Polymer coatings for brachytherapy devices

Abstract

The invention relates to a polymer coating for a brachytherapy device. The described embodiments include an apparatus (20, 21) comprising a support (22) comprising an outer surface (24) and configured for insertion into a body of a subject. The apparatus further includes a plurality of atoms (26) of a radionuclide that radionuclide decays radioactively to produce sub-radionuclides, the plurality of atoms of the radionuclide being coupled to the outer surface; and a layer (28, 33) of a polymer that is permeable to the child radionuclides, the layer of the polymer covering the atoms. Other embodiments are also described.

Description

[0001] This application is a divisional application of an application filed on May 9, 2018, with application number 201880029827.1 and invention name “Polymer coating for close-range radiotherapy device”. CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 504,800, filed May 11, 2017, entitled “Production of radiation sources,” the disclosure of which is incorporated herein by reference. Field of the Invention

[0003] The present invention relates to the field of brachytherapy, such as for the treatment of cancerous tumors. background

[0004] Brachytherapy involves placing a radiation source inside a subject's body so that the source emits radiation inside the body. The emitted radiation may kill cancerous cells near the source.

[0005] Arazi, Lior et al., "Treatment of solid tumors by interstitial release of recoiling short-lived alpha emitters," Physics in Medicine & Biology 52.16 (2007): 5025 (incorporated herein by reference) describes a method for treating solid tumors using alpha particles. The tumors are treated with interstitial radioactive sources that continuously release short-lived alpha-emitting atoms from their surfaces. The atoms are dispersed within the tumor and deliver a high dose through their alpha decay. The protocol is implemented using a thin-wire source impregnated with Ra-224, which is released by recoiled Rn-220, Po-216, and Pb-212 atoms.

[0006] U.S. Patent No. 8,894,969 to Kelson et al., the disclosure of which is incorporated herein by reference, describes a radiotherapy method comprising positioning 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 the predetermined period of time are sufficient for the radionuclide to deliver a predetermined therapeutic dose of decay chain nuclei and alpha particles to the tumor. SUMMARY OF THE INVENTION

[0007] According to some embodiments of the present invention, a device is provided, comprising a support including an outer surface and configured for insertion into a subject's body, the device further comprising a plurality of atoms of a radionuclide that radioactively decays to produce daughter radionuclides, the plurality of atoms of the radionuclide being coupled to the outer surface, and a layer of a polymer that is permeable to the daughter radionuclides, the layer of the polymer covering the atoms.

[0008] In some embodiments, the atoms are disposed on an exterior surface.

[0009] In some embodiments, the support is cylindrical.

[0010] In some embodiments, the radionuclide is an alpha-emitting radionuclide.

[0011] In some embodiments, the radionuclide comprises an isotope of radium selected from the group of isotopes consisting of Ra-224 and Ra-223.

[0012] In some embodiments, the daughter radionuclide is an alpha-emitting daughter radionuclide.

[0013] In some embodiments, the layer has a thickness between 0.1 microns and 2 microns.

[0014] In some embodiments, the thickness is between 0.1 micrometers and 1 micrometer.

[0015] In some embodiments, the diffusion coefficient of the daughter radionuclide in the polymer is at least 10 -11 cm 2 / sec.

[0016] In some embodiments, the polymer is selected from the group of polymers consisting of polypropylene, polycarbonate, polydimethylsiloxane, polyethylene terephthalate, poly(methyl methacrylate), and polysulfone.

[0017] In some embodiments, This layer is the outer layer, The polymer is a first polymer, and The device also includes an inner layer of a second polymer, the inner layer of the second polymer being permeable to the daughter radionuclide, coating the outer surface, the atoms being coupled to the outer surface by being coupled to the inner layer.

[0018] In some embodiments, the inner layer has an inner layer thickness between 0.1 microns and 2 microns.

[0019] In some embodiments, the inner layer has a thickness between 0.1 microns and 1 micron.

