Radioactive isotope source

Abstract

1. A layered radioisotope source for producing a medically useful dose of a daughter radioisotope through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, the layered radioisotope source comprising: an inert ceramic substrate layer; a metal oxide surface layer bonded onto the inert ceramic substrate layer; and a parent radioisotope immobilized on or within the metal oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source.

Description

[Technical Field]

[0001] The present disclosure relates generally to radioisotope sources, and more particularly to layered radioisotope sources comprising at least an inert ceramic substrate layer and a metal oxide surface layer having a radioisotope immobilized thereon, processes for preparing the layered radioisotope sources, and processes, generators, systems, and the like for producing and capturing radioisotopes using the layered radioisotope sources, including preparing radioisotope solutions for use in radiopharmaceuticals and / or other clinical applications. [Background technology]

[0002] Radioisotopes have a variety of uses, including medical applications as radiopharmaceuticals, where they can effectively deliver lethal radiation directly to cancer cells with little collateral damage to surrounding healthy tissue. However, the clinical uptake of this form of therapy is limited by the availability of suitable radioisotopes, and global supply is also limited by various manufacturing constraints. The current supply of alpha-emitting isotopes worldwide is only sufficient to support a small number of early-stage trials. Furthermore, radioisotopes produced by current methods are often contaminated with impurities, including radiochemical impurities, which can be difficult to filter or remove from the desired radioisotope, potentially hindering clinical application.

[0003] A few alpha-emitting radioisotopes, such as actinium-225 ( 225 Ac) are being produced for therapeutic / clinical trial use. However, producing these isotopes in clinically useful quantities requires complex operations involving, for example, large particle accelerators or nuclear reactors. Therefore, the supply chain for these radioisotopes is cumbersome and expensive and, as a result, is limited to only a few manufacturing facilities worldwide.

[0004] Lead 212( 212Pb) is an excellent alpha-emitting radioisotope for radioligand therapy. 212 Current generators for producing Pb use parent radioisotopes with relatively short half-lives (e.g., radium-224 ( 224 Ra) from the parent radioisotope bound to a resin-based ion exchange material. 212 Ion-exchange-based generators based on such resins are subject to significant damage from radiolysis, limiting their overall durability and limiting their clinical application. Furthermore, isolated Pb from such resin-based ion-exchange-based generators 212 Extracting Pb radioisotopes often requires significant amounts of wash solution, thus complicating and prolonging the subsequent radiolabeling chemistry. 212 Pb generators require overly complicated loading procedures to immobilize the parent radioisotope, which can result in significantly reduced yields over time and / or expose users to significant radiation doses due to radiolytic degradation of the organic materials, such as barium stearate, used to immobilize and house the parent radioisotope.

[0005] Therefore, there is a need for improved radioisotope sources and processes for producing therapeutic radioisotopes that can enable the production of clinically useful doses of therapeutic isotopes. Summary of the Invention

[0006] The present inventors have undertaken research and development to identify new and improved medical radioisotope sources that address one or more of the above problems, or at least provide the public with a useful alternative. In particular, the present inventors have developed a layered radioisotope source that can be configured to immobilize a parent radioisotope that can be used as a source for producing daughter radioisotopes.

[0007] According to some embodiments or examples described herein, the inventors have developed a "sol-gel" process that can provide a substantially homogeneous dispersion of radioisotopes immobilized within a surface layer of a ceramic substrate. Importantly, unlike other deposition and precipitation methods that can form large, discrete particles / deposits of radioisotopes loosely attached to the substrate surface (e.g., wool or paper substrates contain loose deposits of radioisotopes that are difficult to handle due to potential contamination), not only are the immobilized radioisotopes strongly anchored / embedded within the surface layer, but in some embodiments, the surface layer itself is firmly bonded to the underlying ceramic substrate. Due to these properties, the layered radioisotope source is expected to have one or more additional advantages over existing radioisotope sources, including increased resistance to damage from radioactive degradation, higher purity of the radionuclide product due to lower breakthrough of the parent radioisotope into collected daughter radioisotopes, increased production efficiency due to effective separation of gaseous intermediate radioisotopes as they decay and evolve away from the immobilized parent radioisotope, and / or a longer source lifetime. These advantageous properties have enabled the development of radioisotope generators that allow for "line-of-sight" gravity-assisted collection of daughter radioisotopes with minimal contamination.

[0008] In one aspect, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: an inert ceramic substrate layer; a metal oxide surface layer bonded to an inert ceramic substrate layer; a parent radioisotope immobilized on or within a metal oxide surface layer so as to allow for effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0009] In another aspect, a sol-gel process for preparing a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a) providing a gel formed from a solution (e.g., a sol) containing a metal alkoxide and a parent radioisotope species on the surface of an inert ceramic substrate layer; b) heating the gel under conditions effective to form a bonded metal oxide surface layer on the inert ceramic substrate layer; Including, The parent radioisotope is immobilized on or within the metal oxide surface layer in a manner that allows for efficient release of the gaseous intermediate radioisotope away from the layered radioisotope source; A sol-gel process is provided.

[0010] In another aspect, a radioisotope generator is provided that defines a chamber for generating and capturing a population of daughter radioisotopes, the chamber configured to accommodate a layered radioisotope source as described herein within the chamber.In another aspect, a radioisotope generator is provided that defines a chamber for generating and capturing a population of daughter radioisotopes, the chamber configured to accommodate a layered radioisotope source as described herein within the chamber.

[0011] In another aspect, a system for generating and capturing a population of daughter radioisotopes comprises: a) a radioisotope generator defining a chamber for generating and capturing a population of daughter radioisotopes as described herein; b) a layered radioisotope source as described herein housed within a chamber; The present invention provides a system including:

[0012] In another aspect, a process for generating and capturing a population of daughter radioisotopes is provided, comprising: a) enabling the release of gaseous intermediate radioisotopes generated through a chain of spontaneous decays from parent radioisotopes immobilized on or within the layered radioisotope source described herein; b) collecting at least some of the gaseous intermediate radioisotope for a period of time effective for it to decay into daughter radioisotopes; The present invention provides a process including:

[0013] Other aspects and embodiments related to the present disclosure are described herein. It will be understood that each example, aspect, and embodiment of the present disclosure described herein applies mutatis mutandis to all other examples, aspects, or embodiments, unless specifically stated otherwise. For example, each example, aspect, and embodiment of a layered radioisotope source described herein may equally apply to one or more of the generators, systems, or processes described herein, and vice versa. The present disclosure is not limited in scope by the specific examples described herein, which are for illustrative purposes only. Functionally equivalent products, compositions, and processes are expressly within the scope of the present disclosure described herein.

[0014] Embodiments of the present disclosure are further described and illustrated below, by way of example only, with reference to the accompanying drawings in which: [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 is a schematic diagram of one embodiment of an inert ceramic substrate containing an immobilized radioisotope. [Figure 2] 1 is an SEM micrograph and associated EDX area scan spectrum of a layered radioisotope source prepared according to Table 1. [Figure 3] 1 is an SEM micrograph and associated EDX area scan spectrum of a layered radioisotope source prepared according to Table 1. [Figure 4] 1 is an SEM micrograph and associated EDX area scan spectrum of a layered radioisotope source prepared according to Table 1. [Figure 5] 1 is an SEM micrograph and associated EDX area scan spectrum of a layered radioisotope source prepared according to Table 1. [Figure 6] 1 is an SEM micrograph and associated EDX area scan spectrum of a layered radioisotope source prepared according to Table 1. [Figure 7] 1 is an SEM micrograph and associated EDX area scan spectrum of a layered radioisotope source prepared according to Table 1. [Figure 8] 1 is an SEM micrograph and associated EDX area scan spectrum of a layered radioisotope source prepared according to Table 1. [Figure 9] 1 is an SEM micrograph and associated EDX area scan spectrum of a layered radioisotope source prepared according to Table 1. [Figure 10] 1 is an SEM micrograph and associated EDX area scan spectrum of a layered radioisotope source prepared according to Table 1. [Figure 11] 1 is an SEM micrograph and associated EDX area scan spectrum of a layered radioisotope source prepared according to Table 1. [Figure 12] 1 is an SEM micrograph and associated EDX area scan spectrum of a layered radioisotope source prepared according to Table 1. [Figure 13] 1 is an SEM micrograph and associated EDX area scan spectrum of a layered radioisotope source prepared according to Table 1. [Figure 14] 1 is an SEM micrograph and associated EDX area scan spectrum of a layered radioisotope source prepared according to Table 1. [Figure 15] 1 is an SEM micrograph and associated EDX area scan spectrum of a layered radioisotope source prepared according to Table 1. [Figure 16] 1 is an SEM micrograph and associated EDX area scan spectrum of a layered radioisotope source prepared according to Table 1. [Figure 17] 1 is an SEM micrograph and associated EDX area scan spectrum of a layered radioisotope source prepared according to Table 1. [Figure 18] In some embodiments, the radioisotopes disclosed herein include the radioactive decay series of thorium-228 (228Th). DETAILED DESCRIPTION OF THE INVENTION

[0016] The present disclosure describes the following various non-limiting embodiments related to research conducted to develop radioisotope sources, processes, generators, and / or systems for producing radioisotopes.

[0017] term In the following description, reference may be made to the accompanying figures and / or drawings that form a part hereof, and which show, by way of illustration, several embodiments, It is understood that other embodiments may be utilized and structural changes may be made without departing from the scope of the present disclosure.

[0018] With respect to the definitions provided herein, unless otherwise stated or implied from the context, the defined terms and phrases include the meaning provided. Unless expressly stated otherwise or apparent from the context, the following terms and phrases do not exclude the meaning that the term or phrase would have acquired by one of ordinary skill in the art. Definitions are provided to help describe particular embodiments and are not intended to limit the invention as claimed, as the scope of the invention is limited only by the claims. Further, unless otherwise required by context, singular terms shall include the plural and plural terms shall include the singular.

[0019] All publications discussed and / or referenced herein are incorporated herein in their entirety.

[0020] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present disclosure and is not to be construed as an admission that any or all of such matters form part of the prior art document or were common general knowledge in the art relevant to the present disclosure as they existed prior to the priority date of each claim of this application.

[0021] Throughout this disclosure, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps, or group of compositions of matter shall be construed to encompass one and more (i.e., one or more) of that step, composition of matter, group of steps, or group of compositions of matter. Accordingly, as used herein, the singular forms "a," "an," and "the" include plural aspects unless the context clearly dictates otherwise. For example, reference to "a" includes two or more and not just one, reference to "an" includes two or more and not just one, reference to "the" includes two or more and not just one, etc.

[0022] Those skilled in the art will understand that the disclosure herein is susceptible to variations and modifications other than those specifically described. The present disclosure should be understood to include all such variations and modifications. The present disclosure includes all examples, steps, features, processes, substrates, etc., referred to or shown in this specification, individually or collectively, as well as any combination of any two or more of the steps or features.

[0023] In describing examples and embodiments, specific terms are used herein for the sake of clarity. For purposes of description, specific terms are intended to include at least technical and functional equivalents that operate in a similar manner to achieve a similar result. Furthermore, in some instances where a particular embodiment or example includes multiple system elements or method steps, those elements or steps may be replaced with a single element or step. Similarly, a single element or step may be replaced with multiple elements or steps that serve the same purpose.

[0024] The term "and / or," e.g., "X and / or Y," shall be understood to mean "X and Y" or "X or Y," and shall be deemed to provide explicit support for both meanings or for either meaning.

[0025] Unless otherwise indicated, terms such as "first," "second," etc. are used herein merely as labels, and are not intended to impose any order, position, or hierarchy on the items to which they refer. Furthermore, a reference to a "second" item does not require or preclude the presence of lower-numbered items (e.g., the "first" item) and / or higher-numbered items (e.g., the "third" item).

[0026] Where a method / process is enumerated, and where steps / stages are enumerated in a particular order (with or without the addition of an ordering prefix for ease of reference), the steps / stages should not be construed as being limited in time to the order in which they are enumerated, unless otherwise specified or implied by the terms and wording.

[0027] As used herein, the phrase “at least one of,” when used in conjunction with a list of items, means that different combinations of one or more of the listed items may be used, and that only one of the items in the list may be required. An item may be a specific object, thing, or category. In other words, “at least one of” means that any combination or number of items from the list may be used, but not all items in the list may be required. For example, “at least one of item A, item B, and item C” may mean item A, item A and item B, item B, item A, item B, and item C, or item B and item C. In some cases, “at least one of item A, item B, and item C” may mean, for example, but not limited to, two of item A, one of item B, and ten of item C, four of item B, and seven of item C, or some other suitable combination.

[0028] As used herein, the term "about" typically refers to + / -10%, for example + / -5%, of the specified value, unless stated to the contrary.

[0029] Where various properties or other value parameters are specified herein for examples or embodiments, those parameters or values ​​can be adjusted up or down by 1 / 100, 1 / 50, 1 / 20, 1 / 10, 1 / 5, 1 / 3, 1 / 2, 2 / 3, 3 / 4, 4 / 5, 9 / 10, 19 / 20, 49 / 50, 99 / 100, etc. (or by factors of 1, 2, 3, 4, 5, 6, 8, 10, 20, 50, 100, etc.) unless otherwise specified, or by truncated approximations thereof, or within the range of the specified parameter up to or below any of the above-specified variations (e.g., for a particular parameter of 100 and a variation of 1 / 100, the value of the parameter can be in the range of 0.99 to 1.01).

[0030] It should be understood that certain features that are, for clarity, described herein in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment, can also be provided separately or in any subcombination.

[0031] Throughout this specification, various components / features of the present disclosure may be presented in a range format. This range format is included for convenience and should not be construed as an inflexible limitation on the scope of the present invention. Accordingly, the description of a range should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within that range, unless otherwise indicated. For example, the description of a range such as 1 to 5 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 5, 3 to 5, etc., as well as individual and partial numbers within the recited range, e.g., 1, 2, 3, 4, 4.5, and 5, unless a specific integer is required or implied by context. This applies regardless of the breadth of the disclosed range. Where specific values ​​are required, they are set forth herein.

[0032] Throughout this specification, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of the specified elements, components or steps, or group of elements, components or steps, but to the exclusion of any other elements, components or steps, or group of elements, components or steps. The phrase "consisting of" means the listed elements, but excludes other elements.

[0033] As used herein, the term "decay" refers to the spontaneous change of a radioactive nuclide into its daughter nuclide or a different nuclide called its "decay product." The daughter nuclide may be stable or may itself be radioactive and therefore undergo further spontaneous decay into a different daughter nuclide. It is understood that these radioactive decay processes occur spontaneously without the need for human intervention.

[0034] As used herein, the terms "isotope" and "nuclide" are synonymous and can be used interchangeably, including when used in compound words such as, for example, radioisotope and radionuclide.

[0035] Layered Radioisotope Source The present inventors 212 We have developed a layered radioisotope source that can be configured to immobilize parent radioisotopes that can be used as sources for producing daughter radioisotopes, including those provided in the decay series of Figure 2, such as Pb. The parent radioisotope can be used as a source of gaseous intermediate radioisotopes that can be captured and then used as a source for producing daughter radioisotopes using the processes and generators described herein.

[0036] It has been found that, according to some embodiments or examples described herein, by strongly anchoring / embedding the parent radioisotope within a metal oxide surface layer that is firmly adhered to the underlying inert ceramic substrate, the resulting layered radioisotope source is expected to have one or more additional advantages, including increased resistance to radiolytic damage, improved yield / purity of daughter radioisotopes, and / or longer lifetime.

[0037] In one embodiment, a layered radioisotope source is provided that includes an inert ceramic substrate layer, a metal oxide surface layer bonded to the inert ceramic substrate layer, and a parent radioisotope immobilized on or within the metal oxide surface layer.

[0038] The layered radioisotope source may have a form suitable for insertion into a radioisotope generator, such as a source chamber described herein. In one embodiment, the layered radioisotope source may be provided as a discrete unit, such as a disk (e.g., cylindrical), plate, membrane, platen, slab, tube, tube section, or monolith. The unit may have any desired shape, including, but not limited to, a spherical or hemispherical shape. In one embodiment, the inert ceramic substrate is a disk or slab. The disk or slab may be configured to be inserted into a radioisotope generator, including, for example, an "upside-down" configuration relative to an external observer. The disk is not limited to any particular cross-sectional shape (i.e., spherical, rectangular, etc.), so long as the slab or disk is substantially planar.

