Electron beam irradiation device and electron beam irradiation method

Abstract

This electron beam irradiation device includes: a disposition part for disposing an irradiation target including a photosensitive substance on the inside; and an irradiation unit for emitting an electron beam with energy higher than 1 MeV towards the photosensitive substance inside the irradiation target disposed on the disposition part. The irradiation unit causes the photosensitive substance to react by irradiating the photosensitive substance with the electron beam, and also causes Cherenkov light to be radiated due to propagation of the electron beam in the irradiation target and causes the photosensitive substance to react due to the Cherenkov light.

Description

Electron beam irradiation device and electron beam irradiation method

[0001] One aspect of the present invention relates to an electron beam irradiation apparatus and an electron beam irradiation method.

[0002] For example, a technique is known in which a photosensitizer (photosensitive substance) is accumulated inside an irradiation target, an optical fiber (endoscope) is inserted into the irradiation target, and light is guided by the optical fiber to irradiate the photosensitizer (see, for example, Non-Patent Document 1). In this case, the photosensitizer reacts with the light irradiation to generate active oxygen.

[0003] Yuji Morimoto, "Photodynamic Therapy: Light-Based Cancer Treatment," [online], [searched July 28, 2023], Internet: <https: / / cancer.qlife.jp / series / as005 / article8352.html>

[0004] In the above-mentioned technology, it is difficult for optical fibers to reach deep inside the target, and it is therefore not easy to deliver light to a photosensitive substance deep inside the target, and therefore the above-mentioned technology is difficult to apply when reacting a photosensitive substance deep inside the target.

[0005] Therefore, an object of one aspect of the present invention is to provide an electron beam irradiation device and an electron beam irradiation method that are capable of causing a photosensitive substance to react even deep within an irradiation target.

[0006] As a result of extensive research, the present inventors have found that irradiating a photosensitive substance with a high-energy electron beam can induce a reaction (function expression) in the photosensitive substance. Furthermore, they have found that propagating a high-energy electron beam through an irradiated object can cause Cherenkov light to be emitted, and that this Cherenkov light can induce a reaction in the photosensitive substance. Furthermore, they have found that because high-energy electron beams have low energy attenuation in materials, the electron beam and Cherenkov light can be sufficiently delivered to photosensitive substances even if they are located deep within the object, thereby completing one aspect of the present invention.

[0007] (1) That is, an electron beam irradiation device according to one aspect of the present invention includes a placement section for placing an irradiation target containing a photosensitive material therein, and an irradiation section for irradiating an electron beam having energy greater than 1 MeV toward the photosensitive material inside the irradiation target placed in the placement section, wherein the irradiation section irradiates the photosensitive material with the electron beam to cause a reaction in the photosensitive material, and also emits Cherenkov light as the electron beam propagates through the irradiation target, causing the photosensitive material to react with the Cherenkov light.

[0008] This electron beam irradiation device utilizes the above-mentioned knowledge and makes it possible to cause a photosensitive substance to react even deep within the target to be irradiated, due to the synergistic effect of the electron beam and Cherenkov light.

[0009] (2) In the electron beam irradiation device described in (1) above, the photosensitive substance may be a photosensitizer used in photodynamic therapy, and the irradiation unit may react the photosensitizer by irradiation with the electron beam and also by Cherenkov light to generate active oxygen. In this case, the electron beam irradiation device can be used for photodynamic therapy.

[0010] (3) In the electron beam irradiation device described in (1) above, the photosensitive substance may be a photoimmunotherapy drug used in photoimmunotherapy, and the irradiation unit may react the photoimmunotherapy drug by irradiating it with the electron beam and also by emitting Cerenkov light, thereby destroying cells to which the photoimmunotherapy drug is attached and releasing antigens from the cells. In this case, the electron beam irradiation device can be used for photoimmunotherapy.

[0011] (4) In the electron beam irradiation device according to any one of (1) to (3), the irradiation unit may irradiate an electron beam having an energy of 100 MeV or more. In this case, the directionality of the irradiated electron beam within the irradiation target is increased, and Cherenkov light can be effectively emitted.

[0012] (5) In the electron beam irradiation device according to any one of (1) to (4), the irradiation unit is configured to be able to set the dose per pulse of the electron beam to be irradiated and the number of pulses of the electron beam to be irradiated, and the dose per pulse of the electron beam may be smaller than a predetermined value. By reducing the dose per pulse of the electron beam in this way, it is possible to reduce damage to the irradiation target due to exposure to the electron beam even if the total dose of the electron beam is the same.

[0013] (6) The electron beam irradiation device according to any one of (1) to (5) above may further include a first applying unit that applies an external magnetic field to the electron beam along the direction of travel of the electron beam. In this case, the directionality of the electron beam can be improved, and the electron beam can be selectively applied with a sufficient dose to a photosensitive material present deep inside the irradiation target.

[0014] (7) In the electron beam irradiation device described in any one of (1) to (6) above, the irradiation unit may include an electron beam source that generates an electron beam having an energy chirp, and a chirp adjustment unit that adjusts the energy chirp of the electron beam generated by the electron beam source so that higher energy components are positioned further back in the beam propagation direction. In this case, as the electron beam propagates to the photosensitive material in the irradiation target, the pulse width of the electron beam is automatically and gradually compressed, increasing the charge density, thereby reducing energy transfer to materials other than the photosensitive material in the irradiation target while increasing energy transfer to the photosensitive material. In other words, it is possible to use an electron beam to achieve beam irradiation that selectively transfers large amounts of energy to the photosensitive material in the irradiation target.

