JP2008137939A - Auxiliary agent for x-ray therapy - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an auxiliary agent for a low-exposure minimally-invasive X-ray therapy enabling efficient absorption of X-ray to a target cell in the X-ray radiation therapy of the target cell of a diseased part such as tumor and reducing the damage of the surrounding normal cells. <P>SOLUTION: The auxiliary agent for X-ray therapy comprises making at least one kind of energy-conversion fine particles disperse in a medium having an average particle diameter of 1 nm to 10 μm, absorbing long-acting X-ray, and converting the absorbed X-ray energy to oxidation-reduction reaction to generate active oxygen species or free radicals. Suitable energy-conversion fine particle is selected from the group consisting of CdTe, CeF<SB>3</SB>, ZnS:Ag, Nb<SB>2</SB>O<SB>5</SB>, ZrO<SB>2</SB>, CsI, CsF, SrTiO<SB>2</SB>, CdSe and KTaO<SB>3</SB>. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an adjuvant for X-ray treatment capable of damaging or killing malignant neoplasms such as cancer cells, cancer precursor cells, cells infected with viruses and bacteria by X-ray irradiation.

  In conventional radiotherapy, when high-energy X-rays or gamma rays are intensively irradiated to a tumor, intracellular water is decomposed into hydroxy radicals and hydrogen atoms, and reacts with intracellular oxygen to produce superoxide and hydroperoxy Radicals are generated. These active oxygens and free radicals cause direct damage to the DNA in the cell, or indirectly by drawing hydrogen from the lipid in the cell membrane and transforming it into a lipid peroxide through a chain of peroxide radicals, causing cell membrane damage. There are two systems of damage paths. However, since it is not possible to selectively irradiate only the target cells with radiation, these reactions also proceed in normal cells around the affected area, and there are tumor cells and normal cells in the path and around the affected area. The result is damaging without discrimination.

As a method for damaging a target cell in an affected area, a treatment method using ultraviolet rays or radiation and photocatalyst fine particles has been proposed so far. For example, Fujishima et al. Reported that a human-derived cancer cell (Hela cell) was injected with a titanium oxide suspension, irradiated with ultraviolet light in vitro, and killed using the redox reaction of titanium oxide. (Non-Patent Document 1). However, in this method, since ultraviolet rays do not reach the inside of the affected area, treatment is performed only on the surface of the affected area. Therefore, when the affected part is deep in the body surface or when the affected part itself is large, it is difficult to treat the deep part.
DENKI KAGAKU, vol.60, pp.314-321, 1995

Moreover, although the cancer treatment apparatus provided with the optical fiber which carry | supported the photocatalyst on one end part surface, and the near-ultraviolet light source arrange | positioned at the other edge part of this optical fiber is proposed (patent document 1). ) Even with this device, ultraviolet rays are not permeable and can only treat the surface near the fiber end face.
Furthermore, a method is also known in which a therapeutic aid made of visible light responsive titanium oxide is injected into a tumor site and the photocatalyst is activated with visible light (Patent Document 2). Visible light is also deep in the tumor. Can not be reached, so only surface treatment is possible.
JP-A-9-56836 Japanese Patent Laid-Open No. 2001-302548

In general, the radiation dose is proportional to the product of the radiation energy and the number of photons. However, in the conventional disclosure examples, there are many examples assuming high photon energy on the order of MeV from analogy of gamma ray treatment. However, since these high-energy photons have a low interaction probability with a substance, the problem is that they are not easily absorbed by fine particles.
For the purpose of treatment in the deep part of the affected area, there has been proposed a method using a mixture of a photocatalyst particle and a radioactive agent that emits gamma rays (Patent Document 3), and the radiation energy from these radionuclides is several hundred. Very large with KeV. For this reason, the photocatalyst absorbs very little, and most other gamma rays damage the surrounding normal cells or are released outside the body, and a therapeutic effect cannot be expected.
JP 2005-334524

Similarly, a method and an apparatus for destroying a target cell by irradiating a titanium oxide suspension with radiation have been proposed (Patent Document 4). As shown in the calculation example, the photon energy is generally as high as 500 keV. The absorption rate to titanium oxide particles at this level is considerably low. Rather, such high energy is not absorbed by the titanium oxide, and there is a high rate of damage to surrounding normal cells or scattering outside the body. Also, in the method of exciting photocatalyst using gamma rays or some radioactive isotopes as the radiation source, the particle fluence rate (unit time, number of photons per unit area) of the gamma ray source or radioactive isotope is converted to X-rays. Since it is extremely low in comparison, the probability of being absorbed by particles is low, and it is unknown whether an effective therapeutic effect can be expected.
Japanese Patent No. 3242026

  Therefore, the present invention eliminates the problems of these prior arts, and allows X-rays to be efficiently absorbed by target cells when treating target cells in affected areas such as tumors by irradiating X-rays. An object of the present invention is to provide a low-exposure and minimally invasive X-ray treatment aid that can reduce damage to surrounding normal cells.

In order to solve the above problems, the present invention employs the following configurations 1 to 9.
1. At least an energy conversion fine particle having an average particle diameter of 1 nm to 10 μm, which absorbs X-rays with long-distance power, converts the absorbed X-ray energy into a redox reaction, and generates active oxygen species or free radicals. An auxiliary agent for X-ray treatment in which one kind is dispersed in a medium.
2. The energy conversion fine particles are selected from the group consisting of CdTe, CeF ₃ , ZnS: Ag, Nb ₂ O ₅ , ZrO ₂ , CsI, CsF, SrTiO ₂ , CdSe, and KTaO ₃ An adjuvant for X-ray treatment described in 1.
3. 3. The X-ray therapeutic aid according to 1 or 2, wherein the energy conversion fine particles have an average particle diameter of 1 to 200 nm.
4). 4. The adjuvant for X-ray treatment according to any one of 1 to 3, wherein the content of the energy conversion fine particles is 1.0 × 10 ⁻⁷ to 50% by weight based on the dispersion medium.
5. The adjuvant for X-ray treatment according to any one of 1 to 4, wherein the medium is water or an aqueous solvent.
6). 6. The adjuvant for X-ray treatment according to 5, wherein the medium is water or an aqueous solvent in which oxygen is dissolved in advance.
7). The adjuvant for X-ray treatment according to any one of 1 to 5, wherein the energy conversion fine particles contain a photocatalyst or a fluorescent material as an auxiliary component.
8). The adjuvant for X-ray treatment according to 7, wherein the photocatalyst is TiO ₂ .
9. The auxiliary agent for X-ray treatment is used by irradiating an X-ray having a long reach of 10 ⁷ to 10 ¹³ photons / cm ² / sec. X-ray treatment aid.