[0039] In one embodiment, the layered radioisotope source has a cross-sectional aspect ratio (i.e., the ratio of length to width, where length and width are measured perpendicular to one another and length refers to the longest linear dimension) of greater than 1.0 to about 10.0, e.g., at least about 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, or 10.0. According to some embodiments or examples described herein, layered radioisotope sources having higher cross-sectional aspect ratios (e.g., greater than 2.0) provide planar shapes, such as disks or slabs, that provide larger radioisotope surface layer areas for efficient release of gaseous intermediate radioisotopes.

[0040] In one embodiment, the layered radioisotope source has an overall thickness of about 1 mm to about 100 mm. The layered radioisotope source may have a thickness (in mm) of at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 25, 30, 40, 50, or 100. The layered radioisotope source may have a thickness (in mm) of less than about 100, 50, 40, 30, 25, 20, 15, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0.5. The thickness may be within a range provided by any two of these upper or lower limits, e.g., about 1 mm to about 100 mm, about 1 mm to about 20 mm, or about 1 mm to about 15 mm, e.g., about 1 mm to about 10 mm.

[0041] Type of radioisotope Any suitable parent radioisotope may be used. In one embodiment, the parent radioisotope is an alpha-emitting radioisotope, i.e., capable of emitting an alpha particle (i.e., a helium nucleus) that is transformed into a different nucleus whose mass number is reduced by four and whose atomic number is reduced by two.

[0042] In one embodiment, the parent radioisotope is an isotope of thorium or radium, or a combination thereof. In one embodiment, the parent radioisotope is a thorium radioisotope. The thorium radioisotope is thorium-227 ( 227 Th), Thorium-228 ( 228 Th), and thorium-232 ( 232 In one embodiment, the parent radioisotope is radium. The radium radioisotope may be selected from at least one of: 224 Ra and 228 Ra, or a combination thereof.

[0043] In one embodiment, the parent radioisotope is 228 Th. 228 Th has a half-life of approximately 2 years and is commercially available. 228 These and other properties of Th make it: 212This makes it a desirable parent radioisotope for producing Pb. 212 Pb is an alpha particle emitter via beta particle emission 212 decays to Bi and is therefore problematic 212 Because Bi has a short half-life, it is a promising medical isotope for targeted therapy, including cancer treatment. 212 If Pb is bound to a targeting molecule, such as one for cancer cells, it can be used for targeted alpha therapy.

[0044] When immobilized within the layered radioisotope source described herein, according to some embodiments or examples: 228 Th only gradually reduces productivity, 212 It can be used as the parent radioisotope in a Pb generator for more than a year.

[0045] In one embodiment, the gaseous intermediate radioisotope is a radon radioisotope. The radon radioisotope is radon-219( 219 Rn) or radon 220 ( 220 In one embodiment, the daughter radioisotope is a lead radioisotope. The lead radioisotope is lead-211 ( 211 Pb) or lead 212( 212 Pb).

[0046] In one embodiment, the parent radioisotope is immobilized on or within the metal oxide surface layer in a manner that allows for efficient release of the gaseous intermediate radioisotope away from the layered radioisotope source.

[0047] In one embodiment, the parent radioisotope is immobilized on or within the metal oxide surface layer in an amount effective to produce a medically useful dose of the daughter radioisotope through a chain of spontaneous decays of the gaseous intermediate radioisotope. Similarly, in one embodiment, the layered radioisotope source is for producing a medically useful dose of the daughter radioisotope through a chain of spontaneous decays from the parent radioisotope via the gaseous intermediate radioisotope.

[0048] As used herein, the term "medically useful" with respect to a dose of a daughter radioisotope refers to a daughter radioisotope (e.g., 212 Pb). The parent radioisotope may be provided in an amount effective to produce a medically useful dose (e.g., a preclinically and / or clinically useful amount) of the daughter radioisotope.

[0049] In one embodiment, the parent radioisotope is provided on or within a metal oxide surface layer bonded to an inert ceramic substrate layer at a medical dose or preclinical research dose of about 1 to about 1,000 MBq of a daughter radioisotope (e.g., 212 In one embodiment, the parent radioisotope can be immobilized on or within a metal oxide surface layer bound to an inert ceramic substrate layer in an amount effective to produce a medical dose or preclinical research dose of at least about 1, 2, 5, 10, 50, 60, 90, 120, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, or 1,000 MBq of the daughter radioisotope (e.g., 212 In another embodiment, the parent radioisotope may be immobilized on or within a metal oxide surface layer bound to an inert ceramic substrate layer in an amount effective to produce less than about 1,000, 900, 800, 700, 600, 500, 400, 300, 250, 200, 150, 120, 90, 60, 50, 10, 5, 2, or 1 daughter radioisotope (e.g., Pb) at a medical dose or preclinical research dose. 212 In one embodiment, the parent radioisotope can be immobilized on or within a metal oxide surface layer bound to an inert ceramic substrate layer in an amount effective to produce a medical dose of at least about 50, 70, 100, 120, 140, 160, 180, or 200 MBq of a daughter radioisotope (e.g., 212The parent radioisotope can be immobilized on or within a metal oxide surface layer bound to an inert ceramic substrate layer in an amount effective to produce a daughter radioisotope (e.g., Pb) in a range provided by any two of these upper and / or lower medical dose limits, e.g., about 50 MBq to about 200 MBq. 212 Pb).

[0050] In one embodiment, the parent radioisotope immobilized on or within a metal oxide surface layer bound to an inert ceramic substrate layer has an activity (per cm of metal oxide surface) of about 1 to about 1500. 2 The parent radioisotope is present in an amount effective to provide at least about 0.01, 0.05, 1, 2, 5, 10, 20, 50, 70, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1200, or 1500 activities (MBq per cm of metal oxide surface) on or within the metal oxide surface layer bound to the inert ceramic substrate layer. 2 The parent radioisotope may be immobilized on or within a metal oxide surface layer bound to an inert ceramic substrate layer in an amount effective to provide an activity of less than about 1500, 1200, 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 70, 50, 20, 10, 5, 2, 1, 0.05, or 0.01 (MBq per cm of metal oxide surface). 2 The parent radioisotope can be immobilized on or within a metal oxide surface layer bound to an inert ceramic substrate layer in an amount effective to provide an activity in the range provided by any two of these upper and / or lower limits, e.g., about 100 to about 1500, about 10 to about 1000, or about 50 to about 500, e.g., about 100. The activity of the parent radioisotope immobilized on or within the metal oxide surface layer can be measured using an appropriate radioactivity measuring device or by inference from the amount of daughter radioisotope(s) collected at a distance from the substrate. Activity can also be obtained through appropriate simulation and modeling.

[0051] Immobilization of parent radioisotopes within metal oxide surface layers. The parent radioisotope is immobilized on or within the metal oxide surface layer of the layered radioisotope source. In one embodiment, the layered radioisotope source includes a parent radioisotope immobilized on or within the metal oxide surface layer. For example, the parent radioisotope can be immobilized / bound within the metal oxide surface layer.

[0052] The immobilized parent radioisotope may be interspersed within the metal oxide surface layer. The immobilized parent radioisotope may be interspersed within the lattice of the metal oxide surface layer. The parent radioisotope may be incorporated or embedded within the metal oxide surface layer. By immobilizing the parent radioisotope within the metal oxide surface layer, the parent radioisotope atoms cannot migrate from the surface, but the intermediate daughter radioisotope, which is gaseous, can be emitted and diffuse away from the layered radioisotope source, effectively separating the emitted daughter radioisotope from the immobilized parent radioisotope.

[0053] In one embodiment, the parent radioisotope is immobilized on or within the metal oxide surface layer to allow for efficient release of the gaseous intermediate radioisotope away from the layered radioisotope source.

[0054] In one embodiment, the metal oxide surface layer is a heat-treated metal oxide surface layer. As used herein, the term "heat-treated" metal oxide surface layer refers to a surface layer formed by heat treatment (i.e., heating) to not only chemically and / or physically bind the parent radioisotope therein, but also to firmly bond the metal oxide surface layer to the underlying inert ceramic substrate layer.

[0055] In one embodiment, at least some of the metal oxide surface layer is a calcined metal oxide surface layer. As used herein, the term "calcined" metal oxide surface layer refers to at least a portion of the surface of a metal oxide surface layer formed by thermal treatment (i.e., heating) of a metal oxide precursor, such as a gel (e.g., a xerogel or aerogel) formed by a sol-gel process, to oxidize, reduce, or lose one or more volatiles and form a metal oxide surface layer.

[0056] The calcined metal oxide surface layer can be obtained by a process comprising: a) providing a gel formed from a solution (e.g., a sol) comprising a metal alkoxide and a parent radioisotope species on the surface of an inert ceramic substrate layer; and b) heating (e.g., calcining) the gel under conditions effective to form a metal oxide surface layer bonded to the inert ceramic substrate layer, thereby forming a calcined metal oxide surface layer comprising the immobilized parent radioisotope so as to enable effective release of the gaseous daughter radioisotope away from the inert ceramic substrate.

[0057] In a related embodiment, the metal oxide surface layer may be a sol-gel reaction product. For example, the metal oxide surface layer may be a reaction product of a sol-gel process described herein. In another related embodiment, the metal oxide surface layer may be a sol-gel derived metal oxide surface layer. That is, the metal oxide surface layer is derived from a sol-gel process described herein.

[0058] The calcined metal oxide surface layer and / or sol-gel reaction product may be obtained by the process described herein under the section headed "Process for Preparing Layered Radioisotope Sources."

[0059] According to some embodiments or examples described herein, the inventors have demonstrated that the immobilized parent radioisotopes within the calcined metal oxide surface layer are firmly bound / embedded therein and uniformly distributed within the calcined metal oxide surface layer. Furthermore, in some embodiments, the calcined metal oxide surface layer can be effectively "fused" to the underlying inert ceramic substrate layer, providing, in most cases, a thin, firmly bound surface layer containing uniformly distributed immobilized parent radioisotopes. Such calcination allows for little or no parent radioisotopes to be released along with the gaseous intermediate radioisotopes as they are released away from the calcined metal oxide surface layer. In other words, the immobilized parent radioisotopes within the calcined metal oxide surface layer spontaneously decay into gaseous intermediate radioisotopes, which are then released from the tightly bound calcined metal oxide surface layer.

[0060] In one embodiment, immobilization of the parent radioisotope within a metal oxide surface layer bonded to an inert ceramic substrate layer allows for capture of a population of daughter radioisotopes in use with a contamination level of the parent radioisotope expressed in terms of activity relative to the daughter radioisotope of less than about 5, 2, 1, 0.1, 0.01, or 0.001%. An example of a contaminant is a radioisotope produced using a layered radioisotope source. 212 Pb 228 For example, even if a metal oxide surface layer containing immobilized parent radioisotopes comes into contact with a collection surface (e.g., the inner wall of a collection chamber) within a radioisotope generator, little or no cross-contamination of the parent radioisotopes occurs because the metal oxide surface layer tightly binds the immobilized parent radioisotopes therein and also fuses / adheres to the underlying inert ceramic substrate layer.

[0061] The tight binding of the parent radioisotope immobilized within the metal oxide surface layer can be quantified. In one embodiment, the metal oxide surface layer containing the immobilized parent radioisotope retains at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more of the parent radioisotope after immersion in 0.1 M HNO. The percent parent radioisotope retention can be in the range provided by any two of these lower limits; for example, the metal oxide surface layer containing the immobilized parent radioisotope retains from about 30% to about 90% of the parent radioisotope after immersion in 0.1 M HNO. The percent parent radioisotope retention can be measured using alpha spectroscopy.

[0062] According to some embodiments or examples described herein, metal oxide surface layers prepared using the sol-gel processes described herein have been confirmed to be substantially free of detectable discrete deposits of radioisotopes. The term "discrete deposits" in reference to radioisotopes refers to the fusion / aggregation of radioisotopes into discrete particles, islands, or phases of radioisotopes, such as crystalline or amorphous particles (including oxide particles) of radioisotopes, on or within the surface of the metal oxide surface layer. The presence of discrete deposits of radioisotopes may inhibit the release of gaseous intermediate radioisotopes to some extent and / or limit the shelf life of the source, as such discrete deposits (e.g., in the form of large oxide particles) likely impede the emission of decay products, and poor adhesion of the deposits to the underlying substrate may increase breakthrough of the parent radioisotope and reduce the daughter radioisotope yield over the lifetime of the source.

[0063] In some embodiments, the metal oxide surface layer is formed from a metal oxide surface layer having a thickness of 1 cm. 2The metal oxide surface layer may comprise less than about 1000, 5000, 1000, 500, 100, 80, 60, 40, 20, 10, 5, or 1 discrete deposit of radioisotope having a particle size of about 20 nm or greater bound on or within the surface of the metal oxide surface layer. The number of discrete deposits of radioisotope may be in a range provided by any two of these upper values, e.g., the metal oxide surface layer may comprise less than about 1000, 5000, 1000, 500, 100, 80, 60, 40, 20, 10, 5, or 1 discrete deposit of radioisotope having a particle size of about 20 nm or greater bound on or within the surface of the metal oxide surface layer. 3 per about 10 to about 10,000, about 100 to about 1,000, or about 1 to about 10 discrete deposits of radioisotopes with a particle size of about 20 nm or greater bound on or within the surface of the metal oxide surface layer. In some embodiments, the metal oxide surface layer is substantially free of discrete deposits of radioisotopes with a particle size of about 20 nm or greater bound on or within the surface of the metal oxide surface layer.

[0064] The presence or absence of detectable deposits of radioisotopes can be determined by scanning electron microscopy (e.g., using a Zeiss Sigma VP SEM with a 30 μm aperture size acquired using VP mode set at an accelerating voltage of 15 kV, 21 Pa), and a backscattered electron detector (providing up to 50,000x magnification to enable qualitative determination of the smallest detectable feature on or within the metal oxide surface layer down to about 20 nm).

[0065] The immobilized parent radioisotope may be uniformly distributed within the metal oxide surface layer, with the immobilized parent radioisotope being substantially free of detectable deposits of the radioisotope on or within the metal oxide surface layer.

[0066] In one embodiment, the metal oxide surface layer has a molar ratio (M:R) of the metal forming the oxide of the surface layer to the immobilized parent radioisotope of greater than 1 to about 10. In one embodiment, the metal oxide surface layer can have an M:R molar ratio of at least about 1, 1.2, 1.5, 1.8, 2, 2.5, 3, 3.5, 4, 5, 6, 8, or 10. In one embodiment, the metal oxide surface layer can have an M:R molar ratio of less than about 10, 8, 6, 5, 4, 3.5, 2, 1, 1.8, 1.5, 1.2, or 1. The M:R ratio can be in a range provided by any two of these upper and / or lower limits, e.g., greater than 1 to about 3. According to some embodiments or examples described herein, metal oxide surface layers having an M:R molar ratio greater than 1, e.g., greater than 1 to about 3, provided uniform dispersion of the parent radioisotope within the surface layer and good adhesion to the underlying inert ceramic substrate layer.

[0067] One advantage of the sol-gel process developed by the inventors is that the immobilized parent radioisotope (e.g., as its atoms or small oxide particles) can be embedded in the metal oxide surface layer matrix and dispersed uniformly within one or more sections of the surface layer, and in most cases evenly throughout the surface layer.

[0068] In one embodiment, the parent radioisotope immobilized on or within the metal oxide surface layer is an oxide of the radioisotope (e.g., ThO2). In one embodiment, the metal oxide surface layer and at least some of the immobilized parent radioisotope together form one or more mixed oxide phases within the metal oxide surface layer. In one embodiment, the metal oxide surface layer and the immobilized parent radioisotope form a mixed oxide surface layer on an inert ceramic substrate.

[0069] In one embodiment, the mixed oxide phase or mixed oxide surface layer has the formula R x M y O zhaving, wherein R is the parent radioisotope in cationic form described herein, M is one or more metals in cationic form described herein, 0.1 ≦ x ≦ 5, 1.0 ≦ y ≦ 20, 1.0 ≦ z ≦ 50, and preferably x < y. Examples of the mixed oxide phase / layer are Ta x Th y O z phase / surface layer. In one embodiment, the mixed oxide phase or the mixed oxide surface layer has the formula Th x Ta y O (2x+2.5y) having, wherein 0.1 ≦ x ≦ 5, 1.0 ≦ y ≦ 20, and preferably x < y.

[0070] Properties of the metal oxide surface layer The parent radioisotopes described herein are immobilized within the metal oxide surface layer. As understood in the art, the term "metal oxide" refers to a solid containing one or more metal cations in a lattice of oxide anions.

