Controlled release of radionuclides

Abstract

The brachytherapy device (20, 21) comprises a base (22) adapted to be at least partially introduced into the body of a human subject; and a plurality of radionuclide atoms of a first alpha-emitting isotope bound to the base such that no more than 25% of the radionuclide atoms leave the base in a 24-hour period by means other than radioactive decay. When placed in a human subject, the brachytherapy device emits radionuclide atoms of the first alpha-emitting isotope at a rate of at least 0.1% per 24-hour period of the number of radionuclide atoms of the first alpha-emitting isotope bound to the base. [Selected Figure] Figure 1

Description

[Technical field]

[0001] The present invention relates generally to methods of radiation therapy, and in particular to alpha brachytherapy.

[0002] (Cross reference to related applications) This application claims the benefit of U.S. Provisional Patent Application No. 62 / 651,274, entitled "Controlled Release of Radium Isotopes in the Framework of DaRT (Diffuse Alpha Radiotherapy)," filed April 2, 2018, the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0003] Radiation is used to kill cancerous or other malignant cells. There are various methods known for the delivery of 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 use atoms that emit beta and gamma radiation, which have a relatively long range and are therefore easier to deliver to the targeted cancer tissue. However, alpha radiation has a much higher energy and is therefore more effective at killing cancer cells. However, the effective range of alpha radiation is very short, so to be effective, the radioactive atoms that emit alpha particles need to 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. During circulation, the liposome attaches to the malignant cells, and when alpha particles are emitted by the radioactive atom, at least a portion of the emitted alpha particles destroy the malignant cells.

[0005] PCT Patent Application Publication No. WO 01 / 60417 to Larsen, entitled "Radiotherapy Liposomes," PCT Patent Application Publication No. WO 02 / 05859 to Larsen, entitled "Method of Radiotherapy," and U.S. Patent Application Publication No. 2004 / 0208821 to Larsen, entitled "Method of Radiotherapy," the disclosures of which are incorporated herein by reference in their entireties, describe liposomes that encapsulate heavy radionuclides that emit alpha particles. Radionuclides can include radium-223, radium-224, and thorium-227, among others. The daughter radionuclides generally remain trapped during transmutation of the radionuclide.

[0006] Another method of delivering alpha radiation to malignant tissue is brachytherapy, in which one or more seeds carrying a radioactive material, also called a radionuclide, are implanted into the tumor.

[0007] U.S. Patent No. 8,834,837 and U.S. Patent Application Publication No. 2009 / 0136422, both of which are incorporated herein by reference in their entireties, describe the use of devices for brachytherapy using alpha radiation. Radioactive materials not only emit alpha radiation, but also daughter nuclei of the radioactive material, which in a chain reaction emit further alpha particles. This increases the range of cells affected by the alpha radiation.

[0008] A variety of radionuclides have been proposed for use in brachytherapy. US Patent Application Publication No. 2004 / 0242953 to Good, the disclosure of which is incorporated herein by reference, describes various isotopes that can be used in brachytherapy, including thorium-228.

[0009] US Patent Application Publication No. 2013 / 0253255 to Van Niekerk, the disclosure of which is incorporated herein by reference, describes brachytherapy seeds that carry two different isotopes of the same substance.

[0010] US Patent Application Publication No. 2008 / 0249398 to Harder et al., the disclosure of which is incorporated herein by reference, describes a hybrid multi-radionuclide sealed source for use in brachytherapy.

[0011] It is generally desirable to prevent the radionuclides from being washed out of the source by bodily fluids before they have a chance to decay. PCT Patent Application Publication WO 2018 / 207105, entitled "Polymer Coating for Brachytherapy Devices," which is incorporated herein by reference in its entirety, describes coatings selected to prevent the radionuclides from being washed out while not inhibiting the desorption of the daughter nuclei from the source.

[0012] Mavity et al., U.S. Patent Application Publication No. 2002 / 0055667, the disclosure of which is incorporated herein by reference in its entirety, describes radionuclides with bioabsorbable structures that have a predetermined duration, usually substantially longer than the half-life, such that the radionuclides remain localized and sequestered at a desired target site with substantial residual radioactivity.

