ULTRA EFFICIENT ACCELERATOR PRODUCTION

OF ISOTOPICALLY PURE ACTINIUM 225

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119 to U.S. Provisional Patent Application No. 63/062,941, filed August 7, 2020, the entireties of which are incorporated by reference herein.

TECHNICAL FIELD

The invention is generally in the field related to the efficient production of ²²⁹ Th, and the subsequent production of isotopically-pure ²²⁵ Ac and/or ²¹³ Bi without long-lived contaminants, the use of isotopically-pure ²²⁵ Ac and/or ²¹³ Bi in the preparation of radiopharmaceutical agents for treating cancer, and methods of treating cancer using these agents, as well as efficient multiple neutron capture processes useful for producing other radioisotopes.

BACKGROUND

In nuclear medicine, radioactive substances are used in diagnostic and therapeutic medical procedures. Elemental radionuclides are often combined with other elements to form chemical compounds, or combined with existing pharmaceutical compounds to form radiopharmaceuticals. These radiopharmaceuticals, once administered to a patient, can localize to specific organs or cellular receptors. This property of radiopharmaceuticals allows for efficient and effective cancer treatments.

Alpha radiation therapy is essential in radiotherapy for cancer patients. The radioisotopes of actinium and bismuth ( ²²⁵ Ac and ²¹³ Bi, respectively) are particularly effective alpha radiation emitters. These isotopes can be used for radiolabeled isotopes in clinical trials.

²²⁵ Ac has a 10-day half-life. The full decay chain of ²²⁵ Ac down to ²⁰⁹ Bi leads collectively to the emission of four alpha particles with emission energies in the range of 5-8 MeV. Studies in vitro and in animal models have shown that this radionuclide is significantly more effective per unit radioactivity than ²¹³ Bi, a first-generation alpha-emitter that is currently under clinical investigation.

²²⁵ Ac has a longer half-life than ²¹³ Bi, has a larger number of decays, and allows prolonged irradiation of targeted cells. Furthermore, ²²⁵ Ac decay leads to the release of three alpha-particle- emitting daughters. Including the parent ²²⁵ Ac, a total of 4 alpha particles are emitted per ²²⁵ Ac decay to a stable nuclide.

Global supplies of ²²⁵ Ac are insufficient to fulfill the clinical demands for therapy (Engle, Curr Radiopharm., 2018; 11(3): 173-179), where demands are projected to increase with a growing demand for radiopharmaceuticals in research and medicine. The isotopes are typically prepared using a combination of public and private funding, involving government agencies which handle the finite supply of decaying nuclear fuel and private chemical processing plants which isolate the elements.

The most common current method of producing ²²⁵ Ac involves initially converting ²³² Th to ²³³ U using neutron capture followed by radioactive decays, a process known as nuclear fuel breeding. In this process, ²³² Th captures a neutron, producing ²³³ Th, which subsequently undergoes radioactive beta decay to ²³³ Pa, and finally undergoes further radioactive beta decay to become ²³³ U. ²³³ U decays via alpha emission to form ²²⁹ Th, a radioactive isotope of thorium that further decays by alpha emission with a half-life of 7917 years [Varga, et al., (2014). "Determination of the 229Th half-life". Physical Review C. 89 (6): 064310. doi: 10.1103/PhysRevC.89.064310], Once ²³³ U is formed, the subsequent transformation to ²²⁹ Th does not involve any actual human intervention. The ²³³ U decays by emitting an alpha particle, forming ²²⁹ Th.

The principal use of ²²⁹ Th is for producing the medical isotopes actinium-225 and bismuth- 213 [Report to Congress on the extraction of medical isotopes from U-233 Archived 2011-09-27 at the Wayback Machine. U.S. Department of Energy. March 2001],

The transformation of ²²⁹ Th to ²²⁵ Ac involves two natural radioactive decay steps, via the initial emission of an alpha particle (which results in a ²²⁵ Ra intermediate) and subsequent emission of a beta particle. The resulting ²²⁵ Ac material can be dissolved in nitric acid to form a ²²⁵ Ac nitrate salt, and ion exchange chromatography can be used to separate out radium and uranium impurities. There are several limitations associated with this process. ²³³ U is a fissile isotope which can therefore be made into reactor fuel or bomb material, and as such the regulatory and security costs associated with manufacturing and manipulating it are large, increasing production costs and decreasing national safety. Also, the half-life of ²³³ U is sufficiently high (approximately 160,000 years) that when combined with ²²⁹ Th's already high half-life, the full process constitutes a slow, inefficient, and costly method of producing ²²⁵ Ac. While some stockpiles of ²³³ U are sufficiently aged that the ²²⁹ Th has “grown in” sufficient to harvest, the cost, safety and radiological challenges associated with this method are quite high as well, and it has proved unpopular in practice over the last several decades.

As a result, the placeholder production technology has not proved itself sustainable enough to provide a complete solution.

Several alternative potential methods of producing ²²⁵ Ac include those described below, including direct methods of ²²⁵ Ac production, which bypass the intermediate ²²⁹ Th “generator,” and indirect methods, which produce the ²²⁹ Th generator which supplies a stable and continuous supply of ²²⁵ Ac.

Direct methods of production include the following nuclear reactions: ²²⁶ Ra(y,n) ²²⁵ Ac, 2 ²⁶ Ra(p,2n) ²²⁵ Ac, ²²⁶ Ra(p,pn) ²²⁵ Ra which decays to ²²⁵ Ac, ²²⁶ Ra(n,2n) ²²⁵ Ra which decays to 2 ²⁵ Ac, and ²³² Th(p,x) ²²⁵ Ac. In order, these five nuclear reactions would be accomplished via electron accelerator, proton accelerator, proton accelerator, nuclear reactor, and high energy proton accelerator (spallation).

Indirect production methods include the following nuclear reactions: ²³⁰ Th(y,n) ²²⁹ Th, 2 ³⁰ Th(n,2n) ²²⁹ Th, ²³⁰ Th(p,pn) ²²⁹ Th, ²²⁶ Ra(a,n) ²²⁹ Th, ²³² Th(p,x) ²²⁹ Th, and ²²⁶ Ra(3n, y) ²²⁹ Th. In order, these six nuclear reactions would be accomplished via electron accelerator, nuclear reactor, proton accelerator, alpha particle accelerator, high energy proton accelerator (spallation), and nuclear reactor.

Each of these production methods currently suffers from some combination of economic, regulatory, safety, political, or scalability problems, which currently renders market adoption and scaleup infeasible. Electron, alpha and non-high energy proton accelerator schemes have low target yields and high target heat loads, often combined with the safety challenges associated with elevated temperature radioactive (alpha-emitting in this case) beam targets. (n,2n) reactions in nuclear reactors are challenging to implement practically, because of insufficiently high (n,2n) neutron fluxes, even in high power research reactors. The high energy proton spallation production method tends to produce an abundance of unwanted ²²⁷ Ac contaminant along with the desired ²²⁵ Ac product, rendering the output undesirable from a medical perspective due to the long-lived ²²⁷ Ac. For example, in addition to its decades-long half-life, ²²⁷ Ac and its daughter contaminants tend to seek out the human skeleton, causing them to stick around for a long time, potentially causing unwanted doses of radiation, and potential additional tumors. Such ‘dirty’ actinium is of reduced value to the medical community.

The reactor method, whereby three neutrons are successively captured on starting ²²⁶ Ra to ultimately produce ²²⁹ Th is also of limited practicality, because the number of nuclear reactors that have sufficient neutron flux to transmute costly ²²⁶ Ra efficiently and economically is small. The small number of reactors with sufficiently large output powers and with sufficiently high thermal neutron fluxes within their “flux traps” - in this case “research” reactors owned by universities or DoE-affiliated national laboratories - are still at an economic disadvantage because the required irradiation times to produce useful amounts of ²²⁹ Th (many years), the required irradiation target mass (many kgs of ²²⁶ Ra) and the required parasitic neutron current necessary for efficient transmutation collectively rule out other parallel reactor research uses. A reactor making ²²⁹ Th in this way would have to be primarily or entirely devoted to producing commercial isotopes for years on end.

It would be advantageous to provide a practical process for producing ²²⁹ Th, which minimizes harmful isotopic impurities (in this context, ²²⁸ Th is not considered a harmful isotopic impurity), and which overcomes the limitations of the ²²⁵ Ac production methods discussed above. The present invention provides such production methods, as well as treatment methods using the relatively isotopically-pure ²²⁵ Ac.

SUMMARY

Processes, systems, and apparatuses for producing ²²⁹ Th, for producing ²²⁵ Ac, for producing ²¹³ Bi, and for producing targeted radiologic treatments for cancer, are disclosed. Methods for treating and diagnosing cancer are also disclosed.

Processes, systems, and apparatuses for producing generic isotopes via both single and multiple neutron capture are also disclosed. Techniques for isotope production are disclosed that involve cryogenic methods. Techniques that increase or decrease the magnitude of neutron flux are also disclosed. Techniques that facilitate single neutron capture on reactant nuclei and other techniques that facilitate multiple neutron captures by the same reactant nuclei are disclosed. Techniques that select or alter the composition of the reactant and/or moderating nuclei, or a collection of nuclides, so as to select, create, or cause reactant nuclei that have experienced multiple neutron captures are also described in the following paragraphs. Techniques for producing reaction-product nuclei that experience subsequent neutron capture are described.

In some embodiments, these techniques describe the production of ²²⁹ Th and/or ²²⁵ Ac. Other techniques for producing ²³³ U or ²²⁹ Th or ²²⁵ Ac, as well as other generic neutron capture reaction-product nuclei, whether using a single neutron capture or multiple, are also disclosed.

In one embodiment of a process for producing ²²⁹ Th, the process involves introducing ²²⁶ Ra and a plurality of moderating nuclei into an apparatus comprising a neutron source. The apparatus is cooled in the region where the ²²⁶ Ra and/or a plurality of moderating nuclei are located to a temperature at or below about 250 degrees K, and the neutron source is in proximity to the ²²⁶ Ra sufficient to produce ²²⁷ Ra by neutron capture. The neutrons produced by the neutron source are reacted with the ²²⁶ Ra to form ²²⁷ Ra via neutron capture. The ²²⁷ Ra undergoes subsequent radioactive decay to ²²⁷ Ac, and neutrons produced by the neutron source are reacted with the ²²⁷ Ac to form ²²⁸ Ac via neutron capture. The ²²⁸ Ac undergoes subsequent radioactive decay to ²²⁸ Th, and neutrons produced by the neutron source are reacted with the ²²⁸ Th to form ²²⁹ Th via neutron capture.

In one aspect of this embodiment, the moderating nuclei comprise nuclides selected from the group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen- 15, oxygen, fluorine, neon-20, and neon-22.