[0071] The metal oxide surface layer can be disposed anywhere on the inert ceramic substrate. For example, the metal oxide surface layer may be a continuous layer on the inert ceramic substrate layer. Alternatively, the metal oxide surface layer may be discontinuous with respect to the entire surface of the inert ceramic substrate layer. For example, if the metal oxide surface layer does not uniformly and completely cover the surface of the inert ceramic substrate layer, it may include two or more sections. It will be understood that such a form of a discontinuous layer is still considered a "surface layer" for the purposes of the present disclosure.

[0072] In some embodiments, the metal oxide surface layer (including any calcined / sol-gel derived metal oxide surface layer) can have a thickness of from about 0.1 nm to about 1,000,000 nm (i.e., 1 mm), from about 0.1 nm to about 100,000 nm (i.e., 100 μm), or from about 0.1 nm to about 1,000 nm (i.e., 1 μm). The metal oxide surface layer can have a thickness (in nm) of at least about 0.1, 0.2, 0.4, 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 30, 50, 100, 150, 200, 300, 400, 500, 700, 900, 1,000, 10,000, 100,000, or 1,000,000. The metal oxide surface layer can have a thickness (in nm) of less than about 1,000,000, 100,000, 10,000, 1,000, 900, 700, 500, 400, 300, 200, 150, 100, 50, 30, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3.5, 3, 2.5, 2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6, 0.4, 0.2, or 0.1. The thickness may be within a range provided by any two of these upper and / or lower limits, for example, about 0.1 nm to about 1,000,000 nm, about 0.1 nm to about 100,000 nm, about 0.1 nm to about 1,000 nm, about 0.1 nm to about 500 nm, about 1 nm to about 100 nm, or about 1 nm to about 20 nm.

[0073] According to some embodiments or examples described herein, a metal oxide surface layer having a thickness of about 0.1 nm to about 500 nm can provide additional benefits, such as improved adhesion to the underlying inert ceramic substrate layer, since thicker metal oxide surface layers may have a tendency to flake off from the underlying substrate. Alternatively or additionally, such a sufficiently shallow thickness can allow for enhanced release of gaseous intermediate radioisotopes away from the layered radioisotope source.

[0074] The thickness of the metal oxide surface layer can vary depending on, for example, the parameters of the sol-gel process described herein. For example, the metal oxide surface layer can have a thickness of, for example, about 1 to about 1500 active (1 cm of the inert ceramic substrate), as described above. 2 The thickness may be effective to provide a concentration of the parent radioisotope in an amount effective to provide a concentration of the parent radioisotope in an amount effective to provide a radioisotope concentration of 10 ...

[0075] In one embodiment, the metal oxide surface layer is an oxide of a valve metal, a refractory metal, or other transition metal or main block metal. The metal oxide surface layer may be an oxide of a metal on which the oxide can form a continuous, impermeable film. The metal oxide surface layer may be an oxide of tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, or titanium, or a mixed oxide thereof. In one embodiment, the metal oxide surface layer is tantalum pentoxide (Ta2O5). Other metals are also contemplated.

[0076] The metal oxide surface layer may have a degree of porosity effective to allow for the immobilization of a certain amount of parent radioisotope while still allowing for the effective release of gaseous daughter radioisotopes away from the metal oxide surface layer, thereby effectively separating the released daughter radioisotope from the immobilized parent radioisotope. As used herein, the term "porosity" is a measure of voids in a material, and is the ratio of the volume of voids to the total volume as a percentage from 0% to 100% by volume.

[0077] In some embodiments, the metal oxide surface layer has a porosity of about 0.01 vol% to about 30 vol%, based on the total volume of the metal oxide surface layer. The metal oxide surface layer may have a porosity (unit: volume % based on the total volume of the metal oxide surface layer) of at least about 0.01, 0.1, 1, 2, 5, 10, 20, or 30. The metal oxide surface layer may have a porosity (unit: volume % based on the total volume of the metal oxide surface layer) of less than about 30, 20, 10, 5, 2, 1, 0.1, or 0.01. In one embodiment, the metal oxide surface layer may have a porosity (unit: volume % based on the total volume of the metal oxide surface layer) of less than about 10, 5, 2, 1, 0.1, or 0.01. The porosity may be within a range provided by any two of these upper and / or lower limits, for example, about 10 vol% to about 30 vol%, or about 0.01 vol% to about 5 vol%. The volume percent porosity can be measured by any suitable technique known to those skilled in the art, including, for example, using standard mercury intrusion porosimetry and / or optical or electron microscopy analysis of a cross-section of the metal oxide surface layer. According to some embodiments or examples described herein, a metal oxide surface layer having low porosity can provide one or more advantages, including a high yield of daughter isotopes. For example, a metal oxide surface layer having a low porosity morphology, and in some cases being substantially non-porous (e.g., less than about 1, 0.1, or 0.01 volume percent), allows for more efficient and substantially unimpeded release of gaseous intermediate isotopes away from the metal oxide surface layer.

[0078] In relation to porosity, the metal oxide surface layer has a low surface area, for example, a surface area (units: m) of less than about 200, 100, 50, 20, 10, 5, 4, 3, 2, 1, or 0.5. 2 / g). Surface area can be measured using standard ASTM C1274 or using N2 adsorption applying Brunauer-Emmett-Teller (BET) theory over a relative pressure range of 0.05 to 0.20 P / P0 at 77K.

[0079] The metal oxide surface layer has a suitable density, for example to provide a degree of robustness. In some embodiments, the metal oxide surface layer has a density of about 2.0 g / cm 3 ~Approx. 15g / cm 3 The metal oxide surface layer has a density (g / cm) of at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. 3 The metal oxide surface layer may have a density (g / cm) of less than about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2. 3 The density may be in the range provided by any two of these upper and / or lower limits, for example, about 4 to 13 g / cm. 3 may be.

[0080] Properties of the inert ceramic substrate layer In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: an inert ceramic substrate layer (e.g., quartz, tantalum oxide, zirconia, etc.); a metal oxide surface layer (e.g., tantalum oxide) bonded onto an inert ceramic substrate layer; a parent radioisotope immobilized on or within a metal oxide surface layer so as to allow for effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0081] The metal oxide surface layer is bonded onto (e.g., bonded to) the surface of) an inert ceramic substrate layer. The term "inert" is understood to mean that the ceramic substrate is substantially chemically inert, e.g., does not chemically react to any significant extent with immobilized radioisotopes dispersed on or within the substrate. The inert ceramic substrate layer may also be substantially unreactive with atmospheric oxygen and water. Furthermore, the inert ceramic substrate layer may comprise a ceramic material that has a certain robustness that makes it less susceptible to radiation damage (i.e., structural damage) that occurs when the parent radioisotope immobilized therein decays into daughter radioisotopes. For example, the crystallographic properties of the inert ceramic substrate layer provide a certain degree of robustness against radiation damage.

[0082] The inert ceramic substrate has a degree of porosity effective to allow for the immobilization of a certain amount of parent radioisotope while still allowing for the effective release of gaseous daughter radioisotopes away from the surface of the inert ceramic substrate, thereby effectively separating the released daughter radioisotope from the immobilized parent radioisotope. The degree of porosity may be greater at the surface of the inert ceramic substrate. The degree of porosity may facilitate the immobilization of a significant amount of parent radioisotope. As used herein, the term "porosity" is a measure of voids in a material, the ratio of the volume of voids to the total volume as a percentage from 0% to 100% by volume.

[0083] In some embodiments, the inert ceramic substrate layer has a porosity of about 0.01 volume % to about 30 volume %, based on the total volume of the inert ceramic substrate layer. The inert ceramic substrate layer may have a porosity (unit: volume % based on the total volume of the inert ceramic substrate layer) of at least about 0.01, 0.1, 1, 2, 5, 10, 20, or 30. The inert ceramic substrate layer may have a porosity (unit: volume % based on the total volume of the inert ceramic substrate layer) of less than about 30, 20, 10, 5, 2, 1, 0.1, or 0.01. In one embodiment, the inert ceramic substrate layer may have a porosity (unit: volume % based on the total volume of the inert ceramic substrate layer) of less than about 10, 5, 2, 1, 0.1, or 0.01. The porosity may be within a range provided by any two of these upper and / or lower limits, for example, about 10 volume % to about 30 volume %, or about 0.01 volume % to about 5 volume %. Volume percent porosity can be measured by any suitable technique known to those skilled in the art, including, for example, using standard mercury porosimetry and / or optical or electron microscopy of a cross-section of the inert ceramic substrate layer.

[0084] With respect to porosity, the inert ceramic substrate layer may have a low surface area, for example, a surface area (units: m) of less than about 200, 100, 50, 20, 10, 5, 4, 3, 2, 1, or 0.5. 2 / g). Surface area can be measured using standard ASTM C1274 or using N2 adsorption applying Brunauer-Emmett-Teller (BET) theory over a relative pressure range of 0.05 to 0.20 P / P0 at 77K.

[0085] The inert ceramic substrate layer may have a suitable density, for example, to provide a degree of robustness. In some embodiments, the inert ceramic substrate layer has a density of about 2.0 g / cm 3 ~Approx. 15g / cm 3 The inert ceramic substrate layer has a density (g / cm) of at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. 3The inert ceramic substrate layer may have a density (g / cm) of less than about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2. 3 The density may be in the range provided by any two of these upper and / or lower limits, for example, about 4 to 13 g / cm. 3 may be.

[0086] The inert ceramic substrate layer has a suitable thickness. In some embodiments, the inert ceramic substrate layer has a thickness (unit: μm) of about 0.01 to about 100,000, about 0.1 to about 10,000, about 1 to about 1000, or about 1 to about 100, or about 1 to about 10. The inert ceramic substrate layer can have a thickness (unit: μm) of at least about 0.001, 0.002, 0.005, 0.01, 0.015, 0.02, 0.05, 0.1, 0.5, 1, 5, 10, 50, 100, 200, 500, 700, 1000, 5000, 10,000, or 100,000. The inert ceramic substrate layer can have a thickness (in μm) of less than about 100,000, 10,000, 10,000, 5000, 1000, 700, 500, 200, 100, 50, 10, 5, 1, 0.5, 0.1, 0.05, 0.02, 0.015, 0.01, 0.005, 0.002, or 0.001. The thickness can also be within a range provided by any two of these upper and / or lower limits, such as about 1 μm to about 1000 μm, about 1 μm to about 500 μm, or about 1 μm to about 100 μm. In one embodiment, the thickness of the metal oxide surface layer is less than the thickness of the underlying inert ceramic substrate layer.

[0087] The inert ceramic substrate layer can be formed from any suitable ceramic material, including, for example, a suitable ceramic material that can have a chemical affinity for the overlying metal oxide surface layer.

[0088] In some embodiments, the inert ceramic substrate layer can be selected from an inert oxide, an inert nitride, an inert carbide, an inert sulfide, an inert phosphate, or a combination thereof. In some embodiments, the inert ceramic substrate layer can be selected from quartz, a metal oxide, a metal phosphate, a metal nitride, a metal carbide, a metal sulfide, or a combination thereof. The inert ceramic substrate layer can be selected from a metal oxide, a metal phosphate, a metal nitride, a metal carbide, a metal sulfide, or a combination thereof. Other suitable ceramic materials include inert intermetallic compounds, such as metal silicides, metal borides, or metal selenides. In one embodiment, the inert ceramic substrate layer is a metal oxide (i.e., the inert ceramic substrate layer is a metal oxide substrate layer).

[0089] In one embodiment, the inert ceramic substrate layer is an inert oxide substrate layer, such as quartz, zirconia, or tantalum oxide, hi one embodiment, the inert ceramic substrate layer may be an oxide of silicon, tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, titanium, or aluminum, or mixed oxides thereof.

[0090] In one embodiment, the inert ceramic substrate layer is a metal oxide substrate layer. The metal oxide substrate layer may be an oxide of a valve metal, a refractory metal, or other transition metal or main block metal. The metal oxide substrate layer may be an oxide of tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, titanium, or aluminum, or a mixed oxide thereof. The metal oxide substrate layer may be an oxide of tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, or titanium, or a mixed oxide thereof. In one embodiment, the inert ceramic substrate layer is quartz, tantalum oxide (TaO), or zirconium oxide (ZrO). In one embodiment, the inert ceramic substrate layer is tantalum oxide (TaO) or zirconium oxide (ZrO), preferably tantalum oxide. Other metal oxides are also contemplated.

[0091] In one embodiment, the inert ceramic substrate layer is an inert oxide layer, and a metal oxide surface layer is provided on the inert oxide layer. In one embodiment, the inert ceramic substrate layer is an inert oxide substrate layer such as quartz, zirconia, or tantalum oxide, and the metal oxide surface layer bonded thereto is an oxide of a valve metal, a refractory metal, or another transition metal or main block metal. In one embodiment, the inert ceramic substrate layer is an inert oxide substrate layer such as quartz, zirconia, or tantalum oxide, and the metal oxide surface layer bonded thereto is an oxide of a valve metal, a refractory metal, or an oxide of tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, or titanium, or a mixed oxide thereof. In one embodiment, the inert ceramic substrate layer is an inert oxide substrate layer such as quartz, zirconia, or tantalum oxide, and the metal oxide surface layer bonded thereto is an oxide of a tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, or titanium, or a mixed oxide thereof.

[0092] In one embodiment, the metal oxide surface layer is tantalum pentoxide (TaO), which may be bonded to the surface of the inert oxide substrate layer by the sol-gel process described herein. In one embodiment, the inert ceramic substrate layer is quartz, and the metal oxide surface layer bonded thereto is an oxide of a valve metal, a refractory metal, or an oxide of tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, or titanium, or a mixed oxide thereof. In one embodiment, the inert ceramic substrate layer is tantalum oxide, and the metal oxide surface layer bonded thereto is an oxide of a valve metal, a refractory metal, or an oxide of tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, or titanium, or a mixed oxide thereof.

[0093] In one embodiment, the inert ceramic substrate layer and the metal oxide surface layer are each independently an oxide of a valve metal, a refractory metal, or another transition metal or main block metal. The inert ceramic substrate layer and the metal oxide surface layer may each independently be an oxide of a valve metal, a refractory metal, or an oxide of tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, titanium, or aluminum, or a mixed oxide thereof. The inert ceramic substrate layer and the metal oxide surface layer may each independently be an oxide of tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, or titanium, or a mixed oxide thereof. The inert ceramic substrate layer and the metal oxide surface layer may each independently be tantalum oxide (TaO) or zirconium oxide (ZrO), preferably tantalum oxide. Other metal oxides are also contemplated.

[0094] In a preferred embodiment, the inert ceramic substrate layer is a metal oxide substrate layer that comprises or consists of the same metal oxide as the overlying metal oxide surface layer described herein. In other words, the inert ceramic substrate layer and the metal oxide surface layer can be compositionally the same metal oxide. For example, the metal oxide surface layer and the inert ceramic substrate layer can both comprise or consist of tantalum oxide or zirconium oxide.

[0095] In a related embodiment, the inert ceramic substrate layer and the metal oxide surface layer together form a single metal oxide layer containing the parent radioisotope immobilized within the surface of the metal oxide layer as the radioisotope surface layer. As with the previous embodiment, in this case, both the metal oxide surface layer and the underlying inert ceramic substrate layer form the same metal oxide. When using the sol-gel process described herein according to some embodiments or examples, the gel formed using a metal alkoxide contains branched metal-oxide-metal chains that can effectively attach / graft to existing hydroxyl ends naturally present on the surface of the underlying metal oxide substrate layer. As the gel dries, the colloidal network can evolve into an amorphous xerogel containing the parent radioisotope species firmly bound to the substrate. This is ultimately converted into a metal oxide surface layer during a final heat treatment (e.g., a calcination step), effectively intermixing with the metal oxide bonds of the underlying metal oxide substrate layer and uniformly dispersing throughout the deposition area. Thus, while the underlying metal oxide substrate layer and the overlying metal oxide surface layer are each produced by different reactions (e.g., the substrate layer can be formed by oxidation, such as thermal or anodic oxidation, of a metal substrate, and the surface layer is formed by the sol-gel process described herein), the boundary between the metal oxide surface layer and the underlying metal oxide substrate layer may be indistinguishable, and thus a single metal oxide layer (e.g., a tantalum oxide underlayer and a tantalum oxide surface layer that are, to most extent, indistinguishable) is formed.