[0015] (8) In the electron beam irradiation device according to any one of (1) to (7), the electron beam may have a pulse width of subpicoseconds or less. In this case, the effect of the electric field of the electron beam on the photosensitizer is enhanced, and the photosensitizer can be reacted more efficiently than when the electron beam has a pulse width in the range of nanoseconds to picoseconds.

[0016] (9) The electron beam irradiation device described in any one of (1) to (8) above may include an input unit capable of inputting photosensitizer information related to a photosensitizer, and a control unit that controls the time structure of multiple electron pulses included in the electron beam irradiated by the irradiation unit based on the photosensitizer information. In this case, by controlling the time structure of the multiple electron pulses (e.g., intensity, intensity ratio, time interval, each pulse width, etc.) based on the photosensitizer information, it is possible to control the chemical reaction caused by the interaction between the electron pulses and the photosensitizer and control, for example, the structure, type, yield, yield ratio, etc. of the active substance converted from the photosensitizer. The time structure of the multiple electron pulses may include, for example, at least one of the intensity, intensity ratio, each time interval, and each pulse width of the multiple electron pulses.

[0017] (10) In the electron beam irradiation device according to any one of (1) to (9), the irradiation unit may emit electron beams with a uniform spin direction. In this case, it is possible to control, for example, the structure, type, yield, and yield ratio of the active substance converted from the photosensitizer to correspond to the spin direction of the electron beam.

[0018] (11) The electron beam irradiation device according to any one of (1) to (10) above may further include a second application unit that applies an external electric field or an external magnetic field to a photosensitizer inside an irradiation target placed in the placement unit so as to align the polarity of the photosensitizer. In this case, it is possible to control, for example, the structure, type, yield, yield ratio, etc. of the active substance converted from the photosensitizer to correspond to the polarity of the photosensitizer.

[0019] (12) In the electron beam irradiation device according to any one of (1) to (11), the irradiation unit may be capable of irradiating the photosensitive material inside the irradiation target placed in the placement unit with the electron beam from multiple directions. In this case, by irradiating the photosensitive material with the electron beam from multiple directions, it is possible to suppress energy transfer to parts other than the photosensitive material in the irradiation target, while increasing energy transfer to the photosensitive material.

[0020] (13) An electron beam irradiation method according to one aspect of the present invention includes the steps of placing an irradiation target containing a photosensitive material in a placement section, and irradiating an electron beam having energy greater than 1 MeV toward the photosensitive material inside the irradiation target placed in the placement section, wherein in the step of irradiating the electron beam, the photosensitive material is reacted by being irradiated with the electron beam, and Cherenkov light is emitted by the propagation of the electron beam within the irradiation target, and the Cherenkov light reacts the photosensitive material.

[0021] According to one aspect of the present invention, it is possible to provide an electron beam irradiation device and an electron beam irradiation method that are capable of causing a photosensitizer to react even deep within an irradiation target.

[0022] FIG. 1 is a schematic diagram showing the configuration of an electron beam irradiation device according to an embodiment. FIG. 2(a) is a schematic diagram showing a phase rotator. FIG. 2(b) is a schematic diagram showing a path adjuster. FIG. 3 is a schematic diagram showing an example of electron beam irradiation. FIG. 4 is a diagram for explaining Cherenkov light. FIG. 5 is a diagram showing an example of electron beam dose distribution. FIG. 6 is a graph showing the relationship between the dose per pulse and damage to a patient due to exposure.

[0023] Hereinafter, the embodiments will be described in detail with reference to the drawings. In the following description, the same or equivalent elements will be designated by the same reference numerals, and redundant description will be omitted.

[0024] 1 , an electron beam irradiation device 100 according to an embodiment is a device that irradiates a high-energy electron beam E toward a photosensitive substance D inside the body of a patient (irradiation target) P, causing a reaction of the photosensitive substance D. The electron beam irradiation device 100 includes a patient table 1, an irradiation unit 10, a spin controller 2, a first magnetic field application unit 3, a second magnetic field application unit 4, an electric field application unit 5, a beam monitor 41, a beam dump 6, an operation input unit 20, and a control unit 21.

[0025] Photosensitizer D is a substance that has the property of undergoing a reaction such as a chemical change when exposed to light. For example, photosensitizer D may be a photosensitizer used in photodynamic therapy. Furthermore, for example, photosensitizer D may be a photoimmunotherapy drug used in photoimmunotherapy. Examples of photosensitizers include porphyrin derivatives. Examples of photoimmunotherapy drugs include drugs containing phthalocyanine. Photosensitizer D is administered to patient P by, for example, infusion or injection. The administered photosensitizer D reaches a target site (a lesion, a tumor, cancer cells (including HeLa cells), etc.) in the body of patient P and adheres to and accumulates at the target site.

[0026] The photosensitizer D can exhibit activity and function at the targeted location. The photosensitizer D is not particularly limited and may be any photosensitizer. For example, the photosensitizer D may be a drug that is inactive until it reaches the target site. The photosensitizer D may be present at a deep position (trunk) within the body of the patient P.

[0027] The patient table 1 is a placement section on which a patient P containing a photosensitive material D is placed. The irradiation unit 10 is a unit that irradiates the photosensitive material D inside the patient P on the patient table 1 with an electron beam E. The irradiation unit 10 has a laser plasma-driven electron accelerator 11, a phase rotator 12, and a path adjuster 13.

