Alpha emitter source

Abstract

A radiotherapy source (20, 30, 40) for treating tumors comprises a radon-impermeable flexible core (22) and a polymer coating (28, 48) on the flexible core. The polymer coating is impermeable to radium and allows radon to diffuse through it. The radiotherapy source also comprises an alpha-emitting radium radionuclide (26) in the polymer coating or between the flexible core and the polymer coating.

Description

[Technical Field]

[0001] This invention generally relates to tumor treatment, and more particularly to intratumor alpha-emitting radiotherapy. [Background technology]

[0002] Ionizing radiation is commonly used to destroy the cells of certain types of tumors, including malignant cancerous tumors, in the treatment of these tumors. Alpha radiation is the most powerful type of radiation for cell destruction, but its range is very short, and therefore its delivery to tumors is a challenge.

[0003] For example, diffusing alpha-emitting radiotherapy (DaRT), as described in U.S. Patent No. 8,834,837 granted to Kelson, involves implanting alpha-emitting radionuclides onto a source (also called a seed) in a way that prevents them from detaching from the source, as a large percentage of the alpha-emitting radionuclides are flushed through the bloodstream before they undergo radioactive decay. Alternatively, the alpha-emitting radionuclides are implanted onto the source in a way that a substantial percentage of their daughter radionuclides (radon-220 in the case of radium-224, radon-219 in the case of radium-223) detach from the source during decay and enter the tumor. These daughter radionuclides and their own radioactive daughter atoms diffuse around the source over a radial distance of several millimeters before they decay due to alpha emission. That is, the distance of destruction in the tumor is increased compared to radionuclides that remain on the source with their daughters.

[0004] PCT Publication WO / 2018 / 207105, titled "Polymer Coatings for Brachytherapy Devices," describes a DaRT source having a relatively thick polymer coating that allows for the diffusion of daughter radionuclides through it.

[0005] Another method used to deliver alpha-emitting radioactive atoms to malignant cells is targeted radionuclide therapy using radioimmune complexes. In targeted therapy, a carrier such as a liposome is attached to the radioactive atom and injected into the patient's bloodstream. While circulating, the liposome attaches to malignant cells, and when alpha particles are released by the radioactive atom, at least some of the released alpha particles destroy the malignant cells.

[0006] PCT Publication WO01 / 60417, entitled “Radioactive Therapeutic Liposomes,” PCT Publication WO02 / 05859, entitled “Method of Radiotherapys,” and U.S. Patent Publication 2004 / 0208821, entitled “Method of Radiotherapys,” all of which are incorporated herein by reference, describe liposomes that encapsulate heavy radionuclides that emit alpha particles. The radionuclides may include, among others, radium-223, radium-224, and thorium-227. Daughter radionuclides generally remain trapped during the transmutation of the radionuclide.

[0007] PCT Publication WO / 2006 / 110889, titled "Multi-Layer Structure having a Predetermined Layer Pattern Including an Agent," describes a polymer multilayer structure that can be used to deliver radioisotopes for radiotherapy.

[0008] Alpha-emitting radioactive atoms may also be delivered to tumors during intracavitary treatment. U.S. Patent Publication 2017 / 0000911, titled "Radiotherapeutic Particles and Suspensions," describes the intracavitary delivery of alpha emitters bound to microparticles or nanoparticles within a carrier, diluent, or excipient. The microparticles and nanoparticles are described as stable or slowly degrading.

[0009] PCT Publication WO / 2010 / 028048, titled "Brachytherapy Seed with Fast Dissolving Matrix for Optimal Delivery of Radionuclides to Cancer Tissue," describes a polymer seed in which microspheres containing beta-emitting or alpha-emitting radionuclides are embedded. After the seed is embedded in the tumor, the seed dissolves so that the radionuclides within the microspheres can destroy tumor cells.

[0010] U.S. Patent No. 7,776,310, granted to Kaplan, is titled "Flexible and / or elastic Brachytherapy Seed or Strand" and describes a nonmetallic polymer brachytherapy flexible strand supporting alpha or beta-emitting particles.

[0011] The paper "Ra-224 labeling of calcium carbonate microparticles for internal α-therapy: Preparation, stability, and biodistribution in mice" by Westrom S, Malenge M, Jorstad IS, Napoli E, Bruland OS, Bonsdorff TB, and Larsen RH, published in J Labelled Comp Radiopharm. 2018 May 30;61(6):472-486.doi:10.1002 / jlcr.3610.Epub 2018 Mar 12.PMID:29380410;PMCID:PMC6001669, proposes the use of calcium carbonate microparticles as carriers for radium-224 designed for local therapy of disseminated cancer in the cavity. [Prior art documents] [Patent Documents]

