Controlled release of radioactive nuclides

Abstract

To provide a brachytherapy device for irradiating malignant tissue with an alpha ray.SOLUTION: A brachytherapy device 21 includes a seed base 22 adapted for being at least partially introduced into a body of a subject; a first coating layer 30 disposed on the seed base 22 and configured to prevent passage of radium-224 or radium-223 therethrough; particles 26 of a radium-224 or radium-223 radionuclide placed on the first coating layer 30; and a second coating layer 33 disposed on the radium particles 26 and configured to allow diffusion of at least 0.1% of the radium particles from the brachytherapy device 21 within 24 hours of the introduction into the body of the subject.SELECTED DRAWING: Figure 3

Description

[Technical Field]

[0001] The present invention relates in general to radiotherapy, and more particularly to a method of alpha-ray proximity irradiation therapy.

[0002] (Cross-reference of related applications) This application claims the benefit of U.S. Provisional Patent Application 62 / 651,274 (Patent Document 1), filed on 2 April 2018, entitled “Controlled Release of Radium Isotopes in the Framework of DaRT (Diffusion Alpha Radiation Therapy),” the disclosure thereof, which is incorporated herein by reference in its entirety. [Background technology]

[0003] Radiation is used to kill cancerous or other malignant cells. Various methods are known for delivering radiation to cancer cells. One of these methods involves the use of radioactive atoms that emit radiation. Most methods involving the use of radioactive atoms utilize atoms that emit beta and gamma radiation, which have a relatively long range and are therefore easier to deliver to the target cancerous tissue. However, alpha rays have much higher energy and are therefore more effective at killing cancer cells. However, the effective range of alpha rays is very short, so to be effective, radioactive atoms emitting alpha particles must be placed very close to the malignant cells.

[0004] One method used to deliver alpha-emitting radioactive atoms to malignant cells is targeted radionuclide therapy. In targeted therapy, a carrier such as a liposome is attached to the radioactive atom and injected into the subject's bloodstream. While circulating, the liposome attaches to malignant cells, and when alpha particles are released by the radioactive atom, at least some of the released alpha particles destroy the malignant cells.

[0005] The PCT patent applications published by Larsen, titled "Radiotherapy Ribosomes" (Patent Document 2), "Method of Radiotherapy" (Patent Document 3), and "Method of Radiotherapy" (US Patent Application Publication 2004 / 0208821) (Patent Document 4), which are incorporated herein by reference in their entirety, describe liposomes that encapsulate heavy radionuclides that emit alpha particles. The radionuclides may include, among other things, radium-223, radium-224, and thorium-227. The daughter radionuclides generally remain trapped during the transmutation of the radionuclide.

[0006] Another method of irradiating malignant tissue with alpha radiation is brachytherapy, in which one or more seeds carrying radioactive materials, also known as radionuclides, are implanted in the tumor.

[0007] U.S. Patent No. 8,834,837 (Patent Document 5) and U.S. Patent Application Publication 2009 / 0136422 (Patent Document 6), which are incorporated herein by reference in their entirety, describe the use of devices for close-range irradiation therapy using alpha particles. Radioactive materials emit not only alpha particles but also daughter nuclei of the radioactive material, which further emit alpha particles in a chain reaction. This expands the range of cells affected by alpha particles.

[0008] Various radionuclides have been proposed for use in close-range irradiation therapy. Good's U.S. Patent Application Publication 2004 / 0242953 (Patent Document 7), the disclosure of which is incorporated herein by reference, describes various isotopes, including thorium-228, that can be used in close-range irradiation therapy.

[0009] U.S. Patent Application Publication 2013 / 0253255 (Patent Document 8) by Van Niekerk, the disclosure of which is incorporated herein by reference, describes a seed for close-range irradiation therapy that carries two different isotopes of the same substance.

[0010] Harder et al., U.S. Patent Application Publication 2008 / 0249398 (Patent Document 9), the disclosure of which is incorporated herein by reference, describes a hybrid multi-radionuclide sealed source for use in close-range radiation therapy.

[0011] It is generally desirable to prevent radionuclides from being washed away from their source by bodily fluids before they have a chance to decay. PCT Patent Application Publication WO2018 / 207105 (Patent Document 10), titled "Polymer Coating for Proximity Irradiation Therapy Devices," which is incorporated herein by reference in its entirety, describes a coating selected to prevent radionuclides from being washed away while not inhibiting the desorption of daughter nuclei from the source.