[0028] The laser plasma-driven electron accelerator 11 is an electron accelerator that accelerates an electron beam E by laser plasma acceleration. The acceleration energy of the laser plasma-driven electron accelerator 11 is, for example, 1 to 300 MeV. The laser plasma-driven electron accelerator 11 constitutes an electron beam source that emits an electron beam E of ultrashort electron pulses with an energy spread. The laser plasma-driven electron accelerator 11 includes, for example, an optical waveguide forming device that forms an optical waveguide that propagates a high-intensity laser pulse over a long distance by gas discharge in a discharge tube.

[0029] The electron beam E generated by the laser plasma-driven electron accelerator 11 has an energy chirp due to the broadening of its energy spectrum caused by the disruption of plasma waves. The energy chirp refers to a state in which the energy components of the electron beam E are strongly correlated with the direction of propagation, and the energy components gradually change from the front to the rear of the direction of propagation of the electron beam E. The electron beam E generated by the laser plasma-driven electron accelerator 11 has, for example, a ΔE / E of 100 to 0.1%. Here, E is the acceleration energy, and ΔE is the energy width (spectral width). ΔE corresponds, for example, to the half-width of the acceleration energy distribution. For example, ΔE / E = 10 MeV / 100 MeV = 10%.

[0030] The phase rotator 12 is a chirp adjustment unit that spatially rotates the electron beam E by 180° and inverts the energy chirp of the electron beam E. The phase rotator 12 adjusts the energy chirp of the electron beam E so that higher energy components are positioned further back in the beam traveling direction (in other words, lower energy components are positioned further forward in the beam traveling direction). An electron bunch stretcher or the like can be used as the phase rotator 12.

[0031] 2A, the phase rotator 12 includes magnetic field generators 12a, 12b, 12c, and 12d, each of which is made up of a dipole magnet. In the phase rotator 12, the magnetic fields of the magnetic field generators 12a, 12b, 12c, and 12d cause electrons to move in semicircular orbits. As a result, the emitted electron beam E has an energy chirp in which higher energy components are positioned further backward in the beam propagation direction.

[0032] The path adjuster 13 compresses the pulse width of the electron beam E adjusted by the phase rotator 12. The path adjuster 13 adjusts the optical path of each energy component of the electron beam E to compress the pulse width of the electron beam E. The path adjuster 13 compresses the electron beam E in the vertical direction (the direction along the traveling direction of the electron beam E). The path adjuster 13 adjusts the optical path of each energy component of the electron beam E so that the pulse width of the electron beam E is most compressed at the position of the photosensitive material D. An electron bunch compressor or the like can be used as the phase rotator 12.

[0033] 2(b), the path adjuster 13 includes electromagnets 13a, 13b, 13c, and 13d. In the path adjuster 13, the magnetic fields of the electromagnets 13a, 13b, 13c, and 13d cause the electrons to move so as to form an arc-shaped trajectory. This adjusts the optical path of each energy component of the electron beam E, and sets the optical path distance from the path adjuster 13 to the photosensitive material D to the distance at which the pulse width of the electron beam E is most compressed at the position of the photosensitive material D.

[0034] 3, the irradiation unit 10 configured in this manner irradiates the photosensitive material D inside the body of the patient P with an electron beam E, causing a reaction of the photosensitive material D with the electron beam E. Specifically, the irradiation unit 10 irradiates the photosensitive material D with the electron beam E, thereby causing a reduction reaction in the photosensitive material D by hydrated electrons resulting from the radiolysis of water and / or a reaction by radicals (such as OH radicals) resulting from the radiolysis of water.

[0035] At the same time, the irradiation unit 10 emits Cherenkov light Lc due to the propagation of the electron beam E through the patient P, and the Cherenkov light Lc reacts with the photosensitive material D. As shown in FIG. 4, Cherenkov light Lc is a shock wave of light emitted when the speed of a substance in a medium exceeds the speed of light in the medium. The emission intensity of the Cherenkov light Lc has a delta function time profile. The radiation angle θc of the Cherenkov light Lc with respect to the propagation direction of the electron beam E is expressed by the following equation (1). For example, the Cherenkov light Lc is present in front of (around the front of) the traveling direction of the electron beam E. cos θc=1 / (n·β), β=v / c (1) where n: refractive index of the medium, v: speed of the substance, c: speed of light

[0036] The photosensitizer D reacts with the synergistic effect of the electron beam E and Cherenkov light Lc, activating the photosensitizer D. For example, the photosensitizer D as a photosensitizer generates active oxygen. This generates active oxygen, which kills the target site (cancer cells, etc.). Furthermore, for example, the photosensitizer D as a photoimmunotherapy drug destroys the target site to which the photoimmunotherapy drug adheres, causing antigens to be released from the target site. This activates the immune system against the same target site.

[0037] The electron beam E has the following characteristics, for example: the electron beam E has a pulse width of subpicoseconds or less; the electron beam E has a pulse width of 300 femtoseconds or less; specifically, the electron beam E has a pulse width of 100 femtoseconds or less, more specifically, a pulse width of several femtoseconds or less; the electron beam E has energy that allows it to pass through the patient P and reach the photosensitizer D; the electron beam E has energy greater than 1 MeV, here greater than 10 MeV, specifically greater than 200 MeV. Returning to FIG. 1 , each condition of the electron beam E may be set via the operation input unit 20. When the irradiation target is the patient P as in this embodiment, the electron beam E may have energy of 1 to 10 MeV, energy of 100 MeV or more, or energy of 100 to 200 MeV.

