WO2023181623A1 - 電子ビーム照射装置及び電子ビーム照射方法 - Google Patents

電子ビーム照射装置及び電子ビーム照射方法 Download PDF

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Publication number
WO2023181623A1
WO2023181623A1 PCT/JP2023/002326 JP2023002326W WO2023181623A1 WO 2023181623 A1 WO2023181623 A1 WO 2023181623A1 JP 2023002326 W JP2023002326 W JP 2023002326W WO 2023181623 A1 WO2023181623 A1 WO 2023181623A1
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Prior art keywords
electron beam
prodrug
irradiation
unit
section
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PCT/JP2023/002326
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English (en)
French (fr)
Japanese (ja)
Inventor
知直 細貝
泰信 山下
裕佐 室屋
孝禎 鈴木
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University of Osaka NUC
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Osaka University NUC
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Priority to US18/847,682 priority Critical patent/US20250205517A1/en
Priority to EP23774223.4A priority patent/EP4474008A4/en
Priority to JP2024509796A priority patent/JPWO2023181623A1/ja
Publication of WO2023181623A1 publication Critical patent/WO2023181623A1/ja
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N5/1077—Beam delivery systems
    • G—PHYSICS
    • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
    • G21K—HANDLING OF PARTICLES OR IONISING RADIATION NOT OTHERWISE PROVIDED FOR; IRRADIATION DEVICES; GAMMA RAY OR X-RAY MICROSCOPES
    • G21K5/00—Irradiation devices
    • G21K5/04—Irradiation devices with beam-forming means
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N2005/1085—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy characterised by the type of particles applied to the patient
    • A61N2005/1089—Electrons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N2005/1092—Details
    • A61N2005/1098—Enhancing the effect of the particle by an injected agent or implanted device

Definitions

  • One aspect of the present invention relates to an electron beam irradiation device and an electron beam irradiation method.
  • a prodrug is, for example, a drug that, after reaching a target site in the body, is converted into an active substance by endogenous or external triggers, and can express activity at the targeted site.
  • endogenous triggers methods using an oxidative or acidic environment, and methods using azoreductase derived from enteric bacteria are known.
  • external triggers methods using light irradiation, methods using metal catalysts or biocatalysts, etc. are known.
  • Non-Patent Document 1 a method has been developed in which a prodrug is irradiated with X-rays, the irradiated site is changed into an active substance, and the activity is expressed.
  • the above-described method can be applied when the prodrug activity is expressed near the surface of the irradiation target, but it is difficult to apply when the prodrug activity is expressed deep within the irradiation target.
  • One aspect of the present invention is to provide an electron beam irradiation device and an electron beam irradiation method that are capable of expressing the activity of a prodrug even in the deep part of an irradiation target.
  • the present inventors discovered that by irradiating a prodrug with a high-energy electron beam, the high-energy electron beam acts as a trigger and can transform the prodrug into an active substance. Ta. They also discovered that high-energy electron beams can sufficiently reach prodrugs that exist deep within the irradiation target because of their low energy attenuation in substances, leading to the completion of one aspect of the present invention. Ta.
  • the electron beam irradiation device includes an arrangement part in which an irradiation target containing a prodrug is arranged, and an energy larger than 1 MeV applied to the prodrug inside the irradiation target arranged in the arrangement part. and an irradiation unit that irradiates the prodrug with an electron beam to convert the prodrug into an active substance.
  • An electron beam irradiation method includes the steps of: arranging an irradiation target containing a prodrug therein in a placement section; irradiating the prodrug with a beam to convert the prodrug into an active substance.
  • the electron beam irradiation device and electron beam irradiation method even if the prodrug is present deep inside the irradiation target, it is possible to selectively apply the electron beam to the prodrug at a sufficient dose to develop its activity. It becomes possible. Therefore, it becomes possible to express the activity of the prodrug deep within the irradiation target.
  • the electron beam irradiation device may include a first application unit that applies an external magnetic field along the traveling direction of the electron beam to the electron beam.