[0013] U.S. Patent No. 8,821,364 to Fisher et al., the disclosure of which is incorporated herein by reference in its entirety, describes brachytherapy seeds comprised of microspheres 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. Provisional Patent 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 No. 2004 / 0208821 [Patent Document 5] U.S. Patent No. 8,834,837 [Patent Document 6] U.S. Patent Application Publication No. 2009 / 0136422 [Patent Document 7] U.S. Patent Application Publication No. 2004 / 0242953 [Patent Document 8] U.S. Patent Application Publication No. 2013 / 0253255 [Patent Document 9] U.S. Patent Application Publication No. 2008 / 0249398 [Patent Document 10] PCT Patent Application Publication WO2018 / 207105 [Patent Document 11] U.S. Patent Application Publication No. 2002 / 0055667 [Patent Document 12] U.S. Patent No. 8,821,364 Summary of the Invention

[0015] One aspect of some embodiments of the invention relates to a brachytherapy device having: a base adapted to be at least partially introduced into a body of a subject; and a plurality of radionuclide atoms of a first alpha emitting isotope bound to the base such that no more than 25% of the radionuclide atoms leave the base in a 24 hour period by any means other than radioactive decay; wherein the brachytherapy device, when placed in a human subject, emits radionuclide atoms of the first alpha emitting isotope at a rate of at least 0.1% per 24 hour period of the number of radionuclide atoms of the first alpha emitting isotope bound to the base.

[0016] Optionally, the first alpha emitting isotope comprises radium-224 and / or radium-223. Optionally, further comprising a semi-porous polymer coating layer on the radionuclide atoms configured to allow a rate of diffusion of the radionuclide atoms to provide a release of at least 0.1% of the number of radionuclide atoms of the first alpha emitting radioisotope bound to the base per 24 hours. Optionally, the semi-porous polymer coating layer comprises PDMS (polydimethylsiloxane). Optionally, the semi-porous polymer coating layer has a thickness of 0.5 microns or less. Optionally, the semi-porous polymer coating layer allows diffusion of the radionuclide atoms from the brachytherapy device at a rate of at least 0.5% per 24 hours.

[0017] In some embodiments, the device further comprises a base polymer coating layer on the base, where a plurality of radionuclide atoms are attached to the base polymer coating layer, such that the radionuclide 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 diffusion of the radionuclide atoms therethrough. 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 brachytherapy device releases radionuclide atoms of the first alpha-emitting isotope at a rate of at least 3% of the number of radionuclide atoms of the first alpha-emitting isotope bound to the base per 24 hours. Optionally, no more than 15% of the radionuclide atoms leave the base in a 24-hour period by a method other than radioactive decay.

[0018] In some embodiments, a plurality of radionuclide atoms are bound to the base such that 8% or less of the radionuclide atoms leave the base in a 24-hour period by a method other than radioactive decay. Optionally, the base further comprises a bioabsorbable polymer coating layer, where when the radionuclide atoms are embedded in the bioabsorbable polymer coating layer and placed in a subject, the bioabsorbable polymer coating layer dissolves in a manner that causes at least 0.1% of the number of radionuclide atoms of the first alpha-emitting isotope bound to the base to be released from the device per 24-hour period. Optionally, the radionuclide atoms are substantially uniformly distributed throughout the thickness of the bioabsorbable polymer coating layer. Optionally, the base further comprises a plurality of radionuclide atoms of a second alpha-emitting isotope that decays to a first alpha-emitting isotope, where the radionuclide atoms do not leave the brachytherapy device, but are bound to the base in a manner such that upon decay, daughter nuclei of the decaying radionuclide atoms are released from the device.

