Radiation therapy sheet

Abstract

A sheet for radiation therapy includes a sheet base configured for placement on tissue of a patient and a radium bonding material coupled with the sheet base. And the alpha-emitting radium radionuclide is coupled with the radium binding material. The radium radionuclides do not leave the sheet, but radon and lead generated by decay of the radium radionuclides easily leave the sheet.

Description

Field of the Invention

[0001] The present invention relates generally to radiation therapy and, in particular, to sources carrying particles for use in radiation therapy.

[0002] background

[0003] Ionizing radiation is commonly used to treat certain types of tumors, including malignant cancerous tumors, to destroy the cells of the tumor. A variety of methods have been used to deliver ionizing radiation to tumors. One of these methods is to implant a source (commonly referred to as a "seed") in or near the tumor, encapsulating atoms that emit radiation (also known as radionuclides). The precise placement of more than one source is not a simple task, and it has been suggested to attach more than one source to place together.

[0004] Horowitz, US Patent No. 4,754,745, describes a conformable sheet of material absorbable in living tissue having more than one radioactive source embedded in the sheet in a predetermined array.

[0005] Nardi, US Patent 5,030,195, describes a nonabsorbable seed patch having radioactive seeds connected therein by threads.

[0006] US Patent 6,099,457 to Good, entitled: "Endocurietherapy," describes more than one radiation emitter spaced across a fabric base.

[0007] U.S. Patent Publication 2003 / 0092957 to Scott et al. describes a brachytherapy device that includes a substrate having a radioactive coating formed thereon. In addition, the reference describes a radioactive sol-gel having an insoluble radioisotope dispersed therein and a malleable implant containing ribs for radioactive rods. The radioisotope is embedded in the surface to avoid delamination.

[0008] US Patent Publication No. 2004 / 0076579 to Coniglione et al. describes a membrane formed in a single step, such as by extrusion or molding from a radioactive composite material containing radioactive particles.

[0009] PCT publication WO2017 / 200298 describes placing liquid radioisotopes at a constant thickness on irregular skin surfaces to treat skin cancer.

[0010] US Patent Publication No. 2014 / 0296609 to Desantis et al. describes a layer structure for epidermal radionuclide therapy.

[0011] US Patent 9,022,915 to Nakaji describes radioactive seeds embedded in a corresponding radioactive seed carrier.

[0012] Alpha particles are a powerful means for radiation therapy because they produce complex DNA damage that is difficult to repair and are also effective against cells that show high resistance to other types of radiation. In addition, alpha particles have a short range, so that when an alpha-emitting atom is brought into the immediate vicinity of a cancer cell, the emitted alpha particle has a high chance of killing the cell while avoiding surrounding healthy tissue.

[0013] For example, the diffusing alpha-emitter radiation therapy (DaRT) described in U.S. Patent 8,834,837 of Kelson et al., has expanded the therapeutic range of alpha radiation by using radium-223 or radium-224 atoms, which have several chains of radioactive decay in a relatively short time span. In DaRT, the radionuclide is attached to the source implanted in the tumor with sufficient intensity so that the radionuclide does not leave the source in the way that they become waste, but a considerable percentage of the daughter radionuclide leaves the source and enters the tumor when decaying. These daughter radionuclides are propagated in a region measured as a few millimeters in size by diffusion and possible convection. Therefore, relative to the source of the radionuclide left on the source with its daughter, the destruction range in the tumor increases. The advantage of DaRT is the ability to destroy tumors using a source with low levels of radioactivity.

[0014] The effective range of DaRT sources is limited to a few millimeters, and therefore when treating large tumors, dozens or even hundreds of sources may need to be implanted in the tumor to ensure destruction of the entire tumor volume. In addition, in order to avoid cold spots, the sources need to be placed at specific relative angles and positions. Implanting such a large number of sources is a tedious task that can take a lot of time.

[0015] Lior Arazi, in a paper presented to the Senate of Tel Aviv University in September 2008, “Diffusing Alpha-Emitters Radiation Therapy: Theoretical and Experimental Dosimetry” (the disclosure of which is incorporated herein by reference), describes the use of plaques loaded with radium-224 on their surfaces to irradiate the walls of a surgically created cavity following tumor resection. The planar source is described as having a radiation density of 1 μCi / cm 2 or 3μCi / cm 2 activity.

[0016] Overview

[0017] Therefore, according to an embodiment of the present invention, a sheet for radiotherapy is provided, the sheet comprising: a sheet base configured to be placed on a patient's tissue; a radium binding material coupled to the sheet base; and an alpha-emitting radium radionuclide coupled to the radium binding material, wherein the radium radionuclide does not leave the sheet, but radon and lead generated by the decay of the radium radionuclide easily leave the sheet.

[0018] Optionally, the sheet base is formed of a radium-binding material. Optionally, the sheet base is formed of a material different from the radium-binding material. Optionally, the radium-binding material is coated on the sheet base. Optionally, the radium-binding material comprises mini-particles, micro-particles and / or nano-particles dispersed on the sheet base. Optionally, the alpha-emitting radium radionuclide has an activity of at least 1 microcurie per centimeter of length. Optionally, the radium-binding material comprises manganese oxide. Optionally, the radium-binding material comprises alginate. Optionally, the sheet base comprises a silicone substrate. Optionally, the sheet base comprises a mesh. Optionally, the mesh comprises a titanium mesh.