  • the directivity of the electron beam can be increased, and the above effects of being able to selectively apply a sufficient dose of the electron beam to prodrugs present deep inside the irradiation target are significantly exhibited. becomes possible.
  • the irradiation unit includes an electron beam source that generates an electron beam having an energy chirp, and an energy chirp of the electron beam generated by the electron beam source. and a chirp adjustment section that is adjusted to be disposed at the rear in the direction.
  • the pulse width is automatically gradually compressed and the charge density increases, imparting energy to other parts of the irradiation target other than the prodrug. This makes it possible to increase the energy imparted to the prodrug while suppressing the That is, it becomes possible to realize beam irradiation that selectively imparts large energy to prodrugs within the irradiation target using an electron beam.
  • the electron beam may have a pulse width of sub-picoseconds or less.
  • the effect of the electric field of the electron beam on the prodrug is enhanced, and the activity of the prodrug can be expressed more efficiently than, for example, when the electron beam has a pulse width in the nanosecond to picosecond range. becomes.
  • An electron beam irradiation device includes an input section into which prodrug information regarding a prodrug can be input, and a time structure of a plurality of electron pulses included in an electron beam irradiated by the irradiation section. and a control section that performs control based on.
  • the temporal structure of multiple electron pulses based on prodrug information
  • the chemical reaction caused by the interaction between the electron pulses and the prodrug can be controlled, and the structure and type of the active substance changed from the prodrug can be controlled. , yield, yield ratio, etc.
  • the time structure of the plurality of electron pulses may include, for example, at least one of the intensity, intensity ratio, each time interval, and each pulse width of the plurality of electron pulses.
  • the irradiation unit may emit an electron beam with aligned spin directions.
  • An electron beam irradiation device is provided with an electron beam irradiation device that applies an external electric field or an external magnetic field to the prodrug inside the irradiation target placed in the placement part so that the polar directions of the prodrug are aligned. It may be provided with two application sections. In this case, it becomes possible to control, for example, the structure, type, yield, yield ratio, etc. of the active substance changed from the prodrug, depending on the polarity direction of the prodrug.
  • the irradiation section may be able to irradiate the prodrug inside the irradiation target placed in the placement section with the electron beam from a plurality of directions.
  • the prodrug by irradiating the prodrug with electron beams from a plurality of directions, it is possible to increase the energy imparted to the prodrug while suppressing the imparting of energy to other than the prodrug in the irradiation target.
  • an electron beam irradiation device and an electron beam irradiation method that are capable of expressing the activity of a prodrug even in the deep part of an irradiation target.
  • FIG. 1 is a schematic configuration diagram showing an electron beam irradiation apparatus according to a first embodiment.
  • FIG. 2(a) is a schematic diagram showing a phase rotator.
  • FIG. 2(b) is a schematic diagram showing the course adjuster.
  • FIG. 3 is a graph showing an example of the time structure of an electron beam.
  • FIG. 4 is a diagram showing an example of the dose distribution of an electron beam.
  • FIG. 5 is a graph showing the relationship between the relative dose of the electron beam and the depth of the irradiation target.
  • FIG. 6A is a schematic diagram for explaining the relationship between the pulse width of an electron beam and the shielding effect.
  • FIG. 6(b) is another schematic diagram for explaining the relationship between the pulse width of the electron beam and the shielding effect.
  • FIG. 6A is a schematic diagram for explaining the relationship between the pulse width of an electron beam and the shielding effect.
  • FIG. 7 is a schematic configuration diagram showing an electron beam irradiation device according to the second embodiment.
  • FIG. 8(a) is a schematic configuration diagram showing an irradiation section according to a modification.
  • FIG. 8(b) is a schematic configuration diagram showing an irradiation section according to another modification.
  • the electron beam irradiation apparatus 100 irradiates an electron beam E to a prodrug D in the body of a patient (irradiation target) P, and uses the electron beam E as a trigger. It is a device that acts to convert prodrug D into an active substance.