[0019] Optionally, the plurality of radionuclide atoms of the second alpha-emitting isotope have a radioactivity level that is less than 20%, less than 10%, or less than 5% of the radioactivity level of the radionuclide atoms of the first alpha-emitting isotope contained in the device. Optionally, the plurality of radionuclide atoms of the second alpha-emitting isotope have a radioactivity level that is greater than 1% of the radioactivity level of the radionuclide atoms of the first alpha-emitting isotope contained in the device. Optionally, the plurality of radionuclide atoms of the first alpha-emitting isotope constitute at least 50% of the radionuclide atoms in the brachytherapy device. Optionally, the plurality of radionuclide atoms of the first alpha-emitting isotope provide at least 50% of the radioactivity of the radionuclide atoms in the brachytherapy device. Optionally, the plurality of radionuclide atoms of the first alpha-emitting isotope are at least 5X10 per square centimeter of base. 10 It has the density of atoms.

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

[0021] Optionally, the seed base is comprised of a tube defining an internal channel. Optionally, the first coating layer comprises polycarbonate. Optionally, the first coating layer has a thickness of at least 0.05 microns, at least 0.1 microns, or at least 0.3 microns. Optionally, the first coating layer has a thickness of 1 micron or less, or 0.5 microns or less. Optionally, the second coating layer comprises PDMS (polydimethylsiloxane). Optionally, the second coating layer has a thickness of 0.5 microns or less, or 0.3 microns or less. Optionally, the second coating layer has a thickness of at least 0.1 microns. Optionally, the device allows for the diffusion of particles of radium through the second coating layer at a rate of at least 0.5%, or at least 5%, in 24 hours. Optionally, the device allows for the diffusion of particles of radium through the second coating layer at a rate of no more than 10%, or no more than 2% in 24 hours.

[0022] An aspect of some embodiments of the invention relates to a brachytherapy device having: a probe adapted to be introduced at least partially into a subject's body; particles of radium-224 retentively embedded on or under a surface of the probe, the particles of radium-224 being embedded in a manner that ensures that the particles of radium-224 remain within the probe while a therapeutic dose of radium-224 particle decay chain nuclei and alpha particles are emitted outside the surface of the probe; and particles of thorium-228 retentively embedded on or under a surface of the probe, the particles of thorium-228 being embedded in a manner that ensures that the particles of thorium-228 remain within the probe while a therapeutic dose of thorium-228 particle decay chain nuclei and alpha particles are emitted outside the surface of the probe. The radioactivity level of the thorium-228 particles in the device is less than 50% of the radioactivity level of the radium-224 particles.

[0023] Optionally, the probe comprises a removable probe. Optionally, the removable probe includes a needle, an endoscope tip, a laparoscope tip, or an imaging device tip. Optionally, the probe comprises a tube defining an internal channel. Optionally, the probe further comprises a protective coat coating the probe and the thorium-228 radionuclide, the thickness and material of the protective coat being selected so as not to impede the emission of decay chain nuclei and alpha particles. Optionally, the probe comprises 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, whereby the radionuclide is on or below the surface of the distal end. Optionally, the probe and the thorium-228 particles are uncoated. Optionally, the probe comprises brachytherapy seeds.

[0024] An aspect of some embodiments of the invention relates to a method of brachytherapy treatment comprising: determining at least one characteristic of a malignant tumor in a subject; selecting a layout of one or more seeds loaded with radionuclide atoms of a first isotope emitting alpha radiation to be implanted in the malignant tumor in response to the determined at least one characteristic; selecting for each of the one or more seeds an emission rate of the first isotope from the seed that does not include emission of alpha particles and daughter nuclei; and placing seeds of the selected emission rate in the malignant tumor according to the selected layout. Optionally, the first isotope comprises radium-224. Optionally, determining at least one characteristic of the malignant tumor comprises determining a shape and / or size of the malignant tumor. Optionally, placing the seeds comprises placing seeds having at least two substantially different emission rates of the first isotope. [Brief description of the drawings]

[0025] [Figure 1] 1 is a schematic diagram of a brachytherapy device, in accordance with an embodiment of the present invention. [Diagram 2] 1 is a schematic cross-sectional view of a brachytherapy device according to another embodiment of the present invention. [Diagram 3] 1 is a schematic diagram of a brachytherapy device, in accordance with yet another embodiment of the present invention; [Figure 4] FIG. 2 is a schematic diagram of a brachytherapy device, according to another embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0027] In some embodiments, the desired atomic detachment rate is achieved by coating the brachytherapy implant with a coating having a thickness and / or other properties selected to enable the desired detachment rate.