[0019] According to an embodiment of the present invention, there is also provided a sheet for radiotherapy, the sheet comprising: a sheet base configured to be placed on a patient's tissue; and a source having a length of at least one millimeter, the source carrying an alpha-emitting radionuclide having an activity of at least 1 microcurie per centimeter of length, the source being coupled to the sheet base so that at least a portion of the source is outside the sheet base. Optionally, the sheet base is configured to be molded to the contour of the patient's skin. Optionally, the sheet base comprises a silicone sheet. Optionally, the sheet base comprises a mesh, and the source has an internal channel connected by a line on the mesh. Optionally, the sheet base has an area of ​​at least 2 square centimeters. Optionally, the sheet comprises a gel layer on the sheet. Optionally, the alpha-emitting radionuclide comprises a radium-224 radionuclide. Optionally, the alpha-emitting radionuclide is coupled to the source in a manner that prevents the alpha-emitting radionuclide from detaching from the source but allows daughter radionuclides of the alpha-emitting radionuclide to escape from the source when decaying. Optionally, the alpha emitting radionuclide has an activity of at least 5 microcuries per centimetre of length. Optionally, the source protrudes at least 1 millimetre from the sheet base. Optionally, the source is coupled to the sheet base by an adhesive.

[0020] According to an embodiment of the present invention, there is also provided an apparatus for radiotherapy, the apparatus comprising more than one source, each of the more than one source having a length of at least one millimeter, carrying an alpha-emitting radionuclide, coupled to each other in a manner to form a sheet suitable for placement on patient tissue. The more than one source covers at least 50% of the area of ​​the sheet. Optionally, the source has an internal channel and is coupled to each other by one or more wires passing through the internal channel of the source. Optionally, the more than one source covers at least 90% of the area of ​​the sheet. Optionally, the more than one source each has a length of at least 5 millimeters.

[0021] According to an embodiment of the present invention, a method of radiotherapy is also provided, the method comprising covering a tumor on a patient's skin with a gel; providing a sheet having a radium-224 radionuclide having an activity density of at least 1 microcurie per square centimeter coupled to the sheet; and placing the sheet on the gel for a duration suitable for radiotherapy.

[0022] Optionally, the radium-224 radionuclide has an activity of at least 10 microcuries per square centimeter. Optionally, the gel has a thickness of less than 0.6 mm. Optionally, the gel has a thickness of less than 50 microns. Optionally, covering the tumor with the gel includes placing the gel on a sheet and placing the sheet with the gel on it on the patient's skin. Optionally, placing the sheet on the gel is performed after the tumor is covered with the gel. Optionally, the method includes identifying the contour of the tumor, and wherein providing the sheet includes coupling the radium-224 radionuclide to the sheet in an area selected in response to the identified contour before placing the sheet on the gel. Optionally, the method includes identifying the contour of the tumor, and wherein placing the sheet on the gel includes placing a mask around the tumor along the contour of the tumor, and placing the sheet on the gel and the mask. Optionally, the gel does not contain alpha-emitting radionuclides.

[0023] According to an embodiment of the present invention, there is also provided a device for radiotherapy, comprising: a sheet configured to be placed on a surface of a patient; and a radium-224 radionuclide coupled to the sheet at an activity density of at least 10 microcuries per square centimeter. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1A is a schematic diagram of a radiotherapy sheet including an embedded cylindrical source according to an embodiment of the present invention;

[0026] Figure 1B yes Figure 1A A cross section of a radiotherapy sheet;

[0027] Figure 1Cis a schematic diagram of a radioactive sheet according to another embodiment of the present invention;

[0028] Figure 2A is a schematic diagram of a radiotherapy sheet formed by sources coupled to each other according to an embodiment of the present invention;

[0029] Figure 2B is a schematic diagram of a radiotherapy sheet formed by sources coupled to each other according to another embodiment of the present invention;

[0030] Figure 2C is a cross-section of a radiotherapy sheet formed by a source according to another embodiment of the present invention;

[0031] Figure 2D is a cross-section of a radiotherapy sheet formed by a source according to yet another embodiment of the present invention;

[0032] Figure 3A is a schematic diagram of a radiotherapy sheet according to an embodiment of the present invention;

[0033] Figure 3B yes Figure 3A Schematic cross-sectional view of a radioactive sheet.

[0034] Figure 4A is a schematic cross-section of a radioactive sheet according to another embodiment of the present invention;

[0035] Figure 4B is a schematic cross-section of a radioactive sheet according to another embodiment of the present invention; and

[0036] Figure 5 is a flow chart of a method for treating a tumor with a radioactive sheet according to an embodiment of the present invention.

[0037] Detailed description of implementation plan

[0038] An object of an aspect of some embodiments of the present invention is to provide a sheet for radiotherapy treatment, the sheet comprising radium-224 coupled to the sheet in such a way that the radium does not leave the sheet prematurely, but daughter radionuclides leave the sheet upon radioactive decay. The radium-224 is optionally coupled to the sheet in such a way that its daughter radionuclides have a desorption probability of at least 10%, at least 30%, at least 50%, at least 70% or even at least 80% leaving the sheet into an adjacent tumor. In some embodiments, this object is achieved by including an intermediary in the sheet that is coupled to the radium on the one hand and fixed to the sheet on the other hand.

[0039] In order to prevent premature release of radium, radium is optionally attached to a carrier at least partially embedded in the sheet. In some embodiments, the carrier is a small particle, a microparticle or even a nanoparticle. In other embodiments, radium-224 is mounted on a source (commonly referred to as a seed), which is partially embedded in the sheet or mounted on the surface of the sheet. The source is optionally placed on the sheet in a manner such that the sheet is not located between the source and the patient's tissue. In still other embodiments, the sheet itself is mainly formed by a radioactive source.