  • the electron beam irradiation apparatus 100 includes a patient table 1, an irradiation unit 10, a spin controller 2, a first magnetic field application section 3, a second magnetic field application section 4, an electric field application section 5, a beam monitor 41, a beam dump 6, and an operation input section. 20 and a control section 21.
  • the prodrug D is a drug that, after reaching the target site in the body of the patient P, changes into an active substance (expresses activity) in response to a trigger.
  • Prodrug D can exhibit activity and function at targeted locations.
  • Prodrug D is not particularly limited and may be any prodrug.
  • the prodrug D used is a drug that is inactive until it reaches the target site, and that can be converted into a drug such as an anticancer drug by a trigger at the target site.
  • the prodrug D may be present deep within the body of the patient P (in the trunk).
  • the patient table 1 is an arrangement section on which the patient P containing the prodrug D is placed.
  • the irradiation unit 10 is a unit that irradiates the prodrug D inside the patient P on the patient table 1 with an electron beam E to convert the prodrug D into an active substance.
  • the irradiation unit 10 includes a laser plasma driven electron accelerator 11, a phase rotator 12, and a path adjuster 13.
  • the laser plasma-driven electron accelerator 11 is an electron accelerator that accelerates an electron beam 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 in the form of an ultrashort electron pulse with a spread in energy.
  • the laser plasma-driven electron accelerator 11 includes an optical waveguide forming device that forms an optical waveguide for propagating a high-intensity laser pulse over a long distance, for example, by gas discharge in a discharge tube.
  • the electron beam E generated by the laser plasma driven electron accelerator 11 has an energy chirp due to the energy spectrum being expanded by the fragmentation of the plasma wave.
  • the energy chirp is a state in which the energy component of the electron beam E has a strong correlation with the traveling direction, and means that the energy component gradually changes from the front to the rear in the traveling direction of the electron beam E.
  • the electron beam E generated by the laser plasma-driven electron accelerator 11 has, for example, a ⁇ E/E of 100 to 0.1%.
  • E here is acceleration energy
  • ⁇ E energy width (spectral width).
  • 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 arranged at the rear in the beam traveling direction (in other words, lower energy components are arranged at the front in the beam traveling direction). adjust.
  • an electronic bunch stretcher or the like can be used as the phase rotator 12.
  • the phase rotator 12 includes magnetic field forming sections 12a, 12b, 12c, and 12d configured by dipole magnets.
  • the phase rotator 12 electrons move to form semicircular orbits due to the magnetic fields of the magnetic field forming sections 12a, 12b, 12c, and 12d.
  • the emitted electron beam E has an energy chirp in which the higher the energy component, the more rearward the electron beam E is located in the beam traveling direction.
  • 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 longitudinal direction (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 prodrug D.
  • an electronic bunch compressor or the like can be used as the phase rotator 12.
  • the path adjuster 13 includes electromagnets 13a, 13b, 13c, and 13d.
  • the electrons move to form an arcuate trajectory due to the magnetic fields of the electromagnets 13a, 13b, 13c, and 13d.
  • the optical path of each energy component of the electron beam E is adjusted, and the optical path distance from the path adjuster 13 to the prodrug D is set to the distance at which the pulse width of the electron beam E is most compressed at the position of the prodrug D. .
  • the electron beam E emitted from the irradiation unit 10 configured in this manner has, for example, the following characteristics. That is, the electron beam E has a pulse width of sub-picoseconds or less. Here, 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 prodrug D.
  • the electron beam E has an energy of more than 1 MeV, here more than 10 MeV, in particular more than 200 MeV. Each condition of the electron beam E may be settable via the operation input section 20, for example. When the irradiation target is the patient P as in this embodiment, the electron beam E may have an energy greater than 10 MeV.
  • the spin controller 2 controls the spins of the electron beam E emitted from the irradiation unit 10 so that they are 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 spin directions aligned.
  • the spin controller 2 here aligns the spins in a direction corresponding to the polarity of the prodrug D aligned by the electric field applying section 5.
  • the spin controller 2 is not particularly limited, and various controllers may be used.