[0012] [Patent Document 1] U.S. Patent No. 8,834,837 [Patent Document 2] PCT Public Statement WO / 2018 / 207105 [Patent Document 3] PCT Publication WO01 / 60417 Specification [Patent Document 4] PCT Publication No. WO02 / 05859 Specification [Patent Document 5] U.S. Patent Publication No. 2004 / 0208821 [Patent Document 6] PCT Public Statement WO / 2006 / 110889 [Patent Document 7] U.S. Patent Publication No. 2017 / 0000911 [Patent Document 8] PCT Public Statement WO / 2010 / 028048

Patent Document 9

Patent Document 10

Patent Document 11

Patent Document 12

Patent Document 13

Patent Document 14

Non-Patent Document

[0013]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

[0014] Accordingly, embodiments of the present invention provide a radiotherapy source for treating tumors comprising a flexible core that is impermeable to radon, a polymer coating on the flexible core that is impermeable to radium and allows the diffusion of radon passing through it, and an alpha-emitting radium radionuclide in the polymer coating or between the flexible core and the polymer coating.

[0015] Optionally, the flexible core contains gold strands. Alternatively, or in addition to this, the flexible core contains a polymer that is impermeable to radon. In some embodiments, the flexible core contains polyether ether ketone (PEEK). Optionally, the flexible core has a thickness not greater than 0.3 millimeters. Optionally, the radium radionuclide is dispersed throughout the entire thickness of the polymer coating. Optionally, the radiotherapy source further contains small particles dispersed within the polymer coating, to which the radium radionuclide is bound. Optionally, the flexible core and polymer coating do not exhibit biodegradability for at least one week after implantation in the tumor. Optionally, the radiotherapy source contains a layer of manganese oxide on the flexible core, to which the radium radionuclide is bound. Optionally, the radiotherapy source contains a layer of parylene or silicone rubber between the flexible core and the manganese oxide layer.

[0016] Furthermore, embodiments of the present invention further provide a method for preparing a radiotherapy source, comprising the steps of: mixing a solvent and a solute to form a mixture that forms a polymer upon curing; mixing an alpha-emitting radium radionuclide into the mixture; placing the mixture of radium and polymer components on a flexible core; and allowing the mixture to (naturally) cure after the step of placing the mixture on the flexible core to form a polymer coating. Optionally, the step of mixing an alpha-emitting radium radionuclide into the mixture includes the step of mixing a solution containing the radium radionuclide into the mixture. Optionally, the method includes the step of removing excess liquid from the mixture before the step of placing the mixture on the flexible core.

[0017] Furthermore, embodiments of the present invention provide a drug for treating tumors comprising microparticles having an outer surface containing manganese oxide and an alpha-emitting radium radionuclide on the outer surface of the microparticles. Optionally, the microparticles comprise a non-manganese oxide core coated with manganese oxide. Optionally, the microparticles comprise gold, titanium, titanium oxide, zirconium oxide, and / or silicon oxide. Optionally, the microparticles have a diameter less than 10 micrometers. [Brief explanation of the drawing]

[0018] [Figure 1] This figure shows a cross-section of a flexible radiotherapy source according to an embodiment of the present invention. [Figure 2] This figure shows a cross-section of a flexible radiotherapy source according to another embodiment of the present invention. [Figure 3] This figure shows a cross-section of a flexible radiotherapy source according to yet another embodiment of the present invention. [Figure 4] This is a flowchart illustrating a method for generating a flexible radiotherapy source according to an embodiment of the present invention. [Figure 5] This figure shows a cross-section of a directional radiotherapy source according to an embodiment of the present invention. [Modes for carrying out the invention]

[0019] Aspects of some embodiments of the present invention relate to a flexible radiotherapy source that supports alpha-emitting radium in such a manner that radium is not emitted from the source, but daughter radons generated by the radioactive decay of radium are allowed to detach from the flexible radiotherapy source. The flexible radiotherapy source comprises a flexible core that is impermeable to radon and an outer polymer coating that is permeable to radon but does not allow substantial passage of radium. Such a flexible radiotherapy source enables the advantages of a flexible source, such as improved adhesion to the contours of body organs and their integration using diffuse alpha-emitting radiotherapy (DaRT).

[0020] Aspects of some embodiments of the present invention relate to delivering an alpha-emitting radium radionuclide to a tumor attached to small particles having an outer manganese oxide surface. Such small particles prevent the emission of radium from the tumor, while allowing daughter radon to diffuse into the tumor.

[0021] Figure 1 shows a cross-section of a flexible radiotherapy source 20 according to an embodiment of the present invention. The source 20 includes an inner flexible core 22, a radium-bonded layer 24, a radium radionuclide 26, and a protective coating 28 that prevents radium leakage and allows radon emission. Note that Figure 1 and the other figures are not drawn to exact scale. In particular, the radium radionuclide 26 is depicted much larger than it actually is so that it can be seen in the figures.