Effects of the present invention

By employing the above configuration, the X-ray treatment auxiliary agent of the present invention has the following effects.
1) In the method in which fine particles of titanium oxide are dispersed in the affected area and the cells are damaged by being excited with ultraviolet rays, a catalytic reaction is advanced using a part of ultraviolet rays or visible light having low permeability, so that the region that acts Is limited to the vicinity of the surface of the affected area. When the affected area is deep in the body surface or when the affected area itself is large, it is difficult to treat the deep area. In the present invention, even when the affected part is in the deep part, X-rays can be efficiently absorbed by the affected part, and damage to surrounding normal cells can be reduced.
2) In addition, by appropriately distributing the X-ray treatment assistant to the affected part of the deep surface of the body, the affected part of the complex shape, and the affected part close to the site where damage is to be avoided, which is difficult with the prior art, The surface and the inside can be treated three-dimensionally along the shape of the affected part.
3) Furthermore, a higher therapeutic effect can be exhibited by utilizing the synergistic effect of energy conversion fine particles selected from scintillators, quantum dots, phosphor materials, and photocatalysts that directly exhibit redox reaction by X-ray irradiation. .
4) In the current radiotherapy, the biological tissue is damaged along the path to the affected area and all the paths after passing through the affected area, so that damage to the normal tissue along the path including the affected area is large, and the treatment site Even if it deteriorated again, irradiation along the same route could not be performed. In the present invention, as in conventional radiotherapy, not all tissues in the transmission path of high-energy gamma rays are damaged, but radiation with a high particle fluence rate is uniformly irradiated to assist the X-ray treatment. Exerts selective therapeutic effects on targets that are selectively localized, damages with fineness of the tissue size order, and reduces damage to normal cells. It is possible to avoid excision and leaving behind the affected area.

Hereinafter, specific modes for carrying out the present invention will be described in detail.
(Summary of drugs, components of drugs)
The auxiliary agent for X-ray treatment of the present invention is an auxiliary agent for X-ray treatment in which at least one kind of energy conversion fine particles having an average particle diameter of 1 nm to 10 μm, which exhibits a therapeutic effect by X-ray irradiation, is dispersed in a medium. is there. As the energy conversion fine particles, those having an average particle diameter of 1 to 200 nm are preferably used.
Such energy conversion fine particles can be selected from the group consisting of (a) a photocatalyst containing an element having an atomic number of 30 or more, (b) quantum dots, (c) a scintillator, and (d) a phosphor material.
And even if X-rays are evenly irradiated by dispersing this X-ray treatment aid in tumor cells, viruses, genes, bacteria, etc. that are the target of the affected area, only the target along the shape of the affected area is tissue size Injury or death at the level of the patient, avoiding excessive removal or leaving behind the affected area, and the X-ray with far-reaching power allows the drug to absorb the energy even if it is deep, causing a therapeutic effect and minimally invasive・ X-ray treatment with low exposure is possible.

  That is, the X-ray therapeutic aid of the present invention absorbs long-distance X-ray energy, induces a strong redox reaction, generates reactive oxygen species and free radicals, and becomes a target in the affected area. It means a drug capable of damaging or killing tumor cells, viruses, genes, bacteria and the like. At this time, chemicals to which X-ray energy is once converted into a luminescence phenomenon such as fluorescence and phosphorescence and a component for converting the luminescence energy into an oxidation-reduction reaction are also included in this range.

As shown in FIG. 1, the auxiliary agent for X-ray treatment of the present invention injects an auxiliary agent dispersion into the affected part, has a high particle fluence rate, and transmits energy to the deep part of the affected part by collimated X-rays. By absorbing the X-ray energy in the therapeutic aid and inducing a redox reaction, the exposure to surrounding normal cells in which the X-ray therapeutic aid is not dispersed is reduced, and reactive oxygen species only in the affected area And free radicals can be generated to selectively damage tumor cells, viruses, genes, bacteria and other targets.
That is, in the present invention, since the X-ray treatment aid is distributed only to the affected area, even if the parallel or conical X-ray beam is uniformly irradiated, even if the affected area has a complicated shape, damage is not caused. What is given is limited to the region where the X-ray treatment aid is dispersed, and normal tissue preservation and treatment of the affected tissue can be controlled at the tissue level. X-ray treatment aids can reach the target by suspending in solution and injecting directly, capsules currently used in the medical field, drug delivery systems (DDS) using nanotechnology, and selecting the target There are methods that utilize an antibody, a receptor, etc.

Examples of the energy conversion fine particles that can be used in the auxiliary agent for X-ray treatment of the present invention include the following.
(Photocatalyst with large atomic number)
When a photocatalyst is used as an auxiliary for X-ray treatment, absorption of X-ray energy is important. Of the X-ray attenuation, it is known that photoelectric absorption corresponding to the absorption component is proportional to the third to fifth power of the atomic number. Therefore, elements with atomic numbers of 30 or more, namely zinc (30), gallium (31), arsenic (33), selenium (34), strontium (38), zirconium (40), niobium (41), molybdenum (42 ), Ruthenium (44), cadmium (48), indium (49), tin (50), tantalum (73), tungsten (74), bismuth (83), and the like, zirconium oxide (ZrO ₂ ), Strontium titanate (SrTiO ₃ ), potassium titanate (K2O · nTiO3), molybdenum sulfide (MoS ₂ ), bismuth oxide (Bi ₂ O ₃ ), indium oxide (In ₂ O ₃ ), ruthenium oxide (RuO ₂ ), oxidation Cadmium (CdO), tungsten oxide (WO ₃ ), niobium oxide (Nb ₂ O ₅ ), cadmium selenide (CdSe), cadmium telluride (CdTe), potassium tantalate (K ₂ O · nTaO ₃ ), cadmium sulfide ( CdS), gallium phosphide (GaP), gallium arsenide (G A solution obtained by mixing fine particles of at least one material selected from the group of aAs), zinc oxide (ZnO), and tin oxide (SnO ₂ ) and dispersing the mixture in an aqueous solution at a constant concentration is used.

(Quantum dot)
Since quantum dots have a small diameter of a few nanometers, the quantum size effect is prominent, and even the same substance has different physicochemical properties. Therefore, it has recently been attracting attention in the fields of biochemistry and information and communication. It is. For the same weight, the surface area of the nano-sized particles increases in proportion to the square of the diameter. Quantum dots are excited by single-wavelength ultraviolet light and emit fluorescence in the visible light region according to their size. In addition, since quantum dots emit stronger fluorescence than conventional fluorescent proteins, they are widely used in biological imaging in recent years. (See Non-Patent Document 2). In addition, since the chemical reaction on the material surface such as active oxygen production is strongly influenced by the surface area, generation of active oxygen is confirmed even with a small amount of quantum dots. Cytotoxicity via reactive oxygen species has also been reported (see Non-Patent Document 3).
Among these compound semiconductors, in particular, cadmium selenide (CdSe), cadmium telluride (CdTe), cadmium sulfide (CdS), mercury cadmium telluride (CdHgTe), cadmium selenite (CdSeTe) ), IV-VI group compounds lead sulfide (PbS), lead selenide (PbSe), lead telluride (PbTe), III-VI group indium sulfide (InS), III-V group indium phosphide (InP) , Indium arsenide (InAs), group IV carbon (C), silicon (Si), etc. are widely used. Many of these quantum dots have large atomic numbers, that is, extremely large X-ray photoelectric absorption. For example, CdTe has been used as a semiconductor radiation detector with high collection efficiency since ancient times, although it is a bulk material.
In the present invention, cadmium telluride quantum dot (CdTe / ZnS) dispersion and cadmium selenide quantum dot (CdSe / ZnS) dispersion were irradiated with X-rays to confirm that significant X-ray absorption occurred. From the above-mentioned reports on cytotoxicity, CdTe / ZnS or CdSe / ZnS quantum dots absorb X-rays by absorbing X-ray energy, and then generate reactive oxygen species or free radicals by energy conversion into a redox reaction. It was thought that it was expressing cytotoxicity.
Bruchez, Science, Vol.281, 25 Sept. 1998 Hardman, Environmental Health Perspectives, vol.114, No.2, 2006

