Alpha-emitter source

Abstract

A radiation therapy source (20, 30, 40) for treating a tumor includes a flexible core (22) impermeable to radon and a polymeric coating (28, 48) on the flexible core. The polymer coating is impermeable to radium and allows radon to diffuse through the polymer coating. The radiation therapy source further includes an alpha-emitting radium radionuclide (26) in the polymer coating or between the flexible core and the polymer coating.

Description

Invention Field

[0001] This invention relates generally to tumor therapy, and more particularly to intratumoral alpha emitter radiotherapy. Background of the Invention

[0002] Ionizing radiation is commonly used to treat certain types of tumors, including malignant cancers, by destroying their cells. Alpha radiation is the most powerful type of radiation that destroys cells, but its range is very short, making its delivery to the tumor a challenge.

[0003] For example, diffuse alpha-emitter radiotherapy (DaRT) described in Kelson's U.S. Patent 8,834,837 mounts alpha-emitting radionuclides onto a source (also known as seeds) in a manner that prevents the radionuclides from leaving the source, because most of the alpha-emitting radionuclides that leave the source are flushed away by the bloodstream before radioactive decay. On the other hand, alpha-emitting radionuclides are mounted onto the source in such a way that a large portion of their daughter radionuclides (radon-220 in the case of radium-224 and radon-219 in the case of radium-223) leave the source and enter the tumor upon decay. These daughter radionuclides, along with their own radioparticles, diffuse around the source to radial distances of up to several millimeters before they decay via alpha emission. Therefore, the extent of destruction within the tumor is increased relative to the radionuclides that remain on the source with their daughters.

[0004] PCT publication WO / 2018 / 207105, entitled “Polymer Coatings for Brachytherapy devices,” describes a DaRT source with a relatively thick polymer coating that allows radionuclides to diffuse through the polymer coating.

[0005] Another method for delivering alpha-emitting radioactive atoms to malignant cells is targeted radionuclide therapy using radioimmunoconjugates. In targeted therapy, a carrier (such as a liposome) is attached to a radioactive atom and injected into the patient's bloodstream. During circulation, the liposome attaches to malignant cells, and when alpha particles are emitted by the radioactive atom, at least some of the emitted alpha particles destroy the malignant cells.

[0006] Larsen's PCT publication WO01 / 60417 entitled "Radioactive Therapeutic Liposomes," PCT publication WO 02 / 05859 entitled "Method of Radiotherapy," and US Patent Publication 2004 / 0208821 entitled "Method of Radiotherapy" describe liposomes encapsulating heavy radionuclides that emit alpha particles. The disclosures of these documents are incorporated herein by reference in their entirety. Radionuclides may include radium-223, radium-224, and thorium-227, among others. Sub-radionuclides are typically trapped during nuclear translocation of the radionuclide.

[0007] PCT publication WO2006 / 110889, entitled “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 can also be delivered to tumors in intracavitary therapy. U.S. Patent Publication 2017 / 0000911, entitled "Radiotherapeutic Particles and Suspensions," describes the intracavitary delivery of alpha emitters coupled to microparticles or nanoparticles in a carrier, diluent, or excipient. The microparticles and nanoparticles are described as stable or slowly degrading.

[0009] The PCT publication WO2010 / 028048, titled "Brachytherapy Seed with Fast Dissolving Matrix for Optimal Delivery of radionuclides to Cancer Tissue," describes polymer seeds embedded within microspheres containing either beta-emitting or alpha-emitting radionuclides. After implantation into a tumor, the seeds dissolve, allowing the radionuclides within the microspheres to destroy tumor cells.

[0010] Kaplan's U.S. Patent 7,776,310, entitled "Flexible and / or elastic Brachytherapy Seed or Strand," describes a non-metallic polymer flexible brachytherapy chain carrying alpha or beta emission particles.

[0011] The article Westrøm S, Malenge M, Jorstad IS, Napoli E, Bruland ØS, BønsdorffTB, Larsen RH. Ra-224 labeling of calcium carbonate microparticles for internal α-therapy: Preparation, stability, and biodistribution in mice. J Labelled Comp Radiopharm. May 30, 2018; 61(6):472-486. doi: 10.1002 / jlcr.3610. Epub March 12, 2018. PMID: 29380410; PMCID: PMC6001669 proposes the use of calcium carbonate microparticles as a carrier of radium-224 for local therapy in cavity-disseminated cancers. Invention Overview

[0012] Therefore, according to an embodiment of the present invention, a radiotherapy source for treating tumors is provided, the radiotherapy source comprising: a flexible core impermeable to radon; a polymer coating on the flexible core, wherein the polymer coating is impermeable to radium and allows radon to diffuse through the polymer coating; and an α-emitting radium radionuclide in the polymer coating or between the flexible core and the polymer coating.