  • the direction of the spins aligned by the spin controller 2 may be fixed or variable. When the direction of the spins aligned by the spin controller 2 is variable, the angle may be changeable via the operation input unit 20, for example.
  • the first magnetic field applying 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 applying section 3 compresses the electron beam E in the lateral direction (direction perpendicular to the traveling direction).
  • a pulse current driven electromagnet time-synchronized with the electron beam E is used as the first magnetic field applying section 3.
  • the first magnetic field application section 3 constitutes a first application section.
  • the first magnetic field applying section 3 is not limited to a material, and a superconducting magnet or the like may be used.
  • the second magnetic field applying unit 4 applies an external magnetic field along the traveling direction of the electron beam E, which is irradiated to the prodrug D in the body of the patient P on the patient table 1.
  • the second magnetic field applying section 4 includes an upstream applying section 4A disposed upstream of the patient table 1 in the traveling direction of the electron beam E, and a downstream side applying section 4A disposed downstream of the patient table 1 in the traveling direction of the electron beam.
  • An application section 4B is included.
  • As the upstream application section 4A and the downstream application section 4B for example, pulsed current-driven electromagnets time-synchronized with the electron beam E are used.
  • the second magnetic field application section 4 focuses the electron beam E between the upstream application section 4A and the downstream application section 4B.
  • the second magnetic field application section 4 compresses the electron beam E in the lateral direction between the upstream application section 4A and the downstream application section 4B.
  • the second magnetic field application section 4 constitutes a first application section.
  • the second magnetic field applying unit 4 is not limited to this, and a superconducting magnet or the like may be used.
  • the electric field applying unit 5 applies an external electric field to the prodrug D inside the patient P placed on the patient table 1 so that the polarity directions of the prodrug D are aligned.
  • the electric field applying section 5 is provided with electrodes 5A and 5B so as to sandwich the patient P therebetween.
  • the direction in which the electrodes 5A and 5B of the electric field application section 5 face each other is perpendicular to the direction in which the electron beam E travels.
  • the direction of polarity aligned by the electric field applying section 5 may be fixed or variable. If the direction of the polarities aligned by the electric field applying section 5 is variable, the angle may be changeable via the operation input section 20, for example.
  • the direction of the polarity aligned by the electric field applying unit 5 may be a direction corresponding to the direction of the spins aligned by the spin controller 2.
  • the electric field application section 5 constitutes a second application section.
  • the beam monitor 41 is a device that measures the electron beam E that has passed through the prodrug 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 prodrug D.
  • the beam monitor 41 is not particularly limited, 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 prodrug D and has been measured by the beam monitor 41.
  • the beam dump 6 is provided on the downstream side of the patient table 1 in the optical path of the electron beam E.
  • the beam dump 6 is not particularly limited, and a known device can be used.
  • the operation input unit 20 is an input unit that can accept various inputs from the user.
  • the operation input unit 20 for example, a touch panel, a microphone, a camera, etc. are used. Inputs from the operation input unit 20 include touch input, voice input, camera input, and the like.
  • the operation input unit 20 inputs, for example, each condition of the electron beam E emitted from the irradiation unit 10, the direction of spins aligned by the spin controller 2, the direction of polarity aligned by the electric field application unit 5, and prodrug information regarding the prodrug D. is configured so that it can be entered.
  • the prodrug information includes at least information regarding the type of prodrug D.
  • the control unit 21 is configured by, for example, one or more computer devices.
  • the control unit 21 includes a CPU (Central Processing Unit) which is a processor, a RAM (Random Access Memory) or a ROM (Read Only Memory) which is a recording medium, and the like.
  • the control unit 21 executes various controls by loading programs and the like onto hardware such as the CPU and RAM.
  • the control section 21 controls each condition of the electron beam E irradiated by the irradiation unit 10 based on input from the operation input section 20 .
  • the control unit 21 controls the time structure of a plurality of electron pulses included in the electron beam E irradiated by the irradiation unit 10 based on the prodrug information input through the operation input unit 20. Specifically, the control unit 21 refers to the data table stored in the storage unit 22 based on the type of prodrug D in the input prodrug information, and controls the time structure of the electron pulses included in the electron beam E. do.
