.

For example, in the composition for radiation dosimetry of the present embodiment, a step of mixing water, the silicate (B), and the compound (A) to prepare a first mixed solution, water, and the like. A step of preparing a second mixed solution by mixing the silicate (B) and an iron compound (C) that is ionized to generate divalent iron ions, and the first mixed solution and the first mixed solution. It is preferable to use a production method having a step of mixing the mixed solution of No. 2 while performing a degassing treatment to obtain a composition for radiation dosimetry (hereinafter, also referred to as "degassing treatment and mixing step"). Can be manufactured.

As a method of mixing each component or each mixed solution, ultrasonic treatment can be used in addition to mechanical or manual stirring, but among these, mechanical stirring is preferable. For mechanical stirring, for example, a magnetic stirrer, a propeller type stirrer, a rotating / revolving mixer, a disper, a homogenizer, a shaker, a vortex mixer, a ball mill, a kneader, an ultrasonic oscillator, or the like can be used. Among these, mixing with a rotating / revolving mixer is preferable.

The temperature at which each component or each mixed solution is mixed is equal to or higher than the freezing point of the aqueous solution or aqueous dispersion, preferably −5 ° C. or higher and 50 ° C. or lower, and more preferably 0 ° C. or higher and 30 ° C. or lower.

The mixed solution (composition for measuring radiation dose) immediately after mixing the first mixed solution and the second mixed solution is typically in the form of a sol, but gels when allowed to stand.
The standing time after mixing is preferably 2 hours or more and 100 hours or less. The standing temperature of the mixed solution is preferably −5 ° C. or higher and 100 ° C. or lower, and more preferably 0 ° C. or higher and 50 ° C. or lower.
In addition, a radiation dosimetry gel having an arbitrary shape can be produced by pouring it into a mold or extruding it immediately after mixing and before the mixed solution gels.
In addition, the mixed solution may remain in a sol form as long as the radiation dosimetry ability is not lost.

In the degassing treatment and mixing step, the concentration of compound (A) or the concentration of divalent iron ions can be adjusted by appropriately changing the mixing ratio of the first mixed solution and the second mixed solution. it can. For example, by setting the silicate (B) concentration of the first mixed solution and the second mixed solution to the same concentration and changing the mixing ratio of both, the concentration of the compound (A) or the divalent concentration can be changed. The concentration of iron ions can be easily adjusted.

In deaeration and mixing step, as a method for the degassing, nitrous oxide (dinitrogen monoxide N _{2 O)} gas, at least one gas selected from the group consisting of argon gas, nitrogen gas and helium gas It is also preferable to adopt a method of bubbling with water. By this bubbling, it is possible to reduce the dissolved oxygen in the liquid.

Further, also when preparing the first mixed solution and the second mixed solution, it is preferable to carry out the degassing treatment from the viewpoint of preventing the oxidation of the compound (A) and the divalent iron ion, respectively.

In the steps of preparing the first mixed solution and the second mixed solution, the degassing treatment method is not particularly limited, and is a replacement degassing method by depressurization or pressurization, a freeze replacement degassing method, and a heat replacement degassing method. It is preferable to adopt one of the degassing methods.
The term "degassing" here means reducing or removing oxygen from a material containing water.

(Radiation dosimeter)
The radiation dosimeter of the present embodiment is characterized by a measuring material, and various known radiation dosimeters can be appropriately applied to other configurations.
The radiation dosimeter of the present embodiment includes the above-mentioned composition for measuring radiation dose as a material for measuring radiation dose, and the composition can be filled in a container to form, for example, a phantom.
The container here is not particularly limited as long as it transmits radiation and has solvent resistance, airtightness, etc., and the material of the container is preferably glass, acrylic resin, polyester, ethylene-vinyl alcohol copolymer, or the like. .. Further, after filling the container, it may be replaced with nitrogen gas or the like.