[0013] Optionally, the flexible core comprises gold wire. Alternatively or additionally, the flexible core comprises a radon-impermeable polymer. In some embodiments, the flexible core comprises polyetheretherketone (PEEK). Optionally, the flexible core has a thickness of no more than 0.3 mm. Optionally, a radium radionuclide is dispersed throughout the thickness of the polymer coating. Optionally, the radiotherapy source also includes small particles dispersed in the polymer coating, wherein the radium radionuclide is coupled to the small particles. Optionally, the flexible core and polymer coating remain non-biodegradable for at least one week after implantation into the tumor. Optionally, the radiotherapy source includes a manganese oxide layer on the flexible core, wherein the radium radionuclide is coupled to the manganese oxide layer. Optionally, the radiotherapy source includes a parylene layer or a silicone rubber layer between the flexible core and the manganese oxide layer.

[0014] According to embodiments of the present invention, a method for preparing a radiotherapy source is also provided, the method comprising mixing a solvent and a solute to form a mixture, the mixture forming a polymer upon solidification; mixing an α-emitting radium radionuclide into the mixture; placing the mixture of radium and polymer components onto a flexible core; and allowing the mixture to solidify into a polymer coating after placing the mixture onto the flexible core. Optionally, mixing the α-emitting radium radionuclide into the mixture comprises mixing a solution containing the radium radionuclide into the mixture. Optionally, the method includes removing excess liquid from the mixture prior to placing the mixture onto the flexible core.

[0015] According to embodiments of the present invention, a medicament for treating tumors is also provided, the medicament comprising microparticles having an outer surface comprising 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 of less than 10 micrometers. Brief description of the attached diagram

[0016] Figure 1 This is a cross-sectional view of a flexible radiotherapy source according to an embodiment of the present invention; Figure 2 This is a cross-sectional view of a flexible radiotherapy source according to another embodiment of the present invention; Figure 3 This is a cross-sectional view of a flexible radiotherapy source according to another embodiment of the present invention; Figure 4 This is a flowchart of a method for producing a flexible radiotherapy source according to an embodiment of the present invention; and Figure 5 This is a cross-sectional view of a targeted radiotherapy source according to an embodiment of the present invention. Detailed implementation plan

[0017] Some embodiments of the present invention relate to flexible radiotherapy sources carrying radium as an alpha emitter, in a manner such that radium is not released from the source, but radon progeny generated by the radioactive decay of radium is allowed to leave the flexible radiotherapy source. The flexible radiotherapy source comprises a radon-impermeable flexible core and an outer polymer coating that is radon-permeable but does not allow substantial passage of radium. Such flexible radiotherapy sources allow for the advantages of flexible sources, such as improved anchoring and matching to the contours of body organs in the case of diffuse alpha emitter radiotherapy (DaRT).

[0018] Some embodiments of the present invention involve delivering an alpha-emitting radium radionuclide to a tumor, the tumor being attached to small particles having an external manganese oxide surface. Such small particles prevent radium from being released from the tumor while allowing radon progeny to diffuse into the tumor.

[0019] Figure 1 This is a cross-sectional view 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 coupling layer 24, a radium radionuclide 26, and a protective coating 28 that prevents radium leakage and allows radon release. It should be noted that... Figure 1 Other figures are not drawn to scale. In particular, the radioactive nuclide 26 radium is drawn much larger than it actually is so that it can be seen in the figures.

[0020] In some embodiments, the inner flexible core 22 comprises a flexible ductile metal, such as gold and / or titanium (e.g., pure 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 fine monofilament. Alternatively, the inner flexible core 22 may be woven from more than one fine wire.

[0021] In other embodiments, the inner flexible core 22 comprises a radon-impermeable polymer, such as polyetheretherketone (PEEK), polytetrafluoroethylene (PTFE, sometimes referred to as Teflon), or polyimide (4,4'-oxydiphenylene-pyromellitictetracarboximide, also known as Kapton).