[0022] In some embodiments, the inner flexible core 22 comprises a flexible plastic metal such as gold and / or titanium (e.g., high-purity titanium). In other embodiments, the inner flexible core 22 comprises a flexible elastic metal such as nitinol. The inner flexible core 22 is optionally formed from a single thin monofilament wire. Alternatively, the inner flexible core 22 is braided from multiple thin wires.

[0023] In other embodiments, the inner flexible core 22 comprises a polymer impermeable to radon, such as polyetheretherketone (PEEK), polytetrafluoroethylene (PTFE, sometimes known as Teflon), or polyimide (4,4'-oxydiphenylene-pyromellitoimide, also known as Kapton).

[0024] Optionally, in embodiments in which the inner flexible core 22 includes a polymer, nanoparticles of a material readily identifiable in medical images, such as gold, platinum, bismuth, and / or tantalum, are added to the polymer of the inner flexible core 22 to enable identification of the source 20 in medical images. The concentration of nanoparticles can be low, for example, less than 10%, or less than 5%, or even less than 2%, but can generally remain above 0.5%, or even more than 1%, or it can be high, for example, at least 30%, at least 50%, or even more than 75%.

[0025] The inner flexible core 22 optionally has a cylindrical shape of elongated strands with a diameter of at least 0.1 mm, at least 0.15 mm, or even at least 0.2 mm, in order to give the source sufficient mechanical strength. On the other hand, the diameter of the inner flexible core 22 is optionally smaller than 0.5 mm, or smaller than 0.4 mm, or smaller than 0.35 mm, or even smaller than 0.3 mm, so that the source is flexible. The diameter of the inner flexible core 22 optionally depends on the material of the inner flexible core 22. In one embodiment, the inner flexible core 22 contains a gold wire with a diameter of about 0.25 mm. Optionally, the inner flexible core 22 is solid without an internal channel and therefore different from a tube having a hollow channel.

[0026] Flexible radiotherapy source 20 can optionally be 5 Newtons-millimeter (N * Smaller than (mm), or 3N * Smaller than mm, or 2N *Smaller than mm, or 1N * Smaller than mm, or 0.8N * Smaller than mm, or even smaller than 0.6N * It has a bending moment less than mm. In some embodiments, the flexible radiotherapy source 20 can be bent to a deflection of up to 90° in a range of less than 2 centimeters or not exceeding 1 centimeter.

[0027] However, in some embodiments, the internal flexible core 22 may have any other suitable shape, such as a rod, sphere, cylinder, pyramid, star, or sheet, depending on its intended purpose. In some embodiments, the internal flexible core 22 is manufactured to have a shape that adapts to the body area being treated. For example, the shape of the body area may optionally be determined using imaging means such as CT or by forming a mold on the body area, and the internal flexible core 22 is manufactured to have a shape determined using any suitable method known in the art, such as three-dimensional printing.

[0028] The radium-bonding layer 24 optionally contains a manganese oxide. The manganese oxide optionally contains hydrated manganese oxide (HMO) and / or manganese dioxide (MnO2). Alternatively, the manganese oxide may contain any other manganese oxide that bonds radium, such as manganese(IV) dioxide, manganese(II) oxide (MnO), manganese(II,III) oxide (Mn3O4), manganese(III) oxide (Mn2O3), and manganese(VII) oxide (Mn2O7), or a mixture of various manganese oxides.

[0029] The radium-bonded layer 24 optionally has a thickness of no more than 1 micron, sometimes less than 0.3 microns, less than 0.1 microns, or even less than 0.05 microns. In some embodiments, the radium-bonded layer 24 has a thickness as low as about 10 nanometers.

[0030] The manganese oxide is optionally placed on the inner flexible core 22 by briefly immersing it in an aqueous solution of potassium permanganate (KMnO4). The potassium permanganate (KMnO4) is optionally at a concentration of at least 0.1% by weight, at least 1% by weight, or even more at least 3% by weight of the aqueous solution. Alternatively or in addition, the potassium permanganate (KMnO4) is not greater than 10% by weight or even more than 7% by weight of the aqueous solution. This brief immersion is optionally performed at a temperature of at least 60°C, or even more at least 80°C, for example, about 90°C. However, it should be noted that in some cases the brief immersion is performed at a temperature lower than 60°C, for example, room temperature, or at a higher temperature than 90°C, sometimes as high as 150°C. After briefly immersing the inner flexible core 22, the inner flexible core 22 and the manganese oxide are optionally cooled slowly for at least 1 hour or at least 6 hours.

[0031] In other embodiments, the radium-bonded layer 24 contains a chemical that transforms into a hydrogel upon the addition of calcium ions, such as sodium alginate or Pluronic acid. Optionally, in these embodiments, the chemical that transforms into a hydrogel is dried and solidified, for example, by adding a high percentage of calcium.

[0032] In yet another embodiment, the radium bonded layer 24 includes a cation exchange resin such as polystyrene treated with a sulfonic acid, a copolymer of styrene and divinylbenzene treated with a sulfonic acid, and / or polyacrylate treated with a carboxylic acid.