[0012] U.S. Patent Application Publication 2002 / 0055667 (Patent Document 11) by Mavity et al., the entire disclosure of which is incorporated herein by reference, describes a radionuclide having a bioabsorbable structure that typically has a predetermined duration substantially longer than its half-life. The radionuclide is localized and isolated at a desired target site while retaining considerable radioactivity.

[0013] U.S. Patent No. 8,821,364 by Fisher et al. (Patent Document 12), the entire disclosure of which is incorporated herein by reference, describes a seed for close-range irradiation therapy comprising a sphere containing an alpha-particle emitting radiation source and a rapidly dissolving absorbent polymer matrix. [Prior art documents] [Patent Documents]

[0014] [Patent Document 1] U.S. Patent Provisional Application 62 / 651,274 [Patent Document 2] PCT Patent Application Publication WO 01 / 60417 [Patent Document 3] PCT Patent Application Publication WO 02 / 05859 [Patent Document 4] U.S. Patent Application Publication 2004 / 0208821 [Patent Document 5] U.S. Patent No. 8,834,837 [Patent Document 6]​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​Optionally, the first alpha-emitting isotope contains radium-224 and / or radium-223. Optionally, the device further comprises a semiporous polymer coating layer on the radionuclide atoms configured to allow a constant percentage of the radionuclide atoms to diffuse in order to provide an emission of at least 0.1% of the number of radionuclide atoms of the first alpha-emitting isotope bound to the base per 24 hours. Optionally, the semiporous polymer coating layer contains PDMS (polydimethylsiloxane). Optionally, the semiporous polymer coating layer has a thickness of 0.5 microns or less. Optionally, the semiporous polymer coating layer allows the diffusion of radionuclide atoms from the proximity irradiation device at a rate of at least 0.5% per 24 hours.

[0017] In some embodiments, the base further comprises a base polymer coating layer on the base, where multiple radioactive nuclide atoms are attached to the base polymer coating layer, and thus the radioactive nuclide atoms are bound to the base in a manner that allows them to separate and diffuse without nuclear decay. Optionally, the base polymer coating layer is configured to prevent the diffusion of radioactive nuclide atoms through it. Optionally, the base polymer coating layer comprises polycarbonate. Optionally, the base polymer coating layer has a thickness of at least 0.25 microns. Optionally, the proximity irradiation therapy device emits radioactive nuclide atoms of the first alpha-emitting isotope at a rate of at least 3% per 24 hours of the number of radioactive nuclide atoms of the first alpha-emitting isotope bound to the base. Optionally, less than 15% of the radioactive nuclide atoms leave the base in 24 hours by means other than radioactive decay.

[0018] In some embodiments, multiple radionuclides are bound to a base such that less than 8% of the radionuclide atoms leave the base in 24 hours by means other than radioactive decay. Optionally, the base further comprises a bioabsorbable polymer coating layer in which the radionuclides are embedded, and when placed in a subject, the bioabsorbable polymer coating layer dissolves in such a manner that at least 0.1% of the number of radionuclide atoms of the first alpha-emitting isotope bound to the base are released from the device per 24 hours. Optionally, the radionuclides are distributed substantially uniformly across the thickness of the bioabsorbable polymer coating layer. Optionally, the base further comprises multiple radionuclide atoms of a second alpha-emitting isotope that decay into a first alpha-emitting isotope, and the radionuclide atoms do not leave the proximity irradiation device, but are bound to the base in such a manner that, upon nuclear decay, the daughter nuclei of the decaying radionuclide atoms are released from the device.

[0019] As an option, multiple radionuclide atoms of the second alpha-emitting isotope have an activity level of less than 20%, less than 10%, or less than 5% of the activity level of the radionuclide atoms of the first alpha-emitting isotope included in the device. As an option, multiple radionuclide atoms of the second alpha-emitting isotope have an activity level greater than 1% of the activity level of the radionuclide atoms of the first alpha-emitting isotope included in the device. As an option, multiple radionuclide atoms of the first alpha-emitting isotope constitute at least 50% of the radionuclide atoms in the close-range radiation therapy device. As an option, multiple radionuclide atoms of the first alpha-emitting isotope provide at least 50% of the radioactivity of the radionuclide atoms in the close-range radiation therapy device. As an option, multiple radionuclide atoms of the first alpha-emitting isotope provide at least 5 x 10 per square centimeter of the base. 10 It has atomic density.