[0040] The sheet is optionally suitable for external placement on the patient's skin (including the tumor). The sheet is optionally used to treat skin cancer (e.g., basal cell carcinoma (BCC) or squamous cell carcinoma (SCC)) or precancerous tumors. In other embodiments, the sheet is suitable for placement on the wall of a cavity formed by surgical removal of a tumor. In still other embodiments, the sheet is placed on a cancer tumor surrounding critical body tissues such as major blood vessels, which cannot be removed or damaged during surgery.

[0041] An aspect of some embodiments of the present invention relates to a radioactive sheet comprising a base substrate providing strength to prevent disintegration, on which are placed a radium-binding material and a radium radionuclide and a daughter radionuclide that emit alpha radiation. The base substrate and the radium-binding material are configured so that the radium does not leave the sheet in large quantities, while allowing the daughter radionuclide to leave the sheet and enter a tumor.

[0042] In some embodiments, the base substrate is formed of a material different from the radium-binding material. In other embodiments, the same material is used to form the base substrate and to bind the radium. Optionally, the base substrate includes both a continuous surface and a mesh of reinforcing sheets. Alternatively or additionally, the radium-binding material is provided as a mesh carrying radium.

[0043] Aspects of some embodiments of the present invention relate to a radioactive sheet material that is largely formed by a source carrying radium, the source carrying radium having a length greater than 1 mm. Optionally, at least 30% of the weight of the sheet material, at least 40% of its weight, at least 50% of its weight, at least 60% of its weight, at least 70% of its weight, at least 80% of its weight, or even at least 90% of its weight is derived from the source carrying radium. Alternatively or additionally, at least 30% of the area of ​​the sheet material, at least 40% of its area, at least 50% of its area, at least 60% of its area, at least 70% of its area, at least 80% of its area, or even at least 90% of its area is covered by the source carrying radium. In some embodiments, the source carrying radium is cylindrical and has a length of at least 2 mm or even at least 5 mm. Optionally, the source carrying radium is metallic. Alternatively or additionally, the source carrying radium is made of a material different from the material used to combine the source into the sheet material.

[0044] In some embodiments, the radioactive sheet is formed of a source carrying radium, such that in the absence of the source carrying radium, the sheet will not exist (e.g., will break down into a number of pieces). Alternatively, the radioactive sheet is formed of a mesh on which the source carrying radium is mounted. Optionally, in this alternative, the area not covered by the source carrying radium is less than 40%, less than 20%, or even less than 10% of the total area covered by the sheet.

[0045] Aspects of some embodiments of the invention relate to a radioactive sheet comprising a base and more than one cylindrical radium-carrying source partially mounted on the base in a manner such that at least a portion of the cylindrical sources protrude from the sheet. The base of the sheet is optionally flexible, allowing the sheet to conform to patient tissue. In some embodiments, the base of the sheet comprises a mesh. In other embodiments, the base comprises a continuous layer, for example, formed of silicone or a polymer.

[0046] Figure 1A is a schematic diagram of a radiotherapy sheet 100 carrying a source 102 on a base substrate 104 in accordance with an embodiment of the present invention. Figure 1B is a cross-sectional view of a radiation therapy sheet 100 .

[0047] The base substrate 104 comprises a flexible biocompatible material that allows manipulation and placement on the surface of the tumor in a manner that conforms to the tumor so that the radionuclides on the source 102 are adjacent to the tumor. The base substrate 104 optionally has sufficient strength to maintain its integrity, at least until implantation or until most of the activity on the sheet has been consumed.

[0048] Suitable materials for base substrate 104 include, for example, polymers, rubbers, textiles, plastics, metals (e.g., stainless steel, titanium mesh) or combinations of materials. Preferably, sheet 100 is easily moldable to the contour of the tumor surface. Base substrate 104 optionally has low biodegradability, with biodegradability being less than one nanometer of sheet thickness per day, or even less than 0.5 nanometers per day. In some embodiments, base substrate 104 is not biodegradable at all. Alternatively, base substrate 104 has high biodegradability, making it completely biodegradable in less than 6 months, less than 1 month, less than 1 week, less than 1 day or even less than 8 hours. Optionally, base substrate 104 is made of material and sufficient thickness so that alpha particles leaving source 102 do not pass through base substrate 104 and leave sheet 100 from the opposite side of the sheet. In some embodiments, base substrate 104 includes gauze pads, such as vaseline gauze. In other embodiments, the base substrate 104 comprises an alginate wound dressing pad or a poloxamer (eg, pluronics) pad.

[0049] In some embodiments, the base substrate 104 has a thickness of at least 0.1 mm, at least 0.3 mm, at least 0.5 mm, at least 0.7 mm, or even at least 0.9 mm. Optionally, the base substrate 104 has a thickness of less than 6 mm, less than 5 mm, less than 4 mm, or even less than 3 mm.

[0050] In some embodiments, source 102 is cylindrical and has a length X of at least 2 mm, at least 5 mm, or even at least 10 mm. Optionally, source 102 has a length of less than 70 mm, less than 60 mm, or even less than 40 mm (millimeters). Source 102 optionally has a diameter Y of 0.7 mm-1 mm, although in some cases, sources of larger or smaller diameters are used. In particular, for small-spaced treatment arrangements, source 102 optionally has a diameter of less than 0.7 mm, less than 0.5 mm, less than 0.4 mm, or even no greater than 0.3 mm.