[0028] In other embodiments, the desired atomic detachment rate is achieved by including in the brachytherapy implant a bioabsorbable material in which the radionuclide atoms are embedded. When the brachytherapy implant is within the subject's body, the bioabsorbable material degrades and upon decomposition, the radionuclide leaves the implant.

[0029] An aspect of some embodiments of the present invention relates to a brachytherapy implant carrying a plurality of different alpha-emitting radionuclides. In some embodiments, the radionuclides have a high probability that their daughter nuclides will leave the brachytherapy implant within the tumor upon nuclear decay. Optionally, the plurality of different radionuclides include a parent nuclide and a daughter nuclide resulting from 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] 1 is a schematic diagram of a brachytherapy device 20, in accordance with an embodiment of the present invention. The brachytherapy device 20 includes a support 22 that serves as a base for the device 20 and is configured for insertion into a subject's body. The brachytherapy device 20 has a bioabsorbable coating 28 of thickness T0 on an outer surface 24 of the support 22, with radionuclide atoms 26 dispersed therein throughout the thickness of the coating 28. It should be noted that for ease of illustration, the atoms 26 are depicted as being disproportionately large relative to the thickness of the coating 28.

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

[0032] The bioabsorbable coating 28 optionally includes a semi-porous, 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. Meanwhile, the absorption rate is not negligible, and in some embodiments, is greater than 0.05 microns, 0.1 microns, 0.3 microns, or even 0.8 microns per day. Optionally, the absorbable polymer matrix has a daily absorption rate of less than 20%, less than 10%, or even less than 5% of the thickness of the coating 28. The absorption rate is optionally as high as 1%, 3%, 5%, or even 10% per day. The absorption rate is optionally selected according to the half-life of the radionuclide atoms 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 brachytherapy device 20 is implanted. Optionally, the rate of absorption is not too rapid 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 brachytherapy device 20 is implanted.

[0033] The bioabsorbable coating 28 optionally includes polylactide (PLA), polyglycolide (PGA), or a copolymer of PLA and PGA, adjusted to achieve a desired absorption rate. Alternatively or additionally, the coating 28 includes copolylactic / glycolic acid (PLGA). The polymer of the coating 28 optionally has a molecular weight 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 one or more of ultrasonic energy, reaction with body temperature, and / or reaction with bodily fluids. Additional discussion of bioabsorbable polymers that may be used in accordance with embodiments of the present invention after adjustment of the desired absorption rate is provided in U.S. Pat. No. 8,821,364 and U.S. Patent Publication 2002 / 0055667, cited above.

[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 radionuclide atoms 26 from being washed away before the coating 28 dissolves, but thin enough to allow diffusion of the daughter radionuclides.

[0035] The radionuclide atoms 26 are optionally of an element that emits alpha particles upon radioactive decay, and the daughter radionuclide diffuses readily through the coating 28. The diffusion coefficient of the daughter radionuclide in the polymer is at least 10 -11 cm 2 per second. Preferably, the radionuclide atoms 26 are of an isotope that produces a chain of at least three, or even at least five, alpha-emitting decay events until a stable or long half-life element is reached. The radionuclide atoms 26 optionally include an isotope of radium that decays by alpha radiation (e.g., radium-224 or radium-223) that decays by alpha radiation to produce a daughter isotope of radon (e.g., Rn-220 or Rn-219) that decays by alpha radiation to produce an isotope of polonium (e.g., Po-216 or Po-215) that decays by alpha radiation to produce an isotope of lead (e.g., Pb-212 or Pb-211).

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

[0037] Typically, the density of radionuclide atoms 26 in coating 28 is greater than 10 per square centimeter. 11 ~10 14 Atoms 26 are optionally evenly distributed throughout the thickness of coating 28.

