Polymer coating for devices used in close-range radiotherapy.

Abstract

A device is provided having a support having an outer surface and configured for insertion into a subject's body. The present invention relates to a device (20) having a support (22) configured for insertion into a subject's body, the support (22) having an outer surface (24). The device further has a plurality of atoms (26) of a radionuclide bound to the outer surface that radioactively decay to produce daughter radionuclides, and a layer (28) of polymer that is permeable to the daughter radionuclides and covers the atoms.

Description

[Technical Field]

[0001] This invention relates to the field of close-range radiotherapy for the treatment of cancerous tumors and the like. [Background technology]

[0002] (Cross-reference of related applications) This application claims the interests of U.S. Provisional Patent Application 62 / 504,800 (Patent Document 1), filed on 11 May 2017, entitled “Production of a Radiation Source,” the disclosure of which is incorporated herein by reference.

[0003] Proximity radiation therapy involves positioning a radiation source within a subject's body so that it emits radiation inside the body. The emitted radiation can kill cancer cells located near the radiation source.

[0004] The following is incorporated herein by reference: Arazi, Lior et al., “Therapy of Solid Tumors by Recoiling, Short-Lited Alpha-Particle Emissions in Tissue,” Physics in Medicine & Biology 52.16(2007):5025 (Non-Patent Literature 1), which describes a method of utilizing alpha-particles for the treatment of solid tumors. The tumor is treated with an intratissue radiation source that continuously emits short-lived alpha-emitting atoms from its surface. The atoms disperse within the tumor and deliver high doses through alpha decay. This scheme is carried out using a thin wire radiation source impregnated with Ra-224, which emits Rn-220, Po-216, and Pb-212 atoms by recoil.

[0005] U.S. Patent No. 8,894,969 (Patent Document 2) by Kelson et al., whose disclosure is incorporated herein by reference, describes a radiotherapy comprising placing a predetermined amount of a radionuclide selected from the group consisting of radium-223, radium-224, radon-219, and radon-220 near and / or within a tumor of a subject for a predetermined period of time. The predetermined amount and predetermined period are sufficient to deliver a predetermined therapeutic dose of decay chain nuclides and alpha particles to the tumor with respect to the radionuclide. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] U.S. Provisional Patent Application 62 / 504,800 [Patent Document 2] U.S. Patent No. 8,894,969 [Non-patent literature]

[0007] [Non-Patent Document 1] Arazi, Lior, et al., "Treatment of Solid Tumors by Rebounding, Short-Lived Alpha-Particle Release into Tissues," Physics in Medicine & Biology 52.16(2007):5025. [Overview of the project]

[0008] According to embodiments of the present invention, a device is provided having a support having an outer surface and configured to be inserted into the body of a subject. The device further has; a plurality of atoms of one radionuclide bonded to the outer surface and undergoing radioactive decay to produce daughter radionuclides; and a layer of polymer covering the atoms that is permeable to the daughter radionuclides.

[0009] In some embodiments, atoms are arranged on the outer surface. In some embodiments, the support is cylindrical in shape. In some embodiments, the radioactive nuclide is an alpha-emitting radionuclide. In some embodiments, the radionuclide has one isotope of radium selected from the group of isotopes consisting of Ra-224 and Ra-223. In some embodiments, the daughter radionuclide is an alpha-emitting daughter radionuclide.

[0010] In some embodiments, the layer thickness is 0.1–2 microns. In some embodiments, the thickness is 0.1–1 micron. In some embodiments, the diffusion coefficient of the daughter radionuclides in the polymer is at least 10 -11 cm 2 It is per second. In some embodiments, the polymer is selected from the group consisting of polypropylene, polycarbonate, polydimethylsiloxane, polyethylene terephthalate, poly(methyl methacrylate), and polysulfone.

[0011] In some embodiments, The layer is the outer layer, The polymer is the first polymer, The apparatus further comprises a second polymer inner layer, which is permeable to daughter radionuclides and coats the outer surface, with atoms bonding to the outer surface by bonding to the inner layer. In some embodiments, the thickness of the inner layer is 0.1–2 microns. In some embodiments, the thickness of the inner layer is 0.1–1 micron.