[0051] Source 102 is optionally made of a material that is combined with radium, such as a conductive metal, such as stainless steel and / or titanium. Alternatively, source 102 includes a non-metallic rod from a material or material mixture, the material or material mixture including a large amount of non-metallic materials combined with radium, such as alginate or poloxamer. Alternatively, source 102 includes a non-metallic material, such as a polymer and / or silicone, in which a metallic material combined with radium, such as manganese oxide, is dispersed. Alternatively or additionally, source 102 includes a material or material mixture that is not combined with radium but is coated with a radium-combining coating. For example, any method described in U.S. Pat. No. 8,894,969 to Kelson et al. can be used to generate source 102, which is incorporated herein by reference, but other production methods can also be used. In some embodiments, source 102 is at least partially made of a relatively flexible material such as gold, a polymer and / or silicone, so as to avoid adding unnecessary rigidity to sheet 100. In some embodiments, source 102 is hollow to allow sutures to pass through source 102. In other embodiments, source 102 is solid (ie, not hollow).

[0052] The source 102 is optionally partially embedded in the base substrate 104 in order to strengthen the bond between the base substrate 104 and the source 102. In some embodiments, at least 20% of the thickness of the source 102, at least 35% of its thickness, at least 60% of its thickness, or even at least 80% of its thickness is embedded in the base substrate 104. On the other hand, to prevent the base substrate 104 from blocking the radionuclide from reaching the tumor, less than 90%, less than 80%, less than 70%, or even less than 60% of the thickness of the source 102 is embedded in the base substrate 104. In embodiments where the source 102 is cylindrical, at least 30°, at least 60°, at least 90°, or even at least 120° of the circumference of the source is outside the base substrate 104. In some embodiments, the source 102 extends beyond the base substrate 104 by at least 0.1 mm, at least 0.2 mm, or even at least 0.3 mm.

[0053] In some embodiments, the source 102 is coupled to the base substrate 104 by an adhesive (e.g., MED 4213, MED-6033, and / or MED-6233). Alternatively or additionally, the base substrate 104 is produced with a slot that is sized and shaped to tightly receive the source 102. In some embodiments, such as when the base substrate 104 includes a silicone base, the source 102 is bonded to the base substrate 104 by heating the radiotherapy sheet 100. Alternatively or additionally, the source 102 is fastened to the base substrate 104 using a suitable suture. Optionally, according to this alternative, the source 102 is hollow and the suture is passed through the source and fastened to the base substrate 104.

[0054] In some embodiments, the base substrate 104 comprises a mesh made of medical wire, such as a knitted mesh, and the source 102 is mounted on the wire at an appropriate position of the mesh. Optionally, not all of the sheet 100 is covered by the source 102 to allow the sheet 100 to have sufficient flexibility. In particular, the edge of the sheet 100 is optionally free of the source 102 to allow the sheet 100 to be simply fixed to the patient. In some embodiments, the surface area of ​​the sheet 100 covered by the source 102 is at least 20%, at least 30%, at least 40%, or even at least 60% of the surface area of ​​the sheet 100. Optionally, the surface area of ​​the sheet 100 covered by the source 102 is less than 90%, less than 80%, or even less than 60% of the surface area of ​​the sheet 100. Adjacent sources 102 are optionally separated from each other by at least 0.1 mm, at least 0.3 mm, or even at least 0.5 mm. On the other hand, the distance between adjacent sources 102 is optionally less than 1.5 mm, less than 1.2 mm, or even less than 1 mm.

[0055] As shown, the sources 102 are all placed in the same orientation in the sheet 100. In other embodiments, the sources 102 are placed in the sheet 100 in different orientations.

[0056] Figure 1C 1 is a schematic diagram of a radioactive sheet 150 according to another embodiment of the present invention. The sheet 150 shows the use of partially embedded sources 102 of different lengths, as well as irregular arrangements of the sources, including diagonal placement. Such irregular arrangements may be used, for example, where the sheet is intended to be folded around a tumor in a three-dimensional folded manner.

[0057] Source 102 carries a radionuclide that provides the therapeutic dose of radiation. Typically, the radionuclide, its daughter radionuclide, and / or its subsequent nuclei in the decay chain are alpha-emitting, since alpha particles are emitted upon the decay of any given nucleus. For example, the radionuclide may include an isotope of radium (e.g., Ra-224 or Ra-223) that decays by alpha emission to produce a daughter isotope of radon (e.g., Rn-220 or Rn-219) that decays by alpha emission to produce an isotope of polonium (e.g., Po-216 or Po-215) that decays by alpha emission to produce an isotope of lead (e.g., Pb-212 or Pb-211), as described, for example, in U.S. Pat. No. 8,894,969, which is incorporated herein by reference. Alternatively, the radionuclide includes actinium-225.

[0058] Source 102 optionally has an activity of at least 1 microcurie per centimeter of length, at least 3 microcuries per centimeter of length, at least 5 microcuries per centimeter of length, or even at least 10 microcuries per centimeter of length. The radionuclide is optionally coupled to source 102 in such a way that daughter radionuclides have a desorption probability of at least 20%, at least 35%, at least 45%, at least 60%, or even at least 70% leaving the source. Optionally, source 102 has a low desorption probability of less than 30%, less than 25%, or even less than 20% in order to increase the contribution of beta radiation relative to alpha radiation. According to this alternative, source 102 optionally has a relatively high activity of at least 6 microcuries per centimeter of length.

[0059] For ease of production, the radionuclides of source 102 may be evenly dispersed around the circumference of source 102 , or may be primarily (at least 60%), predominantly (at least 80%), or completely (at least 99%) concentrated in areas not embedded in base substrate 104 .

