Beta-ray therapy enhanced with diffused alpha radiation therapy

Abstract

This invention relates to a device and method for providing a radiotherapy source that, in addition to supplying alpha rays, also supplies beta rays at a significant level through diffuse alpha radiation therapy (DaRT) in radiotherapy using an implantable radioactive source. [Solution] An interstitial radiation source (21) comprising a base (22) suitable for implantation in a tumor and alpha-emitting atoms (26) attached to the base (22) having a concentration of at least 6 μCi per centimeter length. The alpha-emitting atoms (26) attach to the base with a radioactive decay desorption probability of 30% or less.

Description

Technical Field

[0001] The present invention generally relates to radiation therapy, and more specifically, to devices and methods for providing an implantable radiation source that combines alpha rays and non-alpha rays.

Background Art

[0002] In the treatment of some types of tumors, including malignant cancerous tumors, ionizing radiation is generally used to destroy the cells. However, ionizing radiation may also damage the patient's healthy cells, and thus care is taken to maximize the radiation dose to the tumor while minimizing the radiation dose delivered to healthy tissues other than the tumor.

[0003] Ionizing radiation destroys cells by damaging the DNA of the cells. The biological effects of different types of radiation in killing cells are determined by the type and severity of the DNA damage they cause. Alpha particles induce scattered double-strand breaks on DNA, and cells cannot repair this, so they are a powerful means for radiation therapy. Different from conventional types of radiation, the destructive effect of alpha particles is not very affected by low cell oxygen concentration, so they are equally effective against hypoxic cells, which are the main cause of failure of conventional photon- or electron-based radiation therapy when present in tumors. Also, since the range of alpha particles in tissue is short (less than 100 micrometers), if the atoms that emit them are confined within the tumor volume, they will not harm the surrounding healthy tissues.

[0004] For example, Diffusing alpha-emitters radiation therapy (DaRT), described in U.S. Patent No. 8,834,837 granted to Kelson, expands the therapeutic range of alpha rays by using radium-223 or radium-224 atoms that produce a chain reaction of multiple radioactive decays, with governing half-lives of 3.6 days for radium-224 and 11.4 days for radium-223. In DaRT, radium atoms adhere strongly to a source (also called a "seed") embedded in the tumor, and therefore these radium atoms do not detach from the source in a wasteful manner (by being removed from the tumor through the blood), and a considerable proportion of daughter radionuclides (radon-220 in the case of radium-224, and radon-219 in the case of radium-223) detach from the source and enter the tumor during radium decay. These radionuclides and their own radioactive daughter atoms diffuse out over a radial distance of several millimeters around the source before decaying by alpha emission. Therefore, the extent of destruction within the tumor is increased compared to the radionuclides that remain on the source along with their daughter atoms.

[0005] Furthermore, some daughter atoms emit beta radiation in addition to alpha radiation. Beta radiation is much weaker than alpha radiation and has a longer range.

[0006] For tumor treatment to be effective, the DaRT seed used in the treatment should emit a sufficient number of radon atoms to destroy the tumor with a high probability. If the amount of radiation used is insufficient, extra cancer cells may remain in the tumor, and these cells may proliferate and reform the malignant tumor. On the other hand, if too many radon atoms are emitted from the seed, some of these daughters may be removed from the tumor through the bloodstream, thus potentially damaging distant healthy tissues, including the patient's bone marrow, kidneys, and / or ovaries.

[0007] The amount of radium atoms on a DaRT source is quantified in terms of radioactivity, i.e., the rate of radium decay. The radioactivity of a DaRT source is measured in units of microcuries (μCi) or kilobecquerels (kBq), where 1 μCi = 37 kBq = 37,000 decays per second. When using DaRT, the amount of radiation delivered to tumor cells depends not only on the radium radioactivity of the source but also on the probability that radium or its daughter radon atoms enter the tumor from the source. In this specification, the probability that a daughter radon atom leaves the source and enters the tumor during alpha decay of radium is called the "desorption probability." If the diffusion rate of radium from the source can be ignored, instead of referring to the source radioactivity, the "radon release rate," which is defined as the product of the radioactivity on the source and the desorption probability of radon from the source, can be used as a measure of the source radioactivity related to DaRT. Similar to radioactivity, radon emission rates are given in units of μCi or kBq. Unless otherwise specified, the radioactivity and radon emission rate values ​​shown herein refer to the source at the time of implantation in the tumor.

[0008] U.S. Patent No. 8,834,837 to Kelson, mentioned above, proposes the use of radioactivity "about 10 nanocuries to about 10 microcuries, more preferably about 10 nanocuries to about 1 microcury." U.S. Patent Application No. 17 / 343,786, titled "Activity Levels for Diffusing Alpha-Emitter Radiation Therapy," proposes radon emission levels for various tumor types that are high enough to destroy tumors but low enough to avoid damage to distant healthy tissue.

[0009] U.S. Patent Application Publication No. 2010 / 0015042, granted to Keisari et al., mentions in vivo experiments using radon-224 radioactivity in the range of 10-30 kBq, with a radon desorption probability of 22-36%.

[0010] U.S. Patent Application Publication No. 2013 / 0253255, granted to Van Niekerk, describes a brachytherapy seed that carries two heterologous isotopes of the same substance, the disclosure of which is incorporated herein by reference.