  • the time structure of the electronic pulse includes at least one of the intensity, intensity ratio, time interval, and pulse width of the plurality of electronic pulses 30.
  • the type of prodrug D and the time structure of the electronic pulse are associated with each other.
  • the data table can be obtained in advance by actual measurement or simulation.
  • the patient P When using the electron beam irradiation device 100 described above, first, the patient P, to whom the prodrug D has been delivered to the target site in the body, is placed on the patient table 1. At the same time, each condition of the electron beam E to be irradiated, prodrug information, the spin direction of the electron beam E, and the polarity direction of the prodrug D are inputted using the operation input unit 20. Thereby, the irradiation unit 10 is controlled by the control unit 21, and has, for example, an energy larger than 200 MeV, a pulse width of 100 femtoseconds or less, and a time structure of an electron pulse according to the type of prodrug D. An electron beam E is emitted from the irradiation unit 10.
  • the electron beam E emitted from the irradiation unit 10 has its spin direction aligned by the spin controller 2, and is focused by the first magnetic field application unit 3, and then reaches the target inside the body of the patient P placed on the patient table 1.
  • Drug D is selectively irradiated.
  • the electron beam E is focused by the second magnetic field applying section 4.
  • the polarity directions of the prodrugs D are aligned by the electric field applying section 5.
  • the high-energy electron beam E has low energy attenuation in the substance, so the electron beam E can sufficiently reach the prodrug D present deep within the patient P. Therefore, even when the prodrug D exists deep inside the patient P, the electron beam E can be selectively applied to the prodrug D at a sufficient dose and the electron beam E can act as a trigger. Thereby, it becomes possible to activate prodrug D, convert it into an active substance, and express its activity.
  • the electron beam irradiation device 100 and the electron beam irradiation method it is possible to express the activity of the prodrug D deep in the patient P.
  • the irradiation of the electron beam E which can three-dimensionally control the application of energy into the body of the patient P, it becomes possible to express the activity and function of the prodrug D deep in the trunk.
  • the electron beam irradiation device 100 includes a first magnetic field applying section 3 and a second magnetic field applying section 4.
  • the directivity of the electron beam E can be increased, and the pencil beam-shaped electron beam E can be selectively applied at a sufficient dose to the prodrug D present deep inside the patient P. It becomes possible to bring out the effects significantly. It is possible to suppress the problem of scattering of even a high-energy electron beam E in a substance and maintain the directivity of the electron beam E.
  • the prodrug D can be efficiently activated while reducing the effect on the human body.
  • FIG. 4 is a diagram showing an example of the dose distribution of the electron beam E.
  • FIG. 4 shows numerical simulation results showing how an electron beam E having an energy of 200 MeV propagates through water.
  • the horizontal axis is the position of the electron beam E in the traveling direction
  • the vertical axis is the position in the direction perpendicular to the traveling direction.
  • a 3T magnetic field is applied in the traveling direction of the electron beam E. The darker the shading in the figure, the greater the dose (flux) of the electron beam E.
  • FIG. 4 it can be seen that in this embodiment, the diffusion of the electron beam E is suppressed, the electron beam E is focused into a pencil beam shape, and the directivity is enhanced.
  • the irradiation unit 10 includes a laser plasma-driven electron accelerator 11, a phase rotator 12, and a path adjuster 13.
  • the pulse width is automatically gradually compressed and the charge density increases, and It becomes possible to increase the energy imparted to the prodrug D while suppressing the energy imparted to the prodrug D. That is, it becomes possible to realize beam irradiation that selectively imparts large energy to the prodrug D in the body of the patient P using the electron beam E.
  • the prodrug D can be efficiently activated while reducing the effect on the human body.
  • FIG. 5 is a graph showing the dose distribution of the electron beam E.
  • the vertical axis in the figure is the relative dose of the electron beam E
  • the horizontal axis in the figure is the depth of the patient P from the electron beam incident surface.