[0060] Figure 2A is a schematic diagram of a radiotherapy sheet 200 formed from sources 102 according to an embodiment of the present invention. Sheet 200 is formed from more than one cylindrical source 102 carrying a radium radionuclide coupled to each other. Figure 2AIn the embodiment, the sources 102 are arranged parallel to each other in the sheet 200. The medical wire 202 passes through each of the sources 202 and is fastened to the external wire 204 at both ends in a manner that holds the sources 102 together, thereby forming the sheet 200.

[0061] Figure 2B is a schematic diagram of a radiotherapy sheet 210 formed of sources 102 according to another embodiment of the present invention. The sheet 200 includes more than one patch 212 of parallel sources 102. The patches 212 are connected to each other with the ends 214 of their sources 102 connected to the length of the source of another patch.

[0062] It should be noted that Figure 2A and Figure 2B are examples, and other arrangements of sources may be used to form the sheet according to embodiments of the invention.

[0063] Figure 2C is a cross-section of a radiation therapy sheet 220 formed by sources 102 according to another embodiment of the present invention. Sources 102 are optionally attached using an adhesive 222 (e.g., MED 4213 and / or MED-6033). In some embodiments where sources 102 are cylindrical, sources 102 are placed adjacent to each other and adhesive 222 is placed near the upper and lower surfaces of the sheet, wherein sources 102 do not contact each other.

[0064] Figure 2D is a cross-section of a radiation therapy sheet 230 formed by source 102 according to yet another embodiment of the present invention. Sheet 230 and Figure 2C Sheet 220 is different in that the adhesive is spread throughout the thickness of sheet 230. Sheet 230 has a lower area of ​​the sheet covered by source 102 relative to sheet 220 and can be used to provide greater flexibility in situations where flexibility is more important than coverage. In other embodiments, sources 102 are connected to each other by welding. For example, welding can be used when the sheet is relatively small and flexibility is not an issue.

[0065] Figure 3A is a schematic diagram of a radioactive sheet 300 according to another embodiment of the present invention. Figure 3B yes Figure 3A Schematic cross-sectional view of a radioactive sheet 300. In some embodiments, sheet 300 includes a base substrate 302 formed of a flexible material that does not bind firmly to radium, such as, for example, a polymer, rubber, textile, and / or plastic. To retain the radium, a radium-binding element 304 is placed on or very close to the surface of base substrate 302, and a radium radionuclide 306 is coupled to radium-binding element 304. It should be emphasized that Figure 3A and Figure 3BThe drawings are not to scale, and the radionuclides 306 and possibly the radium binding elements 304 are shown much larger than they actually are, so that they may be Figure 3A The radium binding element 304 reduces the diffusion length of the radium in the sheet 300, preventing the radium from leaving the sheet or diffusing within the sheet away from the tumor.

[0066] The base substrate 302 optionally has a structure similar to that of the base substrate 104, and can have the structure of any of the embodiments discussed above. In some embodiments, the base substrate 302 includes a material that is permeable to radon, such as silicone (e.g., polydimethylsiloxane (PDMS)). Thus, radon that enters the base substrate is allowed to diffuse from the base substrate 104 into the tumor being treated. Optionally, the base substrate 104 includes a material that is also permeable to lead, allowing lead generated in the substrate to diffuse from the substrate into the tumor.

[0067] The radium binding elements 304 can bind to radium due to the material they are formed of (e.g., manganese oxide, alginate) and / or due to their structure (e.g., microparticles, nanoparticles). In some embodiments, the radium binding elements 304 include manganese dioxide. Optionally, the radium binding elements 304 are placed as a coating on the base substrate 302. In some embodiments, the radium binding elements 304 are loaded with radium before being coated on the base substrate 302. In other embodiments, the radium radionuclide 306 is added to the radium binding elements 304 after the radium binding elements 304 are coated on the base substrate 302. In some embodiments, a thin protective layer 308 is added over the radium binding element 304 coating to prevent the radium binding element 304 from escaping from the sheet 300. The protective layer 308 optionally includes a material that prevents the release of radium but is permeable to daughter radionuclides of radium (particularly radon and lead). Optionally, protective layer 308 comprises silicone, such as PDMS, optionally NUSIL PDMS.

[0068] Optionally, in these embodiments, protective layer 308 has a thickness of less than 5 microns, less than 1 micron, less than 0.1 microns, such that radium-binding element 304 is within less than 50 nanometers, or even less than 20 nanometers from the surface of sheet 300 .

[0069] In other embodiments, protective layer 308 is a removable layer that is removed from sheet 300 shortly before the sheet is applied to a tumor. In these embodiments, protective layer 308 is not necessarily thin and / or formed of a material that is permeable to daughter radionuclides.

[0070] In some embodiments, radium-binding element 304 includes small particles having a maximum dimension greater than 0.05 mm but less than 0.5 mm or even less than 0.1 mm. In embodiments where sheet 300 is required to be flexible, such as when sheet 300 is relatively large, the density of the small particles is selected so as not to hinder the flexibility of the sheet.

[0071] In other embodiments, radium binding element 304 is a microparticle having a maximum dimension greater than 0.05 microns but less than 250 microns, less than 150 microns, or even less than 100 microns. In one embodiment, the microparticle has a maximum dimension of about 50 microns (e.g., 50 microns ± 20%).

[0072] In still other embodiments, radium binding element 304 is a nanoparticle having a maximum dimension no greater than 50 nanometers or even less than 10 nanometers. The nanoparticles include, for example, gold particles and / or titanium particles that are easily visible through imaging modalities. Optionally, the nanoparticles are made of alginate or poloxamer.