According to the radiation dosimeter of the present embodiment described above, the three-dimensional dose distribution of the particle beam can be measured with higher sensitivity. In addition, according to the radiation dosimeter of the present embodiment, the detection efficiency can be improved to the extent that it is possible to measure the biological dose that reproduces the biological effect ratio.
Further, according to the radiation dosimeter of the present embodiment, the sensitivity to particle beams in the therapeutic dose range (preferably 50 Gy or less, more preferably 40 Gy or less, still more preferably 5 to 40 Gy) used in radiotherapy can be increased.
Further, in the radiation dosimeter of the present embodiment, for example, the sensitivity to the particle beam can be easily controlled by appropriately combining the composition of the composition for measuring the radiation dose and the type of the particle beam.

The measurement principle of the radiation dose meter of the present embodiment is that the divalent iron ion (Fe ²⁺ ) contained in the dose meter becomes a trivalent iron ion (Fe ³⁺ ) by a radiation-induced oxidation reaction and radiation irradiation. It utilizes the fluorescence characteristics of the excitation light that change depending on the highly reactive reactive oxygen species that are generated. As described above, it is generally considered that it is difficult to obtain the combined effect of both, but in the combination of the compound (A) adopted in the present embodiment and the divalent iron ion, the divalent iron ion is used. It is presumed that the reaction of compound (A) with the reactive oxygen species is promoted along with the oxidation reaction. As a result, the value close to the physical dose distribution is shown, the so-called LET dependence is improved, and the peak of the dose distribution becomes sharp.

Since the radiation dosimeter of the present embodiment has excellent sensitivity to irradiation and has high linearity in the amount of increase in fluorescence intensity or increase in absorbance with respect to the absorbed dose, the fluorescence intensity or absorbance is measured. Can be used for possible devices. For example, the radiation dosimeter of the present embodiment can be used as a radiation dosimeter for an optical CT apparatus.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples as long as the gist thereof is not exceeded.

In this embodiment, the devices and conditions used for dose measurement are as follows.

(1) Heavy particle beam irradiation device:
HIMAC (Heavy Ion Medical Accelerator in Chiba, Chiba City, Japan), National Institute of Radiological Sciences
Irradiation conditions:
^{The sample of Example 1 was irradiated with carbon wire (12} C ⁶⁺ ) having an acceleration energy of 290 MeV / u at doses of 10 Gy, 20 Gy, 30 Gy, and 40 Gy, respectively.
Each sample of Example 2 and Example 3 ^{was irradiated with a heavy particle beam (56} Fe ²⁶⁺ ) having an acceleration energy of 500 MeV / u at doses of 10 Gy, 20 Gy, 30 Gy, and 40 Gy, respectively.

(2) Fluorescence intensity measuring device: Gel scanner (Glite 900BW Gel Scanner)

<Manufacturing of composition for radiation dosimetry>
Ultrapure water was used as the solvent or water as the dispersion medium.
As compound (A), dihydrorhodamine 123 (DHR123), which is a cationic fluorescent probe, was used.
LAPONITE® XLG was used as the silicate (B).
Iron compounds as _(C), were used _{(NH 4) 2 SO 4 ·} FeSO 4 · 6H 2 O.

(Example 1)
Step of preparing the first mixture:
To 98.5 mL of ultrapure water, 1.5 g of LAPONITE® XLG was added and stirred to prepare a silicate dispersion having a concentration of 1.5% by mass, and 200 uM of DHR123 was added to this silicate dispersion. The first mixed solution (m1) was obtained by degassing by bubbling with argon gas for 30 minutes in a glove box from which oxygen was removed.

Step of preparing the second mixture:
The and to the silicate dispersion 100mL to be 1.5 mass% was prepared in the same manner, as bivalent iron ions ^{(Fe 2+)} becomes _{1mM (NH 4) 2 SO 4} · FeSO 4 · 6H 2 O was added in a degassed environment and stirred to obtain a second mixed solution (m2).