(Scintillator)
Conventionally, an inorganic scintillator material has been used as an energy conversion element of a radiation detector as a bulk material. In order to extract visible light or ultraviolet light emitted as fluorescence from the scintillator to the detection surface of the photomultiplier tube, it is necessary to form an optically transparent glass plate-like crystal. There are few examination examples about how to use it. In the present invention, fine particles of scintillator for detecting gamma rays called cerium fluoride (CeF ₃ ) are dispersed in water, drip in a certain amount, dried, and then irradiated with high fluence X-rays. That is, it is confirmed by the Examples that the same phenomenon as that when the ultraviolet rays are applied to the titanium oxide is observed. A similar phenomenon is considered to occur in other scintillators that have a band gap and generate carriers by radiation incidence. Therefore, the surface area of inorganic and organic scintillator materials other than cerium fluoride (CeF ₃ ) is also increased by micronization, and the absorbed energy is converted into a redox reaction by interaction with the surrounding environment. It can be a constituent of a therapeutic aid.

Examples of such inorganic scintillator materials include cerium fluoride (CeF ₃ ), barium fluoride (BaF ₂ ), BaF ₂ : La, BaF ₂ : Eu, with the addition of La and Eu as the luminescence center based on barium fluoride. Examples include barium chloride (BaCl ₂ ), and BaCl ₂ : La, cesium iodide (CsI), and cesium fluoride (CsF) added with La as a luminescent center as a base material, and as an organic scintillator material, Examples include at least one material selected from the group of anthracene, chloroanthracene, transstilbene, p-terphenyl, quarterphenyl, diphenylacetylene, and naphthalene. Such a scintillator material is preferably used as a solution that is atomized to a particle size of 200 nm or less and dispersed in an aqueous solution at a constant concentration.

Among inorganic scintillators, YAlO ₃ (Ce), Bi ₄ Ge ₃ O ₁₂ , CdWO ₄ , GSO, LSO, LuAG: Ce, LiF (W), LiF (Eu), and PWO are only transparent glass plate crystals There are many things in circulation. If these can be dispersed in the liquid in the form of fine particles as described above, the same effect as CeF ₃ can be expected, but until now, these solid scintillators have been atomized to a particle size of 200 nm or less and dispersed in the liquid. Few cases have been reported. As an example of a method for atomizing these solid crystals and dispersing them in a liquid, there is laser ablation in liquid, and examples of fine particles of metal and metal oxide have been reported. Not reported.

(Phosphor material)
In the present invention, ZnS: Ag based on ZnS, which is a IIb-VIb group compound semiconductor, with Ag added to the emission center emits blue fluorescence having a peak at 450 nm and simultaneously decolorizes rhodamine by X-ray irradiation. It is confirmed by the Examples that there is a redox reaction. Therefore, a group of phosphor materials containing the elemental elements of zinc selenide (ZnSe) and zinc sulfide (ZnS) of group II-VI compound semiconductors, and trace elements of Ag, Cl, Cu, and Mn, which serve as the luminescence center. By dispersing a phosphor material made of at least one material selected from the above in an aqueous solution at a constant concentration, the X-ray therapeutic aid of the present invention can be obtained. These materials are preferably finely divided to a particle size of 200 nm or less and dispersed in an aqueous solution.

(Particle size)
With the recent expansion of production of industrial nanoparticles such as fullerenes, carbon nanotubes, gold and quantum dots, research on the effects of nanoparticles with submicron size (~ 200nm) on the living body and environment has been actively conducted. It is going According to these, nanoparticles taken into the body permeate epithelial cells or endothelial cells, enter the blood and lymph circulation, reach sensitive organs such as bone marrow, lymph nodes, spleen, heart, and penetrate the skin These nanoparticles are distributed in the body by riding on lymphatic channels, have high physiological activity, and have inflammation, oxidation, and antioxidant effects (Oberdorster, et.al, EHP Vol.113, No.7, July 2005). There is also a report that nanoparticles accumulate in mitochondria and give oxidative stress (Donaldson and Tran, Inhal Toxicol. Jan; 14 (1): 5-27. 2002). Therefore, the X-ray therapeutic aid is preferably 200 nm or less in size in order to be selectively taken up by cells and exert a therapeutic effect. However, on the other hand, if the surface area is large and there are many active parts exposed on the surface like nanoparticles, it is not always necessary to be taken into the cell, and due to oxidative stress on the cell surface, Ca ⁺⁺ concentration increases and IL ^-8 may be induced, or transition metals and organic compounds may activate cell surface receptors and cause oxidative stress (Source: Donaldson and Tran 2002). Therefore, even particles of the order of μm exhibit cytotoxicity from the cell surface or from the outside of the cell and can be used as the X-ray therapeutic aid of the present invention. However, if the particle size is reduced, the radiation irradiation area is also reduced, and the energy absorption rate is reduced. For this purpose, the number of particles per unit volume, that is, the particle concentration in the affected area is increased, or the X-ray absorption is increased by using a material containing an element having a large atomic number and a large photon attenuation coefficient. Measures such as increasing the probability of absorption using photon energy are required.

  When the X-ray treatment aid is composed of a semiconductor, if the particle size is further reduced below 200 nm, the band gap energy increases, and the quantum size effect that shifts the light absorption edge to the short wavelength side is remarkable. Will come. Such a relationship between the particle diameter and the band gap is given by the Brus equation (LE Brus, J. Phys. Chem., 90, 2555 (1986)). It is possible to approach the line area. Of the materials constituting the X-ray treatment aid, the particle size of those belonging to the semiconductor is further reduced to 100 nm or less, whereby the light absorption edge is moved to the short wavelength side due to the quantum size effect, and X having a wavelength shorter than that of ultraviolet rays. Line energy can be absorbed efficiently.

(Content, X-ray energy, X-ray attenuation)
In the conventional disclosure example, although the radiation dose to be irradiated is estimated, how much it is absorbed by the particles is not considered at all. Even if the affected area is irradiated with high-intensity radiation, if the rate of absorption by the particles is low, the effect is not different from conventional gamma ray therapy. Therefore, in the present invention, when a certain material is selected as an auxiliary for X-ray treatment,
1) Photon energy,
2) Particle size,
3) Concentration (dispersion number density),
4) Using the attenuation coefficient for photons of the X-ray treatment aid as a parameter, the X-ray transmission distance and the attenuation rate associated therewith were estimated, and the photon energy range suitable for the treatment of the X-ray treatment aid was clarified. The calculation flow is shown in FIG. In this calculation, it is assumed that the drug fine particles are evenly dispersed in the dispersion medium (affected tissue), the average volume of the dispersion medium in which one particle exists is defined as a unit cube, and its size is obtained. The X-ray attenuation (transmission) rate of a dispersion medium containing a therapeutic aid is obtained.