[0022] Optionally, in embodiments where the inner flexible core 22 comprises a polymer, nanoparticles of materials easily identifiable in medical images, such as gold, platinum, bismuth, and / or tantalum, are added to the polymer of the inner flexible core 22 to allow for the identification of source 20 in medical images. The concentration of the nanoparticles can be low, such as less than 10%, less than 5%, or even less than 2%, but typically greater than 0.5% or even greater than 1%, or can be high, such as at least 30%, at least 50%, or even greater than 75%.

[0023] The internal flexible core 22 optionally has a cylindrical shape with long and narrow wires, having a diameter of at least 0.1 mm, at least 0.15 mm, or even at least 0.2 mm to provide sufficient mechanical strength to the source. Alternatively, the diameter of the internal flexible core 22 optionally is less than 0.5 mm, less than 0.4 mm, less than 0.35 mm, or even less than 0.3 mm, making the source flexible. The diameter of the internal flexible core 22 optionally depends on the material of the internal flexible core 22. In one embodiment, the internal flexible core 22 comprises a gold wire with a diameter of about 0.25 mm. The internal flexible core 22 is optionally solid, without internal channels, and therefore differs from a tube with hollow channels.

[0024] The flexible radiotherapy source 20 optionally has a bending moment of less than 5 Newton-millimeter (N*mm), less than 3 N*mm, less than 2 N*mm, less than 1 N*mm, less than 0.8 N*mm, or even less than 0.6 N*mm. In some embodiments, the flexible radiotherapy source 20 can bend to a 90° deflection within a range of less than 2 cm or even no more than 1 cm.

[0025] 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 matches the body region to be treated. For example, the shape of the body region may be determined using an imaging modality (such as CT) or by forming a mold on the body region, and the internal flexible core 22 with the defined shape may be manufactured using any suitable method known in the art, such as 3D printing.

[0026] The radium coupling layer 24 optionally comprises manganese oxide. The manganese oxide optionally comprises hydrated manganese oxide (HMO) and / or manganese dioxide (MnO2). Alternatively, the manganese oxide may comprise any other manganese oxide bonded to radium, such as manganese dioxide (IV), 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.

[0027] The radium coupling layer 24 optionally has a thickness of no more than 1 micrometer, possibly less than 0.3 micrometers, less than 0.1 micrometers, or even less than 0.05 micrometers. In some embodiments, the radium coupling layer 24 has a thickness as low as about 10 nanometers.

[0028] Optionally, the manganese oxide is placed on the inner flexible core 22 by immersing it in an aqueous solution of potassium permanganate (KMnO4). Potassium permanganate (KMnO4) optionally constitutes at least 0.1%, at least 1%, or even at least 3% of the aqueous solution by weight. Alternatively or additionally, potassium permanganate (KMnO4) may constitute no more than 10% or even no more than 7% of the aqueous solution by weight. Immersion is optionally carried out at a temperature of at least 60 degrees Celsius, or even at least 80 degrees Celsius, for example, about 90 degrees Celsius. However, it should be noted that in some cases, immersion is carried out at temperatures below 60 degrees Celsius, such as at room temperature, or at temperatures above 90 degrees Celsius, possibly up to 150 degrees Celsius. After immersion of the inner flexible core 22, the inner flexible core 22 and the manganese oxide are optionally slowly cooled for at least 1 hour, or even at least 6 hours.

[0029] In other embodiments, the radium coupling layer 24 comprises an agent, such as sodium alginate or Pluronic, that transforms into a hydrogel by adding calcium ions. Optionally, according to these embodiments, the agent that transforms into a hydrogel is dried and cured, for example by adding a high percentage of calcium.

[0030] In other embodiments, the radium coupling layer 24 comprises a cation exchange resin, such as polystyrene treated with sulfonic acid, a copolymer of styrene and divinylbenzene treated with sulfonic acid, and / or a polyacrylate treated with carboxylic acid.

[0031] Optionally, the radium radionuclide 26 comprises the alpha emitter radium-224 or radium-223. Optionally, the radium radionuclide 26 is placed on the radium coupling layer 24 by immersing an internal flexible core 22 having a radium coupling layer 24 into a radium solution, as described, for example, in PCT publication WO2021 / 070029, which is incorporated herein by reference in its entirety. Alternatively, the radium radionuclide 26 is placed on the radium coupling layer 24 by placing the radium coupling layer 24 in a radium radionuclide flux. The flux is optionally generated by a surface source that generates the flux. For example, when the radionuclide is Ra-224, its flux can be generated by a thorium-228 (Th-228) surface source. The Th-228 surface source can be prepared, for example, by collecting Th-228 atoms emitted from a parent surface source of U-232. Such a parent surface source can be prepared, for example, by dispersing a thin layer of acid containing U-232 onto a metal. Alternatively or additionally, any method described in US Patent Publication 2015 / 0104560, entitled “Method and Device for Radiotherapy” by Kelson et al., the disclosure of which is incorporated herein by reference in its entirety.