In one aspect of this embodiment, the apparatus is cooled in the region where the ²²⁶ Ra and/or a plurality of moderating nuclei are located to a temperature at or below 75 degrees K, below about 50 degrees K, below about 30 degrees K, or below about 3 degrees K.

In some embodiments, it can be useful to subject the target to a relatively high flux of neutrons, particularly because at least some of the initial target’s reactant nuclei undergo a “triple hop,” that is, a given reactant nucleus reacts with a first neutron, then reacts with a second neutron, then reacts with a third neutron. Radioactive decay between, after, or before each neutron capture reaction also may be present. Using a relatively higher flux allows for higher rates of neutron capture and/or more neutron capture than can feasibly be achieved using a relatively lower flux. In one aspect, the total neutron flux is greater than approximately IxlO ¹² neutrons/cm ² /s.

In some embodiments, at least a portion of the ²²⁵ Ac formed as the ²²⁹ Th undergoes radioactive decay is periodically isolated, for example, by dissolving the ²²⁵ Ac in nitric acid to form a ²²⁵ Ac nitrate salt, and isolating the salt by ion exchange chromatography.

In some embodiments, the product prepared by this process has lower concentrations of unwanted isotopes than those products produced by other processes. For example, in some embodiments, the ²²⁵ Ac is substantially free, defined herein as less than 1% by weight, of ²²⁷ Ac.

Because the ²²⁵ Ac produced by this process is substantially free of unwanted isotopes, such as ²²⁷ Ac, it can be used in pharmaceutical compositions for use in treating and/or diagnosing cancer. Accordingly, in one embodiment, a composition comprising the ²²⁵ Ac is formed, which includes: a) an ²²⁵ Ac salt substantially free, defined herein as less than 1% by weight of ²²⁷ Ac and b) a pharmaceutically-acceptable carrier or excipient.

In this embodiment, all or a portion of the ²²⁵ Ac salt is chelated with a molecule that comprises a chelating moiety covalently linked, either directly or via a linker, to a targeting moiety. The targeting moieties can be, for example, an antibody, an antibody fragment, or a small molecule. In one aspect of this embodiment, targeting moieties are selected that bind to receptors which are over-expressed by specific types of cancer. In this aspect, the ²²⁵ Ac salt can be selectively targeted to specific cancer types. In another aspect of this embodiment, the chelating moiety is DOTA or DOTA-TATE.

In another embodiment, the ²²⁵ Ac salt, whether or not it is chelated as described above, is encapsulated in a small unilamellar vesicle, or other suitable drug delivery vehicle, with a diameter less than about 50 nm. Encapsulation in a drug delivery vehicle of this size allows the ²²⁵ Ac salt to be delivered via an artery or vein, and get lodged in capillary beds, such as the capillary beds which surround tumors. Thus, this type of encapsulation, followed by intravenous delivery, allows for localized delivery of the ²²⁵ Ac salt to the vicinity of tumors.

In some embodiments, the composition further comprises a second anti-cancer agent. The ²²⁵ Ac salt, or the composition including the ²²⁵ Ac salt, can be used in methods for treating cancer in a patient in need of treatment thereof. The methods involve administering a composition comprising an ²²⁵ Ac salt produced using the methods described herein, which can be substantially free, defined herein as less than 1% by weight of ²²⁷ Ac, to a patient in need of treatment thereof. As with the compositions, in some embodiments of the methods, the ²²⁵ Ac salt is chelated with a molecule that comprises a chelating moiety covalently linked, either directly or via a linker, to a targeting moiety, and in other embodiments, the ²²⁵ Ac salt is encapsulated in a small unilamellar vesicle or other drug delivery vehicle, with a diameter less than 50 nm.

In some embodiments of the processes described herein, at least a portion of the ²²⁵ Ac is allowed to decay and form a composition comprising ²¹³ Bi, and ²¹³ Bi ions can be isolated from the composition. As with the ²²⁵ Ac salt, the ²¹³ Bi ions can be combined with a pharmaceutically-acceptable carrier or excipient to form a pharmaceutical composition. In some embodiments, the ²¹³ Bi salt is chelated with a molecule that comprises a chelating moiety covalently linked, either directly or via a linker, to a targeting moiety, and/or encapsulated in a small unilamellar vesicle, or other drug delivery vehicle, with a diameter less than 50 nm.

As with the ²²⁵ Ac salts, the ²¹³ Bi ions can also be used in methods of treating cancer. In some embodiments of these methods, the ²¹³ Bi ions are chelated with a molecule that comprises a chelating moiety covalently linked, either directly or via a linker, to a targeting moiety and/or encapsulated in a small unilamellar vesicle, or other drug delivery vehicle, with a diameter less than 50 nm.

In still other embodiments, an apparatus for producing ²²⁹ Th, ²²⁵ Ac, or ²¹³ Bi from ²²⁶ Ra is disclosed. The apparatus includes a plurality of ²²⁶ Ra atoms and a plurality of moderating nuclei. In one embodiment, the total mass of ²²⁶ Ra is greater than approximately 10 mg. In another embodiment, the moderating nuclei comprise nuclides selected from the group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen- 15, oxygen, fluorine, neon-20, and neon-22. The apparatus further includes a neutron source in proximity to the ²²⁶ Ra sufficient to produce ²²⁷ Ra by neutron capture.

The apparatus also comprises a means for providing temperature control to at least one region of the apparatus where the ²²⁶ Ra or moderating nuclei are located, such that at least one region of ²²⁶ Ra or moderating nuclei can be cooled to a temperature below 250 about degrees Kelvin. The means for providing temperature control comprises a coolant capable of cooling the at least one region to a temperature below about 250 degrees Kelvin, below about 75 degrees Kelvin, below about 50 degrees Kelvin, below about 30 degrees Kelvin, or below about 3 degrees Kelvin. The temperature control can be provided by a cryogenic fluid, such as liquid helium, liquid hydrogen, liquid oxygen, liquid neon, or liquid nitrogen.

The pluralities can be arranged in one or more approximately parallel layers, and wherein at least one layer is distinct from another layer on the basis of elemental composition, concentration of chemical species, density, or temperature.

The apparatus can further include a first target configured to emit neutrons when impacted by accelerated particles, as well as a second target that captures the emitted neutrons. The first target can include one or more nuclides selected from the group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen- 15, oxygen, fluorine, neon- 20, neon-22, tantalum, tungsten, lead, mercury, thallium, thorium, uranium, neptunium, and other transuranics. In one embodiment, the accelerated particles can enter the system via an access channel configured to accept greater than 50 percent of the accelerated particles that impinge upon the access channel. In one embodiment, the total neutron flux is greater than IxlO ¹² neutrons/cm ² /s.

In another embodiment, a process for producing reaction-product and decay-product nuclei from a reactant isotope using a neutron source is disclosed. The process involves generating neutrons, preparing reactant nuclei, and preparing a collection of nuclides consisting of those nuclides whose nuclei capture at least 0.2% of all generated neutrons and which are not reactant nuclei, wherein at least one of the nuclides from the collection of nuclides has a microscopic thermal neutron capture cross-section that is lower than the microscopic thermal neutron capture cross-section of any reactant nuclei. The reactant nuclei and the collection of nuclides are then combined, and at least one region of the reactant nuclei or the collection is cooled to a temperature below about 250 degrees Kelvin. The collection of nuclides is irradiated with the neutrons such that a reaction product is generated when the neutrons are captured by the reactant nuclei, and the reaction-product nuclei comprise reaction-product nuclei that result from two or more neutron captures by the same reactant nucleus. A reaction product or a decay product that is generated by radioactive decay of the reaction-product nuclei is then extracted from the reactant nuclei. The reactant nuclei can comprise radium-226 and/or the reaction-product nuclei can comprise actinium-227, thorium- 228 or thorium-229. The apparatus can further comprise actinium-225 decay-product nuclei. The collection of nuclides can comprise nuclides selected from the group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen- 15, oxygen, fluorine, neon-20, neon-22, and lead-208.

In some embodiments, the at least one region of the reactant nuclei or the collection is cooled to a temperature below about 75 degrees Kelvin, below about 50 degrees Kelvin, or below about 30 degrees Kelvin.

Products prepared by these processes are also disclosed. For example, ²²⁵ Ac prepared according to the processes described herein, including ²²⁵ Ac comprising less than 1% ²²⁷ Ac, are disclosed.

BRIEF DESCRIPTION OF THE DRAWINGS

The previous summary and the following detailed descriptions are to be read in view of the drawings, which illustrate particular exemplary embodiments and features as briefly described below. The summary and detailed descriptions, however, are not limited to only those embodiments and features explicitly illustrated.

FIG. 1 is a cross-sectional view of an apparatus for producing reaction-product nuclei from reactant nuclei according to at least one embodiment.

FIG. 2 is a cross-sectional view of a system for the production of desired nuclear species according to still another embodiment.

FIG. 3 illustrates a particle accelerator directing a high-energy beam of particles into the system of FIG. 2 according to at least one embodiment.

FIG. 4 illustrates a thermal control system in use with a layered shell vessel.

FIG. 5 is a cross-sectional view of a system for the production of desired nuclear species according to one embodiment described herein. FIG. 6 is a cross-sectional view of a system for the production of desired nuclear species according to another embodiment described herein.

DETAILED DESCRIPTION

Processes systems, and apparatuses for producing ²²⁹ Th, for producing ²²⁵ Ac, for producing ²¹³ Bi, and for producing targeted radiologic treatments for cancer, are disclosed. Methods for treating and diagnosing cancer are also disclosed.

Processes, systems, and apparatuses for producing generic isotopes via both single and multiple neutron capture are also disclosed. Techniques for isotope production are disclosed that involve cryogenic methods. Techniques that increase or decrease the magnitude of neutron flux are also disclosed. Techniques that facilitate single neutron capture on reactant nuclei and other techniques that facilitate multiple neutron captures by the same reactant nuclei are disclosed. Techniques that select or alter the composition of the reactant and/or moderating nuclei, or a collection of nuclides, so as to select, create, or cause reactant nuclei that have experienced multiple neutron captures are also described in the following paragraphs. Techniques for producing reaction-product nuclei that experience subsequent neutron capture are described.

Various embodiments are described herein, including selections of neutron flux, reactant nuclei, reaction-product nuclei, temperatures to which regions of the apparatus are cooled, fast neutron flux magnitude, and the like. All possible combinations of the individual embodiments are contemplated herein.