[0038] FIG. 2 is a schematic diagram of a brachytherapy device 100, according to one embodiment of the present invention. The brachytherapy device 100 is similar to the device 20 of FIG. 1, but its bioabsorbable coating 28 is formed from multiple layers that differ in their polymer matrix composition and / or the concentration of radionuclide atoms 26 therein. As shown, the coating 28 includes three layers, with the concentration of radionuclide atoms 26 increasing the further the layer is from the support 22. The layer 102 closest to the support 22 has the first and lowest concentration of radionuclide atoms 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 radionuclide atoms 26. The device 100 is presented as an example, and in other embodiments, the brachytherapy device may have two layers. Or four or more layers. Additionally, in other embodiments, the concentration of radionuclide atoms 26 in the layers varies. Optionally, the concentration increases as the layer approaches 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 support 22.

[0039] Instead of, or in addition to, differing concentrations of radionuclide atoms 26, the layers of coating 28 differ in their absorption rates of their polymer structures. In one embodiment, the absorption rate is higher in the outer layer than in the inner layer. In another embodiment, the absorption rate is lower in the outer layer than in the inner layer.

[0040] 3 is a schematic diagram of a brachytherapy device 21 according to another embodiment of the present invention. Device 21 differs from device 20 in that device 21 does not include a bioabsorbable coating, but instead has an outer layer 33 that allows radionuclide atoms 26 to diffuse slowly out of device 21 at a desired rate. Optionally, device 21 includes two polymer layers: a first polymeric inner layer 30 that coats outer surface 24, and a second polymeric outer layer 33 that coats inner layer 30. Atoms 26 are bonded to inner layer 30 and covered by outer layer 33, which generally prevents atoms 26 from leaving device 21, but allows radionuclide atoms 26 to diffuse slowly out of device 21. On the other hand, outer layer 33 optionally allows daughter nuclei to easily leave device 21 as a result of nuclear decay and / or due to the properties of the daughter nuclei.

[0041] The outer layer 33 optionally comprises a biocompatible PDMS (polydimethylsiloxane) with a porosity and / or thickness tailored to achieve a desired diffusion coefficient of the radionuclide atoms 26. The thickness of the outer layer 33 is optionally 0.1 to 10 microns, such as 0.1 to 0.3 microns, or 0.5 to 1 micron. The outer layer 33 optionally has a thickness of 0.1 to 10 microns, such as 0.1 to 0.3 microns, or 0.5 to 1 micron, such that the radionuclide atoms 26 are dispersed therein at a density of 100 nm. -13 cm 2 / sec or even less than 2X10 -14 cm 2 Optionally, the radionuclide atoms 26 are formed to have a diffusion coefficient of less than 2×10 / sec in the outer layer 33. -15 cm 2 / sec greater than 8X10 in some cases -15 cm 2 / sec. Meanwhile, the daughter nuclides of the radionuclide atoms 26 optionally have a diffusion coefficient in the outer layer 33 of, for example, at least 10 ―11 cm 2 / sec.

[0042] Inner layer 30 optionally comprises a material that bonds weaker with radionuclide atoms 26 than support 22, such that atoms 26 can escape device 21 without the energy of nuclear decay. In some embodiments, inner layer 30 comprises a polymer, such as polypropylene, polycarbonate (PC), polydimethylsiloxane, polyethylene terephthalate, poly(methyl methacrylate), and / or polysulfone, that coats surface 24. In some embodiments, inner layer 30 is also permeable to daughter radionuclides; for example, the diffusion coefficient of the daughter radionuclides in inner layer 30 is at least 10 -11 cm 2 / sec. 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 of between about 0.2-0.4 microns, for example, about 0.3 microns. However, in other embodiments, the inner layer 30 is thinner than 0.1 microns, or thinner than 50 nanometers. In still other embodiments, the inner layer 30 is omitted, the radionuclide atoms 26 are placed directly on the support 22, and other means are used to prevent strong bonding between the radionuclide atoms 26 and the support 22. Typically, the density of the radionuclide atoms 26 in the device 21 is about 5X10 per square centimeter. 10 ~10 14 It is an atom.