[0032] The thickness of the protective coating 28 is optionally selected to allow radon generated from the desorption of radium radionuclide 26 from the source 20. The protective coating 28 is configured such that radium has a concentration of less than 10 ppm therein. -16 cm 2 / s, less than 2*10 -17 cm 2 / s or even less than 10 -18 cm 2 The diffusion coefficient is / s. On the other hand, radon optionally has a diffusion coefficient of at least 10 in the protective coating 28. -12 cm 2 / s, at least 10 -11 cm 2 / s or even at least 10 -10 cm 2 The diffusion coefficient per second.

[0033] The protective coating 28 is optionally non-biodegradable or does not significantly degrade (e.g., greater 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, such as when radium is coupled to a microparticle and / or when the source carries a drug to be released, the protective coating 28 and / or other portions of the source 20 are biodegradable.

[0034] The protective coating 28 optionally comprises a polymer that is highly permeable 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 micrometers, greater than 20 micrometers, or even greater than 30 micrometers. Optionally, the thickness of the highly permeable protective coating 28 is not greater than 100 micrometers, less than 70 micrometers, less than 50 micrometers, or even less than 20 micrometers. In some embodiments, the thickness of the highly permeable protective coating 28 is less than 10 micrometers or even less than 5 micrometers.

[0035] The term radon-impermeable is used herein to refer to a material for which no more than 1% of radon is permitted to reach the element. However, it should be noted that in some cases, radon-impermeable materials may not allow more than 0.1% or even 0.01% of radon to reach the element.

[0036] Similarly, the term "radium impermeable" is used in this document to refer to an element through which no more than 1% of radium is allowed to reach.

[0037] The term "highly radon-permeable" refers to an element that allows at least 50% of radon to pass through to the element. It should be noted that in some cases, a highly radon-permeable element allows at least 75% or even at least 80% of radon to pass through to the element. The term "moderately permeable" refers to an element that allows between 10% and 50% of radon to pass through to the element. An element that allows radon diffusion is one that allows at least 10% of radon to diffuse to the element. Elements can be moderately or highly radon-permeable. As an alternative to highly permeable polymers, protective coating 28 includes polymers that are moderately permeable to radon diffusion at body temperature, such as polycarbonate, polyethylene terephthalate, poly(methyl methacrylate), polysulfone, and / or parylene. According to this alternative, the thickness of the protective coating 28 is less than 10 micrometers, less than 6 micrometers, or even less than 3 micrometers, so as to allow radon to diffuse through the protective coating 28 and to allow for 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 is optionally greater than 0.1 micrometers, greater than 0.25 micrometers, greater than 0.5 micrometers, greater than 1 micrometer, or even greater than 2 micrometers to prevent radium escape.

[0038] The material and thickness of the protective coating 28 are selected such that at least 20%, at least 35%, at least 40%, at least 45%, at least 60%, at least 80%, or even at least 90% of the radon radionuclide produced by the desorption of radium radionuclide 26 leaves the source 20. The radon radionuclide leaves the protective coating 28 due to desorption energy and / or, at a later time, due to diffusion. When stating that radium radionuclide 26 does not leave the protective coating 28, it is intended that at most a negligible amount, such as less than 1% or even less than 0.1% of radium radionuclide 26, leaves the outer polymer layer 24 before desorption.