According to the procedure described in FIG. 2, as a specific example, assuming that ZnS: Ag and CeF _{3 with} a diameter of 100 nm as an auxiliary for X-ray treatment, water (substantially the same transmittance as that of living soft tissue) as a liquid, and transmission distance is 3 cm Tables 1 and 2 show calculation examples when the average concentration difference (D-ρL) is changed from 0.0001 to 1.0 (g / cm ³ ) (0.01 to 50% by weight).

If the weight ratio in which the X-ray treatment aid is contained can be calculated from the average concentration of the dispersion, the attenuation rate when passing through the dispersion can be obtained. In an affected area containing an X-ray treatment aid, it is desirable that X-rays are sufficiently absorbed, transmitted radiation is attenuated, and exposure to normal tissue is reduced. Therefore, when the conditions of photon energy at which the transmitted X-ray intensity is 10% are obtained, when the transmission distance is 3 cm and the average concentration difference (D-ρL) is 0.0001 to 1.0 (g / cm ³ ), ZnS: Ag 20-90KeV, it was found that the suitable energy range of 20-170keV the CeF _3.

In the X-rays in this range, the attenuation components are photoelectric absorption and Compton scattering. However, in order to transfer energy to the X-ray therapeutic aid, photoelectric absorption needs to be excellent. Therefore, when examining the X-ray attenuation components of ZnS: Ag and CeF _{3 in} the above energy range, there is an energy band where the scattering component increases as the energy increases, but the photoelectric absorption is more than 10 times the Compton scattering component. It can be seen that the main component of X-ray attenuation is photoelectric absorption. Therefore, by performing X-ray irradiation in this energy band, it is possible to increase energy absorption in the affected area of the X-ray treatment aid and reduce damage in surrounding normal tissues.
The same calculation, and ZrO ₂ is greater photocatalytic atomic number, was performed on CdTe quantum dots, the irradiation energy range of the X-ray therapy aids in the case of ZrO _2, 20-120KeV, the CdTe In this case, it will be 20-160keV. Even if the constituents of the X-ray treatment adjuvant change, a suitable X-ray energy range can be obtained by the same calculation method.

(Complex X-ray treatment adjuvant)
The X-ray therapeutic aid of the present invention has an energy selected from the group consisting of (a) a photocatalyst containing an element having an atomic number of 30 or more, (b) a quantum dot, (c) a scintillator, and (d) a phosphor material. When the converted fine particles (first component) are included as a constituent component, X-ray energy alone is converted into energy for redox reaction to generate active oxygen species and free radicals, thereby damaging the affected site target. However, depending on the material, the conversion efficiency is low, so it may be more effective to change the X-ray energy to light emission energy such as fluorescence or phosphorescence and then convert the light emission energy to redox reaction energy. . Therefore, the material that absorbs the fluorescence energy generated from the first component and converts it into the energy of redox reaction to generate active oxygen species or free radicals. The material different from the first component is a scintillator material, phosphor material , Quantum dots, photocatalytic materials containing titanium oxide, or photochemical substances may be selected and added as auxiliary components. In addition, in quantum dots, ZnS is used as a coating material that enhances the fluorescence of CdSe and CdTe, and such a form is also effective as a composite X-ray treatment aid.

  In this way, in an environment where the first component and the auxiliary component coexist, the X-ray energy absorbed by the X-ray treatment aid 1) directly contributes to the redox reaction by the first component 2) second It has the dual conversion effect of being emitted as fluorescence from one component and being absorbed by the auxiliary component and contributing to the redox reaction. As a synergistic effect of these, it generates reactive oxygen species and free radicals, and the redox The target can be oxidatively degraded or damaged by force to enhance the therapeutic effect (see FIG. 3).

  Titanium oxide is known to be excited by high-energy radiation, but in the energy band of 500 keV, the probability of interaction with fine particles with a small atomic number such as titanium oxide is low and is absorbed by titanium oxide. Is estimated to be negligible for its energy. In contrast, mixed or combined X-ray therapeutic agents such as the one described above absorb X-rays with the first component with a high X-ray capture rate, and generate redox reactions that generate reactive oxygen species and free radicals themselves. Induction and conversion to fluorescence, and the auxiliary component converts the energy from ultraviolet to visible and near-infrared, which has a high absorption rate, and transmits energy, so the therapeutic effect of low exposure using incident X-ray energy efficiently Can be obtained.

(Photochemical)
As a photochemical substance that is fluorescently excited and exhibits phototoxicity, berberine chloride has been reported to absorb UVA, generate radicals and singlet oxygen, and damage Ehrlich ascites carcinoma (EAC) cells. (Jantova S, J Photochem Photobiol B. 2006 Aug 11). In addition, irradiation of visible light to hematoporphyrin damages cancer cells, which has been confirmed to be due to singlet oxygen (Weishaupt KR, Cancer Res. 1976 Jul; 36 (7 PT 1 ): 2326-9). Furthermore, research using porphyrin-nanoparticle conjugates for cancer phototherapy (visible light excitation) (Sortino S, Biomaterials. 2006 Aug; 27 (23): 4256-65) and phthalocyanine-nanoparticle conjugates for cancer light Studies for use in therapy (visible light excitation) have also been made (Wieder ME, Photochem Photobiol Sci. 2006 Aug; 5 (8): 727-34). However, since these methods are superficial treatments of the affected area with visible light or ultraviolet rays, energy cannot be transmitted when the affected area is deep. The present invention is a remarkable technique that is not found in these prior arts in that it can irradiate penetrating X-rays and absorb fluorescence in the photochemical substance dispersed in the affected part in the deep part to express phototoxicity only in the affected part. There is an effect. .

(Composite form)
Specifically, the composite type energy conversion fine particles constituting the X-ray therapeutic aid of the present invention are, for example, a scintillator, a phosphor material, a quantum dot, a photocatalyst containing an element having an atomic number of 30 or more, or a photochemical substance. A material composed of a single material or a combination of materials. These are dispersed in water or a buffer to adjust the concentration, mixed or compounded, and injected into the affected area. Energy transfer via fluorescence from the first component to the auxiliary component is performed more efficiently as the distance is shorter. Therefore, in order to make the distance between the two as close as possible, these materials are connected by chemical synthesis in addition to simply mixing. Or a method of joining them in close contact. Alternatively, the periphery of the first component is covered with the auxiliary component, and the X-ray having high permeability is transmitted through the auxiliary component coating to reach the first component to absorb the X-ray energy. A method of transmitting energy from the inside to a surface auxiliary component from a certain first component is also conceivable. As a form of complexing these fine particles, a connection type, a bond type, and a cover type as shown in FIG. 4 can be considered.

(Combination optimization)
In the mixed type or composite type X-ray therapeutic aid, the peak value and the spectral width of the fluorescence wavelength spectrum emitted from the first component excited by the absorbed X-ray are determined depending on the material, and are absorbed. By selecting a combination of particulate materials that maximizes the overlap with the absorption spectrum of the auxiliary component, reactive oxygen species and free radicals can be efficiently generated (FIG. 5).