[0020] According to some embodiments of the present invention, a method is also provided, which includes coupling multiple atoms of a radionuclide to an outer surface of a support, wherein the radionuclide radioactively decays to produce a daughter radionuclide, and the support is configured for insertion into the body of a subject; and after coupling the atoms to the outer surface, covering the atoms with a layer of a polymer that is permeable to the daughter radionuclide.

[0021] In some embodiments, covering the atoms comprises covering the atoms by removing the support from a solution of the polymer such that a layer of polymer wraps around the outer surface.

[0022] In some embodiments, This layer is the outer layer, The polymer is a first polymer, The method further includes, before coupling the atoms to the outer surface, coating the outer surface with an inner layer of a second polymer, and Coupling the atoms to the outer surface includes coupling the atoms to the outer surface by coupling the atoms to the inner layer.

[0023] According to some embodiments of the present invention, a method is also provided, comprising inserting a radiation source into a subject's body. The radiation source comprises a support comprising an outer surface; a plurality of atoms of a radionuclide that radioactively decays to produce a daughter radionuclide, the plurality of atoms of the radionuclide being coupled to the outer surface; and a layer of a polymer that is permeable to the daughter radionuclide, the layer of polymer covering the atoms. The method also comprises leaving the radiation source in the subject's body such that nuclei of the daughter radionuclide diffuse through the layer of polymer.

[0024] In some embodiments, inserting the radiation source into the subject's body comprises inserting the radiation source into a tumor within the subject's body.

[0025] In some embodiments, inserting the radiation source into the subject's body includes inserting the radiation source so that the radiation source is within 0.1 mm of a tumor in the subject's body. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The present invention will be more fully understood through the following detailed description of embodiments of the present invention in conjunction with the accompanying drawings, in which: Figure 1-2 is a schematic diagram of a brachytherapy apparatus according to some embodiments of the present invention; Figure 3 is a schematic diagram of a dip coating technique for manufacturing a brachytherapy device according to some embodiments of the present invention; and Figure 4is a flow chart of a method for manufacturing a brachytherapy device according to some embodiments of the present invention. DETAILED DESCRIPTION

[0027] Overview In an embodiment of the present invention, atoms of a radionuclide such as radium-224 (Ra-224) emitting α are deposited on the surface of a support such as a wire. The support is then inserted into a solid tumor in the body of the subject, and the support also has the radionuclide deposited thereon, which can be referred to as a "radiation source" or simply as a "source". Subsequently, the radionuclide undergoes a series of radioactive decays, whereby the α particles that kill the cancerous cells of the tumor are emitted by the radionuclide atoms and the continuous decay chain nuclei. (Each of these nuclei is referred to herein as the "daughter" of the previous nucleus in the chain. Typically, the terms "atom" and "nucleus" are used interchangeably herein.) Advantageously, the decay chain nuclei migrate through the tumor by diffusion and / or convection, so that the α particles can even be emitted at a relatively significant distance from the source.

[0028] When applying the brachytherapy techniques described above, one challenge is that the radionuclide typically needs to be covered so that it is not washed away from the source by body fluids before the radionuclide has a chance to decay, however, covering the radionuclide may inhibit desorption of the radionuclide's progeny from the source. One option, described in the aforementioned U.S. Patent 8,894,969 to Kelson, is to cover the radionuclide with a very thin cover (e.g., having a thickness of 5-10 nanometers) that can be penetrated by the daughter nuclei as they recoil from the source. However, such a cover can be difficult to manufacture.

[0029] To address this challenge, embodiments described herein provide a thicker polymer layer (e.g., having a thickness of 0.1-1 microns) that covers the radionuclide but still allows daughter nuclei to diffuse through it. Such a layer can be applied by immersing the source in a suitable polymer solution so that the source becomes polymer-coated. Examples of suitable polymers include polypropylene, polycarbonate, polydimethylsiloxane, polyethylene terephthalate, poly(methyl methacrylate), and polysulfone.