[0096] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: an inert ceramic substrate layer; a metal oxide surface layer bonded to an inert ceramic substrate layer; a parent radioisotope immobilized on or within a metal oxide surface layer so as to allow for effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0097] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: an inert ceramic substrate layer; a calcined metal oxide surface layer bonded to an inert ceramic substrate layer; a parent radioisotope immobilized on or within a calcined metal oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0098] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: an inert ceramic substrate layer; a tantalum oxide surface layer bonded to an inert ceramic substrate layer; a parent radioisotope immobilized on or within a tantalum oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0099] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: an inert ceramic substrate layer; a sintered tantalum oxide surface layer bonded to an inert ceramic substrate layer; a parent radioisotope immobilized on or within a calcined tantalum oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0100] In one embodiment, the gaseous220 via Rn 228 Through the natural decay chain from Th isotopes, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: an inert ceramic substrate layer; a tantalum oxide surface layer bonded to an inert ceramic substrate layer; Gaseous layered radioisotope source away from 220 Immobilized on or within the tantalum oxide surface layer to allow for efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0101] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from Th isotopes, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: an inert ceramic substrate layer; a sintered tantalum oxide surface layer bonded to an inert ceramic substrate layer; Gaseous layered radioisotope source away from 220 Immobilized on or within the calcined tantalum oxide surface layer to enable efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0102] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: an inert ceramic substrate layer; a sol-gel derived metal oxide surface layer (e.g., the metal oxide surface layer is a sol-gel reaction product) bonded onto an inert ceramic substrate layer; a parent radioisotope immobilized on or within a sol-gel derived metal oxide surface layer so as to enable efficient release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0103] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: an inert ceramic substrate layer; a sol-gel derived tantalum oxide surface layer bonded onto an inert ceramic substrate layer (e.g., the tantalum oxide surface layer is a sol-gel reaction product); a parent radioisotope immobilized on or within a sol-gel derived tantalum oxide surface layer so as to enable efficient release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0104] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from Th isotopes, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: an inert ceramic substrate layer; a sol-gel derived tantalum oxide surface layer bonded onto an inert ceramic substrate layer (e.g., the tantalum oxide surface layer is a sol-gel reaction product); Gaseous layered radioisotope source away from 220 Immobilized on or within a sol-gel derived tantalum oxide surface layer to allow for efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0105] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: an inert oxide substrate layer; a metal oxide surface layer bonded onto an inert oxide substrate layer; a parent radioisotope immobilized on or within a metal oxide surface layer so as to allow for effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0106] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: an inert oxide substrate layer; a calcined metal oxide surface layer bonded onto an inert oxide substrate layer; a parent radioisotope immobilized on or within a calcined metal oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0107] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: an inert oxide substrate layer; a tantalum oxide surface layer bonded onto an inert oxide substrate layer; a parent radioisotope immobilized on or within a tantalum oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0108] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: an inert oxide substrate layer; a calcined tantalum oxide surface layer bonded onto an inert oxide substrate layer; a parent radioisotope immobilized on or within a calcined tantalum oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0109] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from the Th radioisotope, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: an inert oxide substrate layer; a tantalum oxide surface layer bonded onto an inert oxide substrate layer; Gaseous layered radioisotope source away from 220 Immobilized on or within the tantalum oxide surface layer to allow for efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0110] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from the Th radioisotope, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: an inert oxide substrate layer; a calcined tantalum oxide surface layer bonded onto an inert oxide substrate layer; Gaseous layered radioisotope source away from 220 Immobilized on or within the calcined tantalum oxide surface layer to enable efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0111] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: an inert oxide substrate layer; a sol-gel derived metal oxide surface layer (e.g., the metal oxide surface layer is a sol-gel reaction product) bonded onto an inert oxide substrate layer; a parent radioisotope immobilized on or within a sol-gel derived metal oxide surface layer so as to enable efficient release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0112] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: an inert oxide substrate layer; a sol-gel derived tantalum oxide surface layer bonded onto an inert oxide substrate layer (e.g., the tantalum oxide surface layer is a sol-gel reaction product); a parent radioisotope immobilized on or within a sol-gel derived tantalum oxide surface layer so as to enable efficient release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0113] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from the Th radioisotope, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: an inert oxide substrate layer; a sol-gel derived tantalum oxide surface layer bonded onto an inert oxide substrate layer (e.g., the tantalum oxide surface layer is a sol-gel reaction product); Gaseous layered radioisotope source away from 220 Immobilized on or within a sol-gel derived tantalum oxide surface layer to allow for efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0114] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a metal oxide substrate layer; a metal oxide surface layer bonded onto a metal oxide substrate layer; a parent radioisotope immobilized on or within a metal oxide surface layer so as to allow for effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0115] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a metal oxide substrate layer; a calcined metal oxide surface layer bonded onto a metal oxide substrate layer; a parent radioisotope immobilized on or within a calcined metal oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0116] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a metal oxide substrate layer; a tantalum oxide surface layer bonded onto a metal oxide substrate layer; a parent radioisotope immobilized on or within a tantalum oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0117] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a metal oxide substrate layer; a calcined tantalum oxide surface layer bonded onto a metal oxide substrate layer; a parent radioisotope immobilized on or within a calcined tantalum oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0118] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from the Th radioisotope, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: a metal oxide substrate layer; a tantalum oxide surface layer bonded onto a metal oxide substrate layer; Gaseous layered radioisotope source away from 220 Immobilized on or within the tantalum oxide surface layer to allow for efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0119] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from the Th radioisotope, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: a metal oxide substrate layer; a calcined tantalum oxide surface layer bonded onto a metal oxide substrate layer; Gaseous layered radioisotope source away from 220 Immobilized on or within the calcined tantalum oxide surface layer to enable efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0120] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a metal oxide substrate layer; a sol-gel derived metal oxide surface layer bonded onto a metal oxide substrate layer (e.g., the metal oxide surface layer is a sol-gel reaction product); and a parent radioisotope immobilized on or within a sol-gel derived metal oxide surface layer so as to enable efficient release of a gaseous intermediate radioisotope away from the layered radioisotope source.

[0121] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a metal oxide substrate layer; a sol-gel derived tantalum oxide surface layer bonded onto a metal oxide substrate layer (e.g., the tantalum oxide surface layer is a sol-gel reaction product); a parent radioisotope immobilized on or within a sol-gel derived tantalum oxide surface layer so as to enable efficient release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0122] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from the Th radioisotope, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: a metal oxide substrate layer; a sol-gel derived tantalum oxide surface layer bonded onto a metal oxide substrate layer (e.g., the tantalum oxide surface layer is a sol-gel reaction product); Gaseous layered radioisotope source away from 220Immobilized on or within a sol-gel derived tantalum oxide surface layer to allow for efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0123] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a tantalum oxide substrate layer; a tantalum oxide surface layer bonded onto a tantalum oxide substrate layer; a parent radioisotope immobilized on or within a tantalum oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0124] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a tantalum oxide substrate layer; a calcined tantalum oxide surface layer bonded onto a tantalum oxide substrate layer; a parent radioisotope immobilized on or within a calcined tantalum oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0125] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from the Th radioisotope, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: a tantalum oxide substrate layer; a tantalum oxide surface layer bonded onto a tantalum oxide substrate layer; Gaseous layered radioisotope source away from 220Immobilized on or within the tantalum oxide surface layer to allow for efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0126] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from the Th radioisotope, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: A tantalum oxide substrate layer a calcined tantalum oxide surface layer bonded onto a tantalum oxide substrate layer; Gaseous layered radioisotope source away from 220 Immobilized on or within the calcined tantalum oxide surface layer to enable efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0127] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a tantalum oxide substrate layer; a sol-gel derived tantalum oxide surface layer bonded onto a tantalum oxide substrate layer (e.g., the tantalum oxide surface layer is a sol-gel reaction product); a parent radioisotope immobilized on or within a sol-gel derived tantalum oxide surface layer so as to enable efficient release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0128] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from the Th radioisotope, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: a tantalum oxide substrate layer; a sol-gel derived tantalum oxide surface layer bonded onto a tantalum oxide substrate layer (e.g., the tantalum oxide surface layer is a sol-gel reaction product); Gaseous layered radioisotope source away from 220 Immobilized on or within a sol-gel derived tantalum oxide surface layer to allow for efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0129] Although not required, the inert ceramic substrate layer can be provided as a layer on a metal substrate. For example, the inert ceramic substrate layer can be bonded to or derived from the underlying metal substrate. In one embodiment, the inert ceramic substrate layer can be an oxide bonded to or derived from the underlying metal substrate. In another embodiment, the inert ceramic substrate layer is a metal oxide layer, which is an oxide of the underlying metal substrate. For example, the metal substrate can be tantalum, and the inert ceramic substrate layer, according to some embodiments or examples, can include or consist of tantalum oxide, which can be formed by oxidizing a tantalum metal substrate (e.g., by thermal oxidation or anodic oxidation). According to some embodiments or examples described herein, the metal substrate can provide additional benefits, including radiation shielding, and in some cases, the metal substrate can stably secure a thinner inert ceramic substrate layer within the source chamber described herein, for example, when contacted with a carrier gas.

[0130] It will be appreciated that when a metal substrate is present, the inert ceramic substrate layer can be described as an intervening layer located between the metal oxide surface layer and the metal substrate.

[0131] The metal substrate may have a form suitable for insertion into a generator, such as a source chamber described herein. In one embodiment, the metal substrate may be provided as a discrete unit, such as a disk, plate, membrane, platen, slab, tube, tube section, or monolith. The metal substrate may have any desired cross-sectional shape, including, but not limited to, a spherical or hemispherical shape. In one embodiment, the metal substrate is a disk or slab. The disk may be configured to be inserted into a radioisotope generator.

[0132] In some embodiments, the metal substrate has a thickness of about 1 mm to about 100 mm. The metal substrate can have a thickness (units: mm) of at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 25, 30, 40, 50, or 100. The metal substrate can have a thickness (units: mm) of less than about 100, 50, 40, 30, 25, 20, 15, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0.5. The thickness can be within a range provided by any two of these upper or lower limits, e.g., about 1 mm to about 100 mm, e.g., about 1 mm to about 100 mm, or about 1 mm to about 20 mm, e.g., about 1 mm to about 15 mm. The metal substrate can have a thickness effective to provide a flat surface for the inert ceramic substrate layer. In some embodiments, a thicker metal substrate may be more suitable for recycling / refurbishment / reuse, for example, making it safer and easier to strip unused radioisotopes from the substrate. In one embodiment, the thickness of the inert ceramic substrate is less than the thickness of the underlying metal substrate.

[0133] In one embodiment, the surface of the metal substrate including the inert ceramic substrate layer is approximately 0.125 cm 2 ~about 50cm 2 The metal substrate including the inert ceramic substrate layer has a surface area (in cm) of at least about 0.125, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 cm 2The metal substrate with the inert ceramic substrate layer may have a surface area (in cm) of less than about 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, 4, 3, 2, 1.5, 1, 0.75, 0.5, 0.25, or 1.25. 2 ) Ranges may be provided by any two of these upper and / or lower limits.

[0134] In one embodiment, the metal substrate is a refractory metal, a valve metal, or other transition metal or main block metal. The metal substrate may be tantalum, niobium, tungsten, hafnium, molybdenum, vanadium, zirconium, titanium, or aluminum, or an alloy thereof. The metal substrate may be tantalum, niobium, tungsten, hafnium, molybdenum, vanadium, zirconium, or titanium, or an alloy thereof. In one embodiment, the inert ceramic substrate is a metal oxide and is provided as a layer (e.g., a surface layer) on a metal substrate or electrode thereof selected from tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, titanium, or aluminum, or an alloy thereof.

[0135] In one embodiment, the metal substrate is an anodizable metal. The anodizable metal substrate or its electrode may be selected from tantalum, niobium, titanium, or aluminum, or alloys thereof. The anodizable metal substrate or its electrode may be selected from tantalum, niobium, zirconium, titanium, or aluminum, or alloys thereof.

[0136] In one embodiment, the metal of the metal substrate and the metal of the inert ceramic substrate layer (e.g., on the surface of the metal substrate) are the same. In one embodiment, the inert ceramic substrate layer is a metal oxide substrate layer, and the metal of the metal substrate and the metal of the metal oxide substrate layer are the same. For example, the inert ceramic substrate layer may include or consist of a tantalum oxide layer, and the metal substrate may include or consist of tantalum metal.

[0137] In one embodiment, when the inert ceramic substrate layer is a metal oxide, the metal oxide is produced by pre-oxidizing the surface of the metal substrate (e.g., by strengthening a native oxide layer on the surface of the metal substrate). This oxidation can also be induced by thermally oxidizing the metal substrate in an oxygen atmosphere and / or by exposing the metal substrate to a more aggressive oxidizing environment (e.g., an atmosphere with elevated oxygen levels).

[0138] The metal substrate has a suitable density. In some embodiments, the metal substrate has a density of about 2 g / cm 3 ~About 20g / cm 3 The metal substrate has a density (g / cm) of at least about 1, 2, 5, 8, 10, 12, 15, or 20. 3 The metal substrate may have a density (g / cm) of less than about 20, 15, 12, 10, 8, 5, 4, 3, or 2. 3 ).

[0139] The metal substrate may have a roughened or textured surface. According to some embodiments or examples described herein, it has been found that a roughened or textured surface of a metal substrate results in a textured metal oxide layer on the surface of the metal substrate, which has increased surface area and wettability, enhancing coverage of the surface layer by a gel (e.g., an aerogel or xerogel) described herein and forming a thin, uniform metal oxide surface layer containing the immobilized parent radioisotope. Such surface roughening or texturing is understood to mean that the surface of the metal substrate has been manipulated (i.e., roughened or textured) and does not encompass an inherently "perfectly flat" metal or polished metal, which may have some form of microscopic roughness. In other words, surface roughening is achieved by some physical or mechanical treatment of the substrate surface, such as by grinding the surface with an abrasive powder (e.g., tungsten carbide) on a vibrating table or by blasting the surface with specific abrasive particles such as glass beads. The surface roughness may include an angular pattern. In some cases, the roughened surface has a peak count (R) of less than 180 peaks / cm pc ). Surface roughness can be measured using industry standard ASTM D7127, for example, after a polishing process. In some embodiments, the roughened surface of the metal substrate has an increased % surface area compared to a corresponding non-roughened, "perfectly flat" substrate, for example, at least about a 1%, 2%, 5%, 10%, 15%, or 20% increase in surface area.

[0140] As an example, Figure 1 provides a schematic diagram of a radioisotope source with an immobilized parent radioisotope. The radioisotope source includes a metal substrate (101) and an inert ceramic substrate layer (102) on the metal substrate. In one example, the inert ceramic substrate layer is a metal oxide layer. The metal oxide layer can be prepared by an oxidation process (e.g., heating in air). A metal oxide surface layer is provided on the surface of the underlying metal oxide.

[0141] A metal oxide layer (103) is provided / formed on the surface of the inert ceramic substrate layer and includes a parent radioisotope (104) immobilized on or within the metal oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source.

[0142] It will be understood that the metal oxide surface layer need not be a continuous, uniform layer covering the entire surface of the underlying inert ceramic substrate layer. For example, with reference to Figure 1, one or more small sections of the inert ceramic substrate layer (105) may protrude through the metal oxide surface layer (103) as a result of uneven coating during the sol-gel process used to prepare the radioisotope source. However, this is still considered a "surface layer" as described herein, regardless of whether the metal oxide surface layer forms a continuous layer or one or more phases / sections that decorate the surface of the inert ceramic substrate layer.

[0143] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: A metal substrate; an inert ceramic substrate layer provided on a metal substrate; a metal oxide surface layer bonded to an inert ceramic substrate layer; a parent radioisotope immobilized on or within a metal oxide surface layer so as to allow for effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0144] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: A metal substrate; an inert ceramic substrate layer provided on a metal substrate; a calcined metal oxide surface layer bonded to an inert ceramic substrate layer; a parent radioisotope immobilized on or within a calcined metal oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0145] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: A metal substrate; an inert oxide substrate layer (e.g., quartz, tantalum oxide, or zirconia) provided on a metal substrate; a sol-gel derived metal oxide surface layer (e.g., the metal oxide surface layer is a sol-gel reaction product) bonded onto an inert ceramic substrate layer; a parent radioisotope immobilized on or within a calcined metal oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0146] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: A metal substrate; an inert oxide substrate layer (e.g., quartz, tantalum oxide, or zirconia) provided on a metal substrate; a metal oxide surface layer bonded to an inert ceramic substrate layer; a parent radioisotope immobilized on or within a metal oxide surface layer so as to allow for effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0147] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: A metal substrate; an inert oxide substrate layer (e.g., quartz, tantalum oxide, or zirconia) provided on a metal substrate; a calcined metal oxide surface layer bonded to an inert ceramic substrate layer; a parent radioisotope immobilized on or within a calcined metal oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0148] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: A metal substrate; an inert oxide substrate layer (e.g., quartz, tantalum oxide, or zirconia) provided on a metal substrate; a sol-gel derived metal oxide surface layer (e.g., the metal oxide surface layer is a sol-gel reaction product) bonded onto an inert ceramic substrate layer; a parent radioisotope immobilized on or within a calcined metal oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0149] In one embodiment, the inert ceramic substrate layer is a metal oxide substrate layer, and the metal of the metal substrate and the metal oxide substrate layer are the same. In one embodiment, the inert ceramic substrate layer is a metal oxide substrate layer formed by oxidative pretreatment of the surface of a metal substrate. In one embodiment, the metal substrate is selected from the group consisting of tantalum, niobium, tungsten, hafnium, molybdenum, vanadium, zirconium, titanium, or aluminum, or alloys thereof, and the metal oxide layer is an oxide of the metal substrate. For example, the inert ceramic substrate layer may include or consist of a tantalum oxide layer, and the metal substrate may include or consist of tantalum metal. In another example, the inert ceramic substrate layer may include or consist of a tantalum oxide layer formed by oxidative pretreatment of the surface of a tantalum metal substrate. In one embodiment, the metal oxide surface layer includes or consists of the same metal oxide as the underlying metal oxide substrate layer. For example, the metal oxide surface layer and the inert ceramic substrate layer may both include or consist of tantalum oxide.