I. Apparatuses and Processes for Performing High-Efficiency Multiple Neutron Capture, for Producing Both ²²⁹ Th and Other Isotopes of Interest

According to at least one embodiment, an apparatus for producing reaction-product nuclei from reactant nuclei includes a plurality of reactant nuclei and a plurality of moderating nuclei. The moderating nuclei comprise nuclides that are selected from a group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen- 15, oxygen, fluorine, neon-20, and neon-22. A neutron source is in proximity to the reactant nuclei sufficient to produce reactionproduct nuclei by neutron capture. The reactant nuclei comprise Radium-226. Temperature control capable of maintaining at least one region of reactant or moderating nuclei at a temperature below 250 degrees Kelvin is used. In one embodiment, the total neutron flux experienced by any of the reactant nuclei is greater than approximately IxlO ¹² neutrons/cm ² /s.

The neutron source referenced can be a sealed source, an accelerator (e.g. DT production, spallation production, etc.), a subcritical assembly of fissile material, a nuclear reactor, or any other process capable of producing neutrons.

Cooling at least one region of the reactant nuclei and/or the moderating nuclei to a temperature below 250 degrees Kelvin allows for the possibility that a portion of the reactant nuclei only is cooled below 250 degrees Kelvin, or that a portion of the moderating nuclei only is cooled. Both a portion of the moderating nuclei and reactant nuclei can be cooled. All of either or both can be cooled.

In some embodiments, cooling at least one region of the reactant nuclei and/or the moderating nuclei to less than approximately 75 degrees Kelvin, less than approximately 50 degrees Kelvin, less than approximately 30 degrees Kelvin, or less than approximately 3 degrees Kelvin is performed.

In at least one embodiment, the total mass of radium-226 is greater than approximately 10 milligrams.

In at least one embodiment, at least 0.1% of the reaction-product nuclei result from two or more neutron captures by the same reactant nucleus.

In at least one embodiment, the reaction-product nuclei comprise actinium-227, thorium- 228, or thorium-229.

In at least one embodiment, the reaction-product nuclei comprise actinium-227, thorium- 228, or thorium-229, and the apparatus further comprises actinium-225 decay-product nuclei.

For the purpose of interpreting, “at least 0.1% of reaction-product nuclei present result from two or more neutron captures by the same reactant nucleus” means that at least 0.1% of all reaction-product nuclei present have undergone more than one neutron capture within the apparatus, regardless of whether radioactive decay has occurred between or after neutron captures. These reaction-product nuclei result when a reactant nucleus captures a neutron, becoming a reaction-product nucleus, and then further captures one or more neutrons. As an example, if the reactant nuclei comprise radium-226, actinium-227, and thorium-228,, and if the combined population of produced thorium-228 and thorium-229 nuclei sum to 0.12% of the combined population of actinium-227, thorium-228, and thorium-229 nuclei, then this would be an example of an apparatus where “at least 0.1% of reaction-product nuclei present result from two or more neutron captures by the same reactant nucleus.”

In at least one embodiment, at least 1 mg of the reaction-product nuclei present result from multiple neutron captures by the same reactant nucleus.

In at least one embodiment, the temperature control may include the use of a cryogenic fluid.

In at least one embodiment, the cryogenic fluid is selected from the group consisting of liquid helium, liquid hydrogen, liquid oxygen, liquid neon, and liquid nitrogen.

In at least one example, the pluralities are arranged in one or more approximately parallel layers, at least one layer being distinct from another layer on the basis of elemental composition, concentration of chemical species, density, or temperature.

In at least one example, a target is configured to emit neutrons when impacted by accelerated particles. The target includes nuclides selected from a group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen- 15, oxygen, fluorine, neon- 20, neon-22, tantalum, tungsten, lead, mercury, thallium, thorium, uranium, neptunium, and other transuranics. The accelerated particles enter the system via an access channel configured to accept greater than 50 percent of the accelerated particles that impinge upon the access channel. The access channel here is any effective path for the particle of interest to enter the apparatus and impinge upon a target.

According to at least one embodiment, an apparatus for producing reaction-product nuclei from reactant nuclei includes a neutron source in proximity to the reactant nuclei sufficient to produce reaction-product nuclei by neutron capture. It also includes reactant nuclei. Also included is a collection of nuclides consisting of those nuclides whose nuclei capture at least 0.2% of all emitted neutrons from the neutron source and which are not reactant nuclei, wherein at least one of the nuclides from the collection of nuclides has a microscopic thermal neutron capture cross-section that is lower than the microscopic thermal neutron capture cross-section of any reactant nuclei. At least one region of the reactant nuclei or the collection is cooled to a temperature below 250 degrees Kelvin. The total neutron flux experienced by any of the reactant nuclei is greater than approximately IxlO ¹² neutrons/cm ² /s.

In some embodiments, at least 0.1% of reaction-product nuclei present result from two or more neutron captures by the same reactant nucleus.

The neutron source can be a sealed source, an accelerator (e.g. DT production, spallation production, etc.), a subcritical assembly of fissile material, a nuclear reactor, or any other process capable of producing neutrons.

For the purpose of interpreting, the “collection of nuclides consisting of those nuclides whose apparatus nuclei capture at least 0.2% of all emitted neutrons from the neutron source. . .” should be understood to imply “for the neutron source configuration being utilized.” There may be many ways to configure a neutron source so as to alter the isotopes within the collection of nuclides, but the particular configuration being used to produce reaction-product nuclei is the configuration to which the claims apply.

As used herein, the “collection of nuclides consisting of those nuclides whose apparatus nuclei capture at least 0.2% of all emitted neutrons from the neutron source...” can be understood via the following example: if an apparatus included one type of reactant nuclide - calcium-46; and four types of non-reactant nuclides - oxygen-16, carbon-12, manganese-55, and cobalt-59; and they respectively capture 0.1%, 5%, 10%, and 20% of the total emitted neutrons, then the collection of nuclides would consist of carbon-12, manganese-55, and cobalt- 59, but not oxygen-16, as 0.1% is lower than 0.2%. In this specific example, the carbon-12 would meet the criterion of having a lower microscopic thermal cross-section than the microscopic thermal neutron capture cross-section of any reactant nuclei, because all calcium- 46 nuclei have thermal neutron capture cross-sections higher than those of carbon- 12 nuclei but lower than those of both manganese-55 and cobalt-59 nuclei. In an example where the four named non-reactant nuclei above were retained, but where the reactant nuclei comprised radium- 226 and actinium-227 instead of calcium-46, all three of carbon-12, manganese-55, and cobalt- 59 would meet the criterion of having a lower microscopic thermal cross-section than the microscopic thermal neutron capture cross-section of any reactant nuclei, because all carbon- 12, manganese-55 and cobalt-59 nuclei have lower thermal neutron capture cross-sections than those of actinium-227 nuclei. In these examples, “thermal” is meant to be interpreted in the typical sense that nuclear engineering nuclide charts present it, which is at approximately 300 degrees Kelvin if using temperature, or approximately 0.026 eV if using energy. A representative nuclide chart would be “Nuclides and Isotopes,” 16 ^th ed., published in 2002 by Lockheed Martin.

Cooling at least one region of the reactant nuclei and/or the collection to a temperature below 250 degrees Kelvin allows for the possibility that a portion of the reactant nuclei only is cooled below 250 degrees Kelvin, or that a portion of the collection only is cooled. Both a portion of the collection and reactant nuclei could be cooled. All of either or both could be cooled. The nuclei cooled may comprise moderating nuclei, understood in the art to mean nuclei with effective neutron moderating properties, such as carbon, oxygen, deuterium, beryllium, and others.

In some embodiments, cooling at least one region of the reactant nuclei and/or the collection to less than approximately 75 degrees Kelvin, less than approximately 50 degrees Kelvin, less than approximately 30 degrees Kelvin, or less than approximately 3 degrees Kelvin is performed.

In some embodiments, at least 0.1% of the reaction-product nuclei result from two or more neutron captures by the same reactant nucleus.

In some embodiments, at least 1 mg of the reaction-product nuclei present result from multiple neutron captures by the same reactant nucleus.

For the purpose of interpreting, “at least 0.1% of reaction-product nuclei present result from two or more neutron captures by the same reactant nucleus” can be understood to mean that at least 0.1% of all reaction-product nuclei present have undergone more than one neutron capture within the apparatus, regardless of whether radioactive decay has occurred between or after neutron captures. These reaction-product nuclei result when a reactant nucleus captures a neutron, becoming a reaction-product nucleus, and then further captures one or more neutrons. As an example, if the reactant nuclei comprise radium-226, actinium-227, and thorium-228, and if the combined population of produced thorium-228 and thorium-229 nuclei sum to 0.12% of the combined population of actinium-227, thorium-228, and thorium-229 nuclei, then this would be an example of an apparatus where “at least 0.1% of reaction-product nuclei present result from two or more neutron captures by the same reactant nucleus.”

In at least one example, the reactant nuclei comprise radium-226.

In at least one example, the reactant nuclei comprise radium-226, and the reaction-product nuclei comprise actinium-227, thorium-228, or thorium-229 nuclei. In at least one example, the reactant nuclei comprise radium-226, the reaction-product nuclei comprise actinium-227, thorium-228, or thorium-229, and the decay-product nuclei comprises actinium-225.

In at least one example, the collection of nuclei comprises nuclides that are selected from a group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen-15, oxygen, fluorine, neon-20, neon-22, and lead-208.

In at least one example, the temperature control comprises the use of a cryogenic fluid.

In some embodiments, the cryogenic fluid is selected from the group consisting of liquid helium, liquid hydrogen, liquid oxygen, liquid neon, and liquid nitrogen.

In at least one example, a target is configured to emit neutrons when impacted by accelerated particles, and the target includes nuclides selected from a group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen- 15, oxygen, fluorine, neon- 20, neon-22, tantalum, tungsten, lead, mercury, thallium, thorium, uranium, neptunium, and other transuranics. The accelerated particles enter the system via an access channel configured to accept greater than 50 percent of the accelerated particles that impinge upon the access channel. As used herein, an “access channel” is any effective path for the particle of interest to impinge upon a target with minimal loss of energy.

According to at least one embodiment, a method for producing reaction-product and decay-product nuclei from a reactant isotope involves generating neutrons, preparing a plurality of reactant nuclei and a plurality of moderating nuclei wherein the moderating nuclei comprise nuclides that are selected from a group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron- 11, carbon, nitrogen- 15, oxygen, fluorine, neon-20 and neon-22. The reactant nuclei comprise radium-226. Reaction-product nuclei include at least some of radium-227, actinium-227, actinium-228, thorium-228, and thorium-229. It also includes cooling at least one region of the reactant nuclei and/or the moderating nuclei to a temperature below 250 degrees Kelvin. The pluralities are irradiated with neutrons such that a reaction product is generated when the neutrons are captured by the reactant nuclei. A reaction product or decay product that is generated by radioactive decay of the reaction-product nuclei is extracted from the plurality of reactant nuclei.