[0033] Optionally, the radium radionuclide 26 includes the alpha emitter radium-224 or radium-223. Optionally, the radium radionuclide 26 is placed on the radium binding layer 24 by, for example, immersing the inner flexible core 22 in a radium solution together with the radium binding layer 24 for a short time as described in PCT Publication WO / 2021 / 070029, the entire content of which is incorporated herein by reference. Alternatively, the radium radionuclide 26 is placed on the radium binding layer 24 by placing the radium binding layer 24 within a flux of radium radionuclide. Optionally, the flux is generated by a flux generating surface source. For example, when the radionuclide is Ra-224, the flux can be generated by a surface source of thorium-228 (Th-228). The surface source of Th-228 can be prepared, for example, by collecting Th-228 atoms emitted from a parent surface source, U-232. Such a parent surface source can be prepared, for example, by spreading a thin layer of an acid containing U-232 over a metal. Alternatively or in addition, the flux is generated using any of the methods described in U.S. Patent Publication No. 2015 / 0104560, entitled "Method and Device for Radiotherapy," issued to Kelson et al., the entire disclosure of which is incorporated herein by reference.

[0034] The thickness of the protective coating 28 is optionally selected to allow radon resulting from the desorption of the radium radionuclide 26 to escape from the source 20. The protective coating 28 is configured to have only a diffusion coefficient that is less than 10 -16 cm 2 / second, or less than 2 * 10 -17 cm 2 / second, or less than 10 -18 cm 2 / second. On the other hand, radon optionally has a diffusion coefficient of at least 10 -12 cm 2 / second, at least 10-11 cm 2 / second, or at least 10 -10 cm 2 It has a diffusion coefficient of / second.

[0035] The protective coating 28 is optionally non-biodegradable or does not degrade significantly (e.g., by more than 0.1%) within five half-lives of the radium radionuclide 26 from the time of implantation. However, it should be noted that in some embodiments, for example, when radium is bound to microparticles and / or when the source carries a drug to be released, the protective coating 28 and / or other parts of the source 20 may be biodegradable.

[0036] The protective coating 28 optionally includes a polymer having high permeability to radon diffusion at body temperature, such as silicone rubber (e.g., polydimethylsiloxane (PDMS)) or polypropylene. When highly permeable, the protective coating 28 may have a thickness greater than 10 microns, greater than 20 microns, or even greater than 30 microns. Optionally, the thickness of the highly permeable protective coating 28 may be less than 100 microns, less than 70 microns, less than 50 microns, or even less than 20 microns. In some embodiments, the thickness of the highly permeable protective coating 28 may be less than 10 microns or even less than 5 microns.

[0037] In this specification, the term "radon impermeability" is used to refer to an element that does not allow more than 1% of the radon that reaches it to pass through. However, it should be noted that in some cases, a radon impermeable material does not allow more than 0.1% of the radon that reaches it to pass through, or even 0.01% further.

[0038] Similarly, in this specification, the term impermeability to radium is used to refer to an element that does not allow more than 1% of the radium that reaches it to pass through.

[0039] The term "high permeability to radon" refers to an element that allows at least 50% of the radon that reaches it to pass through. Note that in some cases, an element with high permeability to radon may allow at least 75% or even more than 80% of the radon that reaches it to pass through. The term "moderate permeability" refers to an element that allows between 10% and 50% of the radon that reaches it to pass through. An element that allows radon diffusion is one that allows at least 10% of the radon that reaches it to diffuse. This element can be considered to have moderate or high permeability to radon. Instead of polymers with high permeability, the protective coating 28 includes polymers with moderate permeability to radon diffusion at body temperature, such as polycarbonate, polyethylene terephthalate, poly(methyl methacrylate), polysulfone, and / or parylene. This deformation allows the thickness of the protective coating 28 to be less than 10 microns, or less than 6 microns, or even less than 3 microns, in order to allow radon to diffuse through it and to enable simple measurement of the activity of the radium radionuclide 26 on the source 20. On the other hand, the thickness of the protective coating 28 may be optionally greater than 0.1 microns, or greater than 0.25 microns, or greater than 0.5 microns, or greater than 1 micron, or even greater than 2 microns, in order to prevent radium leakage.

[0040] The material and thickness of the protective coating 28 are selected so that at least 20%, at least 35%, at least 40%, at least 45%, at least 60%, at least 80%, or even more than 90% of the radon radionuclides resulting from the desorption of radium radionuclides 26 desorb from the source 20. The radon radionuclides desorb from the protective coating 28 due to the desorption energy and / or subsequent diffusion. When it is stated that radium radionuclides 26 do not desorb from the protective coating 28, it is intended that only a negligible amount of radium radionuclides 26 prior to desorption, e.g., less than 1% or even less than 0.1%, desorbs from the outer polymer layer 24.