[0150] In one embodiment, the inert ceramic substrate layer is a metal oxide substrate layer, and the metal substrate, metal oxide substrate layer, and metal oxide surface layer are the same metal. In one embodiment, the inert ceramic substrate layer is an oxide of the metal substrate, and together with the metal oxide surface layer, forms a single metal oxide layer on the metal substrate containing the immobilized parent radioisotope.

[0151] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a metal substrate comprising a metal oxide substrate layer on at least a portion of a surface thereof; a metal oxide surface layer bonded onto a metal oxide substrate layer; a parent radioisotope immobilized on or within a metal oxide surface layer so as to allow for effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0152] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from the Th radioisotope, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: a metal substrate comprising a metal oxide substrate layer on at least a portion of a surface thereof; a metal oxide surface layer bonded onto a metal oxide substrate layer; Gaseous layered radioisotope source away from 220 Immobilized on or within a metal oxide surface layer to allow for efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0153] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a metal disk including a metal oxide substrate layer on at least a portion of its surface; a metal oxide surface layer bonded onto a metal oxide substrate layer; a parent radioisotope immobilized on or within a metal oxide surface layer so as to allow for effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0154] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from the Th radioisotope, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: a metal disk including a metal oxide substrate layer on at least a portion of its surface; a metal oxide surface layer bonded onto a metal oxide substrate layer; Gaseous layered radioisotope source away from 220Immobilized on or within a metal oxide surface layer to allow for efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0155] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a tantalum metal substrate including a tantalum oxide substrate layer on at least a portion of a surface thereof; a tantalum oxide surface layer bonded onto a tantalum oxide substrate layer; a parent radioisotope immobilized on or within a tantalum oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0156] In one embodiment, the gaseous 220 via Rn 228Th Through the chain of natural decay from the isotope, a medically useful dose can be obtained. 212 A layered radioisotope source for producing Pb, comprising: a tantalum metal substrate including a tantalum oxide substrate layer on at least a portion of a surface thereof; a tantalum oxide surface layer bonded onto a tantalum oxide substrate layer; Gaseous layered radioisotope source away from 220 Immobilized on or within the tantalum oxide surface layer to allow for efficient release of Rn. 228Th and, The present invention provides a layered radioisotope source comprising:

[0157] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a tantalum metal disk including a tantalum oxide substrate layer on at least a portion of its surface; a tantalum oxide surface layer bonded onto a tantalum oxide substrate layer; a parent radioisotope immobilized on or within a tantalum oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0158] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from the Th radioisotope, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: a tantalum metal disk including a tantalum oxide substrate layer on at least a portion of its surface; a tantalum oxide surface layer bonded onto a tantalum oxide substrate layer; Gaseous layered radioisotope source away from 220 Immobilized on or within the tantalum oxide surface layer to allow for efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0159] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a metal substrate comprising a metal oxide substrate layer on at least a portion of a surface thereof; a calcined metal oxide surface layer bonded onto a metal oxide substrate layer; a parent radioisotope immobilized on or within a metal oxide surface layer so as to allow for effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0160] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a metal substrate comprising a metal oxide substrate layer on at least a portion of a surface thereof; a sol-gel derived metal oxide surface layer bonded onto a metal oxide substrate layer (e.g., the metal oxide surface layer is a sol-gel reaction product); a parent radioisotope immobilized on or within a metal oxide surface layer so as to allow for effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0161] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from the Th radioisotope, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: a metal substrate comprising a metal oxide substrate layer on at least a portion of a surface thereof; a calcined metal oxide surface layer bonded onto a metal oxide substrate layer; Gaseous layered radioisotope source away from 220 Immobilized on or within a metal oxide surface layer to allow for efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0162] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from the Th radioisotope, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: a metal substrate comprising a metal oxide substrate layer on at least a portion of a surface thereof; a sol-gel derived metal oxide surface layer bonded onto a metal oxide substrate layer (e.g., the metal oxide surface layer is a sol-gel reaction product); Gaseous layered radioisotope source away from 220 Immobilized on or within a metal oxide surface layer to allow for efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0163] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a metal disk including a metal oxide substrate layer on at least a portion of its surface; a calcined metal oxide surface layer bonded onto a metal oxide substrate layer; a parent radioisotope immobilized on or within a metal oxide surface layer so as to allow for effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0164] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a metal disk including a metal oxide substrate layer on at least a portion of its surface; a sol-gel derived metal oxide surface layer bonded onto a metal oxide substrate layer (e.g., the metal oxide surface layer is a sol-gel reaction product); a parent radioisotope immobilized on or within a metal oxide surface layer so as to allow for effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0165] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from the Th radioisotope, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: a metal disk including a metal oxide substrate layer on at least a portion of its surface; a calcined metal oxide surface layer bonded onto a metal oxide substrate layer; Gaseous layered radioisotope source away from 220Immobilized on or within a metal oxide surface layer to allow for efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0166] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from the Th radioisotope, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: a metal disk including a metal oxide substrate layer on at least a portion of its surface; a sol-gel derived metal oxide surface layer bonded onto a metal oxide substrate layer (e.g., the metal oxide surface layer is a sol-gel reaction product); Gaseous layered radioisotope source away from 220 Immobilized on or within a metal oxide surface layer to allow for efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0167] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a tantalum metal substrate including a tantalum oxide substrate layer on at least a portion of a surface thereof; a calcined tantalum oxide surface layer bonded onto a tantalum oxide substrate layer; a parent radioisotope immobilized on or within a tantalum oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0168] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a tantalum metal substrate including a tantalum oxide substrate layer on at least a portion of a surface thereof; a sol-gel derived tantalum oxide surface layer bonded onto a tantalum oxide substrate layer (e.g., the tantalum oxide surface layer is a sol-gel reaction product); a parent radioisotope immobilized on or within a tantalum oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0169] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from the Th radioisotope, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: a tantalum metal substrate including a tantalum oxide substrate layer on at least a portion of a surface thereof; a calcined tantalum oxide surface layer bonded onto a tantalum oxide substrate layer; Gaseous layered radioisotope source away from 220 Immobilized on or within the tantalum oxide surface layer to allow for efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0170] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from the Th radioisotope, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: a tantalum metal substrate including a tantalum oxide substrate layer on at least a portion of a surface thereof; a sol-gel derived tantalum oxide surface layer bonded onto a tantalum oxide substrate layer (e.g., the tantalum oxide surface layer is a sol-gel reaction product); Gaseous layered radioisotope source away from 220 Immobilized on or within the tantalum oxide surface layer to allow for efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0171] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a tantalum metal disk including a tantalum oxide substrate layer on at least a portion of its surface; a calcined tantalum oxide surface layer bonded onto a tantalum oxide substrate layer; a parent radioisotope immobilized on or within a tantalum oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0172] In one embodiment, there is provided a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a tantalum metal disk including a tantalum oxide substrate layer on at least a portion of its surface; a sol-gel derived tantalum oxide surface layer bonded onto a tantalum oxide substrate layer (e.g., the tantalum oxide surface layer is a sol-gel reaction product); a parent radioisotope immobilized on or within a tantalum oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source; The present invention provides a layered radioisotope source comprising:

[0173] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from the Th radioisotope, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: a tantalum metal disk including a tantalum oxide substrate layer on at least a portion of its surface; a calcined tantalum oxide surface layer bonded onto a tantalum oxide substrate layer; Gaseous layered radioisotope source away from 220 Immobilized on or within the tantalum oxide surface layer to allow for efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0174] In one embodiment, the gaseous 220 via Rn 228 Through the natural decay chain from the Th radioisotope, a medically useful dose 212 A layered radioisotope source for producing Pb, comprising: a tantalum metal disk including a tantalum oxide substrate layer on at least a portion of its surface; a sol-gel derived tantalum oxide surface layer bonded onto a tantalum oxide substrate layer (e.g., the tantalum oxide surface layer is a sol-gel reaction product); Gaseous layered radioisotope source away from 220 Immobilized on or within the tantalum oxide surface layer to allow for efficient release of Rn. 228 Th and The present invention provides a layered radioisotope source comprising:

[0175] Process for preparing layered radioisotope sources The inventors have developed a sol-gel process for preparing the layered radioisotope sources described herein. According to some embodiments or examples described herein, by controlling the reaction conditions and reagents of the sol-gel process, the thickness of the metal oxide surface layer and the dispersion of the parent radioisotope immobilized therein can be controlled, resulting in radioisotope sources with improved properties, including, for example, low parent radioisotope breakthrough due to effective separation of the gaseous intermediate radioisotope as it decays away from the immobilized parent radioisotope, and high resistance to radiolytic damage. These advantageous properties may result in low levels of parent radioisotope contamination in the collected daughter radioisotopes and / or a longer source lifetime, enabling the development of radioisotope generators that enable "line-of-sight," gravity-assisted collection of daughter radioisotopes with minimal contamination.

[0176] In one embodiment, a sol-gel process for preparing a layered radioisotope source is provided, comprising: a) providing a gel formed from a solution (e.g., a sol) comprising a metal alkoxide and a parent radioisotope species on a surface of an inert ceramic substrate layer; and b) heating the gel under conditions effective to form a bonded metal oxide surface layer on the inert ceramic substrate layer.

[0177] Radioisotope sources, particularly metal oxide surface layers, can be prepared by a sol-gel process. As used herein, the term "sol-gel" refers to the synthesis of a solid material from a solution-state precursor, including converting solubilized species into a colloidal solution (i.e., a sol) that serves as a precursor to a network structure (i.e., a gel), which is then heated to obtain a solid material.

[0178] As an example, the sol-gel technique can generally be summarized in the following steps, noting that some steps may be omitted and / or modified depending on process conditions and / or reagents: (i) preparing a "sol" by hydrolysis and partial condensation of precursor(s) dissolved in a suitable solvent (e.g., a metal alkoxide precursor in an alcohol solution) and initiation of gelation; (ii) Further gelation by polycondensation to form more extensive metal-oxo-metal or metal-hydroxy-metal bonds. (iii) and (iv) aging and drying the gel, where condensation continues within the gel network and solvent is removed to form denser gels, e.g., "xerogels" by collapse of the porous network, "aerogels" by, e.g., supercritical drying, or "cryogels" by, e.g., freeze-drying. (v) Calcination at high temperature to remove surface water / hydroxy groups in the M-OH units to form a ceramic material (e.g., metal oxide).

[0179] A general overview of sol-gel techniques is outlined in Danks et al., Mater. Horiz., 2016, 3, 91.

[0180] The sol-gel process for preparing the layered radioisotope source includes: a) providing a gel formed from a solution (e.g., a sol) containing a metal alkoxide and a parent radioisotope species on the surface of an inert ceramic substrate layer; and b) heating the gel under conditions effective to form a metal oxide surface layer bound on the inert ceramic substrate layer, wherein the parent radioisotope is immobilized on or within the metal oxide surface layer so as to enable effective release of the gaseous intermediate radioisotope away from the layered radioisotope source.

[0181] In one embodiment, the process described herein is for preparing a layered radioisotope source as described herein under the heading "Layered Radioisotope Source."

[0182] Oxidation pretreatment of metal substrates A gel formed from a solution containing a metal alkoxide and a parent radioisotope species is provided on the surface of an inert ceramic substrate layer.

[0183] The underlying inert ceramic substrate layer may comprise any suitable material capable of supporting / anchoring the metal oxide surface layer formed by the sol-gel process described herein, but in one embodiment, the inert ceramic substrate layer may be a metal oxide layer provided by oxidative pretreatment of a metal substrate prior to providing (e.g., depositing) a gel thereon. In one embodiment, the process includes providing a metal oxide substrate layer that has been previously prepared by oxidative pretreatment of a metal substrate.

[0184] In one embodiment, the inert ceramic substrate is a metal oxide layer provided / formed on the surface of a metal substrate. The metal oxide layer can be prepared by surface modification of the metal substrate. In one embodiment, the metal oxide layer can be prepared by oxidizing the metal substrate (i.e., a reaction in which electrons are removed) to prepare a metal oxide layer on the surface of the metal substrate. The oxidation of the surface of the metal substrate can be passive (i.e., occurring naturally in air), thereby forming a natural metal oxide surface layer on the metal substrate, or it can be energy-driven by an oxidative pretreatment of the metal surface. For example, the oxidation of the surface of the metal can involve a chemical reaction with an oxidizing agent to form the inert ceramic substrate as a surface oxide layer on the metal substrate.

[0185] In one embodiment, a metal substrate can be subjected to thermal oxidation (i.e., heating in an oxygen environment) to produce a metal oxide layer. Thermal oxidation is a well-understood process in which a metal (when in an oxidation state of zero) reacts with atmospheric oxygen at its surface to produce a well-defined layer of metal oxide compounds. This reaction relies on oxygen migrating to the metal surface along cracks in a pre-existing thin surface oxide film or by diffusion through such a film. Because oxygen diffusion is temperature-driven, heating the metal increases the reaction rate and the thickness of the metal oxide layer produced on the metal's surface. The metal oxide layer can have a variety of stoichiometries and may initially form as an amorphous material (with no defined lattice structure).

[0186] In one embodiment, the metal substrate is heated in the presence of oxygen to a temperature effective to form a metal oxide layer (e.g., an inert ceramic substrate) on the surface of the metal substrate. In one embodiment, the metal substrate is heated in the presence of oxygen to a temperature of from about 100° C. to about 900° C. The metal substrate may be heated in the presence of oxygen to a temperature (in ° C.) of at least about 100, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, or 900° C. The metal substrate may be heated in the presence of oxygen at a temperature (in °C) of less than about 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 380, 360, 340, 320, 300, 280, 260, 240, 220, 200, or 100. The heating temperature may be within a range provided by any two of these upper and / or lower limits, for example, from about 200°C to about 900°C, or from about 300°C to about 800°C.

[0187] The metal substrate can be heated from room temperature to the desired heating temperature in the presence of oxygen at a rate of at least 1, 1.5, 2, 2.5, 2, 3.5, 3, 4, 4.5, 5, 6, 7, 8, 9, or 10°C / min. The heating rate can be in the range provided by any two of these values.

[0188] Heating the metal substrate may be a two-stage heating process. In one embodiment, the metal substrate may be first heated in the presence of oxygen from ambient temperature (e.g., room temperature) to a first temperature (units: °C) of at least about 100 to about 500. In one embodiment, the metal substrate may be first heated in the presence of oxygen from ambient temperature (e.g., room temperature) to a first temperature (units: °C) of at least about 100, 150, 200, 250, 300, 350, 400, or 500. In one embodiment, the metal substrate may be first heated in the presence of oxygen from ambient temperature (e.g., room temperature) to a first temperature (units: °C) of less than about 500, 400, 250, 300, 250, 200, 150, or 100°C. The first temperature may be within a range provided by any two of these upper and / or lower limits, e.g., about 200 to about 400.

[0189] In a further embodiment, the metal substrate can be further heated to a second temperature higher than the first temperature. In one embodiment, the metal substrate can be heated to a second temperature (in °C) of at least about 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, or 800 °C, provided that the second temperature is higher than the first temperature. The second temperature can be in the range provided by any two of these values, for example, from about 300 to about 900.