[0020] One aspect of several embodiments of the present invention relates to a proximal radiation therapy device comprising: a seed base adapted to be introduced at least partially into the body of a subject; a first coating layer on the seed base configured to prevent the passage of radium-224 or radium-223; particles of a radium-224 or radium-223 radionuclide disposed on the first coating layer; and a second coating layer on the particles configured to allow the diffusion of at least 0.1% of the radium particles.

[0021] As an option, the seed base consists of a tube defining an internal channel. As an option, the first coating layer contains polycarbonate. As an option, the first coating layer has a thickness of at least 0.05 microns, at least 0.1 microns, or at least 0.3 microns. As an option, the first coating layer has a thickness of 1 micron or less, or 0.5 microns or less. As an option, the second coating layer contains PDMS (polydimethylsiloxane). As an option, the second coating layer has a thickness of 0.5 microns or less, or 0.3 microns or less. As an option, the second coating layer has a thickness of at least 0.1 microns. As an option, the device allows the diffusion of radium particles through the second coating layer at a rate of at least 0.5% or at least 5% per 24 hours. As an option, the device allows the diffusion of radium particles through the second coating layer at a rate of 10% or less, or 2% or less per 24 hours.

[0022] One aspect of several embodiments of the present invention relates to a proximal radiation therapy device comprising: a probe adapted to be introduced at least partially into the body of a subject; radium-224 particles embedded retainably above or below the surface of the probe, the radium-224 particles being embedded in such manner that the radium-224 particles remain within the probe, while the therapeutic dose of decay chain nuclei and alpha particles of the radium-224 particles is emitted outside the surface of the probe; and thorium-228 particles embedded retainably above or below the surface of the probe, the thorium-228 particles being embedded in such manner that the thorium-228 particles remain within the probe, while the therapeutic dose of decay chain nuclei and alpha particles of the thorium-228 particles is emitted outside the surface of the probe. The radioactivity level of the thorium-228 particles in the device is lower than 50% of the radioactivity level of the radium-224 particles.

[0023] Option 1: The probe consists of a removable probe. Option 2: The removable probe includes a needle, an endoscope tip, a laparoscope tip, or an imaging device tip. Option 3: The probe consists of a tube defining an internal channel. Option 4: The probe further has a protective coating that coats the probe and the thorium-228 radionuclide, with the thickness and material of the protective coating selected so as not to hinder the emission of decay chain nuclei and alpha particles. Option 5: The probe has an inner elongated member and an outer tubular member having a mouth configured to receive the inner elongated member, the inner elongated member being movable within the outer tubular member, and having a distal end and a proximal end, thereby the radionuclide being on or below the surface of the distal end. Option 6: The probe and the thorium-228 particles are uncoated. Option 7: The probe consists of a close-range irradiation seed.

[0024] One aspect of several embodiments of the present invention relates to a treatment method for close-range radiotherapy, comprising: the steps of: determining at least one characteristic of a malignant tumor of a subject; selecting a layout of one or more seeds loaded with a first isotopic radionuclide atom emitting alpha radiation, to be implanted in the malignant tumor in response to the determined at least one characteristic; for each of the one or more seeds, selecting an emission rate of the first isotope from the seed, which does not include the emission of alpha particles and daughter nuclei; and placing the seeds having the selected emission rates within the malignant tumor according to the selected layout. Optionally, the first isotope comprises radium-224. Optionally, the step of determining at least one characteristic of the malignant tumor comprises determining the shape and / or size of the malignant tumor. Optionally, the step of placing the seeds comprises placing seeds having at least two substantially different emission rates of the first isotope. [Brief explanation of the drawing]

[0025] [Figure 1] This is a schematic diagram of a proximity irradiation therapy device according to an embodiment of the present invention. [Figure 2] This is a schematic cross-sectional view of a proximity irradiation therapy device according to another embodiment of the present invention. [Figure 3] This is a schematic diagram of a proximity irradiation therapy device according to yet another embodiment of the present invention. [Figure 4] This is a schematic diagram of a proximity irradiation therapy device according to another embodiment of the present invention. [Modes for carrying out the invention]