[0041] Figure 2 shows a cross-section of a flexible radiotherapy source 30 according to another embodiment of the present invention. Source 30 is similar to source 20 in Figure 1 in that it comprises an inner flexible core 22, a radium-bonding layer 24, a radium radionuclide 26, and a protective coating 28 that prevents leakage of the radium radionuclide 26 and allows for radon emission. However, source 30 further includes an intermediate layer 32 between the inner flexible core 22 and the radium-bonding layer 24 to reinforce their bond. In embodiments in which the radium-bonding layer 24 contains manganese oxide, the intermediate layer 32 includes a layer of parylene or silicone rubber (e.g., polydimethylsiloxane (PDMS)) bonded to the manganese oxide to reinforce the bond of the manganese oxide to the flexible core 22. The intermediate layer 32 has a thickness of at least 0.2 microns, at least 0.25 microns, at least 0.4 microns, or even more at least 0.5 microns, sufficient to form a bond with both the inner flexible core 22 and the radium-bonding layer 24. Optionally, the intermediate layer 32 has a thickness of less than 10 microns, or less than 6 microns, or less than 4 microns, or even less than 3 microns, so as not to allow the material of the radium bonding layer 24 to sink into the intermediate layer 32, thereby damaging the bonding of the radium radionuclide 26 to the radium bonding layer 24.

[0042] Source 30 is particularly useful when the inner flexible core 22 contains a polymer and the radium-bonded layer 24 contains manganese oxide, and these are not sufficiently bonded.

[0043] Figure 3 shows a cross-section of a flexible radiotherapy source 40 according to yet another embodiment of the present invention.

[0044] Source 40 comprises an inner flexible core 22 discussed in relation to Source 20, and further comprises an outer polymer layer 44 supporting a radium radionuclide 26 thereon. In some embodiments, the structure of the outer polymer layer 44 is such that the radium radionuclide 26 does not detach from the outer polymer layer 44 to a significant extent (e.g., more than 1%, more than 3%, or more than 5%), but a significant percentage of the radon radionuclides resulting from the detachment of the radium radionuclide 26 detach from the outer polymer layer 44. In other embodiments, Source 40 further comprises a protective coating 48 to prevent leakage of the radium radionuclide 26.

[0045] The inner flexible core 22 provides the source 20 with strength to prevent rupture and / or provides visibility of the source 20 in one or more medical imaging means. Optionally, the thickness of the outer polymer layer 44 is selected to allow radon resulting from radium desorption to desorb from the source 40 through the entire outer polymer layer 44.

[0046] The outer polymer layer 44 optionally includes a polymer having high permeability to radon diffusion at body temperature, such as silicone rubber (e.g., polydimethylsiloxane (PDMS)) or polypropylene. The outer polymer layer 44 may have a thickness greater than 10 microns, greater than 20 microns, or even greater than 30 microns when it has high permeability. Optionally, the thickness of the outer polymer layer 44 having high permeability may be less than 100 microns, less than 70 microns, less than 50 microns, or even less than 20 microns. In some embodiments, the thickness of the outer polymer layer 44 having high permeability may be less than 10 microns, or even less than 5 microns.

[0047] Instead of a polymer with high permeability, the outer polymer layer 44 includes a polymer with moderate permeability to radon diffusion at body temperature, such as polycarbonate, polyethylene terephthalate, poly(methyl methacrylate), polysulfone, and / or parylene. This modification allows the thickness of the outer polymer layer 44 to be less than 10 microns, or less than 6 microns, or even less than 3 microns, to allow radon diffusion through it and to enable simple measurement of the activity of radium radionuclides 26 on the source 20.

[0048] The polymer forming the outer polymer layer 44 is optionally non-biodegradable or does not degrade significantly (e.g., by more than 0.1%) within five half-lives of radium from the time of implantation. However, it should be noted that in some embodiments, for example, when radium is bound to microparticles and / or when the source carries a drug that is released, the source may be biodegradable.

[0049] The outer polymer layer 44 contains 10 radium inside. -16 cm 2 Less than / second, or 2 * 10 -17 cm 2 / Less than or 10 -18 cm 2 It is configured to have a diffusion coefficient smaller than / second. On the other hand, radon is optionally configured to have at least 10 -12 cm 2 / second, at least 10-11cm 2 / second, or at least 10 -10 cm 2 It has a diffusion coefficient of / second.

[0050] The protective coating 48, when contained within the source 40, optionally has a thickness greater than 0.1 microns, greater than 0.25 microns, greater than 0.5 microns, greater than 1 micron, or even greater than 2 microns, in order to prevent radium escape. Preferably, the thickness of the protective coating 48 is less than 5 microns, less than 4 microns, less than 3 microns, or even less than 2 microns. The protective coating 48 comprises any of the materials discussed above with respect to the protective coating 28.