[0012] According to embodiments of the present invention, a method is provided that further comprises the steps of: binding a plurality of atoms of one radionuclide that undergoes radioactive decay to produce daughter radionuclides to the outer surface of a support configured to be inserted into the body of a subject; and, after the step of binding the atoms to the outer surface, covering the atoms with a layer of polymer that is permeable to the daughter radionuclides. In some embodiments, the step of covering the atoms comprises covering the atoms by withdrawing a support from a solution of a polymer, thereby coating the outer surface with a layer of the polymer.

[0013] In some embodiments, the layer is an outer layer, the polymer is a first polymer, the method further comprises covering the outer surface with an inner layer of a second polymer before the step of binding the atoms to the outer surface, and the step of binding the atoms to the outer surface comprises binding the atoms to the outer surface by binding the atoms to the inner layer.

[0014] According to an embodiment of the invention, there is provided a method further comprising inserting a radiation source into a subject's body. The radiation source has a support with an outer surface, a plurality of atoms of a single radionuclide that decays radioactively to produce a daughter nuclide and that binds to the outer surface, and a layer of a polymer that is permeable to the daughter radionuclide and covers the atoms. The method further comprises leaving the radiation source in the subject's body such that the nuclei of the daughter radionuclide diffuse through the layer of the polymer. In some embodiments, the step of inserting the radiation source into the subject's body comprises inserting the radiation source into a tumor in the subject's body. In some embodiments, the step of inserting the radiation source into the subject's body comprises inserting the radiation source such that the radiation source is within 0.1 mm of a tumor in the subject's body. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] The present invention will be more fully understood from the following detailed description when taken in conjunction with the accompanying drawings: [Figure 1] Schematic diagram of an apparatus for brachytherapy according to some embodiments of the present invention. [Figure 2] Schematic diagram of an apparatus for brachytherapy according to some embodiments of the present invention. [Figure 3]This is a schematic diagram of an immersion coating technique for manufacturing a device for close-range irradiation therapy, according to several embodiments of the present invention. [Figure 4] This is a flowchart illustrating a method for manufacturing a proximity irradiation therapy device according to several embodiments of the present invention. [Modes for carrying out the invention]

[0016] (overview) In embodiments of the present invention, atoms of an alpha-emitting radionuclide, such as radium-224 (Ra-224), are deposited on the surface of a support, such as a wire. The support, in addition to depositing the radionuclide on it, is then inserted into a solid tumor in the body of a subject, and is referred to as the “radiation source” or simply the “source.” The radionuclide then undergoes a chain of radioactive decay, emitting alpha particles from the radionuclide atoms and the decay chain nuclei in succession, killing cancer cells in the tumor. (Each of these nuclei is referred to herein as the “daughter nucleus” of the preceding nucleus in the chain. In general, the terms “atom” and “nucleus” may be used interchangeably herein.) Advantageously, the decay chain nuclei travel through the tumor by diffusion and / or convection. This allows for the emission of alpha particles even at relatively large distances from the radiation source.

[0017] A challenge in applying the above-mentioned close-range irradiation therapy techniques is that, generally, the radionuclide needs to be covered to prevent it from being washed away from the radiation source by bodily fluids before it has a chance to decay. However, covering the radionuclide may inhibit the desorption of its daughter nuclides from the radiation source. One option described in Kelson's U.S. Patent No. 8,894,969 (Patent Document 2) is to cover the radionuclide with a very thin cover, for example, 5-10 nanometers thick, through which the daughter nuclides may penetrate when they recoil from the radiation source. However, such covers may be difficult to manufacture.

[0018] To address this challenge, embodiments described herein provide a thicker polymer layer (e.g., having a thickness of 0.1–1 micron) that covers the radionuclide while diffusing the daughter nuclei. Such a layer may be applied to the source by immersing it in a suitable polymer solution so that the source is coated with the polymer. Examples of suitable polymers include polypropylene, polycarbonate, polydimethylsiloxane, polyethylene terephthalate, poly(methyl methacrylate), and polysulfone.