[0011] U.S. Patent Application Publication No. 2008 / 0249398, granted to Harder et al., describes a hybrid multi-radionuclide sealed source used in brachytherapy, the disclosure of which is incorporated herein by reference.

[0012] Generally, it is desirable to prevent radionuclides from being washed away from the source by bodily fluids before they have a chance to decay. International Publication No. 2018 / 207105, entitled "Polymer Coatings for Brachytherapy Devices," describes coatings selected to prevent radionuclides from being washed away without hindering the desorption of daughter nuclei from the source, and this document is incorporated herein by whole citation.

[0013] U.S. Patent Application Publication No. 2002 / 0055667, granted to Mavity et al., describes radionuclides having a predetermined duration of bioabsorbable structures that typically have a duration significantly longer than the half-life of the radionuclide, and the disclosure of this document is incorporated herein by whole reference. These radionuclides remain localized and isolated at a desired target site while significant radioactivity persists.

[0014] U.S. Patent No. 8,821,364, granted to Fisher et al., describes a brachytherapy seed comprising a rapidly dissolving microsphere containing an alpha particle-emitting radiation source and a reabsorbable polymer matrix, the disclosure of which is incorporated herein by reference in its entirety. [Prior art documents]

Patent Document

[0015]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

Patent Document 8

Patent Document 9

Patent Document 10

Patent Document 11

Patent Document 12

Non-Patent Document

[0016]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0017] The applicant of the present application has confirmed that there is a significant difference in the amount of radiation involved in the destruction of tumor cells between the inside of the tumor and the area close to the periphery of the tumor. Near the periphery, the tumor tissue is not necrotic, and although the vascular structure is disrupted and chaotic, there is a rich blood supply. Due to this rich blood supply, (1) the tumor tissue in the area close to the periphery has a dense membrane structure, which 220 Rn and 212 reduces the effective diffusion range of some daughter nuclides such as Pb, and (2) 212 Pb is removed at a high rate by blood vessels, so the emission of alpha particles is reduced in the area close to the periphery of the tumor. Due to these two effects, the effectiveness of alpha rays is suppressed. As a result, the destruction range of tumor cells in the area close to the periphery of the tumor becomes narrow, and some tumor areas do not receive sufficient radiation.

[0018] In addition, the destruction range of tissue cells strongly depends on the distance from the radiation source. Therefore, it is desirable to use a regular radiation source array such as a hexagonal array to cover the tumor at a short interval such as an interval less than 5 millimeters or not exceeding 4 millimeters. However, even then, if only alpha rays are relied on, some points of the tumor will be relatively far from any radiation source.

Means for Solving the Problems

[0019] Embodiments of the present invention relate to providing a radiotherapy source that supplies beta rays at a significant level through diffusion alpha emitter radiotherapy (DaRT) in addition to the supply of alpha rays.

[0020] In some embodiments, beta rays are produced by a DaRT radiotherapy source having the required radon emission rate achieved by relatively high radioactivity and a relatively low desorption probability. The use of low desorption probability is wasteful in that a larger-than-necessary portion of the radionuclide on the source does not contribute to alpha-ray cell destruction. However, the high radioactivity made possible by the low desorption probability can increase the amount of beta rays that can contribute to tumor destruction. Achieving beta-ray destruction with the same radionuclide that supplies alpha rays is simpler than preparing a separate radionuclide for beta rays, and this more than compensates for the wastefulness of low desorption probability.

[0021] Accordingly, according to embodiments of the present invention, a radiation source is provided comprising a base suitable for implanting in a tumor and alpha-emitting atoms attached to the base, having a concentration of at least 6 μCi per centimeter, wherein the alpha-emitting atoms attach to the base with a desorption probability upon radioactive decay of 2% to 30%.

[0022] Optionally, the alpha-emitting atoms attached to the base contain at least 8 microcuries (μCi) per centimeter of base length, at least 10.5 microcuries (μCi) per centimeter of base length, or at least 12 microcuries (μCi) per centimeter of base length. Optionally, the alpha-emitting atoms contain radium-224 atoms. Optionally, the alpha-emitting atoms have a radon emission rate of at least 0.5 microcuries per centimeter of base length. Optionally, the alpha-emitting atoms have a decay-desorption probability of at least 4%, at least 5%, at least 7%, or at least 10%. Optionally, the alpha-emitting atoms have a decay-desorption probability of 27% or less, less than 24%, or less than 20%.

[0023] Optionally, the alpha-emitting atoms adhere to the base by heat treatment. Optionally, the alpha-emitting atoms adhere to the base with a desorption probability of less than 15%. In some embodiments, the source includes a low-diffusion polymer coating covering the alpha-emitting atoms in a manner that reduces the desorption probability of daughter nuclides. Optionally, the coating has a thickness of at least 0.5 microns. Alternatively, the coating includes a non-metallic coating. In some embodiments, the source includes an atomic layer deposition coating of aluminum oxide covering the alpha-emitting atoms. Optionally, the atomic layer deposition coating has a thickness of at least 2 nanometers. In some embodiments, an interstitial source further emits beta rays, and the ratio of the asymptotic dose of beta rays at a distance of 2 millimeters from the device to the radon emission rate from the device is greater than 15 Gy / (microcurie / cm). Optionally, at least 90% of the beta rays are emitted from the progeny of the alpha-emitting atoms. Optionally, at least 20% of beta radiation is emitted from isotopes that do not emit alpha radiation.