[0051] The material and thickness of the outer polymer layer 44 are selected such that at least 20%, at least 35%, at least 40%, at least 45%, at least 75%, or even more than 85% of the radon radionuclides resulting from the desorption of radium radionuclides desorb from the outer polymer layer 44. The radon radionuclides desorb from the outer polymer layer 44 due to the desorption energy and / or subsequent diffusion. When it is stated that the radium radionuclides 26 do not desorb from the outer polymer layer 44, it is intended that only a negligible amount of radium prior to desorption, e.g., less than 1% or even less than 0.1%, desorbs from the outer polymer layer 44.

[0052] The radium radionuclide 26 is optionally uniformly dispersed within the outer polymer layer 44. In particular, the radium radionuclide 26 is optionally substantially uniformly dispersed throughout the entire thickness of the outer polymer layer 44. The retention of the radium radionuclide 26 in the polymer layer 44 eliminates the need for a radium-bonding layer 24, and therefore, in some embodiments, the source 40 does not contain a radium-bonding layer 24.

[0053] In some embodiments, the radium radionuclide 26 is contained within the outer polymer layer 44 as a free atom not bound to larger particles. In other embodiments, the radium radionuclide 26 is bound to smaller particles 38. In some embodiments, the smaller particles 38 have a diameter smaller than 100 micrometers, or smaller than 50 micrometers, or smaller than 10 micrometers, or even smaller than 5 micrometers. In some embodiments, even smaller microparticles, such as nanoparticles, are used.

[0054] In this application, the term "microparticle" refers to particles having a diameter between 1 micrometer and 100 micrometers. The term "nanoparticle" refers to particles having a diameter between 100 nanometers and 1000 nanometers. In some embodiments, the small particles are spherical and / or bead-shaped. Alternatively, the small particles may be of any other suitable shape.

[0055] Optionally, the small particles 38 contain material that is readily identifiable using medical imaging techniques such as ultrasound, X-rays, and / or magnetic resonance imaging (MRI). Alternatively, or in addition to this, the small particles contain markers of material that are readily identifiable in medical images.

[0056] The small particles, in some embodiments, include gold, titanium, titanium oxide, aluminum oxide, zirconium oxide, and / or silicon oxide, although other materials may also be used as the base material for the small particles.

[0057] In some embodiments, the small particles are coated with a thin layer of manganese oxide that attracts radium. Optionally, the manganese oxide layer is thick enough to bind the radium, for example, at least 10 nanometers, at least 20 nanometers, at least 30 nanometers, at least 50 nanometers, or even at least 80 nanometers. Optionally, the layer has a thickness of less than 10 microns, or less than 1 micron, or less than 500 nanometers, or less than 250 nanometers, or less than 150 nanometers, or even less than 100 nanometers, in order to minimize the amount of manganese oxide injected into the patient. Alternatively, the small particles are made almost entirely of manganese oxide. The manganese oxide coating on the small particles is thin enough so that radon is released from the small particles when it is produced by the decay of radium radionuclide 26.

[0058] Figure 4 is a flowchart of a method for producing a flexible radiotherapy source according to an embodiment of the present invention. The method includes the steps of mixing a polymer solute that will form an outer polymer layer 44 into a solvent (202) and adding a radium radionuclide 26 to the mixture (204). The mixture is then placed on an inner flexible core 22 (206) and allowed to cure naturally (208).

[0059] Table 1 lists exemplary solutions and solvents that can be used.

[0060] (Table 1) TIFF2026518586000002.tif61155

[0061] The solute and solvent are presented merely as examples, and it will be understood that other suitable combinations of either solute or solvent can be used. The mixing of the solvent and solute is carried out using methods known in the art. As is known in the art, for some materials such as polypropylene, the mixing is carried out at the high temperatures required for extrusion, while for other materials, the mixing is carried out at room temperature.

[0062] In some embodiments, the radium radionuclide 26 is obtained in an acidic aqueous solution having a weakly acidic pH, for example, greater than 3.5, greater than 4, or even greater than 4.5. Alternatively, the radium radionuclide 26 is obtained in a neutral solution such as potassium chloride (KCl).

[0063] In other embodiments, the radium radionuclide 26 is optionally provided as a dry powder in a bound state to small particles 38. Optionally, the radium radionuclide 26 is bound to small particles by placing the small particles within a flux of the radium radionuclide. Optionally, the flux is generated by a flux-generating surface source. For example, when the radionuclide is Ra-224, its flux can be generated by a thorium-228 (Th-228) surface source. A Th-228 surface source can be prepared, for example, by collecting Th-228 atoms emitted from a parent surface source, U-232. Such a parent surface source can be prepared, for example, by spreading a thin layer of acid containing U-232 on a metal. Alternatively, or in addition thereto, the flux may be generated using any of the methods described in U.S. Patent Publication No. 2015 / 0104560, entitled “Method and Device for Radiotherapy,” which is incorporated herein by reference in its entirety.