[0019] In some embodiments, another polymer layer (e.g., having a thickness of 0.1–1 micron) is applied to the surface of the support before the deposition of the radionuclide. The advantage of such embodiments is that even if the daughter nuclei of the radionuclide bounce towards the surface of the support, the daughter nuclei do not adhere to the surface or to the surface. Rather, the daughter nuclei can diffuse outward through the inner polymer layer and then continue to diffuse outward through the outer polymer layer. Typically, the inner polymer layer is applied to the support by immersing the support in a suitable polymer solution. Any of the polymers listed above can be used for the inner layer as long as they do not dissolve in the solution used to coat the subsequent outer polymer layer.

[0020] (Description of the device) First, refer to Figure 1, which is a schematic diagram of a proximity irradiation therapy device 20 according to several embodiments of the present invention.

[0021] The close-range radiotherapy device 20 includes a support 22 configured for partial or complete insertion into the body of a subject. The support 22 may comprise, for example, a needle, wire, rod, endoscope tip, laparoscope tip, or any other suitable probe. Typically, the support 22 is cylindrical. For example, the support 22 may include a cylindrical wire, needle, or rod with a diameter of 0.3–1 mm and / or a length of 5–60 mm. The support 22 includes an outer surface 24.

[0022] The proximity irradiation therapy device 20 further includes multiple atoms 26 of a radionuclide, which decay to produce daughter radionuclides that bind to the outer surface 24. For example, each atom 26 of the radionuclide can be located on or slightly below the outer surface 24. The density of atoms 26 on the outer surface 24 is 10 per square centimeter. 11 from 10 14 It is between atoms.

[0023] Typically, radioactive nuclides, their daughter nuclides, and / or subsequent nuclides in a decay chain are alpha-emitting, meaning that when any given nucleus decays, alpha particles are emitted. For example, a radioactive nuclide may include an isotope of radium (e.g., Ra-224 or Ra-223), which decays by alpha emission to produce a daughter isotope of radon (e.g., Rn-220 or Rn-219), which then decays by alpha emission to produce an isotope of polonium (e.g., Po-216 or Po-215), which in turn decays by alpha emission to produce an isotope of lead (e.g., Pb-212 or Pb-211).

[0024] Typically, atom 26 is produced by the decay of a preceding radionuclide in the decay chain. For example, as described in U.S. Patent No. 8,894,969 by Kelson et al. (Patent Document 2), an atom of Ra-224 can be produced by spreading a thin layer of acid containing uranium-232 (U-232) on a metal. U-232 decays to produce thorium-228 (Th-228), which then decays to produce Ra-224.

[0025] Atoms 26 can be bonded to the support 22 using one or more suitable techniques described in U.S. Patent No. 8,894,969 by Kelson et al. (Patent Document 2) as described above. For example, a source that generates a flux of radionuclides is placed in a vacuum near the support 22, thereby causing nuclei recoiling from the source to cross the vacuum gap and be collected on or embedded in the outer surface 24. Alternatively, radionuclides can be electrostatically collected on the support 22 by applying a suitable negative voltage between the source and the support. In such embodiments, the support 22 may contain a conductive metal such as titanium to facilitate the electrostatic collection of radionuclides. For example, the support 22 may include conductive metal wires, needles, rods, or probes. Alternatively, the support 22 may include non-metallic needles, rods, or probes coated with a conductive metal film including the outer surface 24.

[0026] The proximity irradiation therapy apparatus 20 further includes a layer 28 of a polymer such as polypropylene, polycarbonate, polydimethylsiloxane, polyethylene terephthalate, poly(methyl methacrylate), and / or polysulfone, which covers the outer surface 24 and thus covers the atoms 26. The polymer is permeable to daughter radionuclides, and therefore the daughter radionuclides can diffuse through the polymer layer 28. For example, the diffusion coefficient of the daughter radionuclides in the polymer is at least 10 11 cm 2 This can be as much as / second. Typically, the thickness T0 of the polymer layer 28 is 0.1–2 microns, for example, 0.1–1 micron, and the polymer layer 28 is thick enough to prevent the radioactive nuclide from being washed away, but thin enough to allow the diffusion of daughter radioactive nuclides through it. (For ease of explanation, atoms 26 are depicted as disproportionately large relative to the thickness of the layer 28.)