[0039] Figure 2 This is a cross-sectional view of a flexible radiotherapy source 30 according to another embodiment of the present invention. Source 30 is similar to... Figure 1Source 20 is provided because source 30 includes an inner flexible core 22, a radium coupling layer 24, a radium radionuclide 26, and a protective coating 28, which prevents leakage of the radium radionuclide 26 and allows radon release. However, source 30 further includes an intermediate layer 32 between the inner flexible core 22 and the radium coupling layer 24 to enhance their coupling. In some embodiments where the radium coupling layer 24 comprises manganese oxide, the intermediate layer 32 comprises a parylene layer or a silicone rubber (e.g., polydimethylsiloxane (PDMS)) layer that is coupled to the manganese oxide and enhances the coupling between the manganese oxide and the inner flexible core 22. The intermediate layer 32 has a thickness of at least 0.2 micrometers, at least 0.25 micrometers, at least 0.4 micrometers, or even at least 0.5 micrometers sufficient to form a junction with both the inner flexible core 22 and the radium coupling layer 24. The intermediate layer 32 optionally has a thickness of less than 10 micrometers, less than 6 micrometers, less than 4 micrometers, or even less than 3 micrometers, so as to prevent the material of the radium coupling layer 24 from being deposited into the intermediate layer 32 in a manner that would disrupt the coupling between the radium radionuclide 26 and the radium coupling layer 24.

[0040] The source 30 is particularly useful when the inner flexible core 22 comprises a polymer and the radium coupling layer 24 comprises a manganese oxide (which do not couple well).

[0041] Figure 3 This is a cross-sectional view of a flexible radiotherapy source 40 according to another embodiment of the present invention.

[0042] Source 40 includes an inner flexible core 22 as discussed with respect to source 20, and thereon includes an outer polymer layer 44 therein carrying radium radionuclides 26. In some embodiments, the outer polymer layer 44 is structured such that radium radionuclides 26 do not leave the outer polymer layer 44 significantly (e.g., greater than 1%, greater than 3%, or greater than 5%), but a significant portion of radon radionuclides generated by the desorption of radium radionuclides 26 leaves the outer polymer layer 44. In other embodiments, source 40 further includes a protective coating 48 to prevent leakage of radium radionuclides 26.

[0043] The internal flexible core 22 provides strength to the source 20 to prevent tearing and / or to provide visibility of the source 20 in one or more medical imaging modalities. Optionally, the thickness of the outer polymer layer 44 is selected to allow radon generated from radium desorption throughout the outer polymer layer 44 to leave the source 40.

[0044] The outer polymer layer 44 optionally comprises a polymer that is highly permeable to radon diffusion at body temperature, such as silicone rubber (e.g., polydimethylsiloxane (PDMS)) or polypropylene. When highly permeable, the outer polymer layer 44 may have a thickness greater than 10 micrometers, greater than 20 micrometers, or even greater than 30 micrometers. Optionally, the thickness of the highly permeable outer polymer layer 44 is not greater than 100 micrometers, less than 70 micrometers, less than 50 micrometers, or even less than 20 micrometers. In some embodiments, the thickness of the highly permeable outer polymer layer 44 is less than 10 micrometers or even less than 5 micrometers.

[0045] As an alternative to highly permeable polymers, the outer polymer layer 44 comprises a polymer moderately permeable to radon diffusion at body temperature, such as polycarbonate, polyethylene terephthalate, poly(methyl methacrylate), polysulfone, and / or parylene. According to this alternative, the thickness of the outer polymer layer 44 is less than 10 micrometers, less than 6 micrometers, or even less than 3 micrometers, to allow radon to diffuse through the outer polymer layer 44 and to allow for simple measurement of the activity of the radium radionuclide 26 on the source 20.

[0046] The polymer forming the outer polymer layer 44 is optionally non-biodegradable, or at least does not significantly degrade within five half-lives of radium from the time of implantation (e.g., greater than 0.1%). However, it should be noted that in some embodiments, such as when radium is coupled to microparticles and / or when the source carries a drug to be released, the source is biodegradable.

[0047] The outer polymer layer 44 is configured such that radium has a concentration of less than 10 therein. -16 cm 2 / s, less than 2*10 -17 cm 2 / s or even less than 10 -18 cm 2 The diffusion coefficient is / s. On the other hand, radon optionally has a diffusion coefficient of at least 10 in the outer polymer layer 24. -12 cm 2 / s, at least 10 -11 cm 2 / s or even at least 10 -10 cm 2 The diffusion coefficient per second.

[0048] When included in source 40, protective coating 48 optionally has a thickness greater than 0.1 micrometer, greater than 0.25 micrometer, greater than 0.5 micrometer, greater than 1 micrometer, or even greater than 2 micrometers to prevent radium evaporation. Preferably, the thickness of protective coating 48 is less than 5 micrometers, less than 4 micrometers, less than 3 micrometers, or even less than 2 micrometers. Protective coating 48 includes any of the materials discussed above with respect to protective coating 28.