[0038] The irradiation unit 10 performs multi-fraction irradiation of the electron beam E. The multi-fraction irradiation is an irradiation in which the electron beam E is shot a predetermined number of times or more to achieve a specified total dose. The total dose is the radiation dose irradiated to the target site (the energy imparted by the electron beam E to the target site in the irradiation field). For example, the irradiation unit 10 performs 27 shots of the electron beam E with a dose per pulse of 0.15 Gy (Gy = J / kg) to achieve irradiation of the electron beam E with a total dose of 4.05 Gy. In other words, the irradiation unit 10 irradiates the electron beam E in multi-fraction irradiation with a dose per pulse smaller than a predetermined value. The repetition frequency of the electron beam E irradiated by the irradiation unit 10 is, for example, 0.03 Hz. The predetermined value is not particularly limited, but is, for example, a threshold value determined depending on the type of irradiation target, and in this embodiment, is, for example, 0.2 Gy. The irradiation unit 10 is configured so that the dose per pulse of the irradiated electron beam E and the number of pulses of the irradiated electron beam E (hereinafter also referred to as the "number of shots") can be set, for example, via the operation input unit 20. The irradiation unit 10 may also be configured so that the repetition frequency of the electron beam E can be set.

[0039] The spin controller 2 controls the spin of the electron beam E emitted from the irradiation unit 10 so that it is aligned in a specific direction. The spin controller 2 spin-polarizes the electron beam E input from the irradiation unit 10 and emits the electron beam E with the aligned spin direction. The spin controller 2 here aligns the spin in a direction corresponding to the polarity of the photosensitive material D aligned by the electric field application unit 5. The spin controller 2 is not particularly limited, and various controllers may be used. The spin direction aligned by the spin controller 2 may be fixed or variable. When the spin direction aligned by the spin controller 2 is variable, the angle may be changeable, for example, via the operation input unit 20.

[0040] The first magnetic field application unit 3 applies an external magnetic field to the electron beam E input from the spin controller 2 along the traveling direction (propagation direction) of the electron beam E. The first magnetic field application unit 3 focuses the electron beam E. The first magnetic field application unit 3 compresses the electron beam E in the lateral direction (direction perpendicular to the traveling direction). As the first magnetic field application unit 3, for example, an electromagnet driven by a pulse current that is time-synchronized with the electron beam E is used. The first magnetic field application unit 3 constitutes the first application unit. The first magnetic field application unit 3 is not limited to this, and a superconducting magnet or the like may also be used.

[0041] The second magnetic field applicator 4 applies an external magnetic field along the direction of propagation of the electron beam E to the electron beam E irradiated onto the photosensitive material D inside the body of a patient P placed on a patient table 1. The second magnetic field applicator 4 includes an upstream applicator 4A arranged upstream of the patient table 1 in the direction of propagation of the electron beam E, and a downstream applicator 4B arranged downstream of the patient table 1 in the direction of propagation of the electron beam E. The upstream applicator 4A and the downstream applicator 4B may be, for example, electromagnets driven by pulse currents synchronized with the electron beam E. The second magnetic field applicator 4 focuses the electron beam E between the upstream applicator 4A and the downstream applicator 4B. The second magnetic field applicator 4 compresses the electron beam E in the lateral direction between the upstream applicator 4A and the downstream applicator 4B. The second magnetic field applicator 4 constitutes the first applicator. The second magnetic field applicator 4 is not limited to this, and a superconducting magnet or the like may also be used.

[0042] The electric field application unit 5 applies an external electric field to the photosensitive material D inside the patient P placed on the patient table 1 so as to align the polarity of the photosensitive material D. The electric field application unit 5 is provided with electrodes 5A and 5B on either side of the patient P. The direction in which the electrodes 5A and 5B of the electric field application unit 5 face each other is perpendicular to the direction of travel of the electron beam E. The polarity aligned by the electric field application unit 5 may be fixed or variable. If the polarity aligned by the electric field application unit 5 is variable, the angle may be changeable, for example, via the operation input unit 20. The polarity aligned by the electric field application unit 5 may be aligned according to the spin direction aligned by the spin controller 2. The electric field application unit 5 constitutes a second application unit.

[0043] The beam monitor 41 is a device that measures the electron beam E that has passed through the photosensitive material D. The beam monitor 41 monitors at least one of the position, intensity, shape, and dose of the electron beam E that has passed through the photosensitive material D. There are no particular limitations on the type of beam monitor 41, and any known monitor can be used. The beam dump 6 is a device that absorbs and stops the electron beam E that has passed through the photosensitive material D and been measured by the beam monitor 41. The beam dump 6 is provided downstream of the patient table 1 in the optical path of the electron beam E. There are no particular limitations on the type of beam dump 6, and any known device can be used.

[0044] The operation input unit 20 is an input unit that can accept various inputs from a user. For example, a touch panel, a microphone, a camera, etc. are used as the operation input unit 20. Examples of inputs to the operation input unit 20 include touch input, voice input, and camera input. The operation input unit 20 is configured to allow input of, for example, each condition of the electron beam E emitted from the irradiation unit 10, the spin direction aligned by the spin controller 2, the polarity direction aligned by the electric field application unit 5, and photosensitive substance information related to the photosensitive substance D. The photosensitive substance information includes at least information related to the type of photosensitive substance D.

[0045] The control unit 21 is configured by, for example, one or more computer devices. The control unit 21 is configured to include a CPU (Central Processing Unit) which is a processor, and a RAM (Random Access Memory) or ROM (Read Only Memory) which is a recording medium. The control unit 21 executes various controls by loading programs and the like onto hardware such as the CPU and RAM. The control unit 21 controls each condition of the electron beam E irradiated by the irradiation unit 10 based on input from the operation input unit 20.