  • the relative dose of the electron beam E is maintained at a low level in the depth region up to the prodrug D
  • the relative dose of the electron beam E at the depth of the prodrug D is The relative dose is increasing rapidly.
  • the electron beam E is used, it can be expected that irradiation similar to the Bragg peak characteristics of a hadron beam can be performed with the electron beam.
  • the electron beam E has a pulse width of sub-picoseconds or less.
  • the effect of the electric field of the electron beam E on the prodrug D is enhanced, and the activity of the prodrug D is expressed more efficiently than, for example, when the electron beam E has a pulse width in the nanosecond to picosecond range.
  • the prodrug D can be changed into an active substance with a small total dose), and the radiation exposure dose of the patient P can be reduced.
  • FIG. 6 is a schematic diagram for explaining the relationship between the pulse width of the electron beam E and the shielding effect.
  • the electron beam E propagates in a condensed dipole medium (water)
  • the electrons 7 in the electron beam E are blocked by water molecules 8. Therefore, the electric field 9 created by the electrons 7 is small and does not affect the movement and dynamics of the electron beam E.
  • a finite amount of time is required for the polarization reaction. For example, assuming that the rotational speed v of the dipole is 10 5 cm/s and the length l of the dipole is 3 ⁇ 10 -8 cm, the relaxation time TR obtains 300 fs (3 ⁇ 10 ⁇ 13 s: femtoseconds).
  • the pulse width of the electron beam E is shorter than the relaxation time, the water molecules 8 will block the electric field 9 only on the surface of the electron beam E, as shown in FIG. 6(b). Therefore, a region of strong electric field 9 is formed. From this point of view, it is significant that the electron beam E has a pulse width of sub-picoseconds or less.
  • the electron beam irradiation device 100 includes an operation input section 20 and a control section 21.
  • the time structure for example, intensity, intensity ratio, time interval, each pulse width, etc.
  • the control unit 21 based on prodrug information input via the operation input unit 20. This makes it possible to control the chemical reaction caused by the interaction between the electron pulse 30 and the prodrug D, and to control, for example, the structure, type, yield, yield ratio, etc. of the active substance changed from the prodrug D.
  • the spin controller 2 aligns the spin directions of the electron beam E from the irradiation unit 10. In this case, it becomes possible to control, for example, the structure, type, yield, yield ratio, etc. of the active substance changed from the prodrug D to be in accordance with the direction of the aligned spins of the electron beam E. Note that the spin controller 2 may align the spin directions according to the polarity directions of the prodrug D aligned by the electric field application unit 5, or may align the spins independently.
  • the electron beam irradiation device 100 includes an electric field applying section 5.
  • an electric field applying section 5 it becomes possible to control, for example, the structure, type, yield, yield ratio, etc. of the active substance changed from prodrug D to be in accordance with the aligned polarity direction of prodrug D.
  • the electric field applying section 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.
  • the irradiation unit 10 and the spin controller 2 constitute an irradiation section.
  • the first magnetic field applying section 3 and the second magnetic field applying section 4 constitute a magnetic field applying 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 depending on the case.
  • the positional relationship between the patient table 1 and the irradiation unit 10 is controlled so that the electron beam E from the irradiation unit 10 is appropriately incident on the prodrug D in the body of the patient P on the patient table 1.
  • the control unit 21 may be configured to be controllable.
  • the operation input unit 20 may be configured to be able to input position information of the prodrug D in the body of the patient P.
  • 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 prodrug D based on the positional information.
  • the electric field applying section 5 may be provided so that its relative positional relationship with respect to the patient table 1 can be changed. Thereby, an external electric field can be easily applied toward the prodrug D inside the patient P on the patient table 1.
  • This embodiment includes the following electron beam irradiation method.
  • the electron beam irradiation method includes the steps of arranging an irradiation target containing a prodrug therein in a placement section (placement step), and irradiating the prodrug inside the irradiation target placed in the placement section with electrons having an energy greater than 1 MeV. irradiating the prodrug with a beam to convert the prodrug into an active substance (irradiation step).