In some embodiments, at least 0.1% of the reaction-product nuclei result from two or more neutron captures by the same reactant nucleus. The referenced neutron generation could occur using a sealed source, an accelerator (e.g. DT production, spallation production, etc.), a subcritical assembly of fissile material, a nuclear reactor, or any other process capable of generating neutrons.

Cooling at least one region of the reactant nuclei and/or the collection to a temperature below 250 degrees Kelvin allows for the possibility that a portion of the reactant nuclei only is cooled below 250 degrees Kelvin, or that a portion of the moderating nuclei only is cooled. Both a portion of the moderating nuclei and reactant nuclei could be cooled. All of either or both could be cooled.

In some embodiments, cooling at least one region of the reactant nuclei and/or the moderating nuclei to less than approximately 75 degrees Kelvin, less than approximately 50 degrees Kelvin, less than approximately 30 degrees Kelvin, or less than approximately 3 degrees Kelvin is performed.

In at least one embodiment, the cryogenic fluid is selected from the group consisting of liquid helium, liquid hydrogen, liquid oxygen, liquid neon, and liquid nitrogen. In at least one embodiment, the total mass of radium-226 is greater than approximately 10 milligrams.

In at least one embodiment, the reaction-product nuclei comprise actinium-227, thorium- 228, or thorium-229.

In at least one embodiment, the reaction-product nuclei comprise actinium-227, thorium- 228, or thorium-229, and the decay-product nuclei further comprise actinium-225.

In at least one embodiment, at least 1 mg of the reaction-product nuclei present result from multiple neutron captures by the same reactant nucleus.

For the purpose of interpreting, “at least 0.1% of reaction-product nuclei present result from two or more neutron captures by the same reactant nucleus” can be understood to mean that at least 0.1% of all reaction-product nuclei present have undergone more than one neutron capture due to the method of operation, regardless of whether radioactive decay has occurred between or after neutron captures. These reaction-product nuclei result when a reactant nucleus captures a neutron, becoming a reaction-product nucleus, and then further captures one or more neutrons. As an example, if the reactant nuclei comprise radium-226, actinium-227, and thorium-228, and if the combined population of produced thorium-228 and thorium-229 nuclei sum to 0.12% of the combined population of actinium-227, thorium-228, and thorium-229 nuclei, then this would be an example of a method where “at least 0.1% of reaction-product nuclei present result from two or more neutron captures by the same reactant nucleus.”

In at least one example, the total neutron flux experienced by any of the reactant nuclei is greater than approximately IxlO ¹² neutrons/cm ² /s.

In at least one example, the temperature control may include the use of a cryogenic fluid.

In at least one example, the pluralities are arranged in one or more approximately parallel layers, at least one layer being distinct from another layer on the basis of elemental composition, concentration of chemical species, density, or temperature.

In at least one example, a target is configured to emit neutrons when impacted by accelerated particles. The target includes nuclides selected from a group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen- 15, oxygen, fluorine, neon- 20, neon-22, tantalum, tungsten, lead, mercury, thallium, thorium, uranium, neptunium, and other transuranics. The accelerated particles enter the system via an access channel configured to accept greater than 50 percent of the accelerated particles that impinge upon the access channel. The access channel here is any effective path for the particle of interest to impinge upon a target with minimal loss of energy.

According to at least one embodiment, a method for producing reaction-product nuclei from reactant nuclei includes generating neutrons, and preparing reactant nuclei. It also includes preparing a collection of nuclides consisting of those nuclides whose nuclei capture at least 0.2% of all emitted neutrons from the neutron source and which are not reactant nuclei, wherein at least one of the nuclides from the collection of nuclides has a microscopic thermal neutron capture cross-section that is lower than the microscopic thermal neutron capture cross-section of any reactant nuclei. It also includes cooling at least one region of the reactant nuclei and/or the collection to a temperature below 250 degrees Kelvin. The total neutron flux experienced by any of the reactant nuclei is greater than approximately IxlO ¹² neutrons/cm ² /s. The pluralities are irradiated with neutrons such that a reaction product is generated when the neutrons are captured by the reactant nuclei, wherein the reaction-product nuclei comprise reaction-product nuclei that result from two or more neutron captures by the same reactant nucleus. A reaction product or decay product that is generated by radioactive decay of the reaction-product nuclei is extracted from the plurality of reactant nuclei.

In some embodiments, at least 0.1% of reaction-product nuclei present result from two or more neutron captures by the same reactant nucleus.

The referenced neutron generation could occur using a sealed source, an accelerator (e.g. DT production, spallation production, etc.), a subcritical assembly of fissile material, a nuclear reactor, or any other process capable of generating neutrons.

As used herein, the term “collection of nuclides consisting of those nuclides whose nuclei capture at least 0.2% of all generated neutrons. . . ” should be understood to imply “for the neutron generation configuration being utilized.” There may be many ways to configure neutron generation so as to alter the isotopes within the collection of nuclides, but the particular configuration being used to produce reaction-product nuclei is the configuration to which the claims apply. In the reactions described herein, neutrons are generated for the purpose of interacting with the reactant nuclei.

As used herein, the term “collection of nuclides consisting of those nuclides whose nuclei capture at least 0.2% of all emitted neutrons from the neutron source. ..” can be understood via the following example: if a collection included one type of reactant nuclide - calcium-46; and four types of non-reactant nuclides - oxygen-16, carbon-12, manganese-55, and cobalt-59; and they respectively capture 0.1%, 5%, 10%, and 20% of the total emitted neutrons, then the collection of nuclides would consist of carbon-12, manganese-55, and cobalt-59, but not oxygen-16, as 0.1% is lower than 0.2%. In this specific example, the carbon-12 would meet the criterion of having a lower microscopic thermal cross-section than the microscopic thermal neutron capture cross-section of any reactant nuclei, because all calcium-46 nuclei have thermal neutron capture cross-sections higher than those of carbon- 12 nuclei but lower than those of both manganese-55 and cobalt-59 nuclei. In an example where the four named non-reactant nuclei above were retained, but where the reactant nuclei comprised radium-226 and actinium- 227 instead of calcium-46, all three of carbon-12, manganese-55, and cobalt-59 would meet the criterion of having a lower microscopic thermal cross-section than the microscopic thermal neutron capture cross-section of any reactant nuclei, because all carbon- 12, manganese-55 and cobalt-59 nuclei have lower thermal neutron capture cross-sections than those of actinium-227 nuclei. In these examples, “thermal” is meant to be interpreted in the typical sense that nuclear engineering nuclide charts present it, which is at approximately 300 degrees Kelvin if using temperature, or approximately 0.026 eV if using energy. Cooling at least one region of the reactant nuclei and/or the collection to a temperature below 250 degrees Kelvin allows for the possibility that a portion of the reactant nuclei only is cooled below 250 degrees Kelvin, or that a portion of the collection only is cooled. Both a portion of the collection and reactant nuclei could be cooled. All of either or both could be cooled. The nuclei cooled may comprise moderating nuclei, understood in the art to mean nuclei with effective neutron moderating properties, such as carbon, oxygen, deuterium, beryllium, and others.

In at least one embodiment, the reactant nuclei comprise radium-226.

In at least one embodiment, the total mass of radium-226 is greater than approximately 10 milligrams.

In at least one embodiment, the reactant nuclei comprise radium-226, and the reactionproduct nuclei comprise actinium-227, thorium-228, or thorium-229 nuclei.

In at least one embodiment, the reactant nuclei comprise radium-226, the reaction-product nuclei comprise actinium-227, thorium-228, or thorium-229, and the decay-product nuclei comprises actinium-225.

In at least one embodiment, the collection of nuclei comprises nuclides that are selected from a group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron- 11, carbon, nitrogen-15, oxygen, fluorine, neon-20, neon-22, and lead-208.

In at least one embodiment, the temperature control comprises the use of a cryogenic fluid.

In at least one embodiment, the cryogenic fluid is selected from the group consisting of liquid helium, liquid hydrogen, liquid oxygen, liquid neon, and liquid nitrogen.

In some examples, cooling at least one region of the reactant nuclei and/or the collection to less than approximately 75 degrees Kelvin, less than approximately 50 degrees Kelvin, less than approximately 30 degrees Kelvin, or less than approximately 3 degrees Kelvin is performed.

In at least one example, a target is configured to emit neutrons when impacted by accelerated particles, and the target includes nuclides selected from a group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen- 15, oxygen, fluorine, neon- 20, neon-22, tantalum, tungsten, lead, mercury, thallium, thorium, uranium, neptunium, and other transuranics. The accelerated particles enter the system via an access channel configured to accept greater than 50 percent of the accelerated particles that impinge upon the access channel. The access channel here is any effective path for the particle of interest to impinge upon a target with minimal energy loss. In at least one example, the pluralities are arranged in one or more approximately parallel layers, at least one layer being distinct from another layer on the basis of elemental composition, concentration of chemical species, density, or temperature.

For the purpose of interpreting, “at least 0.1% of reaction-product nuclei present result from two or more neutron captures by the same reactant nucleus” can be understood to mean that at least 0.1% of all reaction-product nuclei present have undergone more than one neutron capture due to the method, regardless of whether radioactive decay has occurred between or after neutron captures. These reaction-product nuclei result when a reactant nucleus captures a neutron, becoming a reaction-product nucleus, and then further captures one or more neutrons. As an example, if the reactant nuclei comprise radium-226, actinium-227, and thorium-228, and if the combined population of produced thorium-228 and thorium-229 nuclei sum to 0.12% of the combined population of actinium-227, thorium-228, and thorium-229 nuclei, then this would be an example of a method where “at least 0.1% of reaction-product nuclei present result from two or more neutron captures by the same reactant nucleus.”

In at least one example, at least 1 mg of the reaction-product nuclei present result from multiple neutron captures by the same reactant nucleus.

Apparatuses and Processes for Performing High-Efficiency Neutron Capture with a Low Fast Neutron Flux, for producing both ²²⁹ Th and other isotopes of interest

According to at least one embodiment, an apparatus for producing reaction-product nuclei from reactant nuclei includes a plurality of reactant nuclei and a plurality of moderating nuclei. The moderating nuclei comprise nuclides that are selected from a group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen- 15, oxygen, fluorine, neon-20, and neon-22. A neutron source is in proximity to the reactant nuclei sufficient to produce reactionproduct nuclei by neutron capture. The reactant nuclei comprise thorium-232. Temperature control capable of maintaining at least one region of reactant or moderating nuclei at a temperature below 250 degrees Kelvin is used. The total flux of neutrons with energy greater than 6 MeV experienced by any of the reactant nuclei is lower than approximately IxlO ¹⁰ neutrons/cm ² /s. While not wishing to be bound to a particular theory, it is believed that higher energy neutrons are more likely to cause potentially unwanted side nuclear reactions (e.g. (n,2n), (n,3n), (n,p) etc.) that may introduce radiologically undesirable products.