[0024] According to embodiments of the present invention, an interstitial radiation source is further provided, comprising a base suitable for implantation in a tumor, and alpha-emitting atoms attached to the base having a concentration of at least 10.5 μCi per centimeter length.

[0025] Optionally, the alpha-emitting atoms attached to the base contain at least 12 microcuries (μCi) per centimeter of base length. Optionally, the alpha-emitting atoms attached to the base contain at least 15 microcuries (μCi) per centimeter of base length. Optionally, the alpha-emitting atoms attached to the base contain at least 21 microcuries (μCi) per centimeter of base length. Optionally, the alpha-emitting atoms contain radium-224 atoms.

[0026] According to embodiments of the present invention, an interstitial radiation source is further provided, comprising a base suitable for implantation in a tumor, and alpha-emitting atoms that adhere to the base by heat treatment and have a radioactive decay desorption probability of 5% to 30%. Optionally, the alpha-emitting atoms adhering to the base may include at least 5 microcuries (μCi) per centimeter of base, at least 8 microcuries (μCi) per centimeter of base, at least 11 microcuries (μCi) per centimeter of base, or at least 14 microcuries (μCi) per centimeter of base.

[0027] According to embodiments of the present invention, an interstitial source is provided which comprises a base suitable for implantation in a tumor and an alpha-emitting atom attached to the base having a radioactive decay desorption probability of 5% to 30%, wherein the interstitial source does not have a metal coating above the alpha-emitting atom.

[0028] Optionally, the alpha-emitting atoms attached to the base contain at least 5 microcuries (μCi) per centimeter of base length. Optionally, the alpha-emitting atoms attached to the base contain at least 8 microcuries (μCi) per centimeter of base length. Optionally, the alpha-emitting atoms attached to the base contain at least 11 microcuries (μCi) per centimeter of base length. Optionally, the alpha-emitting atoms contain radium-224 atoms. Optionally, the alpha-emitting atoms have a decay-desorption probability of at least 7%. Optionally, the alpha-emitting atoms have a decay-desorption probability of at least 9%. Optionally, the alpha-emitting atoms attach to the base with a desorption probability of at least 12%. Optionally, the alpha-emitting atoms have a decay-desorption probability of 27% or less. Optionally, the alpha-emitting atoms attach to the base with a desorption probability of less than 25%. Optionally, the alpha-emitting atoms attach to the base with a desorption probability of less than 21%. Optionally, the alpha-emitting atoms are deposited on the base by heat treatment. Optionally, the alpha-emitting atoms are deposited on the base with a desorption probability of less than 15%. In some embodiments, the source includes a coating of a low-diffusion polymer covering the alpha-emitting atoms in a manner that reduces the desorption probability of daughter nuclides. Optionally, the coating has a thickness of at least 0.5 microns. In some embodiments, the source includes an atomic layer deposition coating of aluminum oxide covering the alpha-emitting atoms. Optionally, the atomic layer deposition coating has a thickness of at least 2 nanometers.

[0029] According to embodiments of the present invention, an interstitial radiation source is provided comprising a base suitable for implantation in a tumor and one or more isotopic radioactive atoms attached to the base, wherein the radioactive atoms emit beta rays having a radon emission rate of at least 0.5 microcuries per centimeter, achieving an asymptotic dose of at least 10 Gy at a distance of 2 millimeters from the base, and the ratio of the asymptotic dose of beta rays at a distance of 2 millimeters from the device to the radon emission rate is greater than 15 Gy / (microcuries / cm).

[0030] Optionally, the ratio of the asymptotic dose to the radon emission rate at a distance of 2 millimeters from the device is greater than 20 Gy / (microcurie / cm). Optionally, the radioactive atom contains radium-224 atoms having a radioactivity of at least 1 microcurie per centimeter length. Optionally, the radioactive atom contains radium-224 atoms having a radioactivity of at least 10.5 microcuries per centimeter length. Optionally, the radioactive atom of one or more isotopes contains one or more isotopes that emit beta rays, achieving an asymptotic dose of at least 5 Gy at 2 millimeters from the base without emitting alpha rays. [Brief explanation of the drawing]

[0031] [Figure 1] This is a schematic diagram of a radiation therapy source according to an embodiment of the present invention. [Figure 2] This is a schematic diagram of an alpha- and beta-ray combined radiation source according to an embodiment of the present invention. [Figure 3] This is a schematic diagram of an alpha- and beta-ray combined radiation source according to another embodiment of the present invention. [Figure 4] This is a schematic diagram of an alpha- and beta-ray combined radiation source according to yet another embodiment of the present invention. [Modes for carrying out the invention]

[0032] Some embodiments of the present invention relate to a radiotherapy source that carries an alpha-emitting atom in such a way that it allows for the desorption of a daughter nuclide with a significant probability (e.g., at least 1%), but the desorption probability is less than 30%. By lowering the desorption probability, the radioactivity on the source can be increased without changing the radon emission rate and, as a result, the systemic alpha radiation that reaches distant healthy tissue. Increased radioactivity on the source leads to an increase in beta radiation supplied by the source, which complements the alpha radiation in the destruction of tumor cells.