As an example of a mixed or composite X-ray treatment aid, NaI: Te, which is a typical inorganic scintillator sodium iodide with a small amount of tellurium, has a peak at 415 nm and emits fluorescence from 300 nm to 550 nm. . Further, a ZnS: Ag phosphor obtained by doping ZnS with a small amount of silver serving as an emission center emits fluorescence in the emission center peak wavelength of 450 nm and in the range of 380 nm to 550 nm. The inorganic scintillator CeF ₃ has emission center peaks at 300 nm and 340 nm, and BaF ₂ has emission center peaks at 210 nm and 310 nm. Furthermore, YaP: Ce, which is known to emit high intensity fluorescence in the ultraviolet region, has a light emission wavelength peak at 350 nm and emits fluorescence in the range of 320 nm to 430 nm.

On the other hand, absorption of photocatalyst that receives fluorescence of radiation-excited fine particles, for example, when using titanium oxide, the wavelength end corresponding to the band gap of 3.0 eV for rutile type and 3.2 eV for anatase type is anatase type. In the case of titanium oxide, it is 380 nm, and in the case of rutile type titanium oxide, it is 410 nm. Therefore, energy is efficiently transmitted by a combination in which the overlap between the absorption edge and the emission wavelength peak from the phosphor material or scintillator material is maximized. As an example, when ZnS: Ag is selected, since the emission center peak is at 450 nm, the energy absorption rate is higher when mixed with rutile type particles than with anatase type. The same applies when NaI: Tl having an emission center peak at 415 nm is used. However, CeF ₃ , BaF ₂ , and YaP: Ce can be used for both because the emission center peak is shorter than the anatase and rutile absorption edges.

(X-ray fluence)
Radiation such as X-rays and gamma rays is characterized by a greater transmission power than visible light and ultraviolet rays. Among these, the particle fluence rate of gamma rays generated by the decay of isotopes is higher than that of X-rays. Usually several orders of magnitude smaller. High-fluence gamma-ray sources are used for therapeutic and nondestructive testing, but are more difficult to handle than X-ray generators in terms of on / off operation, shielding, shutter structure complexity and radiation management. In this regard, the X-ray generator can be turned on and off electrically, and the energy is variable, so it is necessary to activate the drug when the material constituting the X-ray treatment aid is changed. By adjusting to photon energy, it is possible to easily generate much more photons than isotope nuclides per unit time and unit area, so that the probability of drug X-ray energy absorption is increased. For example, in a typical diagnostic fluoroscopic X-ray generator, the voltage is 6.7 × 10 ⁹ pieces / cm ² per second at a position of 50 cm at a 120 kV tube voltage and a tube current of 10 mA. On the other hand, for the therapeutic telecobalt source, cobalt 60 source of 2.22x10 ¹² Bq (= 60Ci) (decay number / second) is used, but the radiation is emitted in all directions. At 1 cm ² at 50 cm away, it is only 2.22x10 ¹² /4x3.14x500 ² = 7.1x10 ⁶ pieces / cm ² . Therefore, in terms of the number of photons, the X-ray generator can generate a fluence that is about 1000 times larger, so that the affected area can be uniformly irradiated and the activation probability of the X-ray treatment aid is greatly increased. improves. Such X-ray generation sources include medical or non-destructive X-ray tubes, linacs, cyclotrons, cockcroft accelerators, electrostatic accelerators, microtrons, soft X-ray generators, synchrotron radiation facilities, X-ray free electrons A laser or the like can be used.

In order to compare the radiation exposure when using an X-ray source and a gamma-ray source, the absorbed dose of photons generated from the X-ray source and the absorbed dose in the case of radiation therapy using a gamma-ray source were calculated. The absorbed dose D (gray: Gy) is generally given by the following equation when charged particle equilibrium is established.
D = (μen / ρ) x (hν0) xΦ'xT
here,
(μen / ρ): Mass energy absorption coefficient [cm ² / g],
(hν0): Incident photon energy [MeV],
Φ ': is the particle fluence rate [photon / cm ² / sec],
T: Total irradiation time [sec]
In the above unit system,
D = 1.602x10 ^-10 x (μen / ρ) x (hν0) xΦ'xT
It becomes.

In the case of X-ray irradiation, assuming that the average photon energy is 50 keV, and using the mass energy absorption coefficient of water close to living soft tissue, the absorbed dose Dx is calculated using the following values:
(μen / ρ) _@ 50keV _{, Water} : Mass energy absorption coefficient 0.0422 [cm ² / g],
(hν0) _@ 50keV ： Incident photon energy 0.05 [MeV],
Φ ': Particle fluence rate 6.7x10 ⁹ [photon / cm ² / sec],
T: Total irradiation time 1800 [seconds]
Dx = 1.602x10 ^-10 x 0.0422 x 0.05 x 6.7 x ^{10 9} x 1800 = 4.07 [Gy]
It becomes.

On the other hand, in the case of a gamma knife using a 223.11 TBq (6030 Ci) cobalt 60 radiation source, the absorbed dose D _γ is obtained from the same calculation,
(μen / ρ) _{@ 1.2MeV, Water} : Mass energy absorption coefficient 0.0296 [cm ² / g],
(hν0) _{@ 1.2MeV} ： Incident photon energy 1.2 [MeV],
Φ ': Particle fluence rate = 7.1x10 ⁸ [photons / cm ² / sec],
T: Total irradiation time 1800 [seconds]
D _γ = 1.602x10 ^-10 x 0.0296 x 1.2 x 7.1 x ^{10 6} x 1800 = 7.23 [Gy]
It becomes.

As shown in these calculation examples, the major difference between gamma rays and X-rays is that the photon energy and the particle fluence rate are greatly different even if the absorbed dose is about the same. The particle fluence rate varies greatly depending on the operating conditions (tube voltage, tube current) of the X-ray generator, the distance from the generator, etc. From the above calculation results, it is desirable that 10 ⁹ to 10 ¹¹ photons / cm ² / sec. More desirably, 10 ⁷ to 10 ¹³ photons / cm ² / sec is suitable.

Also, comparing the ratio of absorbed dose for each term and taking the absorbed dose ratio Dx / D _γ in the case of X-ray and gamma ray treatment,
_{Dx / D γ = [(μen} / ρ) X / (μen / ρ) γ] x [(hν0) X / (hν0) γ] x [Φ X '/ Φ γ'] x [T X / T γ]
It is expressed.
In the above equation, the terms [(μen / ρ) _X / (μen / ρ) _γ ] and [(hν0) _X / (hν0) _γ ] are uniquely determined by the photon energy and the substance. When the energy of X-ray photons is 0.05 MeV and the photon energy of gamma rays is 1.2 MeV,
Mass energy absorption coefficient ratio [(μen / ρ) _X / (μen / ρ) _γ ] = 1.4
Incident photon energy ratio [(hν0) _X / (hν0) _γ ] = 0.042
Therefore, when the X-ray and gamma-ray energies differ greatly, it can be said that if the same fluence and irradiation time are used, the high-energy gamma-ray has a larger absorbed dose in the living body, that is, the exposure is greater.