The neutron source can be a sealed source, an accelerator (e.g. DT production, spallation production, etc.), a subcritical assembly of fissile material, a nuclear reactor, or any other process capable of producing neutrons.

Cooling at least one region of the reactant nuclei and/or the moderating nuclei to a temperature below 250 degrees Kelvin allows for the possibility that a portion of the reactant nuclei only is cooled below 250 degrees Kelvin, or that a portion of the moderating nuclei only is cooled. All or a portion of the moderating nuclei and reactant nuclei can be cooled.

In at least one example, the total mass of ²³² Th is greater than approximately 10 milligrams.

In at least one example, the reaction-product nuclei comprise ²³³ Th, ²³³ Pa, or ²³³ U.

In at least one example, the apparatus further comprises ²²⁹ Th or actinium-225 decay product.

In at least one example, the reactant nuclei comprise radium-228. In one aspect of this embodiment, ²³² Th is absent, or substantially absent, from the reactant nuclei in this particular example. Substantially absent is defined as comprising less than 1 mg of the reactant nuclei. In another aspect of the embodiment, both ²³² Th and ²²⁸ Ra are present.

In at least one example, the temperature control may include the use of a cryogenic fluid.

In at least one example, a target is configured to emit neutrons when impacted by accelerated particles. The target includes nuclides selected from a group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen- 15, oxygen, fluorine, neon- 20, neon-22, tantalum, tungsten, lead, mercury, thallium, thorium, uranium, neptunium, and other transuranics. The accelerated particles enter the system via an access channel configured to accept greater than 50 percent of the accelerated particles that impinge upon the access channel. The access channel here is any effective path for a particle of interest to enter the apparatus and impinge upon a target.

In at least one example, the pluralities are arranged in one or more approximately parallel layers, at least one layer being distinct from another layer on the basis of elemental composition, concentration of chemical species, density, or temperature. In at least one example, the cryogenic fluid is selected from the group consisting of liquid helium, liquid hydrogen, liquid oxygen, liquid neon, and liquid nitrogen.

In some examples, cooling at least one region of the reactant nuclei and/or the moderating nuclei to less than approximately 75 degrees Kelvin, less than approximately 50 degrees Kelvin, less than approximately 30 degrees Kelvin, or less than approximately 3 degrees Kelvin is performed.

According to at least one embodiment, an apparatus for producing reaction-product nuclei from reactant nuclei includes a neutron source in proximity to the reactant nuclei sufficient to produce reaction-product nuclei by neutron capture. It also includes reactant nuclei. Also included is a collection of nuclides consisting of those nuclides whose nuclei capture at least 0.2% of all emitted neutrons from the neutron source and which are not reactant nuclei, wherein at least one of the nuclides from the collection of nuclides has a microscopic thermal neutron capture cross-section that is lower than the microscopic thermal neutron capture cross-section of any reactant nuclei. For this embodiment, at least one region of the reactant nuclei or the collection is cooled to a temperature below 250 degrees Kelvin. For this embodiment, the total flux of neutrons with energy greater than 6 MeV experienced by any of the reactant nuclei is lower than approximately IxlO ¹⁰ neutrons/cm ² /s.

The neutron source referenced could be a sealed source, an accelerator (e.g. DT production, spallation production, etc.), a subcritical assembly of fissile material, a nuclear reactor, or any other process capable of producing neutrons.

For the purpose of interpreting, the “collection of nuclides consisting of those nuclides whose apparatus nuclei capture at least 0.2% of all emitted neutrons from the neutron source. . .” should be understood to imply “for the neutron source configuration being utilized.” There may be many ways to configure a neutron source so as to alter the isotopes within the collection of nuclides, but the particular configuration being used to produce reaction-product nuclei is the configuration to which the claims apply.

Also for the purposes of interpreting, the “collection of nuclides consisting of those nuclides whose apparatus nuclei capture at least 0.2% of all emitted neutrons from the neutron source...” can be understood via the following example: if an apparatus included one type of reactant nuclide - calcium-46; and four types of non-reactant nuclides - oxygen-16, carbon-12, manganese-55, and cobalt-59; and they respectively capture 0.1%, 5%, 10%, and 20% of the total emitted neutrons, then the collection of nuclides would consist of carbon- 12, manganese- 55, and cobalt-59, but not oxygen-16, as 0.1% is lower than 0.2%. In this specific example, the carbon- 12 would meet the criterion of having a lower microscopic thermal cross-section than the microscopic thermal neutron capture cross-section of any reactant nuclei, because all calcium-46 nuclei have thermal neutron capture cross-sections higher than those of carbon- 12 nuclei but lower than those of both manganese-55 and cobalt-59 nuclei. In an example where the four named non-reactant nuclei above were retained, but where the reactant nuclei comprised radium-226 and actinium-227 instead of calcium-46, all three of carbon-12, manganese-55, and cobalt-59 would meet the criterion of having a lower microscopic thermal cross-section than the microscopic thermal neutron capture cross-section of any reactant nuclei, because all carbon- 12, manganese-55 and cobalt-59 nuclei have lower thermal neutron capture cross-sections than those of actinium-227 nuclei. In these examples, “thermal” is meant to be interpreted in the typical sense that nuclear engineering nuclide charts present it, which is at approximately 300 degrees Kelvin if using temperature, or approximately 0.026 eV if using energy.

Cooling at least one region of the reactant nuclei and/or the collection to a temperature below 250 degrees Kelvin allows for the possibility that a portion of the reactant nuclei only is cooled below 250 degrees Kelvin, or that a portion of the collection only is cooled. Both a portion of the collection and reactant nuclei could be cooled. All of either or both could be cooled. The nuclei cooled may comprise moderating nuclei, understood in the art to mean nuclei with effective neutron moderating properties, such as carbon, oxygen, deuterium, beryllium, and others.

It is thought that higher energy neutrons are more likely to cause potentially unwanted side nuclear reactions (e.g. (n,2n), (n,3n), (n,p) etc.) that may introduce radiologically undesirable products.

In at least one example, the reactant nuclei comprise thorium-232.

In at least one example, the total mass of thorium-232 is greater than approximately 10 milligrams.

In at least one example, the reactant nuclei comprise thorium-232, and the reactionproduct nuclei comprise thorium-233, protactinium-233, or uranium-233 nuclei.

In at least one example, the reactant nuclei comprise thorium-232, and the reactionproduct nuclei comprise thorium-233, protactinium-233, or uranium-233 nuclei, and the decay- product nuclei comprise thorium-229 or actinium-225.

In at least one example, the collection of nuclei comprises nuclides that are selected from a group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen-15, oxygen, fluorine, neon-20, neon-22, and lead-208.

In at least one example, the temperature control comprises the use of a cryogenic fluid.

In at least one example, a target is configured to emit neutrons when impacted by accelerated particles, and the target includes nuclides selected from a group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen- 15, oxygen, fluorine, neon- 20, neon-22, tantalum, tungsten, lead, mercury, thallium, thorium, uranium, neptunium, and other transuranics. The accelerated particles enter the system via an access channel configured to accept greater than 50 percent of the accelerated particles that impinge upon the access channel. The access channel here is any effective path for the particle of interest to enter the apparatus and impinge upon a target.

In at least one example, the reactant nuclei comprise radium-228.

In some embodiments, the pluralities are arranged in one or more approximately parallel layers, at least one layer being distinct from another layer on the basis of elemental composition, concentration of chemical species, density, or temperature.

In some embodiments, the cryogenic fluid is selected from the group consisting of liquid helium, liquid hydrogen, liquid oxygen, liquid neon, and liquid nitrogen.

In some embodiments, cooling at least one region of the reactant nuclei and/or the collection to less than approximately 75 degrees Kelvin, less than approximately 50 degrees Kelvin, less than approximately 30 degrees Kelvin, or less than approximately 3 degrees Kelvin is performed.

According to at least one embodiment, a process for producing reaction-product and decay-product nuclei from a reactant isotope involves generating neutrons, combining a plurality of reactant nuclei and a plurality of moderating nuclei wherein the moderating nuclei comprise nuclides that are selected from a group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen- 15, oxygen, fluorine, neon-20 and neon-22. The reactant nuclei comprise thorium-232. It also includes cooling at least one region of the reactant nuclei and/or the moderating nuclei to a temperature below 250 degrees Kelvin. The pluralities are irradiated with neutrons such that a reaction product is generated when the neutrons are captured by the reactant nuclei, wherein the flux of neutrons with energy greater than 6 MeV experienced by any of the reactant nuclei is lower than approximately IxlO ¹⁰ neutrons/cm ² s/. A reaction product or decay product that is generated by radioactive decay of the reaction-product nuclei is extracted from the plurality of reactant nuclei.

The referenced neutron generation could occur using a sealed source, an accelerator (e.g. DT production, spallation production, etc.), a subcritical assembly of fissile material, a nuclear reactor, or any other process capable of generating neutrons.

Cooling at least one region of the reactant nuclei and/or the moderating nuclei to a temperature below 250 degrees Kelvin allows for the possibility that a portion of the reactant nuclei only is cooled below 250 degrees Kelvin, or that a portion of the moderating nuclei only is cooled. Both a portion of the moderating nuclei and reactant nuclei could be cooled. All of either or both could be cooled.

It is thought that higher energy neutrons are more likely to cause potentially unwanted side nuclear reactions (e.g. (n,2n), (n,3n), (n,p) etc.) that may introduce radiologically undesirable products.

In at least one example, the total mass of thorium-232 is greater than approximately 10 milligrams.

In at least one example, the reaction-product nuclei comprise thorium-233, protactinium- 233, or uranium-233.

In at least one example, the reaction-product nuclei comprise thorium-233, protactinium- 233, or uranium-233, and the decay-product nuclei further comprise thorium-229 or actinium-225.

In at least one example, the temperature control may include the use of a cryogenic fluid.

In at least one example, a target is configured to emit neutrons when impacted by accelerated particles. The target includes nuclides selected from a group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen- 15, oxygen, fluorine, neon- 20, neon-22, tantalum, tungsten, lead, mercury, thallium, thorium, uranium, neptunium, and other transuranics. The accelerated particles enter the system via an access channel configured to accept greater than 50 percent of the accelerated particles that impinge upon the access channel. The access channel here is any effective path for the particle of interest to impinge upon a target with minimal energy loss.

In at least one example, the pluralities are arranged in one or more approximately parallel layers, at least one layer being distinct from another layer on the basis of elemental composition, concentration of chemical species, density, or temperature.

In at least one example, the cryogenic fluid is selected from the group consisting of liquid helium, liquid hydrogen, liquid oxygen, liquid neon, and liquid nitrogen.