[0033] Figure 1 is a schematic diagram showing a radiotherapy source 21 according to an embodiment of the present invention. The radiotherapy source 21 includes a support 22 configured to be inserted into the body of a subject, and radioactive nuclide atoms 26 of an alpha-emitting material such as radium-224 on the outer surface 24 of the support 22. For the sake of clarity, the atoms 26 and other components of the radiotherapy source 21 are shown in an exaggeratedly large size. In some embodiments, the support 22 and atoms 26 are covered with a coating 33 in such a way as to control the emission rate of the radioactive nuclide atoms 26 and / or daughter nuclides of atoms 26 during radioactive decay. In some embodiments, as shown in Figure 1, an inner coating 30 of thickness T1 is placed on the support 22 in addition to the coating 33, and the radioactive nuclide atoms 26 adhere to this inner coating 30. However, not all embodiments include an inner coating 30, and instead the radioactive nuclide atoms 26 adhere directly to the source 21. Similarly, some embodiments do not include a coating 33.

[0034] In some embodiments, the support 22 may include a seed that is fully embedded within the patient's tumor and may have any preferred shape, such as a rod or a plate. The support 22 may be partially embedded rather than fully embedded within the patient and may be part of a needle, wire, endoscope tip, laparoscope tip, or any other preferred probe.

[0035] In some embodiments, the support 22 is cylindrical and has a length of at least 2 mm, at least 5 mm, or at least 10 mm. Optionally, the support 22 has a length of less than 70 mm, less than 60 mm, or less than 40 mm. The support 22 optionally has a diameter of 0.7 to 1 mm, although in some cases larger or smaller diameter sources are used. In particular, for treatment layouts with narrow spacing, the support 22 optionally has a diameter of less than 0.7 mm, less than 0.5 mm, less than 0.4 mm, or 0.3 mm or less.

[0036] Typically, radionuclides, daughter nuclides, and / or subsequent nuclei in a decay chain are alpha-emitting in that an alpha particle is emitted when a given nucleus decays. For example, as described in U.S. Patent No. 8,894,969, incorporated herein by reference, the radionuclide includes an isotope of radium (e.g., Ra-224 or Ra-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). Alternatively, the radionuclide includes actinium-225.

[0037] The amount of radiation supplied to the surrounding tissue by the radiotherapy device 21 depends on various parameters of the radiotherapy device. These parameters include: 1) The probability of daughter atom detachment during the decay of radioactive nuclide atom 26, 2) The emission rate of radioactive nuclide atoms 26 by diffusion, and 3) The amount of radioactive nuclide atoms 26 on the source.

[0038] While the risk of radiation overdose is low with a single small tumor, treatment for large tumors and / or multiple tumors may involve the implantation of hundreds of radiation sources. Therefore, the radiation supplied by the sources is adjusted to prevent overdose to the patient.

[0039] The amount of radioactive nuclide atoms 26 within the radiotherapy device 21 is generally given in terms of radioactivity per centimeter length of the support 22. In this specification, radioactivity is measured in units of microcuries per centimeter length of the source. Since the radiation dose reaching most of the tumor is largely comprised of radionuclides that leave the source, the measure of "radon emission rate" is defined here as the product of the radioactivity on the source and the desorption probability. For example, a source with a radioactivity of 2 microcuries per centimeter length and a desorption probability of 40% has a radon emission rate of 0.8 microcuries per centimeter length.

[0040] Typically, the radon emission rate of a radiation source is at least 0.5 microcuries, at least 1 microcurie, or at least 2 microcuries per centimeter. Generally, the radon emission rate is 4 microcuries or less per centimeter. However, the applicant has found that the risk of radionuclides reaching distant healthy tissue is lower than initially anticipated, and therefore, in some embodiments, radon emission rates greater than 4 microcuries per centimeter, greater than 4.5 microcuries per centimeter, greater than 5 microcuries per centimeter, or greater than 6 microcuries per centimeter are used. Optionally, the radon emission rate is selected according to the specific tumor type. For example, U.S. Patent Application Publication No. 17 / 343,786, entitled “Radioactivity Levels for Diffusing Alpha Radiator Radiotherapy,” describes specific radon emission rates that can be used, and this document is incorporated herein by reference.

[0041] Atoms 26 can be bonded to the support 22 using any preferred technique, such as one or more of the techniques described in the aforementioned Kelson '969 patent. For example, a source that generates a flow of radionuclides can be placed in a vacuum near the support 22 so that nuclei recoiling from the source are collected on or embedded in the surface 24 across the vacuum gap. Alternatively, radionuclides can be electrostatically collected on the support 22 by applying a suitable negative voltage between the source and the support. In such embodiments, the support 22 may include a conductive metal such as titanium to facilitate the electrostatic collection of radionuclides. For example, the support 22 may include a conductive metal wire, needle, rod, or probe. Alternatively, the support 22 may include a non-metallic needle, rod, or probe coated with a conductive metal coating including the surface 24.

[0042] In prior art, attempts were made to maximize the desorption probability in order to maximize tissue destruction and avoid wasting radionuclides that do not penetrate the tumor. According to embodiments of the present invention, the desorption probability is intentionally set as low as possible in order to increase the ratio of beta rays to alpha rays supplied by the radiotherapy device 21.