[0046] The control unit 21 controls the time structure of the multiple electron pulses contained in the electron beam E irradiated by the irradiation unit 10 based on the photosensitive substance information input via the operation input unit 20. Specifically, the control unit 21 controls the time structure of the electron pulses contained in the electron beam E by referring to a data table stored in the memory unit 22 based on the type of photosensitive substance D in the input photosensitive substance information. For example, the time structure of the electron pulses includes at least one of the intensities, intensity ratios, time intervals, and pulse widths of the multiple electron pulses 30, as shown in FIG. 3 . For example, in the data table, the types of photosensitive substances D and the time structures of the electron pulses are associated with each other. The data table can be obtained in advance by actual measurement, simulation, or the like.

[0047] In the electron beam irradiation method using the electron beam irradiation device 100 described above, first, a photosensitive substance D is administered to a patient P, and the photosensitive substance D is accumulated at a target site in the patient P's body. The patient P is placed on the patient table 1, and the operation input unit 20 is used to input various conditions for the electron beam E to be irradiated, such as photosensitive substance information, the spin direction of the electron beam E, and the polarity direction of the photosensitive substance D. The control unit 21 controls the irradiation unit 10, and the irradiation unit 10 irradiates the photosensitive substance D with an electron beam E having an energy of 100 to 200 MeV and a pulse width of 100 femtoseconds or less. At this time, the electron beam E is irradiated in a multi-fraction irradiation manner with a dose per pulse that is smaller than a predetermined value (e.g., 0.15 Gy).

[0048] The electron beam E emitted from the irradiation unit 10 has its spin direction aligned by the spin controller 2, is focused by the first magnetic field application unit 3, and then propagates with high directionality through the patient P placed on the patient table 1. At this time, the electron beam E is focused by the second magnetic field application unit 4. In addition, the polarity of the photosensitive material D is aligned by the electric field application unit 5. The electron beam E is selectively irradiated onto the photosensitive material D inside the body of the patient P. At the same time, Cherenkov light Lc is emitted as the electron beam E propagates, and the Cherenkov light Lc irradiates the photosensitive material D. As a result, a synergistic effect between the electron beam E and the Cherenkov light Lc occurs in the photosensitive material D, causing the photosensitive material D to react effectively.

[0049] As described above, in the electron beam irradiation device 100 and electron beam irradiation method of this embodiment, a high-energy electron beam E greater than 1 MeV is irradiated toward the photosensitive material D, causing the photosensitive material D to react (to exhibit function). Additionally, by propagating the high-energy electron beam E greater than 1 MeV through the patient P, Cherenkov light Lc is emitted, and the Cherenkov light Lc reacts with the photosensitive material D. Furthermore, because the high-energy electron beam E has low energy attenuation in matter, the electron beam E and the Cherenkov light Lc can sufficiently reach the photosensitive material D present deep within the patient P. In other words, even if the photosensitive material D is present deep within the patient P, the electron beam E and the Cherenkov light Lc can be selectively and simultaneously applied to the photosensitive material D at sufficient doses to cause the photosensitive material D to react. Therefore, the synergistic effect of the electron beam E and the Cherenkov light Lc makes it possible to cause the photosensitive material D to react even deep within the patient P.

[0050] In the electron beam irradiation device 100, the photosensitizer D may be a photosensitizer used in photodynamic therapy. In this case, the irradiation unit 10 reacts the photosensitizer by irradiation with the electron beam E and also reacts the photosensitizer with Cherenkov light Lc to generate active oxygen. In other words, the electron beam irradiation device 100 can be used for photodynamic therapy.

[0051] In the electron beam irradiation device 100, the photosensitizer D may be a photoimmunotherapy drug used in photoimmunotherapy. In this case, the irradiation unit 10 reacts the photoimmunotherapy drug by irradiating it with the electron beam E and also by emitting Cherenkov light Lc, destroying the target site (e.g., cancer cells) to which the photoimmunotherapy drug is attached and releasing antigens from the target site. In other words, the electron beam irradiation device 100 can be used for photoimmunotherapy.

[0052] In the electron beam irradiation device 100, the irradiation unit 10 may irradiate the electron beam E with an energy of 100 MeV or more. In this case, the directionality of the irradiated electron beam E inside the patient P is increased, and Cherenkov light Lc can be effectively emitted.

[0053] FIG. 5 is a diagram showing an example of the dose distribution of the electron beam E. FIG. 5 is a result of a numerical simulation showing the propagation of an electron beam E having an energy of 200 MeV through water. In FIG. 5, the horizontal axis represents the position in the direction of propagation of the electron beam E, and the vertical axis represents the position perpendicular to the direction of propagation. In the numerical simulation shown in the figure, a magnetic field of 3 T is applied in the direction of propagation of the electron beam E. The darker the shading in the figure, the greater the dose (flux) of the electron beam E. As shown in FIG. 5, in this embodiment, it can be seen that the diffusion of the electron beam E is suppressed, and the electron beam E is focused into a pencil beam shape, thereby improving the directivity.

[0054] Incidentally, when activating the photosensitive material D inside the patient P with the electron beam E, cell damage may also occur in the patient P due to exposure to the electron beam E. In other words, radiation damage may occur not only in tissues related to the target site but also in normal tissues. Therefore, when irradiating the photosensitive material D with the electron beam E, there is a demand to minimize damage to normal tissues due to exposure to the electron beam E.

[0055] In this regard, the electron beam irradiation device 100 irradiates the electron beam E in multiple segments, and is configured so that the dose and number of shots per pulse of the irradiated electron beam E can be set. The dose per pulse of the electron beam E is smaller than a predetermined value. By reducing the dose per pulse of the electron beam E in this way, it is possible to reduce damage to the patient P caused by exposure to the electron beam E, even if the total dose of the electron beam E is the same.