[0026] One aspect of several embodiments of the present invention relates to a radionuclide implant carrying an alpha-emitting radionuclide. The radionuclide is attached to the implant so that a small percentage of the radionuclide atoms leave the implant and diffuse into nearby tissue. Optionally, the emission rate of radionuclide atoms is less than 5%, less than 4%, less than 3%, or even less than 2% per 24 hours. Optionally, the emission rate of radionuclide atoms is greater than 0.1%, greater than 0.5%, or even greater than 1% per 24 hours. Controlled emission of the radionuclide at a desired rate increases the energy of decay particles, which reach more distant points on the tumor where the radionuclide implant is placed, without excessive radiation doses leaving the tumor and penetrating surrounding healthy tissue.

[0027] In some embodiments, the desired atomic desorption rate is achieved by coating the proximity irradiation therapy implant with a coating having a thickness and / or other properties selected to allow the desired desorption rate.

[0028] In other embodiments, the desired atomic desorption rate is achieved by incorporating a bioabsorbable material embedded with radionuclide atoms into a proximal radiation therapy implant. When the proximal radiation therapy implant is in the subject's body, the bioabsorbable material decomposes, and through decomposition, the radionuclide leaves the implant.

[0029] One aspect of several embodiments of the present invention relates to a radiotherapy implant carrying multiple different alpha-emitting radionuclides. In some embodiments, the radionuclides have a high probability that their daughter nuclides will leave the radiotherapy implant within the tumor upon nuclear decay. Optionally, the multiple different radionuclides include a parent nuclide and daughter nuclides arising from the radioactive decay of the parent nuclide. In some embodiments, the parent nuclide includes thorium-228 and the daughter nuclide includes radium-224. In other embodiments, the parent nuclide includes thorium-227 and the daughter nuclide includes radium-223.

[0030] Figure 1 is a schematic diagram of a close-range radiotherapy device 20 according to an embodiment of the present invention. The close-range radiotherapy device 20 includes a support 22 that functions as the base of the device 20 and is configured to be inserted into the body of a subject. The close-range radiotherapy device 20 has a bioabsorbable coating 28 of thickness T0 on the outer surface 24 of the support 22, in which radioactive nuclide atoms 26 are dispersed throughout the entire thickness of the coating 28. Note that for ease of drawing, the atoms 26 are depicted as disproportionately large relative to the thickness of the coating 28.

[0031] In some embodiments, the support 22 contains a seed for complete implantation within the subject's tumor and can have any suitable shape, such as a rod or plate. In some embodiments, the support 22 is cylindrical and has a diameter of 0.3–1 mm and / or a length of 5–60 mm. Instead of being completely implanted, the support 22 is only partially implanted within the subject and is part of a needle, wire, endoscope tip, laparoscope tip, or any other suitable probe.

[0032] The bioabsorbable coating 28 optionally includes a semiporous absorbable biocompatible polymer matrix with a low absorption rate. The absorption rate is optionally less than 1 micron, less than 0.5 microns, less than 0.2 microns, or even less than 0.1 microns per day. Alternatively, the absorption rate is significant and, in some embodiments, exceeds 0.05 microns, 0.1 microns, 0.3 microns, or even 0.8 microns per day. Optionally, the absorbable polymer matrix has an absorption rate per day of less than 20%, less than 10%, or even less than 5% of the thickness of the coating 28. The absorption rate is optionally higher, up to 1%, 3%, 5%, or even 10% per day. The absorption rate is optionally selected according to the half-life of the radionuclide atom 26. In some embodiments, the absorption rate is such that at least 15%, 25%, or 40% of the coating 28 dissolves within the half-life duration from the time the proximity irradiation device 20 is implanted. As an option, the absorption rate is not too fast, and less than 80%, less than 60%, less than 40%, or less than 25% of the coating 28 dissolves within the half-life of the radionuclide atoms 26 from the time the proximity irradiation device 20 is implanted.

[0033] The bioabsorbable coating 28 optionally comprises polylactide (PLA), polyglycolide (PGA), or a copolymer of PLA and PGA, adjusted to achieve a desired absorption rate. Alternatively or additionally, the coating 28 may contain copolymer of polylactic acid / glycolic acid (PLGA). The polymers of the coating 28 optionally have molecular weights ranging from 5,000 to 100,000. The material of the coating 28 dissolves in the subject by any method known in the art, such as ultrasonic energy, reaction with body temperature, and / or reaction with body fluids. Further discussion of bioabsorbable polymers that may be used according to embodiments of the present invention after adjustment of the desired absorption rate is described above in U.S. Patent No. 8,821,364 (Patent Document 12) and U.S. Patent Application Publication 2002 / 0055667 (Patent Document 11).