[0043] The detachment probability is arbitrarily less than 30%, less than 25%, less than 20%, less than 15%, less than 13%, or less than 10%. On the other hand, it is preferable that the detachment probability is not too low, and is arbitrarily greater than 2%, greater than 4%, greater than 6%, or greater than 8%. In some embodiments, the detachment probability is greater than 10%, greater than 12%, or greater than 15%.

[0044] The desorption probability depends on the strength of the binding of the radioactive nuclide atom 26 to the support 22, and / or the type and thickness of the coating 33.

[0045] In some embodiments, a low desorption probability is achieved by using a high bonding strength, but the coating is substantially the same as that used for a high desorption probability, for example, a biocompatible PDMS (polydimethylsiloxane) with a thickness of less than 3 microns. Bonding of the radionuclide atoms 26 to the support 22 is generally achieved by heat treatment of the radiotherapy device 21, and the bonding strength can be controlled by adjusting the temperature and / or duration of the heat treatment. In some embodiments, the temperature used is at least 50°C, at least 100°C, or at least 200°C higher than the temperature used to achieve a desorption probability of about 38-45%. Alternatively or in addition, the heat treatment is 10 1 Less than millibars, 10 -2 Less than millibars, or 10 -3 The heat treatment is performed at a low pressure of less than millibars and / or for a longer period of time, such as at least 10 minutes, at least 20 minutes, at least 40 minutes, or at least 1 hour, which is longer than the time required to achieve, for example, a desorption probability of about 38–45%. Alternatively, or in addition to reducing the desorption probability by varying the heat treatment, the bond strength may also be reduced using any other preferred method.

[0046] In some embodiments, the fixation of radionuclides to the seed surface is performed in a noble gas environment or a vacuum environment. Fixation can be performed at either preferred pressure. Heat treatment is applied for at least 10 minutes, at least 30 minutes, at least 1 hour, at least 3 hours, or at least 10 hours, as is optional. Optionally, the temperature of the heat treatment depends on the pressure, the environment in which the radionuclides are fixed to the surface, and the duration of the fixation process. In some embodiments, the temperature depends on the material of the seed surface.

[0047] In other embodiments, the bond strength is substantially the same as that used for desorption rates of approximately 38–45%, and a lower desorption probability is achieved by modifying the coating 33 to reduce the desorption probability to a desired level.

[0048] For example, in some embodiments, the coating 33 includes a layer of a polymer that is highly permeable to daughter nuclides (e.g., radon), such as biocompatible PDMS (polydimethylsiloxane), so that daughter nuclides can diffuse through the coating 33. For example, the diffusion coefficient of daughter nuclides in the polymer of the coating 33 can be at least 10¹¹ cm² / sec. In these embodiments, the thickness T0 of the coating 33 is arbitrarily greater than 20 microns, greater than 50 microns, greater than 100 microns, greater than 200 microns, or greater than 300 microns.

[0049] The coating 33 includes, in place of or in addition to PDMS (polydimethylsiloxane), any other suitable material that is permeable to daughter nuclides, such as polypropylene, polycarbonate, polyethylene terephthalate, poly(methyl methacrylate), and / or polysulfone, which coats the surface 24 and thus covers the atoms 26.

[0050] In other embodiments, the coating 33 comprises one or more layers of a material with significantly lower permeability to radon than PDMS. In some of these embodiments, the coating 33 is a low-diffusion polymer (e.g., parylene-n) having a thickness of at least 0.2 microns, at least 0.5 microns, at least 1 micron, or at least 2 microns. However, the coating is still not too thick to allow the desired desorption rate of radon, and may have a thickness of arbitrarily less than 100 microns, less than 20 microns, less than 5 microns, or less than 3 microns. In some embodiments, the coating has a thickness of less than 2 microns, less than 1 micron, or less than 0.75 microns. A low-diffusion polymer is a polymer in which radon diffuses to a depth of less than 5 microns. In some embodiments, polymers with even lower diffusion depths are used, such as less than 2 microns, less than 1 micron, or less than 0.5 microns.

[0051] Other embodiments of the low-permeability coating include atomic layer deposition (e.g., with Al2O3). The atomic layer deposition optionally has a thickness of at least 2 nanometers, at least 3 nanometers, or at least 5 nanometers. Optionally, the atomic layer deposition has a thickness of less than 15 nanometers or less than 10 nanometers.

[0052] Optionally, in the embodiments described above, the coating 33 includes a non-metallic coating that does not contain metal. This is because the applicant has found that metal coatings are difficult to work with and the results are less predictable. However, in other embodiments, the coating 33 is a metal coating, such as titanium, either partially or entirely. The applicant has found that a metal coating of a suitable thickness can achieve a low desorption probability of daughter radon radionuclides.

[0053] In yet another embodiment, the desired desorption probability is achieved by a combination of stronger bonding (e.g., by heat treatment) and the properties of the coating 33. For example, the coating 33 can have a thickness greater than that used for desorption rates of about 38-45%, such as over 4 microns, over 6 microns, over 10 microns, over 20 microns, or over 40 microns, but still less than 100 microns or less than 60 microns. Optionally, a further reduction in the desorption rate is achieved by modifying one or more properties of the heat treatment.