[0056] FIG. 6 is a graph showing the relationship between the dose per pulse and damage to patient P due to exposure. In the graph, the vertical axis represents cell viability. Example 1 shows the results of an experiment using an apparatus similar to the electron beam irradiation apparatus 100, except that a normal linear high-frequency electron accelerator is used instead of the laser plasma-driven electron accelerator 11. Example 2 shows the results of an experiment using the electron beam irradiation apparatus 100. In Example 1, the dose per pulse of the electron beam E is 1.1 Gy, the total dose is 4.4 Gy, and the number of shots is 4. In Example 2, the dose per pulse of the electron beam E is 0.15 Gy, the total dose is 4.05 Gy, and the number of shots is 27.

[0057] 6 , it was confirmed that the above-mentioned effect can be achieved by reducing the dose per pulse of the electron beam E, thereby reducing damage to the patient P due to exposure to the electron beam E. The predetermined value can be determined, for example, by simulating the relationship between the dose per pulse and damage to the patient P due to exposure based on the results shown in FIG. 6 , and when the dose per pulse of the electron beam E is smaller than the predetermined value, the effect of reducing damage to the patient P due to exposure to the electron beam E can be specifically achieved. As an example, the predetermined value may be 0.2 Gy or 0.15 Gy.

[0058] Incidentally, before irradiating the patient P with the electron beam E, the same electron beam E may be irradiated onto a sample target (water) and the dose per pulse may be adjusted to a predetermined dose while performing real-time measurement. Real-time measurement can be performed using various techniques, such as radiographic film or pulse radiolysis. The obtained measurement values ​​may be cross-checked. In a high-frequency accelerator such as a linac accelerator, the dose per pulse may be adjusted by adjusting the electron gun or acceleration tube. In a laser accelerator, the dose per pulse may be adjusted by adjusting the laser focusing intensity or target density, etc. The dose corresponds to the charge amount (irradiation dose) of the electron beam. The dose per pulse and the number of shots of the electron beam E may be set so that the total dose falls within a specified range.

[0059] The electron beam irradiation device 100 includes a first magnetic field application unit 3 and a second magnetic field application unit 4. In this case, the directionality of the electron beam E can be increased, and the above-mentioned effect of selectively applying a sufficient dose of the pencil-beam-shaped electron beam E to the photosensitive material D present deep inside the patient P can be significantly achieved. It is possible to suppress the problem of scattering of even a high-energy electron beam E in a material and maintain the directionality of the electron beam E.

[0060] In the electron beam irradiation device 100, the irradiation unit 10 has a laser plasma-driven electron accelerator 11, a phase rotator 12, and a path adjuster 13. In this case, the pulse width of the electron beam E is automatically and gradually compressed and the charge density is increased as the electron beam E propagates to the photosensitive substance D inside the body of the patient P, making it possible to suppress energy transfer to substances other than the photosensitive substance D in the patient P while increasing energy transfer to the photosensitive substance D. In other words, it is possible to realize beam irradiation using the electron beam E that selectively transfers large amounts of energy to the photosensitive substance D inside the body of the patient P. Furthermore, by combining the electron beam E with the first magnetic field application unit 3 and the second magnetic field application unit 4, three-dimensional irradiation control of the electron beam E becomes easy.

[0061] In the electron beam irradiation device 100, the electron beam E has a pulse width of subpicoseconds or less. In this case, the effect of the electric field of the electron beam E on the photosensitive material D is enhanced, and the photosensitive material D can be reacted more efficiently (i.e., the photosensitive material D can be reacted with a small total dose) compared to when the electron beam E has a pulse width in the range of nanoseconds to picoseconds, for example, and the amount of radiation exposure of the patient P can be reduced.

[0062] The electron beam irradiation device 100 includes an operation input unit 20 and a control unit 21. In this case, the time structure (e.g., intensity, intensity ratio, time interval, each pulse width, etc.) of the plurality of electron pulses 30 is controlled by the control unit 21 based on the photosensitizer information input via the operation input unit 20. This makes it possible to control the chemical reaction caused by the interaction between the electron pulses 30 and the photosensitizer D, and to control, for example, the structure, type, yield, yield ratio, etc. of the active substance converted from the photosensitizer D.

[0063] In the electron beam irradiation device 100, the spin direction of the electron beam E from the irradiation unit 10 is aligned by the spin controller 2. In this case, it becomes possible to control, for example, the structure, type, yield, yield ratio, etc. of the active substance converted from the photosensitizer D to correspond to the aligned spin direction of the electron beam E. The spin controller 2 may align the spin direction according to the polarity direction of the photosensitizer D aligned by the electric field application unit 5, or may align the spin direction independently.

[0064] The electron beam irradiation device 100 includes an electric field application unit 5. In this case, it is possible to control, for example, the structure, type, yield, yield ratio, etc. of the active substance converted from the photosensitizer D to correspond to the aligned polarity direction of the photosensitizer D. The electric field application unit 5 may align the polarity direction according to the spin direction of the electron beam E aligned by the spin controller 2, or may align the polarity independently.

[0065] In this embodiment, the relative dose of the electron beam E is maintained low in the depth region up to the photosensitive material D, whereas the relative dose of the electron beam E increases sharply at the depth position of the photosensitive material D. Thus, in this embodiment, despite the use of the electron beam E, it is expected that irradiation with the electron beam will have similar Bragg peak characteristics to that of a hadron beam.