[0030] In some embodiments, a further polymer layer (e.g., having a thickness of 0.1-1 microns) is applied to the surface of the support prior to deposition of the radionuclide. The advantage of such an embodiment is that even if daughter nuclei of the radionuclide recoil toward the surface, the daughter nuclei will not become stuck to or beneath 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, provided that the selected polymer does not dissolve in the solution used to subsequently coat the outer polymer layer.

[0031] Device Description Initial reference Figure 1 , Figure 1 is a schematic diagram of a brachytherapy apparatus 20 according to some embodiments of the present invention.

[0032] Brachytherapy device 20 includes a support 22 configured for partial or complete insertion into a subject's body. Support 22 may comprise, for example, a needle, a wire, a rod, the tip of an endoscope, the tip of a laparoscope, or any other suitable probe. Typically, support 22 is cylindrical; for example, support 22 may comprise a cylindrical wire, needle, or rod having a diameter of 0.3-1 mm and / or a length of 5-60 mm. Support 22 includes an outer surface 24.

[0033] The brachytherapy device 20 also includes a plurality of atoms 26 of a radionuclide coupled to the outer surface 24, the radionuclide decaying to produce daughter radionuclides. For example, each atom 26 of the radionuclide can be disposed on or slightly below the outer surface 24. Typically, the density of the atoms 26 on the outer surface 24 is between 1011 atoms and 1014 atoms per square centimeter.

[0034] Typically, radionuclides, daughter radionuclides, and / or subsequent nuclei in the decay chain are alpha-emitting, in that an alpha particle is emitted after any given nuclear decay. For example, radionuclides may include isotopes of radium (e.g., Ra-224 or Ra-223), which decay by alpha emission to produce daughter isotopes of radon (e.g., Rn-220 or Rn-219), which decay by alpha emission to produce isotopes of polonium (e.g., Po-216 or Po-215), which decay by alpha emission to produce isotopes of lead (e.g., Pb-212 or Pb-211).

[0035] Typically, atoms of 26 are produced by the decay of a radionuclide preceding the decay chain. For example, as described in U.S. Patent 8,894,969 to Kelson et al., atoms 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 in turn decays to produce Ra-224.

[0036] Any suitable technique, such as any one or more of the techniques described in Kelson's aforementioned '969 patent, can be used to couple atoms 26 to support 22. For example, a generating source that generates a flux of radionuclides can be placed in a vacuum near support 22 such that nuclei recoiled from the generating source traverse the vacuum gap and are collected on or implanted in surface 24. Alternatively, the radionuclides can be electrostatically collected on support 22 by applying a suitable negative voltage between the generating source and the support. In such an embodiment, to facilitate electrostatic collection of the radionuclides, support 22 can comprise a conductive metal, such as titanium. For example, support 22 can comprise a conductive metal wire, needle, rod, or probe. Alternatively, support 22 can comprise a non-metallic needle, rod, or probe that includes surface 24 and is coated with a conductive metal coating.

[0037] The brachytherapy device 20 also includes a layer 28 of a polymer, such as polypropylene, polycarbonate, polydimethylsiloxane, polyethylene terephthalate, poly(methyl methacrylate), and / or polysulfone, which coats the surface 24 and thus covers the atoms 26. The polymer is permeable to the daughter radionuclide, such that the daughter radionuclide can diffuse through the layer 28. For example, the diffusion coefficient of the daughter radionuclide in the polymer can be at least 10 -11 cm 2 Typically, the thickness T0 of layer 28 is between 0.1 micrometers and 2 micrometers, such as between 0.1 micrometers and 1 micrometer, so that layer 28 is thick enough to protect the radionuclide from being washed away, but thin enough to allow the daughter radionuclides to diffuse therethrough. (For ease of illustration, atoms 26 are drawn disproportionately large relative to the thickness of layer 28.) To treat a subject, at least one device 20 is fully or partially inserted into the subject's body, typically into the tumor to be treated or in close proximity to the tumor to be treated (e.g., within 0.1 mm, such as within 0.05 mm or 0.001 mm). Subsequently, while the device remains within the body, the radionuclide decays, thereby emitting alpha particles into the tumor. Typically, approximately 50% of the resulting daughter nuclei recoil inward and become stuck to surface 24; however, other daughter nuclei recoil outward, entering layer 28. Due to the diffusivity of these daughter nuclei and / or subsequent nuclei in the decay chain within layer 28, at least some (e.g., greater than 99%) of these nuclei can diffuse through the polymer layer and thus desorb from the device and enter the tumor. Thus, for example, daughter nuclei or other progeny nuclei can enter the tumor at a rate between 102 and 105 atoms per square centimeter per second, such as between 103 and 104 atoms. These nuclei then pass through the tumor by diffusion and / or convection and, while passing through the tumor, undergo further decay.Thus, alpha particles can be emitted even at a significant distance from the source.