[0034] The bioabsorbable coating 28 typically has a thickness T0 between 0.5 and 10 microns, for example between 1 and 5 microns. The coating 28 is thick enough to protect the radioactive nuclide atoms 26 from being washed away before the coating 28 dissolves, but thin enough for daughter radionuclides to diffuse.

[0035] The radioactive nuclide atom 26 is, as an option, an element that emits alpha particles in radioactive decay, and its daughter radionuclides readily diffuse through the coating 28. The diffusion coefficient of the daughter radionuclides in the polymer is at least 10 -11 cm 2 It may be per second. Preferably, the radioactive nuclide atom 26 is an isotope that produces a chain of at least three, or even at least five, alpha-emitting decay events until it reaches a stable or long-half-life element. The radioactive nuclide atom 26 may optionally include an isotope of radium that decays by alpha emission (e.g., radium-224 or radium-223), which decays by alpha emission to produce a daughter isotope of radon (e.g., Rn-220 or Rn-219), which decays by alpha emission to produce an isotope of polonium (e.g., Po-216 or Po-215), which decays by alpha emission to produce an isotope of lead (e.g., Pb-212 or Pb-211).

[0036] In some embodiments, all radioactive nuclide atoms 26 are of the same isotope. In other embodiments, the radioactive nuclide atoms 26 are two or more different isotopes of the same element and / or two or more different isotopes of different elements.

[0037] Typically, the density of radioactive nuclide atoms 26 in the coating 28 is 10 per square centimeter. 11 ~10 14 It is an atom. Atom 26 is, as an option, evenly dispersed throughout the entire thickness of the coating 28.

[0038] Figure 2 is a schematic diagram of a proximity irradiation therapy apparatus 100 according to one embodiment of the present invention. The proximity irradiation therapy apparatus 100 is similar to the apparatus 20 in Figure 1, except that its bioabsorbable coating 28 is formed from multiple layers with different compositions of their polymer matrices and / or concentrations of radioactive nuclides 26 within them. As shown, the coating 28 includes three layers, the further the layer is from the support 22, the greater the concentration of radioactive nuclides 26. The layer 102 closest to the support 22 has the first and lowest concentration of radioactive nuclides 26. The second layer 104 has a higher concentration than the first layer 102, and the third layer 106 furthest from the support 22 has the highest concentration of radioactive nuclides 26. Apparatus 100 is presented as an example, and in other embodiments, the proximity irradiation therapy apparatus may have two layers or four or more layers. Furthermore, in other embodiments, the concentrations of radioactive nuclides 26 within the layers are different. As an option, the concentration of the layer increases as it approaches the support 22. In some embodiments, the concentration of the layer alternates between high and low levels and does not monotonically increase or decrease with distance from the support 22.

[0039] Instead of, or in addition to, having different concentrations of radioactive nuclide atoms 26, the layers of coating 28 have different absorption rates due to their polymer structure. In one embodiment, the absorption rate is higher in the outer layer than in the inner layer. In other embodiments, the absorption rate is lower in the outer layer than in the inner layer.

[0040] Figure 3 is a schematic diagram of a proximity irradiation therapy device 21 according to another embodiment of the present invention. The device 21 differs from the device 20 in that the device 21 does not include a bioabsorbable coating and instead has an outer layer 33 that allows the radionuclide atoms 26 to slowly diffuse from the device 21 at a desired rate. As an option, the device 21 includes two polymer layers: an inner layer 30 of a first polymer that coats the outer surface 24, and an outer layer 33 of a second polymer that coats the inner layer 30. The atoms 26 are bound to the inner layer 30 and covered by the outer layer 33, generally preventing the atoms 26 from exiting the device 21 while allowing the radionuclide atoms 26 to slowly diffuse from the device 21. On the other hand, the outer layer 33, as an option, allows the daughter nuclide to easily leave the device 21 as a result of nuclear decay and / or due to the characteristics of the daughter nucleus.