[0066] In this embodiment, a high-energy electron beam E is irradiated toward the photosensitive material D, and therefore, compared to the case of irradiating a low-energy electron beam E of, for example, 1 MeV or less, it is possible to prevent the electron beam E from scattering within the patient P (especially in its moisture) and preventing the emission of Cherenkov light Lc.

[0067] In the above, the irradiation unit 10 and the spin controller 2 constitute an irradiation section. The first magnetic field application section 3 and the second magnetic field application section 4 constitute a magnetic field application section. At least one of the phase rotator 12, the path adjuster 13, the spin controller 2, the first magnetic field application section 3, the second magnetic field application section 4, and the electric field application section 5 may be omitted in some cases. The electron beam irradiation method corresponds to the method of using the electron beam irradiation device 100.

[0068] In the present embodiment, the positional relationship between the patient table 1 and the irradiation unit 10 may be configured to be controllable by the control unit 21 so that the electron beam E from the irradiation unit 10 is appropriately incident on the photosensitive substance D inside the body of the patient P who is sitting on the patient table 1. Further, for example, the operation input unit 20 may be configured to be able to input positional information of the photosensitive substance D inside the body of the patient P. In this case, the positional relationship between the patient table 1 and the irradiation unit 10 may be configured to be controllable by the control unit 21 so that the electron beam E is incident on the photosensitive substance D based on the positional information. Further, for example, the electric field application unit 5 may be provided so that its positional relationship relative to the patient table 1 can be changed. This makes it possible to easily apply an external electric field to the photosensitive substance D inside the patient P who is sitting on the patient table 1.

[0069] This embodiment may be used to treat neurodegenerative diseases such as Alzheimer's disease and brain diseases such as brain tumors. When targeting brain diseases, the administered drug must migrate from the blood into the brain, and in this case, it must pass through the blood-brain barrier that separates the blood from brain tissue. It is generally known that drugs with high lipid solubility have high brain migration properties. In this embodiment, by masking the low lipid solubility substituents in the drug, a photosensitizer D with improved lipid solubility is created. After the drug reaches the brain, it is activated by irradiating it with an electron beam E, which is expected to improve brain migration properties and to enable it to act specifically on the brain.

[0070] Although the embodiments have been described above, one aspect of the present invention is not limited to the above embodiments. For example, the numerical values ​​described above and in the drawings may include errors in design, measurement, manufacturing, etc.

[0071] The above embodiment may further include a phantom (water cell) placed between the irradiation unit 10 and the patient P (preferably in front of the body of the patient P) on the optical path of the electron beam E. This phantom functions in the same way as the path adjuster 13, and can adjust the compression point of the electron beam E so that it is located within the photosensitive material D inside the body of the patient P. In the above embodiment, the irradiation target is not particularly limited, and may be various targets.

[0072] In the above embodiment, an example in which the electron beam E is irradiated onto the photosensitive substance D from a specific irradiation direction has been described, but this is not limiting. The irradiation unit may be capable of irradiating the prodrug inside the irradiation target placed in the placement unit with the electron beam from multiple directions. For example, the emission side of the irradiation unit 10 may be configured to be movable around the irradiation target, and the electron beam E may be irradiated onto the photosensitive substance D with the electron beam E irradiated multiple times while changing the position of the emission side of the irradiation unit 10. In this case, by irradiating the photosensitive substance D with intensity-modulated electron beams E from multiple directions and overlapping the electron beams E at the position of the photosensitive substance D, it is possible to suppress energy transfer to substances other than the photosensitive substance D in the irradiation target while increasing energy transfer to the photosensitive substance D.

[0073] In the above embodiment, if the spin of the electron beam E emitted from the irradiation unit 10 is aligned, the spin controller 2 may be omitted. When the spin controller 2 is provided, the spin of the electron beam E can be easily and reliably controlled and aligned by the spin controller 2. In the above embodiment, the electric field application unit 5 is provided as the second application unit, but instead of or in addition to this, a magnetic field application unit (e.g., an MRI (Magnetic Resonance Imaging) device) that applies an external magnetic field to the photosensitive material D so as to align the polarity of the photosensitive material D may be provided as the second application unit.

[0074] The above embodiment may be applied to a prodrug instead of the photosensitive substance D. A prodrug is a drug that changes into an active substance (expresses activity) when triggered after reaching a target site in the body of patient P. A prodrug can express activity and function at a targeted site. The prodrug is not particularly limited and may be any prodrug. For example, a prodrug is an inactive drug until it reaches the target site, and can be changed into a drug such as an anticancer drug when triggered at the target site. In a broad sense, a prodrug may also include a drug carrier. A drug carrier is something that encapsulates a drug, such as a polymeric micelle, liposome, or nanomachine.

[0075] The above embodiment may be applied to a drug delivery system. In a drug delivery system, drugs can be delivered to a desired location by utilizing the EPR (enhanced permeability) effect. Specifically, blood vessels have gaps that allow cells outside the blood vessels to take in oxygen or nutrients. In normal blood vessels, these gaps are very small, allowing low-molecular-weight substances to pass through the blood vessel walls while high-molecular-weight substances cannot. In tumor tissue, blood vessels are formed by angiogenesis accompanying tumor growth, resulting in many branches and rougher blood vessel walls than normal blood vessels, with gaps of, for example, approximately 100 to 200 nm. Taking advantage of this difference, drugs can be accumulated in tumor tissue.

[0076] Another aspect of the present invention may be the following electron beam irradiation apparatus and electron beam irradiation method.