[0073] As an alternative to placing the radium binding element 304 and the radium radionuclide 306 on the surface of the base substrate 302, the base substrate 302 is biodegradable, and the radium binding element 304 and the radium radionuclide 306 are embedded in the base substrate 302. When the base substrate 302 degrades, the radium 306 and / or its daughter radionuclides are released into the tumor.

[0074] In other embodiments, the base substrate 302 comprises a metal (e.g., stainless steel, titanium mesh). In some of these embodiments, the radium-binding element 304 is not used, and the radium is affixed directly to the base substrate 302. Affixing the radium to the base substrate 302 may be performed using any suitable method known in the art, such as charging the base substrate 302 in a radium flux from a thorium source.

[0075] Optionally, the sheet 300 has an active area carrying radium radionuclides of at least 0.5 square centimeters, at least 1 square centimeter, at least 2 square centimeters, or even at least 4 square centimeters, at least 10 square centimeters, or even at least 20 square centimeters. The sheet optionally has an edge that does not carry radium radionuclides of at least 1 millimeter, or even at least 2 millimeters.

[0076] The radium-224 optionally has an activity of at least 1 microcurie per square centimeter, at least 3 microcuries per square centimeter, at least 5 microcuries per square centimeter, at least 10 microcuries per square centimeter, at least 20 microcuries per square centimeter, at least 50 microcuries per square centimeter, or even at least 100 microcuries per square centimeter.

[0077] Figure 4Ais a schematic cross-section of a radioactive sheet 400 according to another embodiment of the present invention. Sheet 400 differs from sheet 300 in that, rather than using a radium-binding element 304 to bind radium, sheet 400 includes a radium-binding layer 404 in which a radium radionuclide 306 is embedded.

[0078] In some embodiments, the radium binding layer 404 includes alginate and / or poloxamer, which binds radium and thereby prevents radium radionuclides 306 from leaving the sheet 400, while allowing daughter radionuclides to leave the sheet 400 when decaying and enter the tumor on which the radioactive sheet 400 is placed. The alginate or poloxamer layer is optionally provided as a mesh or a continuous surface. Optionally, calcium is added to the radium binding layer 404 in a selected amount to control its flexibility. In some embodiments, both the base substrate 302 and the radium-based layer 404 are formed of alginate, and sufficient calcium is included therein to ensure the integrity of the sheet 400. Optionally, in this embodiment, the base substrate 302 has a higher concentration of calcium than the radium binding layer 404. In other embodiments, the base substrate 302 includes a mesh or pad that absorbs a significant percentage of the alginate when the alginate is placed on the base substrate 302.

[0079] In one embodiment of the production of radioactive sheet 400, production begins with a base substrate, such as a silicone substrate, used as base substrate 302. A layer of radium binding material, such as manganese oxide, used as radium binding layer 404 is coated onto the base. Thereafter, a liquid radium-224 having an amount of desired activity is loaded onto the manganese oxide. A thin protective layer 406 is added onto radium binding layer 404, and radium is coupled to radium binding layer 404 to prevent release of radium while still allowing daughter radionuclides such as radon and / or lead to leave sheet 400 and enter the tumor. Optionally, the amount of radium binding material in radium binding layer 404 is selected to be suitable for coupling to significantly more radium than the amount required to provide the desired activity, so that the activity is set by the amount of radium used. Alternatively, the amount of radium binding material in radium binding layer 404 is selected to allow up to an amount of radium that provides the desired activity, so that even if more radium is placed on the sheet during production, only radium with the desired activity will remain on the sheet.

[0080] Alternatively or additionally, radium binding layer 404 comprises a semi-rigid sol-gel sheet wherein the radium-224 is within the gel.

[0081] Figure 4Bis a schematic cross-section of a radioactive sheet 430 according to another embodiment of the present invention. Radioactive sheet 430 is similar to sheet 400, but additionally includes a mesh 432 on base substrate 302. Mesh 432 optionally increases the strength of base substrate 302 to prevent undesired tearing. Alternatively or additionally, mesh 432 provides a stronger bond with radium bonding layer 404 (e.g., with manganese oxide) and / or with radium. Mesh 432 optionally includes a metal, such as titanium.

[0082] In one embodiment of the production of the radioactive sheet 430, production begins by immersing the mesh 432 in a manganese oxide or alginate solution to form a radium-binding coating on the mesh. Thereafter, the mesh is immersed in a radium solution. The mesh 432 with radium is optionally attached to the base substrate 302. In some embodiments, after the mesh 432 is attached to the base substrate 302, the mesh is coated with a protective layer that prevents the radium from leaving the sheet 430. It should be noted that this method is given by way of example, and the actions of the method can be performed in a different order, or other production methods can be used. For example, instead of loading the mesh with radium before attaching the mesh 432 to the base substrate 302, the mesh 432 is first attached to the base substrate 302, and then radium is coupled to the mesh 432. In some embodiments, the mesh 432 is not coated with a radium-binding material, but radium is directly coupled to the mesh, for example, using an electric charge and / or heat treatment.

[0083] It should also be noted that in some embodiments, the net is not attached to the base substrate at all, but is strong enough to be used as the base of the sheet alone. In other embodiments, the net 432 is not placed on the base substrate 302, but is embedded in the base substrate 302.

[0084] In some embodiments, the radium is attached to the sheet alone in a free state, and measures are taken to ensure that the sheet is as close to the tumor as possible so that most of the radium and / or its daughter radionuclides reach the tumor. The term free refers to radionuclides such as those that are not coupled to large particles (e.g., particles with a diameter greater than 100 nanometers) that interfere with intercellular flow, are not coupled to targeting elements (e.g., antibodies) that couple to cells, and are not coupled to carriers (e.g., liposomes, radionuclides) that are internalized into cancer cells.