[0041] The outer layer 33, as an option, includes biocompatible PDMS (polydimethylsiloxane) with adjusted porosity and / or thickness to achieve a desired diffusion coefficient of the radionuclide atoms 26. The thickness of the outer layer 33 is, as an option, 0.1 to 10 microns, for example 0.1 to 0.3 microns, or 0.5 to 1 micron. The outer layer 33 is, as an option, formed such that the radionuclide atoms 26 have a diffusion coefficient of less than 10 -13 cm 2 / second, or even less than 2X10 -14 cm[[ID=ll]] 2 / second. As an option, the radionuclide atoms 26 have a diffusion coefficient greater than 2X10 -15 cm 2 / second in the outer layer 33, and in some cases greater than 8X10 -15 cm 2 / second. On the other hand, the daughter nuclide of the radionuclide atoms 26, as an option, has a much higher diffusion coefficient in the outer layer 33, for example, at least 10 -11 cm 2 / second, etc.

[0042] The inner layer 30 optionally includes a material that has weaker bonding to the radionuclide atoms 26 than the support 22, allowing the atoms 26 to escape from the device 21 without nuclear decay energy. In some embodiments, the inner layer 30 includes polymers such as polypropylene, polycarbonate (PC), polydimethylsiloxane, polyethylene terephthalate, poly(methyl methacrylate), and / or polysulfone that coat the surface 24. In some embodiments, the inner layer 30 is also permeable to daughter radionuclides; for example, the diffusion coefficient of the daughter radionuclides in the inner layer 30 is at least 10 -11 cm 2 This is per second. In other embodiments, the inner layer 30 is less permeable to the daughter nuclei, or even substantially impermeable to the daughter nuclei.

[0043] Typically, the thickness T1 of the inner layer 30 is between 0.1 and 2 microns, such as between 0.1 and 1 micron. In some embodiments, the inner layer 30 has a thickness between approximately 0.2 and 0.4 microns, for example, approximately 0.3 microns. However, in other embodiments, the inner layer 30 is thinner than 0.1 microns or thinner than 50 nanometers. In yet another embodiment, the inner layer 30 is omitted, and the radioactive nuclide atoms 26 are placed directly on the support 22, and other means are used to prevent strong bonding between the radioactive nuclide atoms 26 and the support 22. Typically, the density of radioactive nuclide atoms 26 in the apparatus 21 is 5 x 10⁻¹⁶ per square centimeter. 10 ~10 14 It is an atom.

[0044] As an option, the structure of the outer layer 33 of apparatus 21 and / or the coating 28 of apparatus 20 is selected such that at least 0.1%, at least 0.5%, or even at least 1% of the atoms 26 in the apparatus per day leave the apparatus by diffusion or dissolution of the coating 28. In some embodiments, the percentage of radioactive nuclide atoms 26 that leave the apparatus by diffusion or dissolution per day is less than 3%, less than 2%, less than 1%, or even less than 0.5%. As an option, the number of atoms 26 that leave the apparatus by diffusion or dissolution within a given time is less than 5%, less than 3%, less than 1%, or even less than 0.5% of the number of atoms 26 that undergo nuclear decay within that given time. As an option, the number of atoms 26 that leave the apparatus by means other than nuclear decay is more than 0.1%, more than 0.5%, or even more than 1% of the number of atoms 26 that undergo nuclear decay.

[0045] Diffusion or dissolution typically begins immediately or soon after the device 20 or 21 is placed inside the subject. For example, at least 0.1% of the radionuclide atoms 26 inside the device will have already left the device by diffusion or dissolution within the first 24 hours after placement, or at most within 48 hours after placement.

[0046] Figure 4 is a schematic diagram of a proximity irradiation therapy apparatus 120 according to another embodiment of the present invention. The apparatus 120 consists of a support 22 having two different radionuclide atoms 124 and 126 on the outer surface 24 of the support 22. The radionuclide atoms 124 and 126 can be attached to the support 22 using any suitable method known in the art, such as a heat treatment as described in U.S. Patent Publication 2009 / 0136422 (Patent Document 6), or a thin protective layer such as a titanium layer of 5 to 10 nanometers (not shown).