[0077] When a prodrug inside a patient P is activated by an electron beam E, cellular damage may also occur in the patient P due to exposure to the electron beam E. In other words, radiation damage may occur not only in tissues related to the target site but also in normal tissues. Therefore, when irradiating a prodrug with an electron beam E, there is a demand to minimize damage to normal tissues due to exposure to the electron beam E. An object of the present embodiment is to provide an electron beam irradiation device and an electron beam irradiation method that can reduce damage to normal tissues due to exposure to the electron beam E.

[0078] An electron beam irradiation apparatus according to another aspect of the present invention comprises a placement unit for placing an irradiation target containing a prodrug therein, and an irradiation unit that irradiates the prodrug inside the irradiation target placed in the placement unit with an electron beam having energy greater than 1 MeV to convert the prodrug into an active substance, wherein the dose per pulse of the electron beam is smaller than a predetermined value.An electron beam irradiation method according to another aspect of the present invention comprises the steps of placing an irradiation target containing a prodrug inside in a placement unit, and irradiating the prodrug inside the irradiation target placed in the placement unit with an electron beam having energy greater than 1 MeV to convert the prodrug into an active substance, wherein the dose per pulse of the electron beam is smaller than a predetermined value.

[0079] In the electron beam irradiation device and electron beam irradiation method according to another aspect of the present invention, the electron beam E is irradiated in multiple divided pulses, and the dose amount per pulse of the electron beam E is reduced, so that even if the total dose amount of the electron beam E is the same, it is possible to reduce damage to the patient P caused by exposure to the electron beam E.

[0080] 1...Patient table (positioning unit), 2...Spin controller (irradiation unit), 3...First magnetic field application unit (first application unit), 4...Second magnetic field application unit (first application unit), 5...Electric field application unit (second application unit), 10...Irradiation unit (irradiation unit), 11...Laser plasma driven electron accelerator (electron beam source), 12...Phase rotator (chirp adjustment unit), 20...Operation input unit (input unit), 21...Control unit, 10...Irradiation unit, D...Photosensitive material, E...Electron beam, Lc...Cherenkov light, P...Patient (irradiation target).

Claims

1. An electron beam irradiation device comprising: a placement section for placing an irradiation object containing a photosensitive substance inside; and an irradiation section for irradiating an electron beam having energy greater than 1 MeV toward the photosensitive substance inside the irradiation object placed in the placement section, wherein the irradiation section causes a reaction of the photosensitive substance by irradiating the photosensitive substance with the electron beam, and also causes Cherenkov light to be emitted by the propagation of the electron beam through the irradiation object, and causes the photosensitive substance to react due to the Cherenkov light.

2. The electron beam irradiation device described in claim 1, wherein the photosensitive substance is a photosensitizer used in photodynamic therapy, and the irradiation unit reacts the photosensitizer by irradiation with the electron beam and also reacts the photosensitizer by the Cherenkov light to generate active oxygen.

3. The electron beam irradiation device described in claim 1, wherein the photosensitive substance is a photoimmunotherapy drug used in photoimmunotherapy, and the irradiation unit reacts the photoimmunotherapy drug by irradiating it with the electron beam and also reacts the photoimmunotherapy drug with the Cherenkov light, destroys cells to which the photoimmunotherapy drug is attached, and releases antigens from the cells.

4. An electron beam irradiation device according to any one of claims 1 to 3, wherein the irradiation unit irradiates the electron beam with energy of 100 MeV or more.

5. An electron beam irradiation device as claimed in any one of claims 1 to 3, wherein the irradiation unit is configured to be able to set the dose per pulse of the electron beam to be irradiated and the number of pulses of the electron beam to be irradiated, and the dose per pulse of the electron beam is smaller than a predetermined value.

6. An electron beam irradiation device according to any one of claims 1 to 3, comprising a first application unit that applies an external magnetic field to the electron beam along the traveling direction of the electron beam.

7. An electron beam irradiation device as described in any one of claims 1 to 3, wherein the irradiation section comprises: an electron beam source which generates the electron beam having an energy chirp; and a chirp adjustment section which adjusts the energy chirp of the electron beam generated by the electron beam source so that higher energy components are positioned further rearward in the beam propagation direction.

8. An electron beam irradiation device according to any one of claims 1 to 3, wherein the electron beam has a pulse width of sub-picoseconds or less.

9. An electron beam irradiation device as claimed in any one of claims 1 to 3, comprising: an input unit capable of inputting photosensitive substance information relating to the photosensitive substance; and a control unit that controls the time structure of a plurality of electron pulses contained in the electron beam irradiated by the irradiation unit based on the photosensitive substance information.

10. An electron beam irradiation device according to any one of claims 1 to 3, wherein the irradiation unit emits the electron beam with a uniform spin direction.

11. An electron beam irradiation device as described in claim 6, further comprising a second application unit which applies an external electric field or an external magnetic field to the photosensitive material inside the irradiation target placed in the placement unit so as to align the polarity of the photosensitive material.

12. An electron beam irradiation device as described in any one of claims 1 to 3, wherein the irradiation section is capable of irradiating the electron beam from multiple directions to the photosensitive material inside the irradiation target placed in the placement section.

13. An electron beam irradiation method comprising the steps of: placing an irradiation target containing a photosensitive substance in a placement section; and irradiating an electron beam having energy greater than 1 MeV toward the photosensitive substance inside the irradiation target placed on the placement section, wherein in the step of irradiating the electron beam, the photosensitive substance is reacted by being irradiated with the electron beam, and Cherenkov light is emitted by the propagation of the electron beam through the irradiation target, and the photosensitive substance is reacted by the Cherenkov light.

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