[0044] Optionally, the structure of the outer layer 33 of the device 21 and / or the coating 28 of the device 20 is selected such that at least 0.1%, at least 0.5%, or even at least 1% of the atoms 26 in the device leave the device by diffusion or dissolution of the coating 28 per day. In some embodiments, the percentage of radionuclide atoms 26 that leave the device by diffusion or dissolution in a day is less than 3%, less than 2%, less than 1%, or even less than 0.5%. Optionally, the number of atoms 26 that leave the device by diffusion or dissolution in 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 in that given time. The number of atoms 26 that leave the device by a method other than nuclear decay is optionally 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 shortly after the device 20 or 21 is placed in the subject. For example, already within the first 24 hours after placement, or at most within 48 hours after placement, at least 0.1% of the radionuclide atoms 26 in the device will leave the device by diffusion or dissolution.

[0046] 4 is a schematic diagram of a brachytherapy device 120 according to another embodiment of the present invention. The device 120 is comprised of a support 22 having radionuclide atoms 124 and 126 of two different elements on an 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, for example, a heat treatment as described in U.S. Patent Publication 2009 / 0136422, or a thin protective layer (not shown), such as a 5-10 nanometer titanium layer.

[0047] Optionally, radionuclide atom 124 is a daughter nuclide resulting from the decay of radionuclide atom 126. In some embodiments, radionuclide atom 124 comprises radium-224, while radionuclide atom 126 comprises thorium-228. The radioactivity level of radionuclide atom 126 optionally has a radioactivity level that is less than 50%, less than 20%, less than 10%, or even less than 5% of the radioactivity level of radionuclide atom 124.

[0048] In one embodiment, radionuclide atom 124 has a radioactivity level of about 2 microCi and radionuclide atom 126 has a radioactivity level of about 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 of Figures 1-3.

[0049] The brachytherapy devices discussed above with reference to Figures 1-4, when based primarily on radium-224 radionuclide atoms, allow a certain percentage of radium-224 to exit the brachytherapy device without decay. Because the half-life of radium-224 is 3.66 days, some of this radium-224 leaves the tumor completely before it decays. The radium-224 atoms thus lost are not only wasted, but may also reach and damage healthy tissue. Thus, the prior art has avoided the release of radionuclide atoms having such long half-lives into the tumor. In accordance with the present invention, it has been determined that the release of a relatively small amount of radium-224 into the tumor is beneficial and provides much needed energy in the area of ​​the tumor, away from the brachytherapy device. It has been determined that this advantage outweighs the disadvantage of lost radionuclide atoms.

[0050] In some embodiments of the invention, the percentage of radium-224 radionuclide atoms that can leave the brachytherapy device is selected depending on the size of the tumor. Optionally, seeds tailored for different amounts of radium-224 emission are provided to the physician, and the physician selects the appropriate seed depending on the size of the tumor and the location where the seed is to be implanted. Alternatively, the physician determines the size of the tumor and is provided with appropriate seeds with the desired degree of radium-224 emission accordingly. In some embodiments, when multiple seeds are implanted in a single tumor, the different seeds may have different degrees of radium-224 emission. For example, seeds implanted at the periphery of the tumor may optionally emit small amounts or virtually no radium-224, whereas seeds implanted in the center of the tumor may emit a greater degree of radium-224. In some embodiments, the physician determines the size and / or layout of the tumor and selects the number of seeds to be implanted in the tumor and / or the degree of radium-224 emission of each seed implanted accordingly.

[0051] In general, the polymer coating 28 can be applied to the device 20, or the inner layer 30 and outer layer 33 can be applied to the device 21, using any suitable technique known in the art, such as, for example, a dip coating technique as described in the above-mentioned PCT International Patent Application Publication WO2018 / 207105 (Patent Document 10).