[0038] In some embodiments, the device is removed from the subject after radioactive decay of at least some of the radionuclide atoms, for example, after a predetermined duration, and / or in response to monitoring the size of the tumor and / or the fraction of alpha particles emitted. In other embodiments, the device is not removed from the subject.

[0039] Now refer to Figure 2 , Figure 2 is a schematic diagram of an alternative brachytherapy device 21 according to some embodiments of the present invention.

[0040] Device 21 differs from device 20 in that device 21 includes two polymer layers: an inner layer 30 of a first polymer covering outer surface 24 and an outer layer 33 of a second (different) polymer covering inner layer 30. Atoms 26 are coupled to outer surface 24 by being coupled to inner layer 30; for example, each atom 26 can be disposed on the outer surface of inner layer 30 or slightly below the outer surface of inner layer 30 such that the atom is covered by outer layer 33. In general, each layer can include any suitable polymer, such as polypropylene, polycarbonate, polydimethylsiloxane, polyethylene terephthalate, poly(methyl methacrylate), and / or polysulfone, provided that the two layers are compatible with each other, as described below. Figure 4 The description is further described.

[0041] Both the first polymer and the second polymer are permeable to the daughter radionuclide; for example, the diffusion coefficient of the daughter radionuclide in each polymer may be at least 10 -11 cm2 / sec. Typically, the thickness T1 of each layer is between 0.1 microns and 2 microns, such as between 0.1 microns and 1 micron. Atoms 26 can be deposited on (or in) inner layer 30 using any of the techniques described above. (Given the relative thickness of the inner layer, the inner layer generally does not inhibit electrostatic collection of radionuclides.) Device 21 can be deployed similarly to device 20. An advantage of device 21 is that even if daughter nuclei of the radionuclide recoil inward, the daughter nuclei can still diffuse outward through inner layer 30 and then through outer layer 33, so that the probability of desorption of the daughter nuclei from device 21 can be close to 100%. (Even if a given nucleus diffuses all the way inward to the outer surface of the support, the nucleus will not adhere to the surface or penetrate the surface.) Therefore, the required dose of alpha particle emission can be obtained using only half the number of radionuclide atoms 26 that would be required when using device 20. Thus, for example, using device 21, the density of atoms 26 on inner layer 30 can be 5*10 per square centimeter. 10 atoms and 5*10 13 between atoms.

[0042] Generally, any suitable technique may be used to apply polymer layer 28 to device 20, or to apply inner layer 30 and outer layer 33 to device 21. One such technique for device 20 is Figure 3 As shown in Figure 3 is a schematic diagram of a dip coating technique for manufacturing a brachytherapy device according to some embodiments of the present invention.

[0043] like Figure 3 , to fabricate device 20, radionuclide atoms 26 are first deposited onto outer surface 24. Subsequently, the source (i.e., support 22 with the radionuclide atoms deposited thereon) is immersed in a solution containing a polymer solute 29 dissolved in a solvent 34. (For ease of illustration, the dissolved polymer particles are drawn disproportionately large.) Next, the source is removed from the solution (as indicated by the upward arrow), causing the solute 29 to be attracted to the source and, as a result, coating outer surface 24 with a layer 28. The desired thickness of layer 28 can be obtained by controlling the concentration of the polymer solute and the rate at which the source is removed from the solution.