[0054] In some embodiments, the release rate of radionuclide atoms 26 by diffusion, for example, is very low and can be ignored. In other embodiments, the substantial diffusion rate of radionuclide atoms 26 is used by one of the methods described in International Publication No. 2019 / 193464, entitled "Controlled Release of Radionuclides," which is incorporated herein by reference. Optionally, diffusion is achieved by using a bioabsorbable coating 33 that initially prevents premature release of radionuclide atoms 26 but allows decay and diffusion after implantation in the tumor. The release rate of radionuclide atoms 26 is optionally lower than the release rate of daughter nuclides by desorption, preferably less than 50%, less than 30%, or less than 10% of the release rate of daughter nuclides by desorption.

[0055] Typically, the density of atoms 26 on the outer surface 24 is 10 per square centimeter. 11 ~10 14 There are 15 μCi or less per centimeter, and in some embodiments, less than 13 μCi per centimeter. However, in other embodiments, the concentration of radionuclides in the seed is greater than 15 μCi per centimeter.

[0056] The beta rays from the radium-224-carrying radiation device 21 are produced when lead-212 decays into bismuth-212, then into polonium-212, or then into thallium-208, releasing electrons as these decay into lead-208. Some of the beta rays originate from daughter nuclides that remain attached to the source, while other parts of the beta rays originate from daughter nuclides within the tumor after the daughter nuclides or their ancestors have been released from device 21. However, some of the lead-212 that reaches or forms within the tumor is removed from the tumor through the bloodstream before it has a chance to decay.

[0057] The use of a relatively low desorption probability according to embodiments of the present invention enables an increase in beta radiation reaching tumor cells in two ways. First, the low desorption probability allows for an increase in radium radioactivity on device 21 in a manner that increases beta radiation without increasing the alpha radiation side effects of lead-212 leaving the tumor through the bloodstream. Second, the low desorption probability reduces the amount of lead-212 leaving the tumor through the bloodstream, and therefore not supplying beta radiation. Although beta radiation has a broader range than alpha radiation, it still decreases quite rapidly with distance from the source.

[0058] As described in Lior Arazi, “Diffusing Alpha-Emitters Radiation Therapy: Theoretical and Experimental Dosimetry,” a paper submitted to the Senate of Tel Aviv University in September 2008, a radiation device 21 with a radium radioactivity of 3 microcuries per centimeter yields an asymptotic dose of approximately 10 Gy of beta radiation at a distance of 2 millimeters from the source, and the disclosure of this literature is incorporated herein by reference. Increasing the radium radioactivity of device 21 to 9 microcuries per centimeter yields approximately 30 Gy of beta radiation at a distance of 2 millimeters from device 21. When arranged in a hexagon with 4 millimeter spacing, each point in the tumor receives beta radiation from three sources and therefore receives at least approximately 90 Gy. The destructive power of beta radiation is considered to be about 5 to 10 times less than that of alpha radiation, and therefore this 90 Gy is equivalent to approximately 9 to 18 Gy from alpha radiation.

[0059] Therefore, beta radiation can deliver therapeutic levels of emission without increasing the radon emission rate beyond the desired level. In some embodiments, the radiation device 21 is designed to deliver at least 18 Gy, at least 20 Gy, at least 24 Gy, at least 28 Gy, or at least 30 Gy at a distance of 2 millimeters from the device within a tumor where lead removal through the bloodstream is negligible.

[0060] The alpha radiation supplied by the radiation device 21 that yields these beta radiation levels is at least 10 Gy or at least 20 Gy at a distance of 2 millimeters from the device, optionally. In some embodiments, the alpha radiation supplied by the radiation device 21 is less than 100 Gy, less than 60 Gy, or less than 40 Gy. This alpha radiation is supplied by the radiation device 21 having a radon emission rate of at least 0.5 microcuries per centimeter, but less than 4 microcuries per centimeter, less than 3 microcuries per centimeter, less than 2.5 microcuries per centimeter, or less than 2 microcuries per centimeter, optionally. In some embodiments, the ratio of the asymptotic dose at a distance of 2 millimeters from the device to the radon emission rate of the device in a tumor where lead removal through blood flow is negligible is greater than 15 Gy / (microcurie / cm), greater than 20 Gy / (microcurie / cm), greater than 25 Gy / (microcurie / cm), or greater than 30 Gy / (microcurie / cm).

[0061] In the above explanation, beta rays are supplied by the descendants of alpha-emitting radionuclides that supply alpha rays. Generally, at least 90%, at least 95%, or at least 99% of beta rays are attributable to alpha-emitting radionuclides.

[0062] The radiation doses described above can also be achieved by devices that supply beta rays using another radionuclide that does not supply therapeutically effective alpha rays, instead of supplementing alpha rays with beta rays from a radionuclide that supplies alpha rays.

[0063] Figure 2 is a schematic diagram showing an alpha- and beta-ray combined source 50 according to an embodiment of the present invention. The source 50 includes a capsule 54 that encloses a radioactive material 52 of one or more radioisotopes that emit beta rays and / or gamma rays. The alpha-emitting nuclide atom 26 is attached to the outer surface of the capsule 54 in such a manner that its daughter nuclide can detach from the source 50 with a desired desorption probability during radioactive decay. In some embodiments, the radionuclide atom 26 is covered with a coating 33, as described above with respect to Figure 1. As shown, the source 50 does not include a coating 30 between the surface of the capsule 54 and the radionuclide atom 26. However, in some embodiments, a coating 30 is included between the capsule 54 and the radionuclide atom 26.