In addition, since Φ _γ ′ is also determined at the time of processing the gamma ray source, only the irradiation time T _γ can be changed after installation as a parameter relating to the absorbed dose related to exposure in the case of the gamma ray source. An X-ray source having a high degree of freedom in parameters is suitable for dealing with various factors such as the shape and position of the affected part and the type of auxiliary agent for X-ray treatment.
The major difference between X-ray generators and gamma-ray generators is whether energy and fluence can be made variable. In the X-ray generator, the X-ray spectrum generated by changing the tube current and tube voltage can be changed with the same device depending on the size and depth of the affected part and the size of the X-ray treatment aid. The energy of the gamma ray source is determined when the nuclide is selected, and its decay number is uniquely determined during processing. In addition, X-rays can be electrically switched on and off, while gamma rays cannot be switched on and off, so they must be controlled with a mechanical shutter. This is a big difference in terms of ease of handling and safety of the operator.
A more common radiation therapy is to kill tumor cells by performing multiple doses of about 2 Gy once for breast cancer. The amount of X-ray irradiation in this method is similar, and when the target is damaged by this method, the effect expected by X-ray radiation therapy can be expected at the same time.

(Oxygen supply)
In order to absorb the X-ray energy and promote the redox reaction of the X-ray treatment aid, the generated electrons and holes need to be constantly consumed. Even if X-ray irradiation is continuous and electron-hole pair generation occurs continuously, if some electrons and holes accumulate, recombination is likely to occur and carriers are not used for redox reactions. . When dissolved oxygen is low compared to the oxygen concentration in the air, as in the body, electrons are taken into oxygen in the conduction band, and the process of generating reactive oxygen species such as superoxide becomes rate-limiting, then carrier recombination It is thought that the probability increases and the oxidation-reduction reaction rate decreases. Therefore, high reaction efficiency can be maintained by supplying sufficient oxygen in the vicinity of the auxiliary agent for X-ray treatment. For this purpose, it is an effective means to increase the oxygen-dissolved concentration of the auxiliary dispersion for X-ray treatment in advance. Therefore, in order to efficiently and continuously proceed the oxidation-reduction reaction to generate reactive oxygen species or free radicals and kill or damage target cells, bacteria, viruses, genes, etc. in the affected area, It is an effective means to disperse the X-ray therapeutic aid in the dissolved aqueous solution.

EXAMPLES Next, the present invention will be further described with reference to examples, but the following specific examples are not intended to limit the present invention.
(Example 1: Quantum dots)
[Experimental sample]
Quantum dot (Qdot705, Invitrogen) solution sucked into a glass capillary with an outer diameter of 1 mm (CdTe / ZnS quantum dot streptavidin sampler is 1 μM streptavidin-binding QD in borate buffer at pH 8.3. As a control, a glass capillary with an outer diameter of 1 mm was prepared.
〔experimental method〕
X-ray transmission image (tube voltage 40kV, tube current 120μA, magnification 12) using Kevex microfocus X-ray source (PXS5-925EA, focal diameter 7μm), Hamamatsu photonics flat panel detector (C7943CA-02, 1231x1231 pixels) Double, 30mm from the focal point). FIG. 6 shows the result of obtaining the log by subtracting the dark signal and correcting the defective pixel and then taking the ratio with the gain image without the sample.

FIG. 7 shows a comparison of luminance value distributions of X-ray projection data along the center of the glass tube (line AA and line BB in FIG. 6) of water and a CdTe / ZnS quantum dot (QD) dispersion solution.
When X-rays were irradiated to the quantum dot solution and water in the glass tube under the same conditions, the X-ray absorption of the solution containing the quantum dots was high (see FIG. 7). This is thought to be because X-rays were absorbed by CdTe / ZnS nanoparticles dispersed in the solution. CdTe / ZnS is a material that has been used as a radiation detection element for bulk solids because of its high photon collection efficiency, and the brightness value varies depending on the dispersed concentration. This shows that X-ray absorption is remarkable, and when quantum dots such as CdTe / ZnS are used as an auxiliary for X-ray treatment, energy transfer by X-rays is efficiently performed.

(Example 2: phosphor, composite type)
[Experimental sample]
(1) TiO ₂ (90% rutile, 10% anatase) suspended in distilled water at 0.30g / mL, added 7uL points to a circular hole with a diameter of 6mm and a depth of 0.1mm, and dried thoroughly I let you.
(2) A suspension of ZnS: Ag in distilled water so as to be 1.00 g / mL was added with 7 uL in a circular hole having a diameter of 6 mm and a depth of 0.1 mm, and was sufficiently dried.
(3) TiO ₂ (90% rutile, 10% anatase) 0.17g / mL and ZnS: Ag suspended in distilled water to 0.44g / mL are round 6mm in diameter and 0.1mm in depth. 7uL point was added to the hole and dried sufficiently.
(4) To the samples prepared in (1), (2) and (3), 2 uL of 4 mg / mL rhodamine aqueous solution was added in the dark and left for 30 minutes. At this time, a solution to which no rhodamine aqueous solution was added was prepared.

〔experimental method〕
(5) Place the prepared sample at a position 10 cm away from the X-ray irradiation port of the X-ray source (Toshiba, KXO-15E), and irradiate the X-ray continuously for 30 minutes under the conditions of a tube voltage of 100 kV and a tube current of 4 mA. . A sample prepared at the same time and placed in a dark place without X-ray irradiation was designated as Control Group 1.
(6) Images were captured so that the conditions were the same for digital cameras before and after X-ray irradiation (manual mode, ISO: 64, shutter speed: 1/40, aperture: F3.2, exposure: -1).
(7) This image was converted to gray scale with existing software (MATLAB, The MathWorks) to obtain the luminance value (At this time, normalization was performed with the luminance value of the sample without adding rhodamine in the same image) ).
(8) The change in the luminance value of each sample after the test was expressed as a percentage, where the difference between the luminance value to which rhodamine was added before X-ray irradiation and the luminance value to which rhodamine was not added was defined as 100%. 0% indicates that the luminance does not change before and after the experiment and does not decolorize, and 100% indicates that rhodamine has been completely decomposed by the experiment.
Table 3 shows the obtained luminance change.

When ZnS: Ag fine particles were irradiated with X-rays, blue fluorescence was observed. It was also verified that ZnS: Ag fine particles decomposed rhodamine by X-ray irradiation.
It was verified that the measured value of rhodamine decomposition was larger than ZnS: Ag when the mixture of TiO ₂ and ZnS: Ag was irradiated with X-rays. This is because the phosphor material ZnS: Ag alone exhibits redox action under X-ray irradiation, and emits ultraviolet light or visible light. It was confirmed that the redox reaction was synergistically promoted by mixing.