  • the electron beam irradiation method corresponds to the method of using the electron beam irradiation apparatus 100.
  • the electron beam irradiation method includes a magnetic field application step of applying an external magnetic field along the traveling direction of the electron beam to the electron beam.
  • the irradiation step includes a step of generating an electron beam having an energy chirp, and a step of adjusting the energy chirp of the generated electron beam so that higher energy components are arranged at the rear in the beam traveling direction. and has.
  • the electron beam has a pulse width of sub-picoseconds or less.
  • the electron beam irradiation method includes an input step of inputting prodrug information regarding the prodrug, and a control step of controlling the temporal structure of a plurality of electron pulses 30 included in the irradiated electron beam based on the prodrug information. , is provided.
  • the irradiation step emits an electron beam with aligned spin directions.
  • the electron beam irradiation method includes an electric field application step of applying an external electric field to the prodrug inside the irradiation target placed in the placement section so that the polar directions of the prodrug are aligned.
  • the prodrug inside the placed irradiation target is irradiated with an electron beam from a plurality of directions.
  • This embodiment may be used for simultaneous activation of multiple prodrugs.
  • multidrug therapy in which multiple anticancer drugs are used in combination is often performed, but in this case, the toxicity of each anticancer drug becomes an issue.
  • this embodiment by converting each of the anticancer drugs used in combination into prodrugs (inactivating them) and simultaneously activating them by electron beam irradiation, it is expected that the treatment satisfaction level of multidrug combination therapy will be increased ( multi-prodrug therapy).
  • this embodiment may be used for a molecule in which a plurality of anticancer drugs are linked into one molecule via a linker or the like and activated by a plurality of prodrugs D (dual prodrug therapy).
  • the prodrug may include a drug carrier in a broad sense.
  • a drug carrier is something that encapsulates a drug, such as polymer micelles, liposomes, nanomachines, and the like. That is, in one aspect of the present invention, it can also be used for site-specific disruption of drug carriers and drug release. By irradiating drug carriers accumulated in diseased areas such as cancer tissues with high-energy electron beams, selective collapse of drug carriers in the affected areas and subsequent drug release is expected.
  • hydrated electrons are generated from water molecules as a first step by high-energy electron beam irradiation (see the formula below). H 2 0 ⁇ H 2 O + +e aq - (initial step)
  • hydrated electrons act on the amphiphilic molecules constituting the drug carrier, causing the chemical structure to change, and after the drug carrier collapses, the drug (drug-encapsulating core) is released.
  • An example in which hydrated electrons react with such amphiphilic molecules is considered to require a higher dose than the above-mentioned example in which hydrated electrons react with a mask.
  • This embodiment may be used to treat neurodegenerative diseases such as Alzheimer's disease and brain diseases such as brain tumors.
  • the administered drug When targeting brain diseases, the administered drug must move from the bloodstream into the brain, but in this case it must pass through the blood-brain barrier that separates the blood and brain tissue.
  • drugs with high fat solubility have a high ability to penetrate the brain.
  • a prodrug D with improved fat solubility is created by masking substituents with low fat solubility in the drug, and after it reaches the brain, it is activated by irradiation with an electron beam E. , it is expected that it will be possible to improve the penetration into the brain and to have a brain-specific effect.
  • Drug delivery systems can deliver drugs to desired locations by utilizing the EPR (enhanced permeability) effect. That is, blood vessels have gaps that allow oxygen or nutrients to be taken into cells outside the blood vessels. In normal blood vessels, this gap is very small, and while low-molecular substances can pass through the blood vessel wall, high-molecular substances cannot. Blood vessels in tumor tissues have many branches because they are formed by angiogenesis accompanying tumor growth, and the vessel walls are rougher than normal blood vessels, with gaps of, for example, about 100 to 200 nm. Taking advantage of this difference, drug carriers can accumulate drugs in tumor tissues.