[0190] The metal substrate can be heated in the presence of oxygen for a period of time effective to form a layer of metal oxide (e.g., an inert ceramic substrate) on the surface of the metal substrate. The metal substrate can be heated in the presence of oxygen for a period of from about 1 minute to about 24 hours. The substrate can be heated in the presence of oxygen for a period of at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 minutes, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours. The metal substrate can be heated in the presence of oxygen for a period of less than about 24, 22, 20, 18, 16, 14, 12, 10, 8, 6, 5, 4, 3, 2 (hours), 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or 1 (minutes). The heating time can be within a range provided by any two of these upper and / or lower limits, for example, from about 10 minutes to about 6 hours. Other heating temperatures and times relative to those listed herein, including longer heating times, are also contemplated.

[0191] The metal substrate may be subjected to a surface roughening step prior to the thermal oxidation step to provide a textured surface. Surface roughening may be achieved by grinding the metal substrate with an abrasive, such as alumina sandpaper.

[0192] Gel formation on the surface of an inert ceramic substrate The sol-gel process involves providing a gel formed from a solution (eg, a sol) containing a metal alkoxide and a parent radioisotope species on the surface of an inert ceramic substrate layer.

[0193] The gel may be pre-formed in a suitable container and then deposited / coated (i.e., ex-situ formation and subsequent deposition, e.g., by dip-coating, pipetting, or spin-coating, etc.) onto the surface of an inert ceramic substrate, and then subjected to a heat treatment to form a metal oxide surface layer bonded to the underlying inert ceramic substrate. Thus, in one embodiment, step a) of the sol-gel process described herein comprises depositing a gel formed from a solution comprising a metal alkoxide and a parent radioisotope species onto the surface of an inert ceramic substrate.

[0194] Alternatively, the gel can be formed on the surface of an inert ceramic substrate (i.e., in situ formation). In one embodiment, step a) comprises depositing a solution containing a metal alkoxide and a parent radioisotope species onto the surface of an inert ceramic substrate layer (e.g., by dip coating or pipetting, etc.) to form a gel, which is then heat-treated to form a metal oxide surface layer bonded to the underlying inert ceramic substrate.

[0195] The radioisotope species and metal alkoxide can be premixed to form a solution and / or gel, which can then be deposited on the surface of the inert ceramic substrate. Alternatively, in one embodiment, step a) includes preparing a first solution containing a metal alkoxide and a second solution containing the parent radioisotope species, and sequentially depositing the first and second solutions on the surface of the inert ceramic substrate layer in any order to form a gel. The period between depositing the first and second solutions on the surface of the inert ceramic substrate layer can vary but is preferably less than about 10 minutes, e.g., less than about 5 minutes. In one embodiment, the period (in seconds) between depositing the first and second solutions on the surface of the inert ceramic substrate layer is less than about 300, 240, 180, 120, 90, 60, 50, 40, 30, 20, 10, or 5. This period can also be within a range provided by any two of these upper and / or lower limits, e.g., from about 10 seconds to about 60 seconds.

[0196] It will be appreciated that over time, either naturally or immediately after mixing with the solution, the metal alkoxide will undergo hydrolysis / condensation to form a gel comprising an interconnected viscous and / or porous structure. The rate of hydrolysis / condensation can be controlled by the solvent (e.g., aqueous or non-aqueous / organic solvent) used to prepare the solution. Although not required, the solution and / or gel can be aged, which can further promote condensation and water loss within the gel network. This aging step can be performed before depositing the gel onto the surface of the inert ceramic substrate (e.g., in the case of ex-situ gel formation and deposition) or while the solution / gel is on the surface of the inert ceramic substrate (e.g., in the case of in-situ gel formation). However, it will be appreciated that this aging step is distinct from heating the gel in step b) to obtain the metal oxide surface layer. Thus, in one embodiment, the solution / gel is aged prior to step b).

[0197] The gel may be aged for at least about 1, 2, 6, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, or 336 or more hours prior to heating in step b). The gel may be aged for a period within the range provided by any two of these aging times, for example, for a period of about 24 to 192 hours. Aging may be carried out at ambient temperature or under low-temperature heating.

[0198] In one embodiment, the gel may be dried. Such drying may convert the viscous and / or porous gel network (which may be a mature gel as described herein) into a denser, amorphous, thin gel layer, e.g., in the form of a xerogel, on the surface of the inert ceramic substrate. In one embodiment, after step a) but before step b), the gel is dried under conditions effective to form, e.g., a xerogel.

[0199] In one embodiment, the gel can be dried at a temperature (units: °C) of about 10 to about 180. The gel can be dried at a temperature (units: °C) of at least about 10, 20, 30, 50, 100, or 150. The gel can be dried at a temperature (units: °C) of less than about 180, 150, 100, or 50. The drying temperature can be within the range provided by any two of these upper and / or lower values. However, it will be understood that the drying temperature can vary depending on the solvent used to prepare the solution containing the metal alkoxide and parent radioisotope species. The length of drying time can vary depending on the reagents, but in one embodiment, the gel can be dried for a period (units: hours) of about 0.1 to about 100, e.g., about 1 to about 48.

[0200] It will be understood that in order to carry out the sol-gel process, a certain amount of water will be included in the solution containing the metal alkoxide and parent radioisotope species. The amount of water present can vary, but in some embodiments is kept relatively low, which can provide additional benefits such as controlled / slowed rates of hydrolysis / condensation. Furthermore, a low amount of water in the solution can enhance grafting of the metal-oxide-metal chains / network to existing hydroxyl terminations that may be naturally present on the surface of the underlying inert ceramic substrate layer (preferably a metal oxide substrate layer).

[0201] In one embodiment, the water present in the solution is provided by the water of hydration of the parent radioisotope species, e.g., Th(NO3)4.5(HO). It will be understood that in this embodiment, no exogenous water is added and the amount present in the solution / solvent is relatively small. In a related embodiment, the solution comprises from about 0.0001% w / w to about 15% w / w, based on the total weight of the solution.

[0202] The solution used to prepare the gel in step a) may contain any suitable solvent capable of solubilizing / suspending the metal alkoxide and the parent radioisotope species. The solvent may be a single solvent or a mixture of solvents. The solvent may be water, an alcohol, an ester, a ketone, or an ether (including mixtures thereof).

[0203] In one embodiment, the solution in step a) comprises an alcoholic solution of a metal alkoxide and a parent radioisotope species. In one embodiment, the alcoholic solution of a metal alkoxide and a parent radioisotope species comprises an alcoholic solvent in an amount of about 50-99% v / v (unit: % v / v based on the total volume of the solution). According to some embodiments or examples described herein, the relative amount of alcoholic solvent (e.g., ethanol) can control the hydrolysis rate of the metal alkoxide and suppress the formation of larger spherical clusters within the gel, resulting in a metal oxide surface layer with little or no "coffee ring"-like deposits.

[0204] In one embodiment, the metal alkoxide is in stoichiometric excess (i.e., greater than 1 equivalent) relative to the parent radioisotope species. In one embodiment, the molar ratio of metal alkoxide to parent radioisotope species is greater than 1, e.g., greater than 1 to less than about 10. In one embodiment, the molar ratio of metal alkoxide to parent radioisotope species is greater than 1 to less than about 5, preferably greater than 1 to less than about 3. According to some embodiments or examples described herein, a slight excess of metal alkoxide, e.g., 1.2 to 3 equivalents, can achieve fine dispersion of the radioisotope within the metal oxide surface layer as well as good adhesion of the surface layer to the underlying inert ceramic substrate layer.

[0205] The metal alkoxide may be an alkoxide of a valve metal, a refractory metal, or other transition metal or main block metal. The metal alkoxide may be an alkoxide of tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, titanium, or aluminum, or a mixed oxide thereof. The metal alkoxide may be an alkoxide of tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, or titanium, or a mixed oxide thereof. In one embodiment, the metal alkoxide is a tantalum alkoxide, such as tantalum ethoxide (e.g., Ta(OEt)5).

[0206] In one embodiment, the inert ceramic substrate layer is a metal oxide substrate layer, and the metal alkoxide and the metal of the underlying metal oxide substrate layer are the same. For example, the inert ceramic substrate layer may comprise or consist of a tantalum oxide layer, and the metal alkoxide is a tantalum alkoxide (e.g., Ta(OEt)5).

[0207] According to some embodiments or examples described herein, the gel formed using metal alkoxides effectively traps the parent radioisotope species, thereby preventing significant radioisotope migration and the formation of larger, discrete deposits, while the branched metal-oxide-metal chains of the gel can effectively adhere / graft to existing hydroxyl ends naturally present on the surface of the underlying metal oxide substrate layer. As the gel dries, the colloidal network can evolve into an amorphous xerogel containing the parent radioisotope species firmly bound to the substrate. This is ultimately converted into a metal oxide surface layer during a final heat treatment (e.g., a calcination step), effectively intermixing with the metal oxide bonds of the underlying metal oxide substrate layer, thereby generating very small radioisotope particles / phases embedded within the matrix of the metal oxide surface layer and uniformly dispersed throughout the deposition area.

[0208] In one embodiment, the metal alkoxide is provided in solution at a concentration of about 0.00001 moles per liter (M) to about 1 M. In one embodiment, the metal alkoxide is provided in solution at a concentration (units: M) of at least about 0.00001, 0.00005, 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.02, 0.05, 0.08, 0.1, 0.2, 0.5, 0.8, or 1. In one embodiment, the metal alkoxide is provided in solution at a concentration (units: M) of less than about 1, 0.8, 0.5, 0.2, 0.1, 0.08, 0.05, 0.02, 0.01, 0.005, 0.001, 0.0005, 0.0001, 0.00005, or 0.00001. The concentration of the metal alkoxide in the solution may be within the range provided by any two of these upper and / or lower limits, for example, from about 0.00005M to about 0.010M.

[0209] The parent radioisotope species may be provided as a salt or hydrate thereof selected from one or more of hydroxides, halides, phosphates, nitrates, acetates, sulfates, perchlorates, ammonium compounds, and anionic oxo-metallate compounds. In one embodiment, the parent radioisotope species is provided in a solvated or complexed cationic form. In one embodiment, the parent radioisotope species is provided in an anionic oxo-metallate form (e.g., [ThO(HPO4)3(H2PO4)] 5- ) is available.

[0210] In one embodiment, the parent radioisotope species may be a thorium compound or a radium compound, or a combination thereof. In one embodiment, the parent radioisotope species is a thorium species. The thorium radioisotope species is 227 Th, 228 Th, and 232 The parent radioisotope species may be selected from at least one of Th, Th(NO3), ... 224 Ra and228 In one embodiment, the parent radioisotope species is a radium species provided as its nitrate salt or hydrate, e.g., radium nitrate. The radium radioisotope species may be provided as its hydrated cation, e.g., hydrated radium divalent cation (Ra(HO)). n 2+ )

[0211] In one embodiment, the parent radioisotope species is provided in solution at a concentration of about 0.000001 M to about 1 M. In one embodiment, the parent radioisotope species is provided in solution at a concentration (in M) of at least about 0.000001, 0.000005, 0.00001, 0.00005, 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.02, 0.05, 0.08, 0.1, 0.2, 0.5, 0.8, or 1. In one embodiment, the parent radioisotope species is provided in solution at a concentration (units: M) of about 1, 0.8, 0.5, 0.2, 0.1, 0.08, 0.05, 0.02, 0.01, 0.005, 0.001, 0.0005, 0.0001, 0.00005, 0.00001, 0.000005, or less than 0.000001. The concentration of the parent radioisotope species in solution can be within a range provided by any two of these upper and / or lower limits, e.g., from about 0.00005 M to about 0.010 M.

[0212] The solution may further include an acid, such as nitric acid (HNO) or triflic acid (CFSOH), which can aid in the solubilization and extraction of the parent radioisotope species into solution. According to some embodiments or examples described herein, by acidifying the solution to a lower pH (i.e., a more acidic pH), the soluble radioisotope species / ions remain sufficiently solvated and can be dispersed throughout the gel without substantial aggregation across the surface of the inert ceramic substrate. In one embodiment, the acid is provided in the solution at a concentration of about 0.1 M to about 3 M.

[0213] Although not required, the solution of step a) may further comprise one or more additional additives, such as binders, chelating agents, plasticizers, etc., as will be understood by those skilled in the art.

[0214] The gel is heated to obtain a metal oxide surface layer containing the immobilized parent radioisotope. The gel is heated in step b) under conditions effective to form a bonded metal oxide surface layer on the inert ceramic substrate. This heating step is essentially a pyrolysis of the gel to burn and volatilize residual organic components and dehydrate the gel to yield the metal oxide surface layer. Heating in step b) may also convert the parent radioisotope species (e.g., if the parent radioisotope species is provided as a nitrate, denitration, in which nitrate ions are volatilized and expelled) to individual atoms and / or small oxide phases (e.g., less than 20 nm) uniformly distributed throughout the metal oxide surface layer, e.g., as a mixed oxide.

[0215] The gel in step b) can be heated to a suitable temperature effective to calcinate the gel and form a metal oxide surface layer. In some embodiments, the gel is heated in step b) to a temperature (in degrees Celsius) of about 200 to 900. In some embodiments, the gel is heated in step b) to a temperature (in degrees Celsius) of at least about 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, or 900. In some embodiments, the gel is heated in step b) to a temperature (in degrees Celsius) of less than about 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, or 250. The temperature may be within a range provided by any two of these upper and / or lower limits, for example, from about 200 to about 500.

[0216] Any suitable heating rate (fast or slow) may be used, for example, the gel may be heated from ambient temperature (e.g., room temperature) to the desired calcination temperature, for example, the gel may be heated from ambient temperature at a rate of about 10°C / hour to about 250°C / hour in step b).

[0217] The gel in step b) is heated for a period of time effective to calcine the gel and form a metal oxide surface layer. In some embodiments, the gel is heated in step b) for a period of time (units: minutes) from about 30 to about 360. In one embodiment, the gel is heated in step b) for a period of time (units: minutes) of at least about 10, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, or 360. In some embodiments, the gel is heated in step b) for a period of time (units: minutes) of less than about 460, 330, 300, 270, 240, 210, 180, 150, 120, 90, 60, 45, 30, 15, or 10. The gel can be heated for a period of time within the range provided by any two of these upper and / or lower limits, for example, from about 100 minutes to about 350 minutes. Any combination of one or more of the above temperatures and times is possible, for example, the gel may be heated in step b) at a temperature of about 200°C to 500°C for a period of about 30 minutes to about 360 minutes.

[0218] According to some embodiments or examples described herein, calcining the gel at a low temperature of about 200°C to about 500°C in step b) may provide one or more additional benefits, including the formation of a metal oxide surface layer with a desired degree of crystallinity yet sufficient to decompose the initial gel / radioisotope species. An optimal degree of crystallinity may allow for better immobilization of the parent radioisotope, as the surrounding atomic lattice is more able to self-repair after atomic displacements caused by high-energy alpha decay events. Furthermore, an optimal degree of crystallinity in the metal oxide surface layer may also contribute to reducing breakthrough of the parent radioisotope, thereby extending the lifetime of the radioisotope source.

[0219] Heating (eg, calcining) can be carried out using a suitable furnace (eg, a muffle furnace), kiln, autoclave, microwave reactor, or hot plate.

[0220] Radioisotope Generator The present disclosure also provides a radioisotope generator for capturing a population of daughter radioisotopes. In embodiments, a radioisotope generator is provided that defines a chamber for capturing a population of daughter radioisotopes, the chamber configured to house a layered radioisotope source according to any aspect, embodiment, or example described herein. In embodiments, a radioisotope generator is provided that defines a chamber for capturing a population of daughter radioisotopes, the chamber housed a layered radioisotope source according to any aspect, embodiment, or example described herein.

[0221] As described herein, a layered radioisotope source housed within a chamber can include a parent radioisotope immobilized on or within a metal oxide surface layer in an amount effective to generate (i.e., produce) a medically useful dose of daughter radioisotopes through a chain of spontaneous decays from the parent radioisotope via a gaseous intermediate radioisotope. It is therefore understood that a chamber housing a layered radioisotope source both produces (i.e., generates) and captures a population of daughter radioisotopes.

[0222] In one embodiment, the chamber comprises a collection surface and is configured to house the layered radioisotope source therein with a metal oxide surface layer facing (but e.g., not touching) the collection surface to collect at least some of the emitted gaseous intermediate radioisotope for a period effective for it to decay into daughter radioisotopes. In one embodiment, the chamber comprises a collection surface and is configured to house the layered radioisotope source therein with a metal oxide surface layer facing (but e.g., not touching) the collection surface to collect at least some of the emitted gaseous intermediate radioisotope for a period effective for it to decay into daughter radioisotopes. In one embodiment, the emitted gaseous intermediate radioisotope may be collected for a period sufficient to accumulate into a medically useful dose of daughter radioisotope. For example, 220 The Rn is released from the metal oxide surface layer and accumulates on the collection surface, where it 212 It can decay to Pb.