(Example 3: Scintillator)
[Experimental sample]
(1) TiO ₂ (90% rutile, 10% anatase) suspended in distilled water at 0.30g / mL, added 7uL points to a circular hole with a diameter of 6mm and a depth of 0.1mm, and dried thoroughly I let you.
(2) TiO ₂ (anatase type 98%) suspended in distilled water at 1.00 g / mL was added with 14 uL in a circular hole having a diameter of 6 mm and a depth of 0.1 mm, and was sufficiently dried.
(3) CeF ₃ suspended in distilled water at 1 g / mL was added with 7 uL in a circular hole having a diameter of 6 mm and a depth of 0.1 mm, and was sufficiently dried.
(4) A suspension of Nb ₂ O ₅ in distilled water at 0.30 g / mL was added with 7 uL in a circular hole having a diameter of 6 mm and a depth of 0.1 mm, and was sufficiently dried.
(5) A suspension of ZrO ₂ in distilled water at 0.31 g / mL was added with 7 uL in a circular hole having a diameter of 6 mm and a depth of 0.1 mm, and was sufficiently dried.
(6) A 4 mg / mL rhodamine aqueous solution was added to the sample prepared in (1), (2), (3), (4), and (5) in the dark and left for 30 minutes. At this time, a solution to which no rhodamine aqueous solution was added was prepared.

〔experimental method〕
(7) Place the prepared sample at a position 10 cm away from the X-ray irradiation port of the X-ray source (Toshiba, KXO-15E), and irradiate the X-ray continuously for 30 minutes under the conditions of a tube voltage of 100 kV and a tube current of 4 mA. . Samples prepared at the same time, which were placed in the dark without being irradiated with X-rays, were designated as control group 1, and those which were placed indoors (under a fluorescent lamp) without being irradiated with X-rays were designated as control group 2.
(8) Images were captured so that the conditions were the same for digital cameras before and after X-ray irradiation (manual mode, ISO: 64, shutter speed: 1/40, aperture: F3.2, exposure: -1).
(9) This image was converted to gray scale with existing software (MATLAB, The MathWorks) to obtain the luminance value (At this time, normalization was performed with the luminance value of the sample without adding rhodamine in the same image) ).
(10) The change in the luminance value of each sample after the test was expressed as a percentage, where the difference between the luminance value to which rhodamine was added before X-ray irradiation and the luminance value to which rhodamine was not added was defined as 100%. 0% indicates that the luminance does not change before and after the experiment and does not decolorize, and 100% indicates that rhodamine has been completely decomposed by the experiment.
Table 4 shows changes in luminance obtained by the above experiment.

It was verified that TiO ₂ (rutile 90%, anatase 10%) and TiO ₂ (anatase 98%) were excited by X-rays and decomposed the rhodamine dye by oxidation-reduction reaction under the X-ray irradiation conditions in this experiment.
The CeF ₃ fine particles were irradiated with X-rays and confirmed to emit ultraviolet rays with an ultraviolet meter. In addition, it was confirmed that CeF ₃ fine particles, Nb ₂ O ₅ fine particles, and ZrO ₂ fine particles decompose rhodamine by X-ray irradiation. Furthermore, it was verified that TiO ₂ decomposes rhodamine by the UV light contained in the fluorescent lamp, but CeF ₃ microparticles do not decompose rhodamine by the fluorescent lamp under the experimental conditions.

(Example 4: Effect of shielding by aluminum plate)
[Experimental sample]
(1) TiO ₂ (90% rutile, 10% anatase) 0.17g / mL and ZnS: Ag suspended in distilled water so as to be 0.32g / mL have a circular shape with a diameter of 6mm and a depth of 0.1mm. 7uL point was added to the hole and dried sufficiently.
(2) To the sample prepared in (1), 2 uL of 4 mg / mL rhodamine aqueous solution was added in the dark and left for 30 minutes. At this time, a solution to which no rhodamine aqueous solution was added was prepared.

〔experimental method〕
(3) The prepared sample was placed at a position 10 cm away from the X-ray irradiation port of the X-ray source (Toshiba, KXO-15E). Aluminum plates with thicknesses of 0.3 mm, 1 mm, and 2 mm were placed between the sample and the X-ray at a position 5 mm from the sample. In addition, a sample without an aluminum plate was also prepared. X-rays were continuously irradiated for 30 minutes under the conditions of a tube voltage of 100 kV and a tube current of 4 mA. Samples prepared at the same time, which were placed in the dark without being irradiated with X-rays, were designated as control group 1, and those which were placed indoors (under a fluorescent lamp) without being irradiated with X-rays were designated as control group 2.
(4) Images were captured so that the conditions were the same for digital cameras before and after X-ray irradiation (manual mode, ISO: 64, shutter speed: 1/40, aperture: F3.2, exposure: -1).
(5) This image was converted to gray scale using existing software (MATLAB, The MathWorks) to obtain the luminance value (At this time, normalization was performed with the luminance value of the sample without adding rhodamine in the same image) ).
(6) The change in the luminance value of each sample after the test was expressed as a percentage, where the difference between the luminance value to which rhodamine was added before X-ray irradiation and the luminance value to which rhodamine was not added was defined as 100%. 0% indicates that the luminance does not change before and after the experiment and does not decolorize, and 100% indicates that rhodamine has been completely decomposed by the experiment.
Table 5 shows changes in luminance obtained by the above experiment.

It was verified that the mixture of TiO ₂ and ZnS: Ag was excited by X-rays and decomposed rhodamine by an oxidation-reduction reaction under the X-ray irradiation conditions in this experiment even when shielded by an aluminum plate.
In the past, methods for treating cancer by dispersing fine particles of titanium oxide in an affected area and exciting them with ultraviolet rays have been studied as a method for treating cancer. However, since ultraviolet rays and visible light have low transmissivity, they are effective on the surface of the object but are ineffective at the deep part of the object.
50keV X-rays are attenuated by about 10% with a 2mm thick aluminum plate. The equivalent water thickness is 8.8mm. Similarly, an aluminum plate with a thickness of 1 mm is equivalent to attenuation of 4.4 mm of water and an aluminum plate with a thickness of 0.3 mm is equivalent to attenuation of a thickness of 1.5 mm, so this experiment is about 9 mm deep from the body surface by X-ray irradiation. It is shown that the energy transfer of is sufficiently possible. At the same time, since ultraviolet rays do not penetrate the aluminum plate at all, it is shown that even in places where excitation by ultraviolet rays is difficult, energy can be transmitted by X-rays to induce a redox reaction.

(Example 5: active oxygen)
[Experimental sample]
(1) As experimental samples, the following were suspended in distilled water so as to be 3.0 mg / mL and 1 mL of distilled water alone was dispensed into petri dishes each having a diameter of 35 mm.
- photocatalytic _{material: ZrO 2, SrTiO 2, KTaO} 3, TiO 2 (90% rutile, anatase 10%), CdSe
-Phosphor material: ZnS: Ag
・ Scintillator materials: CeF ₃ , CsI, CsF
Quantum dots: Qdot525 (CdSe / ZnS), Qdot655 (CdSe / ZnS), Qdot705 (CdTe / ZnS) average particle diameter of 1 to 20 nm
The photocatalyst, the phosphor, and the scintillator material are dispersed in distilled water, and are composed of primary particles with an average diameter of 2-10 μm and aggregated average diameters of 50-200 μm. Confirmed with. Moreover, the particle diameter of a quantum dot is 1-20 nm. Further, TiO ₂ (rutile 90%, anatase 10%) and ZnS: Ag were mixed at 3.0 mg / mL and suspended in distilled water, and dispensed into a petri dish having a diameter of 35 mm. Quantum dots are Qdot525 (Invitrogen), Qdot655 (Invitrogen), and Qdot705 (Invitrogen) suspended in distilled water at 1.0 ng / mL and 1 mL of distilled water only in a petri dish with a diameter of 35 mm. Dispensed.
(2) Dihydroethidium (Invitrogen-Molecular Probes) was added to the sample prepared in (1) so that the final concentration was 25 μM.
(3) Each sample of (2) was irradiated for 0 hours, 30 minutes in the dark, 30 minutes in the light (2 m under indoor fluorescent light), and 30 minutes in X-rays (100 kV, 4 mA, irradiation distance 40 cm). .