[0049] 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 at least 85% of the radon radionuclides produced by the desorption of radium radionuclides leave the outer polymer layer 44. The radon radionuclides leave the outer polymer layer 44 due to desorption energy and / or due to diffusion at a subsequent time. When stating that radium radionuclides 26 do not leave the outer polymer layer 44, it is intended that at most a negligible amount, such as less than 1% or even less than 0.1% of radium, leaves the outer polymer layer 44 before desorption.

[0050] Radioactive radium 26 is optionally uniformly dispersed in the outer polymer layer 44. In particular, radioactive radium 26 is optionally substantially uniformly dispersed over the entire thickness of the outer polymer layer 44. Containing radioactive radium 26 in the polymer layer 44 eliminates the need for a radium coupling layer 24, and therefore, in some embodiments, the source 40 does not include a radium coupling layer 24.

[0051] In some embodiments, radium radionuclide 26 is included as a free atom not coupled to larger particles in the outer polymer layer 44. In other embodiments, radium radionuclide 26 is coupled to small particles 38. In some embodiments, the small particles 38 have a diameter of less than 100 micrometers, less than 50 micrometers, less than 10 micrometers, or even less than 5 micrometers. In some embodiments, even smaller particles, such as nanoparticles, are used.

[0052] In this application, the term "microparticle" refers to a particle having a diameter between 1 micrometer and 100 micrometers. The term "nanoparticle" refers to a particle having a diameter between 100 nanometers and 1000 nanometers. In some embodiments, the small particles are spheres and / or beads. Alternatively, the small particles may have any other suitable shape.

[0053] Optionally, the small particles 38 include materials that are easily identifiable using medical imaging modalities such as ultrasound, X-ray, and / or magnetic resonance imaging (MRI). Alternatively or additionally, the small particles may include markers of materials that are easily identifiable in medical images.

[0054] In some implementations, the small particles include gold, titanium, titanium oxide, aluminum oxide, zirconium oxide, and / or silicon oxide, although other materials may also be used for the small particle matrix.

[0055] In some embodiments, the small particles are coated with a thin layer of manganese oxide that attracts radium. The thin layer of manganese oxide is optionally thick enough to couple radium, for example, having a thickness of at least 10 nanometers, at least 20 nanometers, at least 30 nanometers, at least 50 nanometers, or even at least 80 nanometers. Optionally, the thin layer has a thickness of less than 10 micrometers, less than 1 micrometer, less than 500 nanometers, less than 250 nanometers, less than 150 nanometers, or even less than 100 nanometers to minimize the amount of manganese oxide injected into the patient. Alternatively, the small particles are made mostly or even entirely of manganese oxide. The manganese oxide coating on the small particles is thin enough that radon is released from the small particles when produced by the decay of the radioactive isotope 26 of radium.

[0056] Figure 4 This is a flowchart of a method for producing a flexible radiotherapy source according to an embodiment of the present invention. The method includes mixing (202) a polymer solute forming an outer polymer layer 44 in a solvent, and adding (204) radium radionuclide 26 to the mixture. The mixture is then placed (206) on an inner flexible core 22 and allowed to cure (208).

[0057] Exemplary solutions and solvents that can be used are listed in Table 1.

[0058]

[0059] The solute and solvent are presented by way of example only, and it should be understood that any other suitable combination of solute and solvent may be used. The mixing of solvent and solute is carried out using methods known in the art. As is known in the art, for some materials, such as polypropylene, mixing is carried out at the high temperatures required for extrusion, while for other materials, mixing is carried out at room temperature.

[0060] In some embodiments, radium radionuclide 26 is obtained in an acidic aqueous solution having a mild acidity, such as a pH higher than 3.5, 4, or even 4.5. Alternatively, radium radionuclide 26 is obtained in a neutral solution such as potassium chloride (KCl).

[0061] In other embodiments, radium radionuclide 26 is optionally provided as a dry powder to be incorporated into small particles 38. Radium radionuclide 26 is optionally coupled to small particles by placing the small particles in a radium radionuclide flux. The flux is optionally generated by a surface source that produces the flux. 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 of U-232. Such a parent surface source can be prepared, for example, by dispersing a thin layer of acid containing U-232 onto a metal. Alternatively or additionally, the flux can be generated using any of the methods described in US Patent Publication 2015 / 0104560, entitled “Method and Device for Radiotherapy” by Kelson et al., the disclosure of which is incorporated herein by reference in its entirety.