In some examples, cooling at least one region of the reactant nuclei and/or the moderating nuclei to less than approximately 75 degrees Kelvin, less than approximately 50 degrees Kelvin, less than approximately 30 degrees Kelvin, or less than approximately 3 degrees Kelvin is performed.

In at least one example, the reactant nuclei comprise radium-228.

According to at least one embodiment, a process for producing reaction-product nuclei from reactant nuclei includes generating neutrons, and preparing reactant nuclei. It also includes preparing a collection of nuclides consisting of those nuclides whose nuclei capture at least 0.2% of all emitted neutrons from the neutron source and which are not reactant nuclei, wherein at least one of the nuclides from the collection of nuclides has a microscopic thermal neutron capture cross-section that is lower than the microscopic thermal neutron capture cross-section of any reactant nuclei. It also involves combining the reactant nuclei and the collection of nuclides. It also includes cooling at least one region of the reactant nuclei and/or the collection to a temperature below 250 degrees Kelvin. The pluralities are irradiated with neutrons such that a reaction product is generated when the neutrons are captured by the reactant nuclei, wherein the flux of neutrons with energy greater than 6 MeV experienced by any of the reactant nuclei is lower than approximately IxlO ¹⁰ neutrons/cm ² s/. A reaction product or decay product that is generated by radioactive decay of the reaction-product nuclei is extracted from the plurality of reactant nuclei.

The referenced neutron generation could occur using a sealed source, an accelerator (e.g. DT production, spallation production, etc.), a subcritical assembly of fissile material, a nuclear reactor, or any other process capable of generating neutrons.

For the purpose of interpreting, the “collection of nuclides consisting of those nuclides whose nuclei capture at least 0.2% of all generated neutrons. ..” should be understood to imply “for the neutron generation configuration being utilized.” There may be many ways to configure neutron generation so as to alter the isotopes within the collection of nuclides, but the particular configuration being used to produce reaction-product nuclei is the configuration to which the claims apply. In this context, generated neutrons are assumed to be generated with the intent of interacting with the reactant nuclei.

Also, for the purposes of interpreting, the “collection of nuclides consisting of those nuclides whose nuclei capture at least 0.2% of all emitted neutrons from the neutron source. ..” can be understood via the following example: if a collection included one type of reactant nuclide - calcium-46; and four types of non-reactant nuclides - oxygen- 16, carbon- 12, manganese-55, and cobalt-59; and they respectively capture 0.1%, 5%, 10%, and 20% of the total emitted neutrons, then the collection of nuclides would consist of carbon- 12, manganese- 55, and cobalt-59, but not oxygen-16, as 0.1% is lower than 0.2%. In this specific example, the carbon- 12 would meet the criterion of having a lower microscopic thermal cross-section than the microscopic thermal neutron capture cross-section of any reactant nuclei, because all calcium-46 nuclei have thermal neutron capture cross-sections higher than those of carbon- 12 nuclei but lower than those of both manganese-55 and cobalt-59 nuclei. In an example where the four named non-reactant nuclei above were retained, but where the reactant nuclei comprised radium-226 and actinium-227 instead of calcium-46, all three of carbon-12, manganese-55, and cobalt-59 would meet the criterion of having a lower microscopic thermal cross-section than the microscopic thermal neutron capture cross-section of any reactant nuclei, because all carbon- 12, manganese-55 and cobalt-59 nuclei have lower thermal neutron capture cross-sections than those of actinium-227 nuclei. In these examples, “thermal” is meant to be interpreted in the typical sense that nuclear engineering nuclide charts present it, which is at approximately 300 degrees Kelvin if using temperature, or approximately 0.026 eV if using energy.

Cooling at least one region of the reactant nuclei and/or the collection to a temperature below 250 degrees Kelvin allows for the possibility that a portion of the reactant nuclei only is cooled below 250 degrees Kelvin, or that a portion of the collection only is cooled. Both a portion of the collection and reactant nuclei could be cooled. All of either or both could be cooled. The nuclei cooled may comprise moderating nuclei, understood in the art to mean nuclei with effective neutron moderating properties, such as carbon, oxygen, deuterium, beryllium, and others.

It is thought that higher energy neutrons are more likely to cause potentially unwanted side nuclear reactions (e.g. (n,2n), (n,3n), (n,p) etc.) that may introduce radiologically undesirable products. In at least one example, the reactant nuclei comprise thorium-232.

In at least one example, the total mass of thorium-232 is greater than approximately 10 milligrams.

In at least one example, the reactant nuclei comprise thorium-232, and the reactionproduct nuclei comprise thorium-233, protactinium-233, or uranium-233 nuclei.

In at least one example, the reactant nuclei comprise thorium-232, and the reactionproduct nuclei comprise thorium-233, protactinium-233, or uranium-233 nuclei, and the decayproduct nuclei comprise thorium-229 or actinium-225.

In at least one example, the collection of nuclei comprises nuclides that are selected from a group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen-15, oxygen, fluorine, neon-20, neon-22, and lead-208.

In at least one example, the temperature control comprises the use of a cryogenic fluid.

In at least one example, a target is configured to emit neutrons when impacted by accelerated particles, and the target includes nuclides selected from a group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen- 15, oxygen, fluorine, neon- 20, neon- 22, tantalum, tungsten, lead, mercury, thallium, thorium, uranium, neptunium, and other transuranics. The accelerated particles enter the system via an access channel configured to accept greater than 50 percent of the accelerated particles that impinge upon the access channel. The access channel here is any effective path for the particle of interest to impinge upon a target with minimal energy loss.

In at least one example, the pluralities are arranged in one or more approximately parallel layers, at least one layer being distinct from another layer on the basis of elemental composition, concentration of chemical species, density, or temperature.

In at least one example, the cryogenic fluid is selected from the group consisting of liquid helium, liquid hydrogen, liquid oxygen, liquid neon, and liquid nitrogen.

In some examples, cooling at least one region of the reactant nuclei and/or the collection to less than approximately 75 degrees Kelvin, less than approximately 50 degrees Kelvin, less than approximately 30 degrees Kelvin, or less than approximately 3 degrees Kelvin is performed.

In at least one example, the reactant nuclei comprise radium-228. II. Processes for Producing ²²⁹ Th, ²²⁵ Ac, and/or ²¹³ Bi

In some embodiments, these techniques describe the production of ²²⁹ Th, ²²⁵ Ac, and or ²¹³ Bi. Other techniques for producing ²³³ U or ²²⁹ Th, ²²⁵ Ac, and/or ²¹³ Bi, as well as other generic neutron capture reaction-product nuclei, whether using a single neutron capture or multiple, are also disclosed.

High Efficiency Multiple Neutron Capture Using High Neutron Fluxes

In one embodiment of a process for producing ²²⁹ Th, a ²²⁶ Ra feedstock mass is placed into a neutron field and irradiated. In this step, the ²²⁶ Ra isotopes have nuclear interactions with the neutron flux, and their nuclei probabilistically ‘capture’ a neutron, which forms ²²⁷ Ra. Here, the efficiency of neutron capture is improved by using cryogenic techniques. Methods for improving the efficiency of neutron capture include those disclosed in U.S. Publication No. 20160042826, the contents of which are hereby incorporated by reference in its entirety for all purposes.

²²⁷ Ra beta decays to ²²⁷ Ac by undergoing radioactive beta decay, which converts one of the neutrons in the ²²⁷ Ra to a proton. As a result, the atomic number is still 227, but instead of being radium, the element is now actinium (i.e., ²²⁷ Ac) See, for example, Lourens, et al., “The decay of 227Ra,” Nuclear Physics A, Volume 171, Issue 2, 16 August 1971, Pages 337-352.

The half-life of ²²⁷ Ra is around 42 minutes, so this decay, and concomitant production of ²²⁷ Ac, occurs relatively quickly compared to the duration of the neutron irradiation thought to be optimal for ²²⁹ Th production from ²²⁶ Ra precursor.

While the half-life of ²²⁷ Ra is around 42.2 minutes, the half-life of ²²⁷ Ac isotopes is around 22 years, so in the relative timeframe of the process described herein, it is assumed that relatively little of the ²²⁷ Ac will undergo radioactive decay.

The resulting ²²⁷ Ac isotopes also have nuclear interactions with the neutron flux, and their nuclei probabilistically ‘capture’ a neutron, becoming ²²⁸ Ac.

The resulting ²²⁸ Ac decays almost entirely by beta decay to ²²⁸ Th by emitting a high energy electron, converting a neutron to a proton. In this decay, ²²⁸ Th is by far the predominant product, and the half-life of ²²⁸ Ac has been reported to be around 6 hours.

It has been reported that around 1 in a million decays are alpha decays, forming ²²⁴ Fr, but this small potential impurity can be effectively neglected. In any event, it is fairly straightforward to separate the thorium products from any francium impurities.

The resulting ²²⁸ Th isotopes have still further nuclear interactions with the neutron flux, and their nuclei probabilistically ‘capture’ a neutron, becoming ²²⁹ Th. The resulting ²²⁹ Th isotopes also have nuclear interactions with the neutron flux; however, if the neutron flux experienced by the neutron capture target and the mass of neutron capture target are selected correctly, e.g. by choosing irradiation durations, thermal flux levels, and radiochemical separation intervals so as to minimize ²²⁹ Th neutron capture, an acceptably small amount of ²²⁹ Th will be lost to unwanted further neutron capture.

This process involves several neutron capture reactions, along with two beta decay reactions, both beta decays occurring relatively quickly compared to a month, months, or years, which are thought to be representative timescales for the irradiation time of ²²⁶ Ra useful for producing optimized quantities of ²²⁹ Th. Performing this irradiation of ²²⁶ Ra over time provides a mixture predominantly including the main six isotopes mentioned above ( ²²⁶ Ra, ²²⁷ Ra, ²²⁷ Ac, ²²⁸ Ac, ²²⁸ Th, and ²²⁹ Th), plus a typically smaller amount of a few others, while the sample is experiencing a neutron flux.

At predetermined time intervals, the irradiation can be halted, for example by removing the sample (now comprising a blend of the six isotopes mentioned above) from the neutron flux; furthermore, preferentially separating out one or more of the elements present is possible using standard radiochemistry techniques. These time intervals can be determined based on neutron flux levels, profitability, or practicality, and depending on which element or elements are desired for removal. In some aspects, the irradiation time interval is one or more weeks, one or more months, or one or more years. In some aspects of the embodiment, actinium can be targeted for permanent removal, for example if one wishes to focus on isolating ²²⁷ Ac for the sake of later producing alpha emitters such as ²²³ Ra. In other aspects of the embodiment, thorium can be targeted for permanent removal, for example if one wishes to focus on isolating ²²⁹ Th for the sake of later producing alpha emitters such as ²²⁵ Ra and/or ²²⁵ Ac and/or ²¹³ Bi for various nuclear medical purposes. In these aspects, ²²⁸ Th will be present along with the ²²⁹ Th after radiochemical separation; however, the ²²⁸ Th produces primarily daughter products that are relatively easily to separate from the ²²⁵ Ac produced by the normal decay of ²²⁹ Th, preserving the method’s utility. In this aspect of the embodiment, the irradiation interval could be weeks, months, a year, or many years, assuming thermal neutron fluxes thought to be practically achievable. Adding additional ²²⁶ Ra feedstock as the original amount is depleted may be profitable or advisable at various intervals. Using the removed ²²⁹ Th as a “generator” of ²²⁵ Ac may be performed in some of these aspects.