[0085] The sheets described above can be provided in a variety of sizes and shapes, including rectangular and circular. In some embodiments, the sheets have a square shape having a size of at least 10 mm, such as 12 mm × 12 mm or 23 mm × 23 mm. In another embodiment, the sheets are circular, having a diameter between 10 mm-20 mm, such as 15 mm.

[0086] Figure 5is a flow chart of a method 500 for treating a tumor with a radioactive sheet according to an embodiment of the present invention. Method 500 begins by identifying (502) a tumor that may benefit from alpha emitter radiation therapy provided by a radioactive sheet. The radioactive sheet is delivered (504) to the identified tumor and placed (506) on the tumor. In some embodiments, a hydrophobic material that allows daughter radionuclides (particularly radon and lead) to diffuse through it is placed (508) on the tumor, between the tumor and the sheet. In some embodiments, the hydrophobic material comprises a gel. Optionally, the hydrophobic material does not include alpha emitting radionuclides, and may not include radionuclides at all. The hydrophobic material is optionally used to enhance the coupling of the sheet to the patient's tissue and prevent daughter radionuclides of radon produced by radium decay from escaping into the air rather than entering the tumor.

[0087] In some embodiments, a protective mask having a solid frame and inner holes matching the contours of the tumor to be treated is placed (510) between the patient and the radioactive sheet to protect the patient's tissue surrounding the tumor from being damaged by the radiation. In some embodiments, the sheet is removed (512) after the treatment session.

[0088] In some embodiments, after the radioactive sheet is placed (506) on the tumor, the radioactive sheet is secured to the tumor, for example, by sutures, bandages, and / or adhesives. Optionally, the radioactive sheet is secured by one or more elastic bands that continuously push the radioactive sheet toward the tumor so that after the first layer of the tumor is destroyed, the sheet moves closer to the current outer layer of the tumor. The elastic bands optionally include nylon bands and / or rubber bands.

[0089] Regarding delivering (504) the sheet, when used to treat internal tumors, the sheet can be delivered to the tumor during surgery to remove the tumor and placed in the cavity of the removed tumor to kill residual cancer cells. In some embodiments, the sheet is rolled or folded and delivered to the tumor via an endoscope, catheter, or other minimally invasive tool.

[0090] Referring to placing (508) the gel in more detail, in some embodiments, the sheet is provided with a thin layer of gel on the surface of the sheet to be placed on the tumor. It should be noted that in these embodiments, when the sheet is placed on the patient's skin, the gel may also cover the sheet in areas that do not contact the tumor. Alternatively or additionally, the gel is provided separately from the sheet to enhance contact between the sheet and the tumor. The gel layer is optionally very thin, for example having a thickness of less than 0.6 mm, less than 0.1 mm, less than 0.05 mm, or even less than 20 microns. The gel is optionally configured to prevent radon produced by radium decay from evaporating or otherwise escaping to a distance from the tumor at which further decay of the radon or daughter radionuclides will not reach the tumor.

[0091] In some embodiments, the activity on the sheet is selected based on the properties of the gel to ensure that sufficient radiation reaches the tumor. For example, for thicker gel layers, higher levels of activity are used. In some embodiments, the gel is formed from a material that allows for high levels of diffusion of lead-212. In some embodiments, the gel includes small protein molecules that have a very strong affinity for lead, such that the lead and small molecules together have a affinity of at least 5·10 -8 .cm 2 / second, at least 2.10 -7 .cm 2 / second or even at least 1·10 -6 .cm 2 / second diffusion coefficient. Examples include ceruloplasmin (molecular weight 132 kDa), albumin (66 kDa), globulin (~10 kDa-60 kDa), α2μ-globulin (19 kDa), acyl-CoA (9 kDa) and thymosin β4 (5 kDa). The number density of small protein molecules in the gel is comparable to the number density of radium-224 in the sheet. Optionally, the number density of small protein molecules in the gel is significantly greater (e.g., at least five times greater or even at least ten times greater) than the number density of lead-212 on the surface of the sheet, so as to ensure that a large percentage of radium-224 and / or lead-212 is bound to small protein molecules.

[0092] Referring in more detail to placing (510) a protective mask, in some embodiments, the contours of a tumor to be treated are determined and a mask is created in the shape of the tumor. The mask allows diffusing atoms, alpha radiation, and optionally beta radiation to pass through the tumor, and blocks diffusing atoms and optionally alpha radiation from reaching the patient's skin or other tissues other than the tumor. The mask may include, for example, a thin metal foil with holes that match the contours of the tumor. In some embodiments, the mask has a gel disposed in the holes. In treatment, the mask is placed on the patient in a manner that matches the contours of the tumor, and a sheet with a radium radionuclide is placed over the mask and the gel. Optionally, the radium is coupled to the radiotherapy sheet in areas that match the contours of the tumor.

[0093] It should be noted that Figure 5 The method includes various actions that are optional and not necessarily included in all embodiments. In some embodiments, application of the radiation therapy sheet includes a single step of placing the sheet on the tissue surface in need of treatment.