[0062] Alternatively, alpha-emitter radium radionuclides 26 are coupled to small particles 38 by mixing radium and small particles in an aqueous solution. The radium solution can be generated by dissolving seeds carrying the radium radionuclides in the solution. Further alternatively or additionally, a high-concentration solution containing alpha-emitter radium radionuclides can be generated, for example, using any method described in PCT Publication 2021 / 070029 entitled “Wet preparation of radiotherapy sources,” the disclosure of which is incorporated herein by reference in its entirety. The small particles and their radium-attracting outer coating are optionally immersed in the high-concentration solution for several hours to coat the small particles 38 with radium radionuclides 26. The solution can be added (204) to the polymer mixture, or it can be dried, and then the remaining dried small particles 38 carrying radium radionuclides 26 are mixed with the polymer mixture. In these embodiments, the small particles 38 are optionally large enough (e.g., having a maximum size of at least 0.1 micrometers, at least 1 micrometer, or even at least 5 micrometers) to allow radium to be handled without a solution as a carrier.

[0063] Regarding the addition (204) of radium radionuclide 26 to the polymer, when radium radionuclide 26 is in an aqueous solution, after adding the radium solution (204) to the mixture (e.g., a mixture of PDMS components), the mixture is optionally emulsified, and then optionally excess liquid is removed by vacuum suction to allow proper curing of the polymer. Optionally, the polymer component mixture is diluted with a waterproofing agent (e.g., hexane) before mixing the polymer components with the radium solution. The radium solution and polymer components are then mixed together and excess liquid is removed.

[0064] In embodiments where radium is provided as a dry powder, the powder is directly mixed into the mixed components of the polymer, and there is no need to remove the liquid.

[0065] In some embodiments, a polymer mixture containing radium radionuclide 26 is placed (206) on the inner flexible core 22 by immersing the inner flexible core 22 in the mixture. Alternatively, the polymer mixture is mixed in a syringe, and when the polymer components and radium are properly mixed, the contents are expelled from a small nozzle of the syringe, the cross-section of which is the desired cross-section of the generated source. The inner flexible core 22 is placed at the outlet of the nozzle, and the polymer mixture exiting the nozzle encapsulates the inner flexible core 22.

[0066] Figure 5 This is a cross-sectional view of a targeted radiotherapy source 50 according to an embodiment of the present invention. As shown, source 50 differs from source 20 in that source 50 is elongated rather than circular. This difference illustrates what has already been stated above, that the source of the present invention can be of various shapes.

[0067] Another difference between source 50 and source 20 is that source 50 is designed to emit radon in a specific direction rather than in all directions. Source 50 includes an inner flexible core 52, which is any material discussed above regarding inner flexible core 22, and has a thickness similar to the diameter of inner flexible core 22. Source 50 also includes a radium coupling layer 54 similar to radium coupling layer 24, a radium radionuclide 26, and a protective coating 58 having a material and thickness similar to protective coating 28. However, the radium coupling layer 54, radium radionuclide 26, and protective coating 58 only cover a portion of the periphery of the inner flexible core 52, such that the radionuclide is released only in those directions. In some embodiments, the remaining periphery of the core 52 is covered by a neutral coating 56 that does not carry radium. Neutral coating 56 optionally includes a radon-impermeable material, such as any material discussed above forming core 22. When it is desired to release radium only in the direction of the tumor, source 50 can be used on the periphery of the tumor.

[0068] Alternatively, the radium coupling layer 54 and the radium radionuclide 26 are placed over the entire periphery of the inner flexible core 52, and the protective coating 58 is made thicker in the direction where radiation is not required, for example, at least 100 micrometers, or even at least 200 micrometers.

[0069] In some embodiments, in addition to the alpha-emitter radium radionuclide 26, sources 20, 30, 40, and / or 50 also include one or more pharmaceuticals administered concurrently with alpha-emitter radiation therapy. One or more pharmaceuticals optionally include substances that activate cytoplasmic sensors of intracellular pathogens in tumors, such as those described, for example, in PCT publication WO 2020 / 089819 entitled “Intratumoral Alpha-Emitter Radiation and Activation of Cytoplasmatic Sensors for Intracellular Pathogen,” the disclosure of which is incorporated herein by reference in its entirety. Alternatively or additionally, one or more pharmaceuticals include immune checkpoint modulators, such as those described in PCT application PCT / IB2022 / 055680 entitled “Intratumoral Alpha-Emitter Radiation in combination with Checkpoint Regulators,” the disclosure of which is incorporated herein by reference in its entirety. Further, alternatively or additionally, one or more drug substances include vascular system inhibitors, such as those described in PCT application PCT / IB2022 / 055679 entitled "Intratumoral Alpha-Emitter Radiation in combination with Vasculature Inhibitors," the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, one or more drug substances are contained in small particles. Alternatively or additionally, one or more drug substances are placed in or on the outer polymer layer 24.