Degassing and mixing process:
The first mixture (m1) and a second mixture (m2), the oxygen in the glove box was removed, while subjected to bubbling for 30 minutes with _{N 2} O gas, the first mixture (m1) / second The mixture of 2 (m2) = 5/5 (mass ratio) was mixed and allowed to stand to obtain a radiation dose measurement composition (gel) of Example 1.

Composition of the composition for radiation dosimetry of Example 1:
Silicate 1.5% by mass, DHR123 100 μM, Fe ²⁺ 0.5 mM

(Example 2)
In the same manner as in Example 1, a first mixed solution (m1) and a second mixed solution (m2) were obtained, respectively.
The first mixed solution (m1) and the second mixed solution (m2) are the first mixed solution (m1) / the second mixed solution (m1) / second mixed solution (m1) while being bubbling with Ar gas for 30 minutes in a glove box from which oxygen has been removed. The mixture was mixed with a mixed solution (m2) = 5/5 (mass ratio) and allowed to stand to obtain a radiation dosimetry composition (gel) of Example 2.

Composition of the composition for radiation dosimetry of Example 2:
Silicate 1.5% by mass, DHR123 100 μM, Fe ²⁺ 0.5 mM

(Example 3)
In the same manner as in Example 1, a first mixed solution (m1) and a second mixed solution (m2) were obtained, respectively.
The first mixed solution (m1) and the second mixed solution (m2) are the first mixed solution (m1) / the second mixed solution (m1) / second mixed solution (m1) while being bubbling with Ar gas for 30 minutes in a glove box from which oxygen has been removed. The mixture was mixed with a mixed solution (m2) = 3/7 (mass ratio) and allowed to stand to obtain a radiation dosimetry composition (gel) of Example 3.

Composition of the composition for radiation dosimetry of Example 3:
Silicate 1.5% by mass, DHR123 60 μM, Fe ²⁺ 0.7 mM

<Irradiation test>
The radiation dosimetry compositions of each of the above obtained were hermetically packed in a spectroscopic measurement cell to obtain a sample for irradiation. Then, the radiation irradiation test was conducted the day after the composition for measuring the radiation dose of each example was hermetically filled in the cell for spectroscopic measurement.

[Irradiation test (1)]
The sample using the radiation dosimetry composition of Example 1 was irradiated with carbon beam 290 MeV / u at doses of 0 Gy, 10 Gy, 20 Gy, 30 Gy, and 40 Gy by the above-mentioned heavy particle beam irradiation device, respectively. .. After irradiation, the relative fluorescence intensity distribution and its intensity, as well as the relative radiation dose and dosimeter sensitivity were evaluated. The above gel scanner was used as the device for measuring the fluorescence intensity. The results are shown in FIGS. 1 and 2.

[Irradiation test (2)]
The samples used radiation dosimetry compositions of Examples 2, the apparatus of the heavy ion irradiation of the heavy particle beam a ^{(56 Fe 26+) 500MeV / u} , 0Gy, 10Gy, 20Gy, 30Gy, 40Gy Each dose was irradiated. After irradiation, the relative fluorescence intensity distribution and its intensity, as well as the relative radiation dose and dosimeter sensitivity were evaluated. The above gel scanner was used as the device for measuring the fluorescence intensity. The results are shown in FIGS. 3 and 4.

[Irradiation test (3)]
The samples used radiation dosimetry compositions of Examples 3, the apparatus of the heavy ion irradiation of the heavy particle beam a ^{(56 Fe 26+) 500MeV / u} , 0Gy, 10Gy, 20Gy, 30Gy, 40Gy Each dose was irradiated. After irradiation, images were taken with a two-dimensional gel scanner to evaluate the relative fluorescence intensity distribution and its intensity, as well as the relative radiation dose and dosimeter sensitivity. The above gel scanner was used as the device for measuring the fluorescence intensity. The results are shown in FIGS. 5, 6 and 7.