[0027] To treat a subject, at least one device 20 is inserted completely or partially into the subject's body, typically into a tumor to be treated or directly adjacent to the tumor (e.g., within 0.1 mm, 0.05 mm, or 0.001 mm, etc.). Thereafter, while the device is in the body, the radionuclide decays and emits alpha particles to the tumor. Usually, about 50% of the resulting daughter nuclei recoil inward and adhere to the outer surface 24. However, other daughter nuclei recoil outward and enter the polymer layer 28. Due to the diffusivity of these daughter nuclei and / or subsequent nuclei in the decay chain within the polymer layer 28, at least some (e.g., 99% or more) of these nuclides can diffuse through the polymer layer, detach from the device, and enter the tumor. Thus, for example, daughter nuclides or other progeny nuclides can enter the tumor at a rate of 10 2 atoms per second per square centimeter to 10 5 atoms, e.g., 10 3 atoms per second per square centimeter to 10 4 atoms. These nuclides pass through the tumor by diffusion and / or convection and further decay while passing through the tumor. Thus, alpha particles can be emitted even at a considerable distance from the radiation source.

[0028] In some embodiments, following at least some radioactive decay of the radionuclide atoms - e.g., after a predetermined period and / or in response to monitoring of the tumor size and / or the fraction of alpha particles emitted - the device is removed from the subject. In other embodiments, the device is not removed from the subject.

[0029] Reference is now made to FIG. 2, which is a schematic view of an alternative brachytherapy device 21 according to some embodiments of the present invention.

[0030] Apparatus 21 differs from apparatus 20 in that it includes two polymer layers. Apparatus 21 has an inner layer 30 of a first polymer covering the outer surface 24 and an outer layer 33 of a second (different) polymer covering the inner layer 30. Atoms 26 are bonded to the outer surface 24 by being bonded to the inner layer 30. For example, each atom 26 is located on or slightly below the outer surface of the inner layer 30, thereby covering the atom with the outer layer 33. In general, each polymer layer may include any suitable polymer such as polypropylene, polycarbonate, polydimethylsiloxane, polyethylene terephthalate, poly(methyl methacrylate), and / or polysulfone, as long as the two layers are compatible with each other, as will be further described below in accordance with the description of Figure 4.

[0031] Both the first and second polymers are permeable to the daughter radionuclides. For example, the diffusion coefficient of the daughter radionuclides in each polymer is at least 10 -11 cm 2 This can be / second. Typically, the thickness T1 of each layer is between 0.1 and 2 microns, such as between 0.1 and 1 micron. Atoms 26 may be deposited on (or within) the inner layer 30 using any of the techniques described above. (Given the relative thinness of the inner layer, it usually does not hinder the electrostatic collection of radionuclides.)

[0032] Device 21 can be configured in the same way as device 20. The advantage of device 21 is that even if the daughter nuclei of a radioactive nuclide recoil inward, the daughter nuclei diffuse outward through the inner layer 30 and then through the outer layer 33, thereby making the probability of the daughter nuclei detaching from device 21 close to 100%. (Even if a particular nuclide diffuses inward to the outer surface of the support, the nuclei do not adhere to or penetrate the outer surface.) Therefore, the desired dose of alpha particle emission can be achieved using only half the amount of radioactive nuclide atoms 26 that would be required when using device 20. Thus, for example, when using device 21, the density of atoms 26 on the inner layer 30 is 5 × 10¹⁶ per square centimeter. 10 -5×10 13 It could be an atom.

[0033] In general, any suitable technique can be used to apply the polymer layer 28 to the apparatus 20, or the inner layer 30 and outer layer 33 to the apparatus 21. One such technique for the apparatus 20 is shown in Figure 3, a schematic diagram of an immersion coating technique for the manufacture of a close-range irradiation therapy apparatus according to some embodiments of the present invention.