[0047] As an option, radioactive nuclide atom 124 is a daughter nuclide resulting from the decay of radioactive nuclide atom 126. In some embodiments, radioactive nuclide atom 124 consists of radium-224, while radioactive nuclide atom 126 consists of thorium-228. The radioactivity level of radioactive nuclide atom 126 may, as an option, be less than 50%, less than 20%, less than 10%, or even less than 5% of the radioactivity level of radioactive nuclide atom 124.

[0048] In one embodiment, radioactive nuclide atom 124 has a radioactivity level of approximately 2 microCi, and radioactive nuclide atom 126 has a radioactivity level of approximately 40-100 nCi. The decay of thorium-228 releases a daughter radionuclide in the form of radium-224, achieving an effect similar to that achieved by the apparatus in Figure 1-3.

[0049] Referring to Figure 1-4, the close-range radiotherapy device discussed above, when primarily based on radium-224 radioactive isotope atoms, allows a certain percentage of radium-224 to leave the device without decay. Since the half-life of radium-224 is 3.66 days, some of this radium-224 completely leaves the tumor before it decays. Thus lost radium-224 atoms are not only wasted but also have the potential to reach and damage healthy tissue. Therefore, prior art avoided the release of radioactive isotope atoms with such long half-lives into the tumor. According to the present invention, it was determined that the release of relatively small amounts of radium-224 into the tumor is beneficial, providing significant necessary energy to the tumor region away from the close-range radiotherapy device. This advantage was deemed to outweigh the disadvantage of lost radioactive isotope atoms.

[0050] In some embodiments of the present invention, the proportion of radium-224 radionuclide atoms that can be released from the proximity irradiation device is selected according to the size of the tumor. As an option, the physician is provided with seeds tuned for the release of different amounts of radium-224, and the physician selects the appropriate seeds according to the size of the tumor and the location where the seeds are to be implanted. Alternatively, the physician determines the size of the tumor and, accordingly, is provided with appropriate seeds with a desired degree of radium-224 release. In some embodiments, when multiple seeds are implanted in a single tumor, different seeds may release different amounts of radium-224. For example, seeds implanted around the periphery of the tumor may, as an option, release small amounts of radium-224 or substantially no radium-224, while seeds implanted in the center of the tumor release a greater amount of radium-224. In some embodiments, the physician determines the size and / or layout of the tumor and, accordingly, selects the number of seeds to be implanted in the tumor and / or the degree of radium-224 release for each seed to be implanted.

[0051] In general, the polymer coating 28 can be applied to the apparatus 20, or the inner layer 30 and outer layer 33 to the apparatus 21, using any suitable technique known in the art, such as the dip coating technique described in the above-mentioned PCT international patent application publication WO2018 / 207105 (Patent Document 10).

[0052] Typically, radioactive nuclide atoms 26 are produced by the decay of preceding radioactive nuclides in their decay chain. For example, as described in U.S. Patent No. 8,894,969 by Kelson et al., radium-224 atoms can be produced by spreading a thin layer of acid containing uranium-232 (U-232) on a metal. Uranium-232 decays to produce thorium-228 (Th-228), which then decays to produce radium-224.

[0053] Atoms 26 can be bonded to the support 22 using one or more suitable techniques, such as those described in U.S. Patent No. 8,894,969 by Kelson et al., as mentioned above. For example, a source that generates a flux of radionuclides is placed in a vacuum near the support 22 so that recoil nuclei from the source cross a vacuum gap and are collected or injected onto the surface 24. Alternatively, radionuclides can be electrostatically collected onto the support 22 by applying a suitable negative voltage between the source and the support. In such embodiments, the support 22 may be made of a conductive metal such as titanium to facilitate electrostatic collection of radionuclides. For example, the support 22 may consist of conductive metal wires, needles, rods, or probes. Alternatively, the support 22, including the surface 24, may consist of non-metallic needles, rods, or probes coated with a conductive metal coating.

[0054] To treat a subject, at least one proximity radiotherapy device is inserted into the subject's body, typically within the tumor to be treated, or immediately adjacent to the tumor (e.g., within 0.1 mm, e.g., 0.05 mm or 0.001 mm, etc.), either whole or partially. While the proximity radiotherapy device remains in the body, the radionuclide decays, thereby releasing alpha particles, daughter nuclei, and some of the radionuclide atoms 26 into the tumor.