[0044] The dip coating technique described above can also be used to manufacture the device 21. In this regard, reference is now made to Figure 4 , Figure 4 is a flow chart of a method 36 for manufacturing device 21 according to some embodiments of the present invention.

[0045] Method 36 begins with a first insertion step 38, in which support 22 is inserted into a first polymer solution. Subsequently, in a first removal step 40, the support is removed from the first polymer solution such that inner layer 30 covers the support. As with layer 28 of device 20, the desired thickness of inner layer 30 can be achieved by controlling the concentration of the polymer solute and the speed at which the support is removed from the solution.

[0046] Subsequently, in a deposition step 42, the radionuclide is deposited onto (and / or into) the inner layer 30. Next, in a second insertion step 44, the source (i.e., the support with the radionuclide deposited thereon) is inserted into a second polymer solution, the second polymer being different from the first polymer. Finally, in a second removal step 46, the source is removed from the second polymer solution, leaving the outer layer 33 covered with the radionuclide. As with the inner layer 30, the desired thickness of the outer layer can be achieved by controlling the concentration of the polymer solute and the rate at which the source is removed from the solution.

[0047] Generally, for layer 28 of device 20, and for outer layer 33 of device 21, solvent 34 can comprise any suitable organic material that does not dissolve radionuclides. Similar solvents can be used for the polymeric inner layer of device 21.

[0048] Table 1 lists, by way of example, six different solutions that can be used to form any of the polymer layers described herein, with each row of the table (after the first row) corresponding to a different respective one of these solutions.

[0049] Table 1

[0050] For device 21, the respective solutions for the two polymer layers are selected taking into account the constraint that the solvent for the outer polymer layer does not dissolve the inner layer. Table 2 lists by way of example five different pairs of solutions that can be used, using the numbering system from Table 1 to identify the solutions.

[0051] Table 2

[0052] Experimental results The inventors prepared several experimental brachytherapy devices using Ra-224 as the radionuclide. Each of these devices was placed in an environment simulating the human body, such as 37°C serum or water, or in a mouse tumor. No radium loss was detected in any of the devices, indicating that the polymer layer covering the radium prevented it from washing away. The devices were then tested for radon desorption using alpha spectroscopy.

[0053] The following paragraphs describe in more detail the preparation of several experimental setups along with the testing of radon desorption.

[0054] (1) Polymer monolayer The Ra-224 atoms produced by Th-228 decay are electrostatically collected on four titanium wires, each of which has a diameter of 0.5 mm. The first wire is immersed in a 5% (by weight) polycarbonate solution with DCM as a solvent, and then removed from the solution at a speed of 8 mm / sec, resulting in a polymer layer thickness of approximately 0.25 micron. The procedure is then repeated for the second wire, wherein the concentration of polycarbonate is increased to 7.5%, resulting in a polymer layer thickness of approximately 0.5 micron. The third wire is immersed in a 15% (by weight) PDMS solution with hexane as a solvent, and then removed at 12 mm / sec, resulting in a polymer layer thickness of approximately 0.25 micron. The procedure is then repeated for the fourth wire, wherein the concentration of PDMS is increased to 30%, resulting in a polymer layer thickness of approximately one micron.

[0055] The measured radon desorption probability is 50% for the first wire, 48% for the second wire, and 50% for each of the third and fourth wires. (50% is the theoretical maximum value of the device 20, considering the above reference Figure 1 As described, 50% of the radon nuclei recoil back to the source.) (2) Polymer bilayer The titanium wire was immersed in a solution of 2% (by weight) PET dissolved in HFIP with a withdrawal rate of 10 mm / sec, resulting in an inner layer thickness of 0.2 microns. Subsequently, Ra-224 atoms were collected on the inner layer. Next, the source was immersed in a solution of 3% (by weight) polycarbonate dissolved in DCM with a withdrawal rate of 10 mm / sec, resulting in an outer layer thickness of 0.25 microns. The measured radon desorption probability was 88%, which is only slightly lower than the theoretical maximum of 100%.