[0034] As shown in Figure 3, to manufacture the apparatus 20, radioactive nuclide atoms 26 are first deposited on the outer surface 24. Then, the radiation source (i.e., the support 22 and the radioactive nuclide atoms deposited thereon) is immersed in a solution consisting of a polymer solute 29 dissolved in solvent 34. (For ease of explanation, the dissolved polymer particles are depicted as disproportionately large.) Next, the radiation source is withdrawn from the solution (as indicated by the upward arrow), thereby attracting the solute 29 to the radiation source, resulting in a polymer layer 28 covering the outer surface 24. The desired thickness of the polymer layer 28 can be obtained by controlling the concentration of the polymer solute and the rate at which the radiation source is withdrawn from the solution.

[0035] The immersion coating technique described above can also be used in the manufacture of the apparatus 21. In this regard, refer to Figure 4, which is a flowchart of a manufacturing method 36 for the apparatus 21 according to several embodiments of the present invention.

[0036] Method 36 begins with a first insertion step 38 in which the support 22 is inserted into a first polymer solution. Then, in a first withdrawal step 40, the support is withdrawn from the first polymer solution, and the inner layer 30 covers the support. Similar to the polymer layer 28 of the apparatus 20, the desired thickness of the inner layer 30 can be obtained by controlling the concentration of the polymer solute and the rate at which the support is withdrawn from the solution.

[0037] Next, in the deposition step 42, the radioactive nuclide is deposited on (and / or in) the inner layer 30. Then, in the second insertion step 44, the radiation source (i.e., the support and the radioactive nuclide deposited on it) is inserted into a second polymer solution different from the first polymer solution. Finally, in the second withdrawal step 46, the radiation source is withdrawn from the second polymer solution and the outer layer 33 covers the radioactive nuclide. Similar to the inner layer 30, the desired thickness of the outer layer can be obtained by controlling the concentration of the polymer solute and the rate at which the radiation source is withdrawn from the solution.

[0038] Generally, for the layer 28 of apparatus 20 and the outer layer 33 of apparatus 21, the solvent 34 may contain any suitable organic material that does not dissolve radionuclides. A similar solvent may be used for the inner polymer layer of apparatus 21.

[0039] Table 1 lists six different solutions as examples that can be used to form any of the polymer layers described herein, with each row in the table (following the first row) corresponding to one of these different solutions. [Table 1]

[0040] In apparatus 21, the respective solutions used for the two polymer layers are selected, taking into account the constraint that the solvent used for the outer polymer layer does not dissolve the inner layer. Using the numbering system in Table 1 to identify the solutions, five different pairs of available solutions are shown in Table 2 as an example. [Table 2]

[0041] (Experimental results) The inventors prepared several experimental close-range irradiation therapy devices using Ra-224 as the radionuclide. Each of these devices was placed in an environment simulating the inside of the human body, such as serum or water at 37°C, or a mouse tumor. For each device, no radium loss was detected, indicating that the polymer layer covering the radium prevented radium washing away. Next, radon desorption of the devices was tested using alpha-ray spectroscopy.

[0042] The following paragraphs provide further details on the preparation of some experimental apparatus, along with the radon desorption test.

[0043] (1) Single polymer layer Ra-224 atoms, generated by the decay of thorium-228 (Th-228), were electrostatically collected on four titanium wires with a diameter of 0.5 mm. The first wire was immersed in a 5 wt% polycarbonate solution with dichloromethane (DCM) as the solvent, and then withdrawn from the solution at a speed of 8 mm / second to obtain a polymer layer thickness of approximately 0.25 microns. Next, the polycarbonate concentration was increased to 7.5 wt%, and this procedure was repeated for the second wire to obtain a polymer layer thickness of approximately 0.5 microns. The third wire was immersed in a 15 wt% polydimethylsiloxane (PDMS) solution with hexane as the solvent, and then withdrawn at 12 mm / second to obtain a polymer layer thickness of approximately 0.25 microns. Next, the PDMS concentration was increased to 30 wt%, and this procedure was repeated for the fourth wire to obtain a polymer layer thickness of approximately 1 micron.