[0064] Optionally, capsule 54 includes a sealed container that does not prevent the emission of beta and / or gamma rays from capsule 54. Optionally, capsule 54 includes a metal such as gold, stainless steel, titanium and / or platinum. Alternatively, capsule 54 includes a plastic such as that described in U.S. Patent No. 7,922,646, entitled “Plastic Brachytherapy Sources,” which is incorporated herein by reference. Optionally, according to this alternative, the plastic capsule is covered with a thin metal coating to which the radionuclide atoms 26 are attached. Capsule 54 is of any preferred size and / or shape well known in the art, such as those described in U.S. Patent No. 6,099,458, entitled “Encapsulated Low-Energy Brachytherapy Sources,” and / or U.S. Patent No. 10,166,403, entitled “Brachytherapy Source Assembly,” the disclosures of which are incorporated herein by reference.

[0065] Radioactive material 52 contains one or more beta-emitting radioisotopes such as iridium-192, californium-252, gold-198, indium-114, phosphorus-32, radium-226, ruthenium-106, samarium-145, strontium-90, yttrium-90, tantalum-182, thulium-107, tungsten-181 and / or ytterbium-169. Alternatively, radioactive material 52 contains one or more gamma-emitting radioisotopes such as iodine-125 (I-125), palladium-103 (Pd-103), cesium-131 ​​(Cs-131), cesium-137 (Cs-137) and / or cobalt-60 (Co-60). Other suitable radioactive materials known in the art may also be used, as well as combinations of multiple beta emitters, combinations of multiple gamma emitters, combinations of beta emitters and gamma emitters, and / or one or more materials that emit both beta and gamma rays.

[0066] The radioactivity of the radioactive material 52 and the thickness of the capsule 54 wall are selected to achieve a sufficient amount of radiation at a distance of approximately 3-4 mm from the source 50. Optionally, the radioactive material 52 has a radioactivity level of at least 0.5 mCi (millicuries), at least 5 mCi, at least 20 mCi, or at least 50 mCi. In some embodiments, the radioactivity of the radioactive material 52 is significantly higher, exceeding 100 mCi, 200 mCi, or 500 mCi.

[0067] In some embodiments, the radioactive material 52 fills the capsule 54. Alternatively, the radioactive material 52 is arranged as an inner coating on the wall of the capsule 54.

[0068] Figure 3 is a schematic diagram showing an alpha- and beta-ray combined radiation source 80 according to another embodiment of the present invention. The source 80 includes a base 82 to which a beta-ray emitting nuclide 84 is attached directly or via one or more coatings. An alpha-ray emitting nuclide 86 is positioned above the beta-ray emitting nuclide 84, either directly attached to the beta-ray emitting nuclide 84 or on a coating that separates the beta-ray emitting nuclide 84 and the alpha-ray emitting nuclide 86.

[0069] Figure 4 is a schematic diagram showing an alpha- and beta-ray combined radiation source 90 according to yet another embodiment of the present invention. In the radiation source 90, beta-ray emitting radionuclides 84 and alpha-ray emitting radionuclides 86 are dispersed on the surface of the base 82.

[0070] In sources 80 and 90, the beta-emitting nuclide 84 is attached to the base 82 in such a way that its emission from source 80 is substantially prevented. In contrast, the alpha-emitting nuclide 86 is attached to the base 82 in such a way that it allows the emission of its daughter nuclide from source 80 during decay.

[0071] In sources 50, 80, and 90, daughter nuclides are optionally emitted from source 80 with desorption probabilities of at least 30%, at least 35%, or at least 40%, and the radioactivity of alpha-emitting nuclide 86 is appropriately set to a level lower than that described above for radiotherapy device 21, which is well known in the art for such desorption probability levels. This is because, in embodiments of sources 50, 80, and 90, beta rays are optionally supplied mainly by beta-emitting nuclide 84, and alpha-emitting nuclide 86 is not relied upon for beta rays.

[0072] Alternatively, a combination of beta rays from beta-emitting nuclide 84 and beta rays from alpha-emitting nuclide 86 can supply a desired level of beta rays, such as at least 60 gray (Gy), at least 70 Gy, or at least 80 Gy. In some embodiments, at least 10%, at least 20%, at least 30%, or at least 40% of the beta rays emitted by sources 50, 80, and 90 are emitted from alpha-emitting nuclide 86. Alternatively, or in addition, at least 10%, at least 20%, at least 30%, or at least 40% of the beta rays emitted by sources 50, 80, and 90 are emitted from beta-emitting nuclide 84.

[0073] conclusion The methods and apparatus described above should be understood to include 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 have all features and / or steps shown in specific figures or described in relation to one of the specific embodiments. Tasks may not necessarily be performed in the exact order described.