[0052] Typically, a radionuclide atom 26 is produced by the decay of a preceding radionuclide in its decay chain. For example, as described in U.S. Patent No. 8,894,969 to Kelson et al., atoms of radium-224 can be produced by spreading a thin layer of an acid containing uranium-232 (U-232) over a metal. The uranium-232 decays to produce thorium-228 (Th-228), which then decays to produce radium-224.

[0053] Atoms 26 can be attached to support 22 using any suitable technique, such as one or more of the techniques described in the aforementioned U.S. Patent No. 8,894,969 to Kelson et al. For example, a source generating a flux of radionuclides can be placed in a vacuum adjacent support 22 such that recoil nuclei from the source cross the vacuum gap and are collected or injected onto surface 24. Alternatively, radionuclides can be electrostatically collected on support 22 by applying a suitable negative voltage between the source and support. In such an embodiment, support 22 can be comprised of a conductive metal, such as titanium, to facilitate electrostatic collection of radionuclides. For example, support 22 can be comprised of a conductive metal wire, needle, rod, or probe. Alternatively, support 22, including surface 24, can be comprised of a non-metallic needle, rod, or probe coated with a conductive metal coating.

[0054] To treat a subject, at least one brachytherapy device is inserted wholly or partially into the subject's body, typically into or immediately adjacent (e.g., within 0.1 mm, such as within 0.05 mm or 0.001 mm) the tumor to be treated. Thereafter, while the brachytherapy device remains in the body, the radionuclide decays, thereby releasing alpha particles, daughter nuclei, and a portion of the radionuclide atoms 26 into the tumor.

[0055] In some embodiments, following radioactive decay of at least some of the radionuclide atoms, the brachytherapy device is removed from the subject, e.g., after a predetermined period of time and / or in response to monitoring the size of the tumor and / or the rate of emitted alpha particles. In other embodiments, the device is not removed from the subject.

[0056] It will be understood that the above methods and apparatus should be construed as including apparatus for performing the methods and methods of using the apparatus. It will be understood that features and / or steps described with respect to one embodiment may be used with other embodiments, and that not all embodiments of the invention have all of the features and / or steps shown in a particular figure or described with respect to one of the particular embodiments. Tasks may not necessarily be performed in the exact order described.

[0057] In some embodiments, combinations of the above embodiments of Figures 1-4 are used. For example, a brachytherapy device may include a bioabsorbable layer for releasing radium embedded therein and may further include thorium atoms attached to an internal support. As another example, a brachytherapy device may include a bioabsorbable and diffusable layer that 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 above embodiments may include structures, operations, or details of structures and operations described as examples that are not essential to the present invention. The structures and operations described herein may be replaced with equivalents that perform the same functions, even if the structures or operations are different, as known in the art. The above-mentioned embodiments 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 variations and modifications thereof that are not disclosed in the prior art and that would occur to one skilled in the art upon 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 "comprising," "including," "having," and their conjugates, when used in the claims, mean "including, but not necessarily limited to."

Claims

1. 1. A brachytherapy apparatus comprising: a seed base adapted to be implanted into the body of a subject at the time of implantation; and a plurality of radionuclide atoms of a first alpha-emitting isotope, the first being radium; the radionuclide atoms are bound to the seed base, and during a 24 hour period from the time of implantation, at least 0.1% and not more than 25% of the radionuclide atoms that are radium bound to the seed base at the time of implantation leave the seed base without radioactive decay.

1. A brachytherapy device comprising:

2. 2. The brachytherapy device of claim 1, wherein said first alpha emitting isotope is radium-224.

3. 2. The brachytherapy device of claim 1, wherein said first alpha emitting isotope is radium-223.

4. 2. The brachytherapy device of claim 1, further comprising a semi-porous polymer coating layer on the radionuclide atoms configured to allow diffusion of a portion of the radionuclide atoms to provide a release of at least 0.1% of the radionuclide atoms of a first alpha-emitting isotope bound to the seed base at the time of implantation during a 24 hour period after the seed base is implanted in the subject.

5. 5. The brachytherapy device of claim 4, wherein the semi-porous polymer coating layer comprises PDMS (polydimethylsiloxane).