In one aspect of the embodiment, occasionally ceasing irradiation, removing the sample, siphoning off all thorium, then returning the sample to irradiation is performed. In others, occasionally ceasing irradiation, removing the sample, adding additional ²²⁶ Ra, then returning the sample to irradiation is performed. In other aspects of the embodiment, doing both of the above is performed.

In an apparatus, system, method, process, etc. that comprises or uses moderating nuclei, changing the distance between the neutron capture target and the source of neutrons may alter both the total neutron flux and the kinetic energy distribution of the neutrons within the flux. This feature allows for design tradeoffs regarding neutron capture because different neutron nuclear reactions have different probabilities (e.g. have different microscopic cross-sections) at different neutron kinetic energies. Additionally, in an apparatus, system, method, process, etc. that comprises or uses nuclides or a collection of nuclides that have microscopic thermal neutron capture cross-sections that are lower than that of any reactant nuclei, and which are not themselves reactant nuclei, changing the distance between the neutron capture target and the source of neutrons may alter neutron fluxes and allow for design tradeoffs in the same manner as related above for moderating nuclei.

In one aspect of the embodiment, following the techniques disclosed in U.S. Publication No. 20160042826, a thermal neutron flux can be produced by 1) using an accelerator to create charged particles (e.g. protons, deuterons, etc.), 2) performing spallation with those charged particles to create spallation neutrons, then 3) using moderating nuclei to thermalize the neutrons, creating a thermal neutron flux. Further following the referenced techniques, introducing temperature control, for example in order to reduce the temperature of moderating and/or reactant nuclei below room temperature, allows neutrons to be moderated to average kinetic energies lower than the average kinetic energies achieved using room temperature (e.g. 300 deg. Kelvin) moderators, which increases the probability of neutron capture over the room temperature baseline probability of neutron capture. Via the operational principles described herein, it is understood in this disclosure that temperature control means altering the temperature of at least one region of the moderating nuclei, reactant nuclei, or apparatus, system, etc., and not only dissipating heat produced during operation. Some aspects that comprise or use nuclides or a collection of nuclides that have microscopic thermal neutron capture cross-sections that are lower than that of any reactant nuclei, and which are not themselves reactant nuclei, are thought to produce similar outcome as those aspects described above which use moderating nuclei.

In one aspect of the embodiment, altering the distance between the neutron capture target (i.e. the material one wishes to have capture neutrons, e.g. ²²⁶ Ra) and a source of neutrons is used as a technique to increase or decrease the rate of neutron capture by correspondingly increasing or decreasing the neutron flux. In some aspects of the embodiment, altering the distance in order to increase or decrease the thermal neutron flux may be performed. Decreasing the distance between the neutron capture target and the source of neutrons below that of some baseline distance (e.g. below 35-38 cm, that disclosed in U.S. Publication No. 20160042826) may be performed in order to increase the neutron flux, either total, thermal, or both. Increasing the distance may be performed in order to decrease the neutron flux, either total, thermal, or both.

For this embodiment, where multiple neutron captures on any one reactant nuclei are necessary to achieve the desired reaction-product nuclei, e.g. to turn ²²⁶ Ra into ²²⁹ Th, it is generally believed to be important to achieve high neutron fluxes, particularly high thermal neutron fluxes, in order to optimize the rate of desired isotope production. The rate of production of the desired end reaction-product nuclei can be highly nonlinear as a function of neutron flux wherever multiple neutron captures are needed to produce those desired end reaction-product nuclei. As a result, providing as high a neutron flux as is practical allows sustainable and safe production, and is thought to be desirable. To achieve this high neutron flux, reducing the distance between the neutron capture target and the neutron-emitting target is thought to be desirable.

One or more of the techniques from the preceding three paragraphs may be combined to effectively produce ²²⁹ Th, ²²⁵ Ac and/or ²¹³ Bi.

Some of the isotope production embodiments and aspects described above may be turned on and off simply by turning on or off the source of neutrons in the aspects where the neutron source is, for example, an accelerator. This can conveniently allow for the insertion or removal of additional feedstock, constituent elements, etc. as described above into many conceivable geometries. This is especially true when compared to the production of isotopes within a nuclear reactor, where the method of reactor operation (nuclear chain reaction) and fission process make loading and unloading a reactor inherently more costly and dangerous.

In a separate embodiment of a process for producing generic nuclei via multiple neutron captures, all or only some of the techniques described previously for producing the reactionproduct nucleus ²²⁹ Th and/or the decay-product nucleus ²²⁵ Ac and/or ²¹³ Bi, using multiple neutron captures, may be used instead to produce other, different reaction-product or decay-product nuclei which require more than one neutron capture to be produced. To reiterate, excepting instruction that specifically relates specifically and exclusively to producing ²²⁹ Th or ²²⁵ Ac from ²²⁶ Ra precursor, the preceding embodiment technique descriptions can also be used for a separate embodiment of a process for producing a generic isotope via multiple neutron captures.

High-Efficiency Single Neutron Capture Using Low Fast Neutron Fluxes

In another embodiment of a process for producing ²²⁹ Th, ²³² Th feedstock is placed into a neutron field and irradiated, initially converting it into ²³³ Th using a single neutron capture. Here, the efficiency of neutron capture is improved by using cryogenic techniques. Methods for improving the efficiency of neutron capture include those disclosed in U.S. Publication No. 20160042826.

²³³ Th beta decays to ²³³ Pa by undergoing radioactive beta decay, which converts one of the neutrons in the ²³³ Pa to a proton. The half-life of ²³³ Th is around 22 minutes, so this decay, and concomitant production of ²³³ Pa, occurs relatively quickly compared to the duration of the neutron irradiation thought to be optimal for ²²⁹ Th production from ²³² Th precursor. ²³³ Pa decays to ²³³ U by emitting a beta particle, which converts one of the neutrons in the ²³³ Pa to a proton. The halflife of ²³³ Pa is roughly 27 days, likewise occurring relatively quickly compared to the duration of the neutron irradiation thought to be optimal for this embodiment.

The resulting ²³³ U isotopes also have nuclear interactions with the neutron flux; however, if the neutron flux experienced by the neutron capture target and the mass of the neutron capture target are chosen correctly, e.g. by choosing irradiation durations, thermal flux levels, and radiochemical separation intervals so as to minimize ²³³ U neutron capture, a commercially acceptable amount of ²³³ U will be lost to unwanted further neutron capture.

This process involves a single neutron capture reaction, along with two beta decay reactions, both beta decays occurring relatively quickly compared to months, or years, which are thought to be representative timescales for the irradiation time of ²³² Th useful for producing optimized quantities of ²²⁹ Th. Performing this irradiation of ²³² Th over time provides a mixture that includes the main four isotopes mentioned above ( ²³² Th, ²³³ Th, ²³³ Pa, and ²³³ U), plus a typically smaller amount of a few others, while the sample is within the neutron flux volume. In any aspect of this embodiment, the resulting ²³³ U forms ²²⁹ Th by natural radioactive decay.

At predetermined time intervals, the irradiation can be halted, for example by removing the sample (now comprising a blend of the four isotopes mentioned above) from the neutron flux volume; furthermore, preferentially separating out one or more of the elements present is possible using standard radiochemistry techniques. These time intervals can be determined based on neutron flux levels, profitability, or practicality, and depending on which element or elements are desired for removal. In some aspects, the irradiation time interval could be months to years, and in some aspects approximately a decade or more. In some aspects of the embodiment, uranium can be targeted for permanent removal, for example if one wishes to focus on isolating ²³³ U or ²³³ Pa for the sake of later producing alpha emitters such as ²²⁹ Th and/or ²²⁵ Ac and/or ²¹³ Bi for various nuclear medical purposes. Adding additional ²³² Th feedstock as the original amount is depleted may be profitable or advisable at various intervals. Using the permanently removed ²³³ U or ²³³ Pa as a “generator” of ²²⁹ Th may be performed in some of these aspects. Further radiochemical separation of the combined uranium/protactinium and thorium may be performed at that point. Using the removed ²²⁹ Th as a “generator” of ²²⁵ Ac may be performed in some of these aspects. These techniques may be combined to form a double generator process for the production of ²²⁵ Ac.

In one aspect of the embodiment, occasionally ceasing irradiation, removing the sample, siphoning off all uranium and/or protactinium, then returning the sample to irradiation is performed. In others, occasionally ceasing irradiation, removing the sample, adding additional ²³² Th, then returning the sample to irradiation is performed. In other aspects of the embodiment, doing both of the above is performed.

In an apparatus, system, method, process, etc. that comprises or uses moderating nuclei, changing the distance between the neutron capture target and the source of neutrons may alter both the total neutron flux and the kinetic energy distribution of the neutrons within the flux. In one embodiment, this does not involve having the ability to physically move the target within the reactor, but rather, involves setting up the apparatus such that the distance is a pre-determined distance that provides a desired total neutron flux (or thermal neutron flux) and kinetic energy distribution of the neutrons within the flux. In another embodiment, the apparatus is set up such that the target can be moved closer or farther from a neutron source. This feature allows for design tradeoffs regarding neutron capture because different neutron nuclear reactions have different probabilities (e.g. have different microscopic crosssections) at different neutron kinetic energies. Additionally, in an apparatus, system, method, process, etc. that comprises or uses nuclides that have microscopic thermal neutron capture crosssections that are lower than that of any reactant nuclei, and which are not themselves reactant nuclei, changing the distance between the neutron capture target and the source of neutrons may alter neutron fluxes and allow for design tradeoffs in the same manner as related above for moderating nuclei.