  • EPR enhanced permeability
  • ADC Antibody-Drug Conjugate
  • ADC antibody-drug complex
  • Antibodies are used as the functional site for precise target recognition and delivery, and the drug is responsible for the actual drug efficacy. Therefore, by using an ADC, a drug can be specifically delivered to cells recognized by the antibody used.
  • the electron beam irradiation device 200 is a drug discovery platform used for the development of prodrug D.
  • the electron beam irradiation device 200 is a device that irradiates the prodrug D inside the test tube (irradiation target) S with an electron beam E, and uses the electron beam E as a trigger to convert the prodrug D into an active substance. It is.
  • the electron beam irradiation apparatus 200 differs from the first embodiment in that it includes a test tube holder 201 instead of the patient table 1 (see FIG. 1) and further includes a beam deflection magnet 205.
  • the test tube holder 201 holds and arranges the test tube S containing the prodrug D therein.
  • Beam deflection magnet 205 is arranged between beam monitor 41 and beam dump 6.
  • the beam deflection magnet 205 deflects the electron beam E, which has passed through the prodrug D and has been measured by the beam monitor 41, toward the beam dump 6.
  • the electron beam E of this embodiment has energy that allows it to pass through the test tube S and reach the prodrug D.
  • the electron beam E may have an energy greater than 1 MeV.
  • the electron beam irradiation device 200 also produces effects similar to those of the first embodiment, that is, effects such as being able to express the activity of prodrug D deep in the patient P.
  • the beam deflection magnet 205 may be omitted depending on the case.
  • 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 patient P's body) on the optical path of the electron beam E.
  • This phantom functions similarly to the path adjuster 13 and can adjust the compression point of the electron beam E to become the prodrug D in the patient P's body.
  • the irradiation target is not particularly limited, and may be various targets.
  • the above embodiment may include an irradiation unit 110 shown in FIG. 8(a) instead of the irradiation unit 10 (see FIG. 1).
  • the irradiation unit 110 includes a high frequency electron accelerator 111 and a pulse compressor 112.
  • the high frequency electron accelerator 111 emits a monochromatic (single energy) electron pulsed electron beam E1.
  • the pulse compressor 112 compresses the pulse of the electron beam E1 emitted by the high-frequency electron accelerator 111, and outputs the compressed pulse to the subsequent spin controller 2 (see FIG. 1).
  • the pulse compressor 112 compresses the pulse width of the electron beam E1 to several nanoseconds to several femtoseconds. Note that the pulse compressor 112 may not be provided depending on the case (see the irradiation unit 210 in FIG. 8(b)).
  • the irradiation units 110 and 210 constitute an irradiation section.
  • the irradiation unit may be capable of irradiating the prodrug inside the irradiation target placed in the placement unit with an electron beam from a plurality of directions.
  • the emission side of the irradiation unit 10 is configured to be movable around the irradiation target, and the prodrug D can be irradiated with the electron beam E multiple times by changing the position of the emission side of the irradiation unit 10. good.
  • the spin controller 2 may not be provided.
  • the spin controller 2 it becomes possible to easily and reliably control and align the spins of the electron beams E by the spin controller 2.
  • the above embodiment includes the electric field application unit 5 as the second application unit, but instead of or in addition to this, an external magnetic field is applied to the prodrug D so that the polarity direction of the prodrug D is aligned.
  • An application unit for example, an MRI (Magnetic Resonance Imaging) device
  • MRI Magnetic Resonance Imaging
  • the above embodiment may further include a phantom (water cell) placed on the optical path of the electron beam E between the phase rotator 12 and the irradiation target (preferably in front of the irradiation target).
  • This phantom functions as an electron beam compressor like the path adjuster 13, and can adjust the compression point of the electron beam E to become the prodrug D inside the irradiation target.
  • the patient P and the test tube S were irradiated with the electron beam E, but the irradiation targets are not particularly limited.
  • the external electric field and external magnetic field for aligning the polar directions of the prodrug D can be generated and applied using various known methods.

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PCT/JP2023/002326 2022-03-23 2023-01-25 電子ビーム照射装置及び電子ビーム照射方法 Ceased WO2023181623A1 (ja)

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