[0070] Sources 20, 30, 40, and 50 are particularly suitable for tumors of cancer types in fragile organs, where soft sources are preferred, such as in the brain and / or lungs. In some embodiments, sources 20, 30, 40, and / or 50 are implanted into the tumor with an orientation having multiple bends, thereby better anchoring the source within the tumor.

[0071] Radium-carrying manganese-coated microparticles can also be used in cancer treatment from sources other than those described above. The manganese-coated microparticles can be delivered on their own, in solution, in a gel, or by any other suitable method. Gels that can be used are listed in Xian Jun Loh, “In-Situ Gelling Polymers, for Biomedical Applications”, 2014, the contents of which are incorporated herein by reference.

[0072] As an alternative to using small particles coated with manganese, radium is provided in its original form in a solution carrying manganese or any other suitable radium coupler. For example, manganese or other suitable radium coupler is optionally provided as a powder that attracts radium.

[0073] It should be understood that the methods and apparatus described above are to be interpreted as including the apparatus for performing the methods and the methods of using the apparatus. It should be understood that features and / or steps described for one embodiment may sometimes be used in other embodiments, and not all embodiments of the invention have all the features and / or steps shown in a particular drawing or described for one particular embodiment. The tasks are not necessarily performed in the exact order described.

[0074] It should be noted that some of the embodiments described above may include details of structure, behavior, or structure and behavior that may not be essential to the present invention and are described as examples. As is known in the art, the structures and behaviors described herein may be replaced by equivalents that perform the same function, even if the structure or behavior differs. The embodiments described above are referred to by way of example, and the invention is not limited to what has been specifically shown and described above. Rather, the scope of the invention includes both combinations and sub-combinations of the various features described above, as well as variations and modifications thereof that would occur to those skilled in the art upon reading the foregoing description and that are not disclosed in the prior art. Therefore, the scope of the invention is defined only by the elements and limitations as used in the claims, wherein the terms “comprise,” “include,” “have,” and their variations, when used in the claims, should mean “including but not necessarily limited to.”

Claims

1. A radiotherapy source for treating tumors, comprising: 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 radon to diffuse through the polymer coating; as well as An alpha-emitting radium radionuclide is present in the polymer coating or between the flexible core and the polymer coating.

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

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

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 of no more than 0.3 mm.

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

7. The radiotherapy source according to any one of claims 1-5 further comprises small particles dispersed in the polymer coating, wherein the radium radionuclide is coupled to the small particles.

8. The radiotherapy source according to any one of claims 1-5, wherein the flexible core and the polymer coating are not biodegradable for at least one week after implantation into the tumor.

9. The radiotherapy source according to any one of claims 1-5, further comprising a manganese oxide layer on the flexible core, wherein the radium radionuclide is coupled to the manganese oxide layer.

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

11. A method for preparing a radiotherapy source, comprising: A solvent and a solute are mixed to form a mixture, which forms a polymer upon curing; The α-emitting radium radionuclide is mixed into the mixture; A mixture of radium and polymer components is placed on a flexible core; as well as After the mixture is placed on the flexible core, it is allowed to cure into a polymer coating.

12. The method of claim 11, wherein mixing the α-emitting radium radionuclide into the mixture comprises mixing a solution containing the radium radionuclide into the mixture.

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

14. A drug for treating tumors, comprising: Particles having an outer surface containing manganese oxide; and The α-emitting radium radionuclide on the outer surface of the particle.

15. The medicament of claim 14, wherein the microparticles comprise a non-manganese oxide core coated with manganese oxide.

16. The medicament of claim 14, wherein the microparticles comprise gold, titanium, titanium oxide, zirconium oxide, and / or silicon oxide.

17. The medicament according to any one of claims 14-16, wherein the particles have a diameter of less than 10 micrometers.

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