〔experimental method〕
(4) The sample was collected and centrifuged at 10000 rpm, 10 min (TOMY, MX-160).
(5) The supernatant was taken and centrifuged again under the same conditions, and the supernatant was collected.
(6) The fluorescence intensity at 585 nm was measured using a spectrofluorometer (Shimadzu Corporation, RF-1500) when excited at a wavelength of 456 nm.
Table 6 shows the fluorescence intensities (Ex 456 nm, Em 585 nm) determined by the above experiment. The numerical value is a relative fluorescence intensity, and shows a difference from 0 hour (immediately after mixing with dihydroethidium).

Dihydroethidium reagents are derived from dihydroethidium (excitation wavelength: 385 nm, fluorescence wavelength: 480 nm) in the presence of active oxygen such as O _2- (superoxide anion), HO ₂ (peroxy radical), and HO (hydroxy radical). Since ethidium (excitation wavelength: 465 nm, fluorescence wavelength: 585 nm) is generated, it is used as one method for measuring active oxygen. (Reference: Nethery D, Stofan D, Callahan L, DiMarco A, Supinski G .: Formation of reactive oxygen species by the contracting diaphragm is PLA (2) dependent. J Appl Physiol. 1999 Aug; 87 (2): 792-800 .)
From Examples 2, 3, and 4, it was confirmed that TiO ₂ (90% rutile, 10% anatase) and ZnS: Ag decompose rhodamine dyes by irradiation with a fluorescent lamp. This is due to the action of several μW / cm ² ultraviolet rays contained in the fluorescent lamp. According to this example, TiO ₂ (90% rutile, 10% anatase), ZnS: Ag, SrTiO ₂ , CdSe, Qdot655, and Qdot705 were confirmed to generate ethidium upon light irradiation and X-ray irradiation to generate active oxygen. . This is consistent with the phenomenon that in Example 3, TiO ₂ (rutile 90%, anatase 10%) and ZnS: Ag decompose the pigment by light irradiation.

On the other hand, CeF ₃ , ZrO ₂ , CsI, CsF, KTaO ₃ , and Qdot525 produced little ethidium by light irradiation, but produced ethidium by X-ray irradiation. This is consistent with the phenomenon that CeF ₃ and ZrO ₂ in Example 3 decompose the dye only by X-ray irradiation and do not decompose the dye by light irradiation. From these examples, it can be confirmed that the decomposition of the pigment is due to generation of active oxygen, and further, TiO ₂ (90% rutile, 10% anatase), ZnS: Ag, CeF ₃ , ZrO ₂ , CsI, CsF, SrTiO ₂ , CdSe, KTaO ₃ , Qdot525, Qdot655, and Qdot705 were confirmed to generate active oxygen by X-ray irradiation. Qdot525 and Qdot655 are quantum dots coated with ZnS using CdSe as a core, and Qdot705 is a quantum dot coated with ZnS using CdTe as a core. In this experiment, Qdot525 and Qdot655 generated the same level of active oxygen at a concentration of 1/3 million of CdSe fine particles. This is because Qdot525 and Qdot655 are ultrafine particles, and the surface area contributing to the reaction is much larger than that of CdSe fine particles, and that Qdot525 and Qdot655 are composite materials of CdSe and ZnS. Qdot705 is a composite material of CdTe and ZnS, and these components were also confirmed to contribute to the generation of active oxygen by X-ray irradiation.

The present invention provides an X-ray therapeutic aid useful for the treatment of damaged or killed malignant neoplasms such as cancer cells, cancer precursor cells, cells infected with viruses and bacteria in radiation therapy. The auxiliary agent for X-ray treatment of the present invention opens the way to a minimally invasive treatment method using radiation at a low exposure dose in which X-ray irradiation is limited to the affected area.
In addition, by using the X-ray treatment auxiliary of the present invention, sterilization of bacteria (E. coli, endotoxin, O157, verotoxin, MRSA (methicillin-resistant Staphylococcus aureus), enterotoxin, chlorophyll), toxin decomposition, and Bactericidal sterilization can be performed by oxidative degradation, damage and death of bacteria and viruses.

It is a figure explaining the method of irradiating and treating an affected part by X-rays using the adjuvant for X-ray treatment of this invention. It is a figure which shows the transmission distance calculation method and parameter in the affected part of the adjuvant for X-ray treatment. It is a figure explaining the synergistic effect of the oxidation-reduction reaction of the mixed or composite type X-ray therapeutic adjuvant of the present invention. It is a figure explaining the form of mixing or compounding of two or more kinds of auxiliary materials for X-ray treatment. It is a figure which shows the optimal combination which considered the fluorescence emission and absorption spectrum of the mixed or composite type X-ray therapeutic aid. It is a figure which shows the result obtained in Example 1. It is a figure which shows the result obtained in Example 1.

Claims (9)

  At least an energy conversion fine particle having an average particle diameter of 1 nm to 10 μm, which absorbs X-rays with long-distance power, converts the absorbed X-ray energy into a redox reaction, and generates active oxygen species or free radicals. An auxiliary agent for X-ray treatment in which one kind is dispersed in a medium. The energy conversion fine particles are selected from the group consisting of CdTe, CeF ₃ , ZnS: Ag, Nb ₂ O ₅ , ZrO ₂ , CsI, CsF, SrTiO ₂ , CdSe, and KTaO _3. Item 2. The X-ray treatment adjuvant according to Item 1.   The average particle size of the energy conversion fine particles is 1 to 200 nm, and the adjuvant for X-ray treatment according to claim 1 or 2. The X-ray therapeutic adjuvant according to any one of claims 1 to 3, wherein the content of the energy conversion fine particles is 1.0 x ^10-7 to 50 wt% based on a dispersion medium.   The adjuvant for X-ray treatment according to any one of claims 1 to 4, wherein the medium is water or an aqueous solvent.   The adjuvant for X-ray therapy according to claim 5, wherein the medium is water or an aqueous solvent in which oxygen is dissolved in advance.   The said energy conversion microparticles | fine-particles contain a photocatalyst or a fluorescent material as an auxiliary | assistant component, The adjuvant for X-ray treatment in any one of Claims 1-5 characterized by the above-mentioned. The adjuvant for X-ray treatment according to claim 7, wherein the photocatalyst is TiO ₂ . The adjuvant for X-ray treatment is used by irradiating X-rays having a long reach of 10 ⁷ to 10 ¹³ photons / cm ² / sec. The adjuvant for X-ray treatment as described.