[0094] It should be noted that some of the embodiments described above may include details of structure, behavior or structure and behavior, which may not be necessary for the present invention and are described as examples. As known in the art, the structures and behaviors described herein can be replaced by equivalents that perform the same functions, even if the structures or behaviors are different. The embodiments described above are mentioned by way of example, and the present invention is not limited to the content that has been particularly shown and described above. Instead, the scope of the present invention includes both the combination and sub-combination of the various features described above, as well as variations and modifications thereof that those skilled in the art will think of after reading the foregoing description and that are not disclosed in the prior art. Therefore, the scope of the present invention is limited only by the elements and restrictions used in the claims, wherein the terms "comprise", "include", "have" and their word forms should mean "including but not necessarily limited to" when used in the claims.

Claims

1. A sheet material for radiotherapy, comprising: a sheet base configured for placement on tissue of a patient; a radium bonding material coupled to the base sheet; as well as An alpha emitting radium radionuclide is coupled to the radium binding material, wherein the radium radionuclide does not leave the sheet material, but radon and lead produced by decay of the radium radionuclide readily leave the sheet material.

2. The sheet material of claim 1, wherein the sheet material base is formed from the radium-binding material.

3. The sheet material of claim 1, wherein the sheet material base is formed of a material different from the radium-binding material.

4. The sheet material of claim 3, wherein the radium binding material is coated on the sheet material base.

5. The sheet material of claim 3, wherein the radium binding material comprises small particles dispersed on a base of the sheet material.

6. The sheet material of claim 3, wherein the radium binding material comprises microparticles dispersed on a base of the sheet material.

7. The sheet material of claim 3, wherein the radium binding material comprises nanoparticles dispersed on a base of the sheet material.

8. The sheet material of claim 1, wherein the alpha-emitting radium radionuclide has an activity of at least 1 microcurie per centimeter of length.

9. The sheet material of claim 1, wherein the radium binding material comprises manganese oxide.

10. The sheet material of claim 1, wherein the radium binding material comprises alginate.

11. The sheet material of claim 1 , wherein the sheet base comprises a silicone substrate.

12. The sheet material of any one of claims 1-11, wherein the sheet material base comprises a mesh.

13. The sheet material of claim 12, wherein the mesh comprises a titanium mesh.

14. A sheet material for radiotherapy, comprising: a sheet base configured for placement on tissue of a patient; as well as A source having a length of at least one millimeter, the source carrying an alpha-emitting radionuclide having an activity of at least 1 microcurie per centimeter of length, is coupled to the sheet base such that at least a portion of the source is external to the sheet base.

15. The sheet material of claim 14, wherein the sheet material base is configured to mold to the contours of the patient's skin.

16. The sheet material of claim 14, wherein the sheet base comprises a silicone sheet.

17. The sheet material of claim 14, wherein the sheet base comprises a mesh and the source has internal channels connected by lines on the mesh.

18. The sheet material of claim 14, wherein the sheet base has an area of ​​at least 2 square centimeters.

19. The sheet material of claim 14, further comprising a gel layer on the sheet material.

20. The sheeting of claim 14, wherein the alpha emitting radionuclide comprises a radium-224 radionuclide.

21. The sheeting of claim 14, wherein the alpha emitting radionuclide is coupled to the source in a manner that prevents the alpha emitting radionuclide from dissociating from the source but allows daughter radionuclides of the alpha emitting radionuclide to escape from the source upon decay.

22. The sheeting of claim 14, wherein the alpha emitting radionuclide has an activity of at least 5 microcuries per centimeter of length.

23. The sheet material of claim 14, wherein the source protrudes at least 1 millimeter from the base of the sheet material.

24. The sheet material of claim 14, wherein the source is coupled to the sheet base by an adhesive.

25. An apparatus for radiotherapy, comprising: more than one source, each having a length of at least one millimeter, carrying an alpha-emitting radionuclide, coupled to one another in such a manner as to form a sheet suitable for placement on patient tissue, wherein the more than one source covers at least 50% of the area of ​​the sheet.

26. The apparatus of claim 25, wherein the sources have an internal passage and are coupled to each other by one or more lines passing through the internal passage of the sources.

27. The apparatus of claim 25, wherein the more than one source covers at least 90% of the area of ​​the sheet.

28. The apparatus of claim 25, wherein the more than one sources each have a length of at least 5 millimeters.

29. A method of radiation therapy comprising: Covering the tumor on the patient's skin with gel; providing a sheet material to which is coupled a radium-224 radionuclide having an activity density of at least 1 microcurie per square centimeter; as well as The sheet is placed over the gel for a duration suitable for use in radiation therapy.

30. The method of claim 29, wherein the radium-224 radionuclide has an activity of at least 10 microcuries per square centimeter.

31. The method of claim 29, wherein the gel has a thickness of less than 0.6 mm.

32. The method of claim 31 , wherein the gel has a thickness of less than 50 microns.

33. The method of claim 31, wherein covering the tumor with the gel comprises placing a gel on the sheet and placing the sheet with the gel thereon on the patient's skin.

34. The method of claim 31, wherein placing the sheet onto the gel is performed after the tumor is covered with the gel.

35. The method of claim 31 further comprising identifying a contour of the tumor, and wherein providing the sheet comprises coupling a radium-224 radionuclide to the sheet in regions selected responsive to the identified contour prior to placing the sheet on the gel.

36. The method of claim 29, further comprising identifying an outline of the tumor, and wherein placing the sheet over the gel comprises placing a mask around the tumor along the outline of the tumor, and placing the sheet over the gel and the mask.

37. The method of claim 29, wherein the gel does not contain alpha emitting radionuclides.

38. An apparatus for radiation therapy, comprising: a sheet configured for placement on a surface of a patient; as well as A radium-224 radionuclide is coupled to the sheet material at an activity density of at least 10 microcuries per square centimeter.

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