[0064] Alternatively, the alpha-emitting radium radionuclide 26 is bound to the small particles 38 by mixing radium with the small particles 38 in an aqueous solution. The radium solution can be generated by dissolving a radium-supported seed in a solution. Furthermore, alternatively or in addition, a high-concentration solution containing the alpha-emitting radium radionuclide can be generated, for example, by any of the methods described in PCT Publication 2021 / 070029, the entire disclosure of which is incorporated herein by reference. To coat the small particles 38 with the radium radionuclide 26, the small particles, along with an outer coating that attracts radium, are optionally immersed in the high-concentration solution for several hours. This solution can be added to the polymer mixture (204) or dried, and the remaining dried small particles 38 supporting the radium radionuclide 26 are then mixed with the polymer mixture. In these embodiments, in order to enable the handling of radium without using a solution as a carrier, the small particles 38 are optionally sufficiently large (for example, having a maximum dimension of at least 0.1 micrometers, at least 1 micrometer, or even more than at least 5 micrometers).

[0065] With respect to the step of adding the radium radionuclide 26 to the polymer (204), if the radium radionuclide 26 is present in an aqueous solution, after adding the radium solution to the mixture (e.g., a mixture of PDMS components) (204), the mixture is optionally emulsified, and then, to allow proper curing of the polymer, the excess liquid is optionally removed by vacuum suction. Optionally, before mixing the polymer components with the radium solution, the polymer component mixture is diluted with a water repellent (e.g., hexane). Thereafter, the radium solution and polymer components are mixed together, and the excess liquid is removed.

[0066] In embodiments where radium is provided as a dry powder, the powder is directly mixed into the polymer mixture without the need to remove any liquid.

[0067] In some embodiments, the polymer mixture containing the radionuclide 26 is placed on the inner flexible core 22 by briefly immersing the inner flexible core 22 in the mixture (206). Alternatively, the polymer mixture is mixed in a syringe, and when the polymer components and radium are properly mixed, the contents are extruded from a small nozzle of the syringe having the same cross-section as the desired cross-section of the generated source. The inner flexible core 22 is placed at the nozzle exit, and the polymer mixture flowing out of the nozzle envelops the inner flexible core 22.

[0068] Figure 5 shows a cross-section of a directional radiotherapy source 50 according to an embodiment of the present invention. Source 50 differs from source 20 in that, as shown in the figure, it is elongated rather than round. This difference demonstrates that, as mentioned above, the source of the present invention can be made into various shapes.

[0069] Source 50 differs from Source 20 in that it is designed to emit radon in specific directions rather than in all directions. Source 50 includes an inner flexible core 52 with a thickness similar to the diameter of the inner flexible core 22 and one of the materials discussed above with respect to the inner flexible core 22. Source 50 further includes a radium-bonding layer 54 similar to the radium-bonding layer 24, a radium radionuclide 26, and a protective coating 58 of a material and thickness similar to the protective coating 28. However, the radium-bonding layer 54, the radium radionuclide 26, and the protective coating 58 cover only a portion of the inner flexible core 52, thereby ensuring that the daughter radionuclides are emitted only in the aforementioned directions. In some embodiments, the remainder around the core 52 is covered by a neutral coating 56 that does not support radium. Optionally, the neutral coating 56 includes a radon-impermeable material such as one of the materials discussed above that form the core 22. Source 50 can be used on the periphery of a tumor when it is desirable to release radium only in the direction of the tumor.

[0070] Alternatively, the radium-bonded layer 54 and the radium radioactive nuclide 26 are placed around the entire perimeter of the inner flexible core 52, and the protective coating 58 is made thicker in the direction where radiation is undesirable, for example, to a thickness of at least 100 microns or even more at least 200 microns.

[0071] In some embodiments, in addition to the alpha-emitting radium radionuclide 26, sources 20, 30, 40, and / or 50 include one or more drugs administered in parallel with alpha-emitting radiotherapy. Optionally, one or more drugs include substances that activate cytoplasmic sensors for intracellular pathogens within a tumor, as described, for example, in PCT Publication WO 2020 / 089819, entitled “Intratumoral Alpha-Emitter Radiation and Activation of Cytoplasmic Sensors for Intracellular Pathogen,” the entire disclosure of which is incorporated herein by reference. Alternatively, or in addition thereto, one or more drugs include an immune checkpoint regulator, such as those described in PCT application PCT / IB2022 / 055680, titled “Intratumoral Alpha-Emitter Radiation in combination with Checkpoint Regulators,” the entire disclosure of which is incorporated herein by reference. Furthermore, or in addition thereto, one or more drugs include a vascular inhibitor, such as those described in PCT application PCT / IB2022 / 055679, titled “Intratumoral Alpha-Emitter Radiation in combination with Vasculature Inhibitors,” the entire disclosure of which is incorporated herein by reference. In some embodiments, one or more drugs are contained within small particles. Alternatively, or in addition thereto, one or more drugs are placed on or on the outer polymer layer 24.