[0056] (Note that the thickness of each polymer layer was measured by alpha energy loss spectroscopy, which is described in Kelson, I. et al., “Recoil implantation of alpha sources forthickness measurement of thin films,” Journal of Physics D: Applied Physics 28.1 (1995): 100, which is incorporated herein by reference.) It will be understood by those skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. Rather, the scope of the present invention includes both combinations and subcombinations of the various features described hereinabove, as well as variations and modifications thereof that are not prior art and which would occur to those skilled in the art upon reading the foregoing description.

Claims

1. A brachytherapy device comprising: a support member, the support member comprising an outer surface; a plurality of atoms of a radionuclide that radioactively decays to produce daughter radionuclides, the plurality of atoms of the radionuclide being disposed on the outer surface; and An outer layer of polydimethylsiloxane covering the atoms so as to protect them from being washed away but allowing the daughter radionuclides to diffuse through the outer layer, wherein the thickness of the outer layer is between 0.1 microns and 2 microns.

2. The apparatus of claim 1, wherein the support member is cylindrical.

3. The apparatus of claim 1, wherein the radionuclide is an alpha-emitting radionuclide.

4. The apparatus of claim 1 , wherein the radionuclide comprises an isotope of radium selected from the group of isotopes consisting of Ra-224 and Ra-223.

5. The apparatus of claim 1, wherein the daughter radionuclide is an alpha-emitting daughter radionuclide.

6. The device of any one of claims 1 to 5, wherein the outer layer has a thickness between 0.1 micrometers and 1 micrometer.

7. The apparatus according to any one of claims 1 to 5, wherein the diffusion coefficient of the daughter radionuclide in the polydimethylsiloxane is at least 10 -11 cm 2 / sec.

8. The device of any one of claims 1-5, further comprising an inner layer of an inner polymer between the outer surface and the atoms.

9. The device of claim 8, wherein the inner layer has a thickness between 0.1 microns and 2 microns.

10. The device of claim 9, wherein the inner layer has a thickness between 0.1 micrometers and 1 micrometer.

11. The apparatus of claim 8, wherein the inner layer allows the daughter radionuclide to diffuse through the inner layer.

12. The apparatus of claim 11, wherein the inner polymer diffusion coefficient of the daughter radionuclide in the inner polymer is at least 10 -11 cm 2 / sec.

13. A method for manufacturing a brachytherapy device, the method comprising: depositing a plurality of atoms of a radionuclide onto an outer surface of the support, the radionuclide radioactively decaying to produce daughter radionuclides; and After the atoms are deposited on the outer surface, they are covered with an outer layer of polydimethylsiloxane that protects the atoms from being washed away but allows the daughter radionuclides to diffuse through the outer layer, wherein the thickness of the outer layer is between 0.1 microns and 2 microns.

14. The method of claim 13, wherein the support member is cylindrical.

15. The method of claim 13, wherein capping the atoms comprises removing the support from a solution of polydimethylsiloxane.

16. The method of claim 13, wherein the radionuclide is an alpha-emitting radionuclide.

17. The method of claim 16, wherein the radionuclide comprises an isotope of radium selected from the group of isotopes consisting of Ra-224 and Ra-223.

18. The method of claim 13, wherein the daughter radionuclide is an alpha-emitting daughter radionuclide.

19. The method of any one of claims 13-18, wherein the outer layer has a thickness between 0.1 micrometers and 1 micrometer.

20. The method of any one of claims 13 to 18, wherein the diffusion coefficient of the daughter radionuclide in the polydimethylsiloxane is at least 10 -11 cm 2 / sec.

21. The method of any one of claims 13-18, further comprising coating the outer surface of the support with an inner layer of an inner polymer, and wherein depositing the plurality of atoms onto the outer surface of the support comprises depositing the plurality of atoms on the inner layer.

22. The method of claim 21, wherein the inner layer has a thickness between 0.1 microns and 2 microns.

23. The method of claim 22, wherein the inner layer has a thickness between 0.1 micrometers and 1 micrometer.

24. The method of claim 21, wherein the inner layer allows the daughter radionuclide to diffuse through the inner layer.

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