[0044] The measured radon desorption probabilities were 50% for the first wire, 48% for the second wire, and 50% for both the third and fourth wires. (As mentioned above with reference to Figure 1, assuming that 50% of the radon nuclide recoils backward and enters the radiation source, 50% is the theoretical maximum for apparatus 20.)

[0045] (2) Bipolymer layer A titanium wire was immersed in a 2% (by weight) solution of polyethylene terephthalate (PET) dissolved in hexafluoroisopropanol (HFIP) and withdrawn at a speed of 10 mm / second to obtain an inner layer thickness of 0.2 microns. Subsequently, Ra-224 atoms accumulated on the inner layer. Next, the radiation source was immersed in a 3% (by weight) solution of polycarbonate dissolved in dichloromethane (DCM) and withdrawn at a speed of 10 mm / second to obtain an outer layer thickness of 0.25 microns. The measured radon desorption probability was 88%, only slightly lower than the theoretical maximum of 100%.

[0046] (Note that the thickness of each polymer layer was measured by alpha-ray energy loss spectroscopy as described in "Recoil Injection of Alpha-Ray Sources for Thin Film Thickness Measurement" by Kelson, I. et al., Journal of Physics D:Applied Physics 28.1(1995):100. This document is incorporated herein by reference.)

[0047] Those skilled in the art will understand that the present invention is not limited to those specifically shown and described above. Rather, the scope of the present invention includes both combinations and subcombinations of the various features described above, as well as variations and modifications thereof that are not in the prior art and can be recalled by those skilled in the art who have read the above description.

Claims

1. It is a device: A support having an outer surface and configured to be inserted into the body of a subject; An alpha-emitting radionuclide having an isotope of radium selected from the group of isotopes consisting of Ra-224 and Ra-223, which undergoes radioactive decay to produce a daughter radionuclide of radon, which is bound to the outer surface, and substantially all of the radium atoms of the radionuclide are located outside the outer surface; A polymer layer having a thickness of 0.1–2 micrometers, being permeable to the daughter radionuclides of radon, and covering the radium atoms to prevent them from being washed away; An apparatus characterized by having the following.

2. The apparatus according to claim 1, characterized in that the thickness of the polymer layer is 0.1 to 1 micrometer.

3. The diffusion coefficient of the daughter radionuclides in the polymer is at least 10 -11 cm 2 The apparatus according to any one of claims 1-2, characterized in that it is per second.

4. The apparatus according to any one of claims 1 to 3, characterized in that the polymer is selected from the group consisting of polypropylene, polycarbonate, polydimethylsiloxane, polyethylene terephthalate, poly(methyl methacrylate), and polysulfone.

5. The apparatus according to any one of claims 1 to 4, characterized in that the polymer has polydimethylsiloxane (PDMS).

6. The density of the radioactive nuclide on the outer surface is 10 per square centimeter. 11 from 10 14 The apparatus according to any one of claims 1 to 5, characterized in that it is between atoms.

7. The steps include: depositing multiple atoms of an alpha-emitting radionuclide having an isotope of radium selected from the group of isotopes consisting of Ra-224 and Ra-223, which undergo radioactive decay to produce daughter radionuclides of radon, onto the outer surface of a support configured to be inserted into the body of a subject; The steps include: depositing the atoms onto the outer surface, then covering the atoms with a layer of polymer having a thickness of 0.1–2 micrometers that is permeable to the daughter radionuclides of radon, such that substantially all of the radium atoms of the radionuclides are located outside the outer surface and are covered with the polymer layer that prevents the radium atoms from being washed away; A method characterized by having the following:

8. After the step of covering the atoms, the density of the radioactive nuclide on the outer surface is 10 per square centimeter. 11 from 10 14 The method according to 7, characterized in that it is between atoms.

9. The method according to 7 or 8, characterized in that the thickness of the polymer layer is 0.1 to 1 micrometer.

10. The method according to 7 or 8, characterized in that the polymer has polydimethylsiloxane (PDMS).

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