[0072] Sources 20, 30, 40, and 50 are particularly useful for cancer-type tumors in delicate organs where it is preferable to implant a soft source, such as in the brain and / or lungs. In some embodiments, sources 20, 30, 40, and / or 50 are implanted in the tumor in an orientation having multiple bends, i.e., to better secure the source within the tumor.

[0073] Small particles with a manganese coating supporting radium may also be used as a source for treating cancer other than those mentioned above. The manganese-coated particles can be delivered on their own into solutions, gels, or by any other suitable method. The gels that can be used are listed in "In-Situ Gelling Polymers, for Biomedical Applications" by Xian Jun Loh, 2014, the disclosures of which are incorporated herein by reference.

[0074] Instead of using manganese-coated small particles, radium is supplied in its raw form in a manganese-supported solution or any other suitable radium coupler. For example, the manganese or other suitable radium coupler is optionally supplied as a powder that attracts radium.

[0075] It will be acknowledged that the methods and apparatus described above are to be interpreted as including apparatus for carrying out the methods and methods for using the apparatus. Features and / or steps described in reference to one embodiment may sometimes be used in other embodiments, and not all embodiments of the present invention have all of the features and / or steps shown in specific figures or described in reference to one of the specific embodiments. Tasks may not necessarily be performed in the order described.

[0076] It should be noted that some of the embodiments described above may not be essential to the present invention and may include structures, operations, or details thereof described as examples. As is known in the art, the structures and operations described herein are interchangeable with equivalents that perform the same function even if the structure or operation differs. The embodiments described above are given as examples only, 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 partial combinations of the various features described above, as well as variations and modifications thereof that a person skilled in the art would think of upon reading the above description and that are not disclosed in the prior art. Accordingly, the scope of the present invention is limited only by the elements and limitations when the terms “comprise,” “include,” “have,” and their inflections are used in the claims, meaning “include, but not necessarily limited thereto.” [Explanation of Symbols]

[0077] 20 Flexible Radiotherapy Source 22 Internal flexible core 24 Radium Bonding Layer 26 Radium radionuclides 28 Protective coating

Claims

1. A source of radiation therapy for treating tumors, A flexible core that is impermeable to radon, A polymer coating on the flexible core, wherein the polymer coating is impermeable to radium and allows the diffusion of radon passing through it, An alpha-emitting radium radionuclide located within the polymer coating, or between the flexible core and the polymer coating, Radiation therapy sources including

2. The radiotherapy source according to claim 1, wherein the flexible core comprises a gold strand.

3. The radiotherapy source according to claim 1, wherein the flexible core comprises a polymer that is impermeable to radon.

4. The radiotherapy source according to claim 3, wherein the flexible core comprises polyetheretherketone (PEEK).

5. The radiotherapy source according to claim 3, wherein the flexible core has a thickness not greater than 0.3 millimeters.

6. The radiotherapy source according to any one of claims 1 to 5, wherein the radium radionuclide is dispersed throughout the entire thickness of the polymer coating.

7. Small particles dispersed within the polymer coating, It further includes, The radium radionuclide is bound to the small particle, A radiation therapy source according to any one of claims 1 to 5.

8. The radiotherapy source according to any one of claims 1 to 5, wherein the flexible core and the polymer coating do not exhibit biodegradability for at least one week after implantation in a tumor.

9. The manganese oxide layer on the flexible core, It further includes, The radium radionuclide is bonded to the manganese oxide layer. A radiation therapy source according to any one of claims 1 to 5.

10. The radiotherapy source according to claim 9, further comprising a layer of parylene or silicone rubber between the flexible core and the manganese oxide layer.

11. A method for preparing a radiation therapy source, The process involves mixing a solvent and a solute to form a mixture that hardens to form a polymer, The steps include mixing an alpha-emitting radium radionuclide into the mixture, The steps include placing the mixture of radium and polymer components onto a flexible core, The step of placing the mixture onto the flexible core is followed by the step of curing the mixture to form a polymer coating. A method that includes this.

12. The method according to claim 11, wherein the step of mixing the alpha-emitting radium radionuclide into the mixture is further comprising the step of mixing a solution containing the radium radionuclide into the mixture.

13. The method according to claim 12, further comprising the step of removing excess liquid from the mixture before the step of placing the mixture on the flexible core.

14. A drug used to treat tumors, Microparticles having an outer surface containing manganese oxide, The alpha-emitting radium radionuclide on the outer surface of the microparticle, A drug containing [this ingredient].

15. The agent according to claim 14, wherein the microparticles comprise a non-manganese oxide core coated with manganese oxide.

16. The agent according to claim 14, wherein the microparticles include gold, titanium, titanium oxide, zirconium oxide, and / or silicon oxide.

17. The drug according to any one of claims 14 to 16, wherein the microparticles have a diameter smaller than 10 micrometers.

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