FIG. 1 shows the relationship of the relative fluorescence intensity with respect to the depth (mm) from the irradiation surface when the sample using the radiation dosimetry composition of Example 1 was irradiated with carbon beam 290 MeV / u. It is a graph.
From FIG. 1, it can be confirmed that the fluorescence intensity increases as the irradiation dose increases.

FIG. 2 shows the relationship of the relative radiation dose to the depth (mm) from the irradiation surface when the sample using the radiation dosimetry composition of Example 1 was irradiated with carbon beam 290 MeV / u. It is a graph. In FIG. 2, the physical dose distribution is a result obtained by repeating the ionization chamber measurement, which is a pinpoint measurement method. In FIG. 2, the result of test (1) is the result of normalizing the amount of change in fluorescence intensity at each depth from the irradiation surface.
From FIG. 2, it can be confirmed that the result of the test (1) shows a behavior close to the physical dose distribution.

Figure 3 is a definitive when was irradiated with heavy ion ^{(56 Fe 26+)} 500MeV / u to samples radiation dosimetry compositions of Examples 2 is used, relative to the depth (mm) from the irradiation surface It is a graph which shows the relationship of fluorescence intensity.
From FIG. 3, it can be confirmed that the fluorescence intensity increases as the irradiation dose increases.

Figure 4 is definitive when was irradiated with heavy ion ^{(56 Fe 26+)} 500MeV / u to samples radiation dosimetry compositions of Examples 2 is used, relative to the depth (mm) from the irradiation surface It is a graph which shows the relationship of radiation dose. In FIG. 4, the physical dose distribution is a result obtained by repeating the ionization chamber measurement, which is a pinpoint measurement method. In FIG. 4, the result of test (2) is the result of normalizing the amount of change in fluorescence intensity at each depth from the irradiation surface.
From FIG. 4, it can be confirmed that the result of the test (2) shows a sharp peak as compared with the physical dose distribution.

Figure 5 is definitive when was irradiated with heavy ion ^{(56 Fe 26+)} 500MeV / u to samples radiation dosimetry compositions of Examples 3 are used, relative to the depth (mm) from the irradiation surface It is a graph which shows the relationship of fluorescence intensity.
From FIG. 5, it can be confirmed that the fluorescence intensity increases as the irradiation dose increases.

Figure 6 is definitive when was irradiated with heavy ion ^{(56 Fe 26+)} 500MeV / u to samples radiation dosimetry compositions of Examples 3 are used, relative to the depth (mm) from the irradiation surface It is a graph which shows the relationship of radiation dose. In FIG. 6, the physical dose distribution is a result obtained by repeating the ionization chamber measurement, which is a pinpoint measurement method. In FIG. 6, the result of test (3) is the result of normalizing the amount of change in fluorescence intensity at each depth from the irradiation surface.
From FIG. 6, it can be confirmed that the result of the test (3) shows a sharp peak as compared with the physical dose distribution.

As described above, in FIGS. 4 and 6, both the test (2) result and the test (3) result showed sharp peaks as compared with the physical dose distribution. From this result, the peak has a sharper shape by increasing the molar ratio of divalent iron ions to DHR123 (divalent iron ions / DHR123) in the radiation dosimetry composition. It was confirmed that the behavior was close to the biodose distribution.

7, a sample radiation dosimetry compositions of Examples 3 are used (heavy ion ^{(56 Fe 26+)} 500MeV / u that after 10Gy irradiation with), the image captured by the 2-dimensional gel scanner is there.
In FIG. 7, the heavy particle beam ( ⁵⁶ Fe ²⁶⁺ ) is irradiated from the left to the right of the sample (radiation dosimeter 10) in the direction of the arrow, and the ^{vicinity of the Bragg peak of the heavy particle beam (56} Fe ²⁶⁺ ) (in the area surrounded by the dotted line). ), That is, it can be confirmed that the radiation dose measurement composition 12 emits strong fluorescence at a position in the sample (radiation dosimeter 10) at a depth of about 26 mm from the irradiation surface 12s.