[0223] The collection surface may be any surface, such as a removable dish / tray / container, that is capable of collecting and retaining the released gaseous intermediate radioisotopes. The collection surface may be composed of any suitable material. In one embodiment, the collection surface may be composed of a cellulose material (such as cellulose filter paper), a polymeric material (e.g., PTFE), or glass. Alternatively, the collection surface may be the interior wall of a collection chamber, as described herein.

[0224] In one embodiment, the chamber may be configured to house a layered radioisotope source in which the metal oxide surface layer is in a line-of-sight configuration with the collection surface. In one embodiment, the chamber houses a layered radioisotope source in which the metal oxide surface layer is in a line-of-sight configuration with the collection surface. It will be understood that "line-of-sight" communication refers to a configuration in which there are no obstructions (e.g., closed valves or retractable seals) between the collection surface and the metal oxide surface layer, thereby allowing efficient transport of released gaseous intermediate radioisotopes. In some embodiments, the chamber may be configured with one or more valves, seals, and / or closures configured to temporarily physically isolate / separate the layered radioisotope source from the collection surface, such as when daughter radioisotopes are extracted from the collection surface. It will be understood that such physical isolation of the layered radioisotope source from the collection surface temporarily blocks line-of-sight communication, but that the chamber is configured at some point to provide line-of-sight communication between the metal oxide surface layer and the collection surface when collection of released radioisotopes is occurring. In other words, such a line-of-sight configuration does not preclude the presence of one or more closures, seals, and / or valves within the chamber to temporarily physically isolate / separate the layered radioisotope source from the collection surface, such as when daughter radioisotopes are extracted from the collection surface.

[0225] In a related embodiment, the chamber may be configured to house a layered radioisotope source with a metal oxide surface layer facing substantially downward, allowing for gravity-assisted collection of at least some of the emitted gaseous intermediates on the collection surface. For example, the chamber may be configured to house the layered radioisotope source above the collection surface. Also, this does not preclude the presence of one or more closures, seals, or valves within the chamber to physically isolate / separate the layered radioisotope source from the collection surface, such as when daughter radioisotopes are extracted from the collection surface. In another related embodiment, the chamber may house a layered radioisotope source with a metal oxide surface layer facing substantially downward, allowing for gravity-assisted collection of at least some of the emitted gaseous intermediates on the collection surface. For example, the chamber houses the layered radioisotope source above the collection surface. Also, this does not preclude the presence of one or more closures, seals, or valves within the chamber to physically isolate / separate the layered radioisotope source from the collection surface, such as when daughter radioisotopes are extracted from the collection surface.

[0226] In one embodiment, the radioisotope generator further comprises a carrier gas inlet port configured to introduce a carrier gas into the chamber to facilitate transport of the released gaseous intermediate radioisotope away from the layered radioisotope source and onto the collection surface.

[0227] In one embodiment, the radioisotope generator further comprises a vacuum pump configured to apply a vacuum to evacuate the chamber to facilitate transport of the released gaseous intermediate radioisotope away from the layered radioisotope source and onto the collection surface.

[0228] In one embodiment, the radioisotope generator further comprises a fluid supply system configured to introduce a collection fluid into the chamber to collect the daughter radioisotopes from the collection surface. In some embodiments, the radioisotope generator comprises one or more valves, seals, and / or closures configured to physically isolate / separate the layered radioisotope source from the collection surface within the chamber, e.g., as the daughter radioisotopes are extracted from the collection surface. In a related embodiment, the radioisotope generator further comprises a collection fluid outlet port configured to transfer the collection fluid containing the daughter radioisotopes from the chamber.

[0229] The radioisotope generator may further comprise a system for flushing the daughter radioisotope products from the collection surface into a product container using a suitable collection fluid. For example, the generator may further comprise a fluid supply system configured to introduce a collection fluid into the chamber to collect the daughter radioisotopes deposited on the collection surface. The fluid supply system may comprise a collection fluid reservoir coupled to a collection fluid inlet port via a collection fluid inlet valve for introducing the collection fluid into the chamber. The fluid supply system may be controlled by a collection fluid inlet valve operably configured to open intermittently to introduce a series of pulses of collection fluid into the chamber through the collection fluid inlet port.

[0230] The generator may further comprise a collection fluid outlet port configured to transfer collection fluid containing the daughter radioisotope from the chamber, for example to a product vessel, The collection fluid outlet port may be controlled by a collection fluid outlet valve and / or a pump operatively configured to open intermittently to extract collection fluid containing the daughter radioisotope from the chamber.

[0231] In one embodiment, the generator in use is configured to produce at least one medical (e.g., clinical or preclinical) dose of the daughter radioisotope within a 24-hour period, e.g., configured to produce at least 1, 2, 3, 4, or 5 medical doses of the daughter radioisotope within a 24-hour period.

[0232] In one embodiment, the generator in use generates at least one medical dose of at least about 1, 2, 5, 10, 50, 60, 90, 120, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, or 1,000 MBq of daughter radioisotope (e.g., 212 In another embodiment, the generator in use may be configured to generate less than about 1,000, 900, 800, 700, 600, 500, 400, 300, 250, 200, 150, 120, 90, 60, 50, 10, 5, 2, or 1 dose of at least one medical dose of a daughter radioisotope (e.g., 212 In one embodiment, the generator in use may be configured to generate at least one medical dose of at least about 50, 70, 100, 120, 140, 160, 180, or 200 MBq of daughter radioisotope (e.g., 212 The generator in use may be configured to generate at least one medical dose of a daughter radioisotope (e.g., Pb) within the range provided by any two of these upper and / or lower limits, e.g., between about 50 MBq and about 200 MBq. 212 Pb).

[0233] It will be understood that any aspect, embodiment or example of the process for producing and capturing daughter radioisotopes and / or layered radioisotope sources described herein may form one or more aspects, embodiments or examples of the generator.

[0234] system The present disclosure also provides a system for generating and capturing a population of daughter radioisotopes generated through a chain of spontaneous decays from a parent radioisotope, the system comprising: a) a generator; and b) a layered radioisotope source according to any aspect, embodiment, or example described herein.

[0235] In one embodiment, there is provided a system for generating and capturing a population of daughter radioisotopes generated through a chain of spontaneous decays from a parent radioisotope, the system comprising: a) a radioisotope generator defining a chamber for generating and capturing the population of daughter radioisotopes; and b) a layered radioisotope source according to any aspect, embodiment, or example described herein housed within the chamber.

[0236] The radioisotope generator may be a generator according to any aspect, embodiment, or example described herein.

[0237] It will be understood that any aspect, embodiment, or example of the radioisotope generator, process for producing and capturing daughter radioisotopes, and / or layered radioisotope source described herein may form one or more aspects, embodiments, or examples of a system.

[0238] Processes for producing and capturing daughter radioisotopes The present disclosure also relates to processes for capturing a population of daughter radioisotopes. The daughter radioisotopes produced by the processes described herein are produced through a chain of natural decays from a parent radioisotope via a gaseous intermediate radioisotope. An example of a natural radioactive decay chain relevant to the present disclosure is provided in Figure 18, 228 The Th decay series is shown.

[0239] In one embodiment, a process for capturing a population of daughter radioisotopes is provided, the process comprising: a) allowing release of gaseous intermediate radioisotopes generated through a chain of natural decays from parent radioisotopes immobilized on or within a layered radioisotope source according to any aspect, example, or embodiment described herein; and b) collecting at least some of the gaseous intermediate radioisotopes for a period of time effective for them to decay into daughter radioisotopes. In one embodiment, the released gaseous intermediate radioisotopes can be collected for a period of time sufficient to accumulate into useful quantities of daughter radioisotopes.

[0240] The process may include a radioisotope generator according to any aspect, embodiment, or example described herein, or a system according to any aspect, embodiment, or example described herein.

[0241] In one embodiment, the parent radioisotope is an alpha-emitting radioisotope. In one embodiment, the parent radioisotope is thorium-227 ( 227 Th) and thorium-228( 228 In one embodiment, the gaseous intermediate radioisotope is radon-219 ( 219 Rn) and radon-220 ( 220 In one embodiment, the daughter radioisotope is lead-211 ( 211 Pb) or lead 212( 212 Pb).

[0242] In one embodiment, the process further comprises recovering at least some of the daughter radioisotopes. The recovered daughter radioisotopes can be used in radiopharmaceuticals. For example, the recovered daughter radioisotopes can be conjugated to targeting molecules, such as cancer cell targeting molecules, including for use as radiopharmaceuticals, such as radioligand therapy. Various applications and uses of the recovered daughter radioisotopes are described herein, including under the heading "Applications" of this disclosure.

[0243] It will be understood that any aspect, embodiment, or example of the radioisotope generators, systems, and / or layered radioisotope sources described herein may form one or more aspects, embodiments, or examples of a process for producing and capturing daughter radioisotopes.

[0244] Purpose The applications of the present disclosure include various applications in the fields of medicine, therapy, and diagnosis, including, for example, as radiopharmaceuticals for treating cancer. For example, in the field of nuclear medicine, radiolabeling of macromolecules, such as antibodies, that bind with high specificity to antigens expressed on specific cancer cells is provided. Alpha particle emitters (including daughter radioisotopes generated, captured, and collected as described herein) are particularly effective as short-range cytotoxic payloads on such targeted molecular vehicles, thereby enabling the destruction of cancer cells while minimizing the impact on surrounding healthy tissue.

[0245] In some embodiments, daughter radioisotopes (e.g., 212 Pb) is of high radiochemical purity and high specific activity (e.g., as a result of using the generators and processes described herein). 208 The generators and processes described herein can be used to generate highly pure daughter radioisotopes (e.g., highly pure 1,2,3,4-trimethylsilyl 1,2 ... 212 Pb), it will be possible to produce this therapeutic isotope on a large scale with a wide geographic distribution.

[0246] Daughter radioisotopes produced using the layered radioisotope sources, processes, generators, and systems described herein, such as 212 Pb can be directly utilized in various clinical applications, including conjugation to targeting molecules / ligands for use in radiopharmaceutical applications such as radioligand therapy. Examples of targeting molecules / ligands include antibodies and / or peptides, such as prostate-specific membrane antigen (PSMA) ligands. Targeting molecules / ligands can include those described in International PCT Application No. PCT / AU / 2023 / 050763, filed August 11, 2023, the contents of which are incorporated herein by reference in their entirety.

[0247] This application claims priority from Australian Provisional Patent Application No. 2023900421, filed on 20 February 2023, the entire contents of which are incorporated herein by reference. [Example]

[0248] In order that the present disclosure may be more clearly understood, certain embodiments of the invention will be described in further detail by reference to the following non-limiting experimental materials, procedures and examples.

[0249] Example 1: Sol-gel process for preparing layered radioisotope sources Preparation of inert ceramic substrate surface layers by thermal oxidation. An inert ceramic substrate layer composed of tantalum pentoxide (Ta2O5) was formed on a tantalum metal disk. Briefly, the tantalum disk was placed on a clean, smooth surface of 240-grit alumina (Al2O3) sandpaper, and one side of the tantalum disk was polished to a uniform matte finish. The disk surface was then cleaned with a detergent solution and rinsed with DI water.

[0250] The cleaned, dried, polished tantalum discs were placed in a furnace and heated according to the following temperature-time profile: heat from ambient temperature (e.g., room temperature) to 300°C over 60 minutes, increase the furnace temperature from 300°C to 575°C over 40 minutes, hold at 575°C for 45 minutes, and begin slow natural cooling (ambient cooling) to ambient temperature.

[0251] Similarly, an inert ceramic substrate layer composed of zirconia (ZrO2) was formed on a zirconium metal disk using the protocol described above, but with the following furnace heating program: heat from ambient temperature (e.g., room temperature) to 750°C over 120 minutes, hold at 750°C for 300 minutes, and allow slow natural cooling to ambient temperature.

[0252] Extraction of parent radioisotope species To prepare a stock solution of thorium nitrate, add 200 μL of EtOH to a small amount of 228 The solution was then transferred to an empty 1.5 mL Eppendorf tube and the previous step was repeated two more times to obtain a total volume of 600 μL of ethanolic 228 The Eppendorf tube was then placed in a heating block set at 70°C and the ethanolic solution was added. 228 The Th(NO3)4 solution was heated until the total volume was reduced to 200 μL.

[0253] In some cases, 4.3 mM 228 To obtain a final solution of Th(NO3)4 and 0.4 mM HNO3, 228 Nitric acid (HNO) was added to aid in the extraction of Th(NO) Next, 58 μL of this solution was transferred to a 1.5 mL Eppendorf tube and the solution was allowed to slowly evaporate on a hot plate until approximately 5–10 μL remained in the tube.

[0254] Preparation of metal alkoxide stock solution A 0.128 M stock solution of Ta(OEt)5 in ethanol was prepared by adding 500 μL of pure Ta(OEt)5 to 14.5 mL of EtOH.

[0255] Deposition of metal alkoxide solutions / gels containing parent radioisotope species onto metal oxide surface layers. Usually, a predetermined amount of Ta(OEt)5 prepared above and 228 Th(NO3)4 stock solutions were mixed and optionally diluted with either H2O and / or EtOH. 228 The mixture was aged in a container for up to 7 days before deposition. The mixture was then deposited onto the center of the roughened surface of a prepared disk containing either a Ta2O5 or ZrO2 surface. The disk was then dried overnight under ambient conditions to complete the sol-gel process and form a gel layer (e.g., xerogel) on the metal oxide surface of the disk.

[0256] Sequential deposition of metal alkoxides and parent radioisotope species onto metal oxide surface layers. Typically, a predetermined amount of the Ta(OEt)5 stock solution prepared above and 228 Separate solutions containing Th(NO3)4 were diluted with water and / or EtOH and then sequentially deposited onto the center of the roughened surface of the prepared disks containing either a Ta2O5 or ZrO2 surface. The disks were then dried overnight under ambient conditions to complete the sol-gel process and form a gel layer (e.g., xerogel) on the metal oxide surface of the disks.

[0257] Calcination / denitration of the gel to form a metal oxide surface layer containing immobilized parent radioisotope The xerogel-coated disk was placed in a furnace heated according to the following program to obtain the final Ta x Th y O z The coated tantalum or zirconia disks were obtained by a) heating from ambient temperature to 280°C over 150 minutes, b) holding the temperature at 280°C for 150 minutes, and c) initiating slow natural cooling (ambient cooling) to ambient temperature.

[0258] Final Ta x Th y O z To optimize the properties of the mixed oxide surface, several layered radioisotope sources were prepared according to the protocol described above, varying the molar ratio of both tantalum and thorium species, deposition mode, solvent and ageing time.

[0259] Table 1 provides a summary of the sol-gel process conditions investigated using the general protocol above. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0260] Example 2: Deposited Ta x Th y O z Film morphology and composition analysis The sol-gel protocol developed produced a surface morphology in which the thorium was present in most cases in the form of a "thin film" of homogeneously mixed tantalum and thorium oxide.

[0261] SEM examination of samples NC028T and NC046T did not reveal discrete particles of thorium oxide or thorium-rich features up to a size of about 20 nm or less (see Figures 2a, 2c, 3a, 3c, and 3e, NC828T and NC046T, respectively). The lack of discrete thorium deposits of this size suggests that thorium atoms / species are not present in the deposited amorphous or semicrystalline Ta. x Th y O z This suggests that the particles are smoothly distributed and uniformly mixed within the film.

[0262] EDX analysis of samples NC028T and NC046T showed a signal at approximately 3 keV, corresponding to the thorium M line, across the entire surface of the disk, and a signal of deposited Ta x Th y O z The film was present in all acquired SEM images of the sample (see Figures 2b, 2d, 3b, 3d, and 3f). In areas near the edge of the disk, the intensity of the thorium M-line signal was greater because the thickness of the deposited film was slightly thicker toward the edge of the disk (see Figure 4b, NC046T). Even in these thicker film regions, the intensity of the thorium M-line signal remained below 0.65%, suggesting that thorium was present in only an atomically thin layer.