[0074] Some of the embodiments described above include structures, actions, or details of structures and actions described as examples, which are not essential to the present invention. The structures and actions described herein can be replaced with equivalents that perform the same function, even if these structures or actions differ, as are well known in the art. The embodiments described above are examples, and the present invention is not limited to those specifically illustrated and described above. Rather, the scope of the present invention includes both combinations and partial combinations of the various features described herein, as well as variations and modifications of these not disclosed in the prior art, which would be apparent to those skilled in the art upon reading the above description. Accordingly, the scope of the present invention is limited only by the elements and limitations used in the claims, and where the terms “comprise, include, have” and their conjugations are used in the claims, they mean “comprise but not necessarily limited to.” [Explanation of Symbols]

[0075] 21. Radiation therapy sources 22 Support 24 Outer surface of the support 26 Radioactive nuclide atoms 30 Inner coating 33 Coating T1 Inner coating thickness

Claims

1. Interstitial type source, A base suitable for implantation in tumors, Alpha-emitting atoms having a concentration of at least 6 μCi per centimeter length attached to the base, Includes, The alpha-emitting atoms adhere to the base with a radioactive decay desorption probability of 30% or less. source.

2. The radiation source according to claim 1, wherein the alpha-emitting atoms attached to the base contain at least 8 microcuries (μCi) per centimeter length of the base.

3. The radiation source according to claim 2, wherein the alpha-emitting atoms attached to the base comprise at least 10.5 microcuries (μCi) per centimeter length of the base.

4. The radiation source according to claim 3, wherein the alpha-emitting atoms attached to the base contain at least 12 microcuries (μCi) per centimeter length of the base.

5. The radiation source according to claim 1, wherein the alpha-emitting atom includes a radium-224 atom.

6. The radiation source according to claim 1, wherein the alpha-emitting atom has a decay desorption probability of at least 2%.

7. The radiation source according to claim 6, wherein the alpha-emitting atom has a decay desorption probability of at least 5%.

8. The radiation source according to claim 1, wherein the alpha-emitting atom has a radon emission rate of at least 0.5 microcuries per centimeter length.

9. The radiation source according to claim 1, wherein the alpha-emitting atom has a decay desorption probability of 27% or less.

10. The radiation source according to claim 9, wherein the alpha-emitting atom adheres to the base with a desorption probability of less than 24%.

11. The radiation source according to claim 10, wherein the alpha-emitting atom adheres to the base with a desorption probability of less than 20%.

12. The alpha-emitting atoms are deposited on the base by heat treatment, according to claim 11.

13. The radiation source according to claim 12, wherein the alpha-emitting atom adheres to the base with a desorption probability of less than 15%.

14. A radiation source according to any one of claims 1 to 13, comprising a coating of a low-diffusion polymer covering the alpha-emitting atom in such a manner as to reduce the desorption probability of the daughter nuclide.

15. The radiation source according to claim 14, wherein the coating has a thickness of at least 0.5 microns.

16. The radiation source according to claim 14, wherein the coating includes a non-metallic coating.

17. A radiation source according to any one of claims 1 to 13, comprising an atomic layer deposition coating of aluminum oxide covering the alpha-emitting atom.

18. The radiation source according to claim 17, wherein the atomic layer deposition coating has a thickness of at least 2 nanometers.

19. The interstitial source further emits beta rays, and the ratio of the asymptotic dose of the beta rays at a distance of 2 millimeters from the device to the radon emission rate from the device is greater than 15 Gy / (microcurie / cm), according to any one of claims 1 to 13.

20. The radiation source according to claim 19, wherein at least 90% of the beta rays are emitted from the descendants of the alpha-emitting atom.

21. The radiation source according to claim 19, wherein at least 20% of the beta rays are emitted from an isotope that does not emit alpha rays.

22. Interstitial type source, A base suitable for implantation in tumors, Alpha-emitting atoms having a concentration of at least 10.5 μCi per centimeter length attached to the base, A radiation source, including a radiation source.

23. The radiation source according to claim 22, wherein the alpha-emitting atoms attached to the base comprise at least 12 microcuries (μCi) per centimeter length of the base.

24. The radiation source according to claim 23, wherein the alpha-emitting atoms attached to the base contain at least 15 microcuries (μCi) per centimeter length of the base.

25. The radiation source according to claim 24, wherein the alpha-emitting atoms attached to the base contain at least 21 microcuries (μCi) per centimeter length of the base.

26. The radiation source according to any one of claims 22 to 25, wherein the alpha-emitting atom has a decay desorption probability of at least 2%.

27. The radiation source according to any one of claims 22 to 25, wherein the alpha-emitting atom has a decay desorption probability of 28% or less.

28. Interstitial type source, A base suitable for implantation in tumors, One or more radioactive isotopes attached to the base, The radioactive atom has a radon emission rate of at least 0.5 microcuries per centimeter and emits beta rays that achieve an asymptotic dose of at least 10 Gy at 2 millimeters from the base. The ratio of the asymptotic dose of the beta rays at a distance of 2 millimeters from the device to the radon emission rate is greater than 15 Gy / (microcurie / cm). source.

29. The radiation source according to claim 28, wherein the ratio of the asymptotic dose to the radon emission rate at a distance of 2 millimeters from the device is greater than 20 Gy / (microcurie / cm).

30. The radiation source according to claim 28, wherein the radioactive atom comprises a radium-224 atom having a radioactivity of at least 1 microcurie per centimeter length.

31. The radiation source according to claim 30, wherein the radioactive atom comprises a radium-224 atom having a radioactivity of at least 10.5 microcuries per centimeter length.

32. The radiation source according to claim 28, wherein the radioactive atoms of the one or more isotopes include one or more isotopes that emit beta rays without emitting alpha rays, thereby achieving an asymptotic dose of at least 5 Gy at 2 millimeters from the base.

Images