[0055] In some embodiments, the proximity irradiation device is removed from the subject, for example, after a predetermined period following the radioactive decay of at least some radioactive nuclide atoms, and / or in response to monitoring of tumor size and / or the percentage of alpha particles emitted. In other embodiments, the device is not removed from the subject.

[0056] It will be understood that the above methods and apparatus should be interpreted as including apparatus for performing the methods and methods for using the apparatus. Features and / or steps described in relation to one embodiment may be used in conjunction with other embodiments, and it should be understood that not all embodiments of the present invention are shown in particular figures or have all features and / or steps described in relation to one particular embodiment. Tasks may not be performed in the order described.

[0057] In some embodiments, combinations of the embodiments shown in Figures 1-4 are used. For example, a proximity irradiation device may include a bioabsorbable layer for releasing radium embedded internally, and further may include thorium atoms attached to an internal support. In another example, a proximity irradiation device may include a bioabsorbable and diffusible layer, which allows for the release of radium or other radionuclide atoms through both diffusion and dissolution of the bioabsorbable layer.

[0058] It should be noted that some of the embodiments described above may include structural, operational, or structural and operational details described as examples, which are not essential to the present invention. The structural and operational details described herein can be replaced by equivalents that perform the same function, even if the structural or operational details differ, as is known in the art. The embodiments described above are cited as examples, and the present invention is not limited to those specifically shown and described above. Rather, the scope of the present invention includes both combinations and subcombinations of the various features described above, as well as their variations and modifications not disclosed in the prior art, which would be recalled by those skilled in the art when reading the foregoing description. Thus, the scope of the present invention is limited only by the elements and limitations used in the claims, and the terms “equipment,” “includes,” “have,” and their conjugates, when used in the claims, mean “includes but not necessarily limited to.”

Claims

1. A close-range radiation therapy device: A seed base adapted for implantation into the subject's body; A first coating layer on the seed base configured to prevent the passage of radium-224 or radium-223; A plurality of particles of radium-224 or radium-223 radionuclides arranged on the first coating layer; A second coating layer on the particles, configured such that at least 0.1% of the plurality of particles can pass through the second coating layer and leave the proximity irradiation device within 24 hours of being implanted in the body of the subject; A proximity irradiation therapy device characterized by having the following features.

2. The proximity irradiation therapy device according to claim 1, characterized in that the seed base is composed of a tube that defines an internal channel.

3. The proximity irradiation therapy apparatus according to claim 1, characterized in that the first coating layer comprises polycarbonate.

4. The proximity irradiation therapy apparatus according to claim 1, characterized in that the first coating layer has a thickness of at least 0.05 micrometers.

5. The proximity irradiation therapy apparatus according to claim 1, characterized in that the first coating layer has a thickness of at least 0.1 micrometers.

6. The proximity irradiation therapy apparatus according to claim 1, characterized in that the first coating layer has a thickness of at least 0.3 micrometers.

7. The proximity irradiation therapy device according to claim 1, characterized in that the first coating layer has a thickness of 1 micrometer or less.

8. The proximity irradiation therapy device according to claim 1, characterized in that the first coating layer has a thickness of 0.5 micrometers or less.

9. The proximity irradiation therapy apparatus according to claim 1, characterized in that the second coating layer contains PDMS (polydimethylsiloxane).

10. The proximity irradiation therapy device according to claim 1, characterized in that the second coating layer has a thickness of 0.5 micrometers or less.

11. The proximity irradiation therapy device according to claim 1, characterized in that the second coating layer has a thickness of 0.3 micrometers or less.

12. The proximity irradiation therapy apparatus according to claim 1, characterized in that the second coating layer has a thickness of at least 0.1 micrometers.

13. The proximity irradiation therapy apparatus according to claim 1, characterized in that the apparatus allows at least 0.5% of the plurality of particles in the apparatus to diffuse through the second coating layer within 24 hours.

14. The proximity irradiation therapy apparatus according to claim 1, characterized in that the apparatus allows at least 5% of the plurality of particles in the apparatus to diffuse through the second coating layer within 24 hours.

15. The proximity irradiation therapy apparatus according to claim 1, characterized in that the apparatus allows 10% or less of the plurality of particles in the apparatus to diffuse through the second coating layer within 24 hours.

16. The proximity irradiation therapy apparatus according to claim 1, characterized in that the apparatus allows 2% or less of the plurality of particles in the apparatus to diffuse through the second coating layer within 24 hours.

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