6. 5. The brachytherapy device of claim 4, wherein the semi-porous polymer coating layer has a thickness of 0.5 micrometers or less.

7. 5. The brachytherapy device of claim 4, wherein the semi-porous polymer coating layer, when the seed base is implanted in the subject, allows for diffusion of at least 0.5% of the radionuclide atoms of the first alpha-emitting isotope bound to the seed base at the time of implantation within 24 hours after implantation in the subject.

8. 5. The brachytherapy device of claim 4, further comprising a base polymer coating layer on said seed base, wherein a plurality of said radionuclide atoms are attached to said base polymer coating layer, and thus bonded to said seed base in such a manner that said radionuclide atoms can separate and diffuse without nuclear decay.

9. 10. The brachytherapy device of claim 8, wherein the base polymer coating layer is configured to prevent diffusion of the radionuclide atoms therethrough.

10. 10. The brachytherapy device of claim 8, wherein the base polymeric coating layer comprises polycarbonate.

11. 9. The brachytherapy device of claim 8, wherein the base polymeric coating layer has a thickness of at least 0.25 micrometers.

12. 2. The brachytherapy device of claim 1, wherein at least 3% of the radionuclide atoms of the first alpha-emitting isotope bound to the seed base at the time of implantation of the seed base leave the seed base within 24 hours after the seed base is implanted in the subject.

13. 13. The brachytherapy device of claim 1, wherein within 24 hours after the seed base is implanted in the subject, not more than 15% of the radionuclide atoms of the first alpha-emitting isotope bound to the seed base at the time of implantation of the seed base leave the seed base without radioactive decay.

14. 2. The brachytherapy device of claim 1, wherein the plurality of radionuclide atoms of the first alpha-emitting isotope are bound to the seed base, and during a 24 hour period after the seed base is implanted in the subject, no more than 8% of the radionuclide atoms of the first alpha-emitting isotope bound to the seed base at the time of implantation of the seed base leave the seed base without radioactive decay.

15. 13. The brachytherapy device of claim 1, further comprising a bioabsorbable polymer coating layer on said seed base, wherein said radionuclide atoms are embedded in said bioabsorbable polymer coating layer and, when placed in a subject, said bioabsorbable polymer coating layer dissolves and at least 0.1% of the number of radionuclide atoms of said first alpha-emitting isotope bound to said seed base are released from the device over a 24 hour period.

16. 16. The brachytherapy device of claim 15, wherein said bioabsorbable polymer coating layer contains said radionuclide atoms at the same density throughout its thickness.

17. a plurality of radionuclide atoms of a second alpha-emitting isotope that decays to the first alpha-emitting isotope; a radionuclide atom of the second alpha-emitting isotope is bound to the seed base and does not leave the brachytherapy device, but upon nuclear decay of the second alpha-emitting isotope, a daughter nucleus of the decaying radionuclide atom of the second alpha-emitting isotope is released from the device.

2. The brachytherapy device of claim 1.

18. 20. The brachytherapy device of claim 17, wherein the plurality of radionuclide atoms of the second alpha-emitting isotope have a radioactivity level that is less than 20% of the radioactivity level of the radionuclide atoms of the first alpha-emitting isotope contained in the device.

19. 20. The brachytherapy device of claim 18, wherein the plurality of radionuclide atoms of the second alpha-emitting isotope have a radioactivity level that is less than 5% of the radioactivity level of the radionuclide atoms of the first alpha-emitting isotope contained in the device.

20. 20. The brachytherapy device of claim 17, wherein the plurality of radionuclide atoms of the second alpha-emitting isotope have a radioactivity level that is greater than 1% of the radioactivity level of the radionuclide atoms of the first alpha-emitting isotope contained in the device.

21. 13. The brachytherapy device of any of claims 1 to 12, wherein the seed base is cylindrical, and the seed base has a length of 5 millimeters or more.

22. A plurality of radionuclide atoms of the first alpha-emitting isotope are present per square centimeter of the seed base at least 5*10 10 13. A brachytherapy device according to any one of the preceding claims, characterized in that it has an atomic density.

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