In Examples 1 to 3, in each of the examples, the three-dimensional dose distribution of the heavy particle beam can be measured with higher sensitivity even when the dose of the heavy particle beam is 10 Gy, and the weight is further increased. The detection efficiency at the depth near the Bragg peak of the particle beam was also good.

In the radiation irradiation sample obtained in this example, any radical generated by ionizing from water when irradiated in the gel formed by the radiation dose measurement composition of each example. ^{And the divalent iron ion (Fe 2+} ) generated by ionization from the iron compound (C) reacts and oxidizes to the trivalent iron ion (Fe ^3+). Further, the radical reacts with DHR123 and is oxidized to produce rhodamine 123 (RD123), which is a strong fluorescent substance. In this way, it functions as a three-dimensional gel dosimeter.
In addition, since DHR123 is a cationic fluorescent probe, it is adsorbed on the silicate (B) LAPONITE® XLG. As a result, the fluorescence intensity distribution of the radiation-irradiated sample obtained in this example is kept stable for a certain period of time.
Further, since the degassing treatment is performed when the composition for measuring radiation dose is produced, the oxidation reaction efficiency of the radical is improved.

The composition for measuring radiation dose according to the present invention and a dosimeter provided with this as a material for measuring radiation dose are dosimeters capable of evaluating the biological effects of radiation, and are planned doses in radiation therapy for cancer. It can be used for various gel dosimeters such as a gel dosimeter for verifying the distribution. The radiation dosimeter according to the present invention is the first dosimeter capable of measuring the biological dose formulated in the treatment plan, and is indispensable for the advancement of heavy ion radiotherapy.

Further, in the radiation dosimetry composition according to the present invention, for example, a biological dose that reproduces a biological effect ratio by setting a molar ratio represented by a divalent iron ion / compound (A). The detection efficiency will be improved before the distribution can be measured. Therefore, a radiation dosimeter provided with the composition for measuring radiation dose according to the present invention as a material for measuring biological dose may be used as a three-dimensional biological dosimeter that mimics the effects of radiation on a living body.
Further, the radiation dosimeter according to the present invention is expected to be usable as a useful tool for formulating an accurate treatment plan in particle beam therapy and developing a new radiotherapy method.

Further, the composition for radiation dose measurement and the radiation dosimetry according to the present invention are used for, for example, verification of a radiation treatment plan in stereotactic radiotherapy, and for three-dimensional dose measurement in a high magnetic field such as image-guided radiotherapy. Is also expected to be used. In the future, the composition for measuring radiation dose and the radiation dose meter according to the present invention can be applied to a therapeutic method using a quantum beam other than heavy ion beam therapy, for example, proton beam therapy or neutron therapy. It is also expected to be used for cancer treatment methods (BNCT: neutron capture therapy) using.

10 Radiation dosimeter, 12 Composition for radiation dose measurement

Claims (5)

With water, which is a solvent or dispersion medium,
Compound (A) whose fluorescence characteristics are changed by excitation light due to the radiolysis product of water, and
Silicate (B) and
A composition for radiation dosimetry containing divalent iron ions. The composition for radiation dosimetry according to claim 1, wherein the compound (A) is a cationic fluorescent probe. The composition for radiation dosimetry according to claim 1 or 2, wherein the silicate (B) is at least one selected from the group consisting of smectite, bentonite, vermiculite and mica. The method for producing a radiation dosimetry composition according to any one of claims 1 to 3.
A step of mixing water, the silicate (B), and the compound (A) to prepare a first mixed solution.
A step of preparing a second mixed solution by mixing water, the silicate (B), and an iron compound (C) that is ionized to generate divalent iron ions, and the first mixed solution. A method for producing a composition for radiation dose measurement, which comprises a step of mixing the second mixed solution with the second mixed solution while performing a degassing treatment to obtain a composition for radiation dose measurement. A radiation dosimeter comprising the composition for measuring radiation dose according to any one of claims 1 to 3 as a material for measuring radiation dose.