[0263] Ta x Th y O zTo further investigate the film composition, sample NC043T was prepared by depositing an ethanolic Ta(OEt)5 / Th(NO3)4 sol-gel onto a ZrO2 surface formed by heat-treating a Zr disk. Using this preparation method, any Ta EDX signal is exclusively attributable to the sol-gel-derived film, not the underlying surface. SEM imaging showed the presence of a small amount of flaky deposits at the boundary of the deposition area (see Figure 5a, NC043T), which was attributed to improper spreading of the deposited sol-gel droplets caused by poor wetting of the ZrO2 surface. Most importantly, the EDX signal within the deposition area (see Figure 5, area 2) showed both a weak Ta signal and a weak Th signal, in atomic ratios consistent with the amounts used in preparing the sol, as outlined in Table 2. This can be seen as further evidence that the Th atoms are homogeneously mixed in the deposited film and do not form individual particles. [Table 2]

[0264] SEM images of the bulk deposition area of ​​sample NC043T showed no discernible features at low magnification (see Figures 6a, 6c, and 6d). The corresponding EDX spectrum shows both weak Ta and Th signals in atomic ratios consistent with the amounts used in the sol-gel preparation, as outlined in Table 3. This provides further evidence that the Th atoms are homogeneously mixed in the deposited film and that no diffusion-based concentration or aggregation of Th particles into discrete particles has occurred. [Table 3]

[0265] Example 3: Small Batch Non-Automated Deposition Test (NC051T) To facilitate small batch fabrication of layered radioisotope sources, larger volumes of sol-gel solution are required, and a small amount of aqueous nitric acid (HNO3) is required from the supplied container. 228These method modifications are required for efficient extraction of Th(NO3)4. x Th y O x To evaluate the film properties, nitric acid was used as outlined in Example 1 above. 228 A deposition experiment using Th extraction was carried out.

[0266] SEM images of this sample, NC051T, showed that the bulk area of ​​the film deposited using this method presented the same relatively featureless morphology as samples NC028T and NC046T (see Figure 7a, NC051T bulk region). A weak Th signal was detected in all bulk regions examined by SEM-EDX spectroscopy (see Figure 7b, NC051T bulk region), with a larger deviation in morphology found in the deposition edge region (see Figure 8, NC051T edge region).

[0267] Example 4: Ta prepared by sol-gel process x Th y O z The membrane was tightly bound 228 Contains Th. Layered radioisotope sources were prepared using either tantalum disk substrates prepared to exhibit a Ta2O5 surface oxide layer according to Example 1, or flat fused silica disk substrates pretreated with 0.1 M HNO3.

[0268] 228 Stock solutions of Th(NO3)4 and Ta(OEt)5 were prepared according to Example 1. 228 The Th(NO3)4 solution was deposited on the surface of the substrate with or without the addition of Ta(OEt)5 solution, followed by heat treatment at 280 °C for 2 hours. 228 The Th content was measured by alpha spectroscopy. Each source was then immersed in 0.1 M HNO3 at room temperature for 20 seconds, dried at 60 °C, and 228 The Th content was re-measured by alpha spectroscopy. 228 The loss of Th is due to the 228Calculated from the integral of the Th peak. [Table 4]

[0269] By the sol-gel process according to Example 1, 228 Ta(OEt)5 was added together with Th(NO3)4 to obtain Ta on the source. x Th y O z When the surface layer is formed, the 228 This significantly improves Th retention, which is essentially an acid etch of the surface. 228 Th-containing sol-gel derived Ta x Th y O z The surface layer is 228 More than 50% of the Ta x Th y O z This is true whether the substrate beneath the surface layer is Ta / Ta2O5 or quartz.

[0270] Those skilled in the art will appreciate that numerous variations and / or modifications may be made to the above-described embodiments without departing from the broad general scope of the present disclosure, and the present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Claims

1. 1. A layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: an inert ceramic substrate layer; a metal oxide surface layer bonded onto the inert ceramic substrate layer; a parent radioisotope immobilized on or within said metal oxide surface layer so as to allow for efficient release of said intermediate gaseous radioisotope away from said layered radioisotope source; A layered radioisotope source comprising:

2. 10. The layered radioisotope source of claim 1, wherein the metal oxide surface layer is a sol-gel reaction product.

3. 3. The layered radioisotope source of claim 1 or claim 2, wherein the metal oxide surface layer is a calcined metal oxide surface layer.

4. The metal oxide surface layer is formed to a thickness of 1 cm ２ 4. The layered radioisotope source of any one of claims 1 to 3, comprising less than about 1000, 5000, 1000, 500, 100, 80, 60, 40, 20, 10, 5, or 1 discrete deposit of said radioisotope bound on or within the surface of said metal oxide surface layer, said discrete deposits having a particle size of about 20 nm or greater per deposit.

5. 4. The layered radioisotope source of claim 1, wherein the metal oxide surface layer is substantially free of discrete deposits of the radioisotope bound on or within the surface of the metal oxide surface layer, the discrete deposits having a particle size of about 20 nm or greater.

6. 6. The layered radioisotope source of any one of claims 1 to 5, wherein the immobilized parent radioisotope is uniformly distributed within the metal oxide surface layer.

7. The layered radioisotope source of any one of claims 1 to 6, wherein the metal oxide surface layer has a thickness of from about 0.1 nm to about 1000 nm.

8. 8. The layered radioisotope source of claim 1, wherein the metal oxide surface layer has a molar ratio (M:R) of metal forming the oxide of the surface layer to the immobilized parent radioisotope of greater than 1 to about 10.

9. 9. The layered radioisotope source of any one of claims 1 to 8, wherein the metal oxide surface layer is an oxide of a valve metal, a refractory metal, or other transition metal or main block metal.

10. 10. The layered radioisotope source of any one of claims 1 to 9, wherein the metal oxide surface layer is an oxide of tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, or titanium, or a mixed oxide thereof.

11. The metal oxide surface layer is made of tantalum pentoxide (Ta ２ O ５ 11. The layered radioisotope source according to claim 1, wherein the layered radioisotope source is:

12. 12. The layered radioisotope source of any one of claims 1 to 11, wherein the metal oxide surface layer and at least some of the immobilized parent radioisotope together form one or more mixed oxide phases within the metal oxide surface layer.

13. 13. The layered radioisotope source of any one of claims 1 to 12, wherein the metal oxide surface layer and the immobilized parent radioisotope form a mixed oxide surface layer on the inert ceramic substrate.

14. The mixed oxide phase or mixed oxide surface layer has the formula R ｘ M ｙ O ｚ 14. The layered radioisotope source of claim 12 or claim 13, having the formula: wherein R is the parent radioisotope in cationic form, M is one or more metals in cationic form, and 0.1≦x≦5, 1.0≦y≦20, 1.0≦z≦50, preferably x<y.

15. The layered radioisotope source of any one of claims 1 to 14, wherein the inert ceramic substrate layer has a thickness in the range of about 1 to about 1000 μm.

16. 16. The layered radioisotope source of any one of claims 1 to 15, wherein the inert ceramic substrate layer is selected from an inert oxide, an inert nitride, an inert carbide, an inert sulfide, an inert phosphate, or a combination thereof.

17. 17. The layered radioisotope source of any one of claims 1 to 16, wherein the inert ceramic substrate layer is selected from a metal oxide, a metal nitride, a metal carbide, a metal sulfide, a metal phosphate, or a combination thereof.

18. 18. The layered radioisotope source of any one of claims 1 to 17, wherein the inert ceramic substrate layer is an oxide of silicon, tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, titanium or aluminium, or a mixed oxide thereof.

19. The inert ceramic substrate layer is made of quartz, tantalum pentoxide (Ta ２ O ５ ) or zirconium dioxide (ZrO ２ 19. The layered radioisotope source according to any one of claims 1 to 18, wherein

20. A layered radioisotope source according to any preceding claim, wherein the inert ceramic substrate layer is provided on a metal substrate.

21. 21. The layered radioisotope source of claim 20, wherein the metal substrate is selected from the group consisting of tantalum, niobium, tungsten, hafnium, molybdenum, vanadium, zirconium, titanium, or aluminum, or alloys thereof.

22. 22. The layered radioisotope source of claim 20 or claim 21, wherein the inert ceramic substrate layer is produced by oxidative pre-treatment of the surface of the metal substrate.

23. The metal substrate has a density (g / cm 3) of about 2.0 to about 20. ３ 23. The layered radioisotope source of any one of claims 20 to 22, comprising:

24. The layered radioisotope source of any one of claims 20 to 23, wherein the metal substrate has a thickness of about 1 to 100 mm.

25. 25. The layered radioisotope source of any one of claims 1 to 24, wherein the immobilized parent radioisotope in the metal oxide surface layer is such that, in use, it is capable of capturing a population of the daughter radioisotopes with a parent radioisotope contamination level, expressed in terms of activity relative to the daughter radioisotope activity, of less than about 5%.

26. The layered radioisotope source of any one of claims 1 to 25, wherein the layered radioisotope source is provided as a disc or a slab.

27. The layered radioisotope source of any one of claims 1 to 26, wherein the layered radioisotope source has a thickness in mm of about 1 to 100.

28. The layered radioisotope source of any one of claims 1 to 28, wherein the parent radioisotope is an alpha-emitting radioisotope.

29. The parent radioisotope is thorium-227 ( ２２７ Th) or thorium 228 ( ２２８ 29. The layered radioisotope source of any one of claims 1 to 28, wherein the thorium radioisotope is selected from the group consisting of thorium, ...

30. The daughter radioisotope is lead-211 ( ２１１ Pb) or lead 212 ( ２１２ 30. The layered radioisotope source of any one of claims 1 to 29, wherein the lead radioisotope is selected from at least one of:

31. The immobilized parent radioisotope has an activity of about 1 to about 1500 (1 cm of the surface of the inert ceramic substrate). ２ 31. The layered radioisotope source of any one of claims 1 to 30, wherein the layered radioisotope source is present in an amount effective to provide a radioisotope concentration of 1000 uM / g (MBq units per uM).

32. 1. A sol-gel process for preparing a layered radioisotope source for producing medically useful doses of daughter radioisotopes through a chain of spontaneous decays from a parent radioisotope via a gaseous intermediate radioisotope, comprising: a) providing a gel formed from a solution (e.g., a sol) containing a metal alkoxide and a parent radioisotope on the surface of an inert ceramic substrate layer; b) heating the gel under conditions effective to form a bonded metal oxide surface layer on the inert ceramic substrate layer; the parent radioisotope is immobilized on or within the metal oxide surface layer in a manner that allows for efficient release of the gaseous intermediate radioisotope away from the layered radioisotope source; Sol-gel process.

33. A sol-gel process according to claim 32, wherein the process is for preparing a layered radioisotope source according to any one of claims 1 to 31.

34. 34. The sol-gel process of claim 32 or claim 33, wherein after step a) but before step b), the gel is dried.

35. The sol-gel process of claim 34, wherein the gel is dried at a temperature of about 10 to about 180° C., preferably for a period of about 0.1 to about 100 hours.

36. The sol-gel process of any one of claims 32 to 35, wherein the solution in step a) comprises an alcoholic solution of the metal alkoxide and parent radioisotope species.

37. 37. The sol-gel process of claim 36, wherein the alcoholic solution of metal alkoxide and parent radioisotope species comprises alcoholic solvent in an amount of about 50-99% (% v / v based on the total volume of the solution).

38. The sol-gel process of any one of claims 32 to 37, wherein the metal alkoxide is in stoichiometric excess relative to the parent radioisotope species.

39. The sol-gel process of any one of claims 32 to 38, wherein the molar ratio of metal alkoxide to parent radioisotope species is greater than 1 to about 10.

40. 40. The sol-gel process of any one of claims 32 to 39, wherein the parent radioisotope species is provided in the solution at a concentration of from about 0.000001 M to about 0.01 M.

41. The sol-gel process of any one of claims 32 to 40, wherein the metal alkoxide is provided in the solution at a concentration of from about 0.000050M to about 0.01M.

42. The sol-gel process of any one of claims 32 to 41, wherein the solution further comprises water and / or an acid.

43. 43. The sol-gel process of claim 42, wherein the acid is provided in the solution at a concentration of about 0.1 M to about 1 M.

44. The sol-gel process according to any one of claims 32 to 43, wherein the gel is heated in step b) at a temperature of about 200 to about 500 °C, preferably for a period of about 30 to about 360 minutes.

45. The sol-gel process of any one of claims 32 to 44, wherein the metal alkoxide is an alkoxide of a valve metal, a refractory metal, or other transition metal or main block metal.

46. The sol-gel process of any one of claims 32 to 45, wherein the metal alkoxide is an alkoxide of tantalum, niobium, tungsten, molybdenum, vanadium, zirconium, or titanium, or a mixed oxide thereof.

47. The sol-gel process according to any one of claims 32 to 46, wherein the metal alkoxide is a tantalum alkoxide, preferably tantalum ethoxide.

48. 48. The sol-gel process of any one of claims 32 to 47, wherein the parent radioisotope species is provided as a salt or hydrate thereof selected from one or more of hydroxides, halides, phosphates, nitrates, acetates, sulfates, perchlorates, ammonium compounds and anionic oxo-metallate compounds.

49. The sol-gel process of any one of claims 32 to 48, wherein the parent radioisotope species is a thorium species.

50. 50. The sol-gel process of claim 49, wherein the thorium species is a nitrate or a hydrate thereof.

51. 32. A radioisotope generator defining a chamber for generating and capturing a population of daughter radioisotopes, said chamber configured to accommodate therein a layered radioisotope source according to any one of claims 1 to 31.

52. 52. The radioisotope generator of claim 51 , wherein the chamber comprises a collection surface and is configured to accommodate the layered radioisotope source within the chamber with the metal oxide surface layer facing the collection surface to collect at least some of the released gaseous intermediate radioisotope for a period of time effective for it to decay into daughter radioisotopes.

53. 53. A radioisotope generator as defined in claim 52, wherein said metal oxide surface layer is in a line-of-sight configuration with said collecting surface.

54. 54. A radioisotope generator according to claim 52 or claim 53, wherein the metal oxide surface layer faces substantially downwards to enable gravity-assisted collection of at least some of the released gaseous intermediate radioisotope on the collection surface.

55. 55. A radioisotope generator according to any one of claims 52 to 54, further comprising a carrier gas inlet port configured to introduce a carrier gas into the chamber to facilitate transport of released gaseous intermediate radioisotope away from the layered radioisotope source and onto the collection surface.

56. 56. A radioisotope generator according to any one of claims 52 to 55, further comprising a vacuum pump configured to apply a vacuum to evacuate the chamber to facilitate transport of released gaseous intermediate radioisotope away from the layered radioisotope source and onto the collection surface.

57. 57. A radioisotope generator according to any one of claims 52 to 56, further comprising a fluid supply system configured to introduce a collection fluid into the chamber to collect daughter radioisotopes from the collection surface.

58. 58. A radioisotope generator according to claim 57, further comprising a collection fluid outlet port configured to transport the collection fluid containing daughter radioisotopes from the chamber.

59. 1. A system for generating and capturing a population of daughter radioisotopes, comprising: a) a radioisotope generator defining a chamber for generating and capturing a population of daughter radioisotopes; b) a layered radioisotope source according to any one of claims 1 to 31 housed within said chamber; and A system comprising:

60. 60. A system as claimed in claim 59, comprising a radioisotope generator as claimed in any one of claims 51 to 57.

61. 1. A process for generating and capturing a population of daughter radioisotopes, comprising: a) enabling the release of gaseous intermediate radioisotopes generated through a chain of spontaneous decay from parent radioisotopes immobilized on or within the layered radioisotope source according to any one of claims 1 to 31; b) collecting at least some of the gaseous intermediate radioisotope for a period of time effective for it to decay into daughter radioisotopes; The process includes:

62. 62. A process according to claim 61, comprising a radioisotope generator according to any one of claims 51 to 57, or a system according to claim 59 or claim 60.

63. 63. The process of claim 61 or claim 62, wherein the process further comprises recovering at least some of the daughter radioisotopes.

64. 64. The process of claim 63, wherein the recovered daughter radioisotope is conjugated to a targeting molecule for use in radioligand therapy.

65. 65. The process of claim 64, wherein the targeting molecule is a cancer cell targeting molecule.

66. 66. The process of any one of claims 61 to 65, wherein the parent radioisotope is an alpha-emitting radioisotope.

67. The parent radioisotope is thorium-227 ( ２２７ Th) and thorium-228 ( ２２８ 67. The process of any one of claims 61 to 66, wherein the thorium radioisotope is selected from at least one of:

68. The gaseous intermediate radioactive isotope is radon 219 ( ２１９ Rn) and radon-220 ( ２２０ 68. The process of any one of claims 61 to 67, wherein the radon radioisotope is selected from at least one of the following:

69. The daughter radioisotope is lead-211 ( ２１１ Pb) or lead 212 ( ２１２ 69. The process of any one of claims 61 to 68, wherein the lead radioisotope is selected from at least one of:

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