In one aspect of this embodiment, following the techniques disclosed in U.S. Publication No. 20160042826, a thermal neutron flux could be produced by 1) using an accelerator to create charged particles (e.g. protons, deuterons, etc.), 2) performing spallation with those charged particles to create spallation neutrons, then 3) using moderating nuclei to thermalize the neutrons, creating a thermal neutron flux. Further following the referenced techniques, introducing temperature control, for example in order to reduce the temperature of moderating and/or reactant nuclei below room temperature, allows neutrons to be moderated to average kinetic energies lower than the average kinetic energies achieved using room temperature (e.g. 300 deg. Kelvin) moderators, which increases the probability of neutron capture over the room temperature baseline probability of neutron capture. Via the operational principles described herein, it is understood in this disclosure that temperature control means altering the temperature of at least one region of the moderating nuclei, reactant nuclei, or apparatus, system, etc., and not only dissipating heat produced during operation. Some aspects that comprise or use nuclides or a collection of nuclides that have microscopic thermal neutron capture cross-sections that are lower than that of any reactant nuclei, and which are not themselves reactant nuclei, are thought to produce similar outcome as those aspects described above which use moderating nuclei.

In one aspect of the embodiment, altering the distance between the neutron capture target (i.e. the material one wishes to have capture neutrons, e.g. ²³² Th) and a source of neutrons is used as a technique to increase or decrease the rate of neutron capture by correspondingly increasing or decreasing the neutron flux. In some aspects of the embodiment, altering the distance in order to increase or decrease the thermal neutron flux may be performed. Increasing the distance between the neutron capture target and the source of neutrons below that of some baseline distance (e.g. below 35-38 cm, that disclosed in U.S. Publication No. 20160042826) may be performed in order to decease the fast neutron flux. In this context, fast is mean to describe neutrons with sufficient kinetic energy to cause unwanted side reactions, e.g. (n,2n) reactions, which might cause the production of isotopes that are undesired for radiological or other reasons, e.g. ²³² U and its daughter decay products. For the purpose of quantitatively interpreting claims, for the entirety of this disclosure, we shall define fast neutrons as neutrons with energy greater than 6 MeV. It is thought that such neutrons contribute disproportionately to unwanted side nuclear reactions, e.g. (n,2n), compared to neutrons with energies below 6 MeV. Decreasing the distance may also be performed, in order to increase the thermal neutron flux, at the potential tradeoff cost of introducing a greater fraction of fast neutrons in the neutron flux.

For this embodiment, where only a single neutron capture by any one reactant nuclei is necessary to achieve the desired reaction-product nuclei, e.g. to turn ²³² Th into ²³³ U, it is generally believed to be useful to achieve low fast neutron fluxes, due to a desire to lessen radiological burdens that arise due to unwanted isotopes e.g. ²³² U and its daughters. Providing as low a neutron flux as necessary or practical to achieve a desired maximum concentration or threshold of contaminant isotope is thought to be desirable, and can be achieved by increasing the distance between the reactant nuclei and the neutron source. All or only some of the techniques from the preceding paragraphs may be combined to effectively produce ²²⁹ Th and/or ²²⁵ Ac.

It is understood throughout the disclosure for the sake of interpreting that altering the distance between the neutron source and the reactant nuclei means altering the distance between the neutron source and at least some reactant nuclei.

In a separate embodiment of a process for producing ²²⁹ Th, ²²⁵ Ac and/or ²¹³ Bi via single neutron capture, using the methods described above for increasing the distance between the source of neutrons and the reactant nuclei in order to prevent unwanted side nuclear reactions, the reactant nuclei comprise ²²⁸ Ra, which can absorb a single neutron to become ²²⁹ Ra, which will further undergo two radioactive decays to become ²²⁹ Th.

Some of the isotope production embodiments and aspects described above may be turned on and off simply by turning on or off the source of neutrons in the aspects where the neutron source is e.g. an accelerator. This allows for the insertion or removal of additional feedstock, constituent elements, etc. as described above into many conceivable geometries. This is especially true when compared to the production of isotopes within a nuclear reactor, where the method of reactor operation (nuclear chain reaction) and fission process make loading and unloading a reactor inherently more costly and dangerous.

In a separate embodiment of a process for producing generic nuclei via single neutron capture, all or only some of the techniques described previously for producing the reaction-product nuclei ²³³ U or ²²⁹ Th and/or the decay-product nucleus ²²⁵ Ac, using a single neutron capture, may be used instead to produce other, different reaction-product or decay-product nuclei which require a single neutron capture to be produced. To reiterate, excepting instruction that specifically relates to producing ²³³ U or ²²⁹ Th or ²²⁵ Ac or ²¹³ Bi from ²³² Th precursor, the preceding embodiment descriptions can also be used for a separate embodiment of a process for producing a generic isotope via a single neutron capture.

All of the embodiments mentioned above can produce either ²²⁹ Th that is relatively isotopically pure, or can produce a mixture of radioisotopes that decay into products that are relatively easily to separate from the ²²⁵ Ac produced by the normal decay of ²²⁹ Th, an example of which is ²¹³ Bi. As such, all of these embodiments also allow for the production of highly pure ²²⁵ Ac and/or ²¹³ Bi.

In another embodiment, a process for producing ²²⁵ Ac from the ²²⁹ Th is disclosed. This process involves allowing the ²²⁹ Th, produced by the above process, to decay. This produces, among other products, ²²⁵ Ac. The ²²⁵ Ac can be isolated, for example, by reacting the actinium and other elements with nitric acid, which forms actinium nitrate, and isolating the desired ²²⁵ Ac nitrate using ion exchange chromatography.

Once the sample has been removed, the various isotopes can be radiochemically separated. Radiochemical separation essentially removes very high fractions of thorium from all of the other elements, and these fractions will initially include all thorium isotopes (e.g. 228, 229, etc.). The desired isotope is ²²⁹ Th, and this isotope undergoes a slow delay, via alpha emission, to form ²²⁵ Ac. The mixture will likely include some proportion of contaminant ²²⁸ Th.

While there is a theoretical possibility that a contaminant from the decay of ²²⁸ Th could be present in the final ²²⁵ Ac, for all practical purposes, in later steps actinium is removed from the thorium blend, leaving almost all of the ²²⁸ Th and ²²⁹ Th behind.

As with ²²⁹ Th, ²²⁸ Th also decays by alpha emission, forming ²²⁴ Ra, which further decays into other elements, but this decay process does not produce significant amounts of any actinium isotopes. These products are easily separable from the desired ²²⁵ Ac.

Because there is no issue with separating the products resulting from the decay of both ²²⁹ Th and ²²⁸ Th, there is no inherent radiochemical need to separate the mixture of thorium isotopes. Rather, the mixture is used in a ‘thorium generator,’ also referred to as a “thorium cow,” since it is periodically “milked” to isolate the ²²⁵ Ac formed as a result of the passive radioactive alpha decay of ²²⁹ Th. By passive, it is meant that no active steps are performed to cause this decay, but rather, the decay simply happens as a result of the normal physical decay process of this particular radioisotope.

The ²²⁹ Th is not directly converted into ²²⁵ Ac, but rather, is initially converted into ²²⁵ Ra plus residual helium (the alpha particle). The passive decay process creates a steady stream of ²²⁵ Ra. The ²²⁵ Ra beta decays to ²²⁵ Ac via beta radioactive decay, converting a neutron to a proton.

The ²²⁵ Ac, which will be essentially pure actinium with little if any contamination, can be ‘milked’ from the generator via appropriately practiced radiochemistry. This process should neither destroy, degrade, nor substantially waste the ²²⁹ Th source, if done correctly.

The “milked” ²²⁵ Ac can be used as a component of a radiopharmaceutical agent by those of skill in the art, for example, using the techniques described herein.

In one embodiment, the ²²⁵ Ac is isolated in the form of a nitrate salt (formed by reaction with nitric acid).

In addition to direct therapeutic applications of ²²⁵ Ac, the ²²⁵ Ac can be immobilized in a device, and daughter isotopes, in particular ²¹³ Bi, can be selectively removed.

For example, ²¹³ Bi can be selectively removed with multiple elutions from the device and used for therapeutic applications. Generally, sufficient quantities of ²¹³ Bi can be obtained within 30 days of producing Ac-225. Preferably, sufficient quantities of ²¹³ Bi will be generated within 1, 3, 5, 7, 10, 12, 15, 18, 20, 25, 30, 60, or 90 days.

III. Use of Multiple Neutron Captures to Create Reaction- and Decay-Product Nuclei

Multiple neutron captures can be used to prepare other products, in addition to the ²²⁹ Th, ²²⁵ Ac and/or ²¹³ Bi discussed above.

According to at least one embodiment, a process for producing reaction-product and decayproduct nuclei from a reactant isotope involves generating neutrons, combining a plurality of reactant nuclei and a plurality of moderating nuclei wherein the moderating nuclei comprise nuclides that are selected from a group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron- 11, carbon, nitrogen- 15, oxygen, fluorine, neon-20 and neon-22. The reactant nuclei comprise radium-226. Reaction-product nuclei include at least some of radium-227, actinium-227, actinium-228, thorium-228, and thorium-229. It also includes cooling at least one region of the reactant nuclei and/or the moderating nuclei to a temperature below 250 degrees Kelvin. The pluralities are irradiated with neutrons such that a reaction product is generated when the neutrons are captured by the reactant nuclei, wherein the reaction-product nuclei comprise reaction-product nuclei that result from two or more neutron captures by the same reactant nucleus. A reaction product or decay product that is generated by radioactive decay of the reaction-product nuclei is extracted from the plurality of reactant nuclei.

In some embodiments, at least 0.1% of the reaction-product nuclei result from two or more neutron captures by the same reactant nucleus

The referenced neutron generation could occur using a sealed source, an accelerator (e.g. DT production, spallation production, etc.), a subcritical assembly of fissile material, a nuclear reactor, or any other process capable of generating neutrons.

Cooling at least one region of the reactant nuclei and/or the moderating nuclei to a temperature below 250 degrees Kelvin allows for the possibility that a portion of the reactant nuclei only is cooled below 250 degrees Kelvin, or that a portion of the moderating nuclei only is cooled. Both a portion of the moderating nuclei and reactant nuclei could be cooled. All of either or both could be cooled.

In at least one example, the total mass of radium-226 is greater than approximately 10 milligrams.

In at least one example, the reaction-product nuclei comprise actinium-227, thorium-228, or thorium-229.

In at least one example, the reaction-product nuclei comprise actinium-227, thorium-228, or thorium-229, and the decay-product nuclei further comprise actinium-225.

In at least one example, at least 1 mg of reaction-product nuclei results from multiple neutron captures by reactant nuclei.

For the purpose of interpreting, “at least 0.1% of reaction-product nuclei present result from two or more neutron captures by the same reactant nucleus” can be understood to mean that at least 0.1% of all reaction-product nuclei present have undergone more than one neutron capture due to the process, regardless of whether radioactive decay has occurred between or after neutron captures. These reaction-product nuclei result when a reactant nucleus captures a neutron, becoming a reaction-product nucleus, and then further captures one or more neutrons. As an example, if the reactant nuclei comprise radium-226, actinium-227, and thorium-228, and if the combined population of produced thorium-228 and thorium-229 nuclei sum to 0.12% of the combined population of actinium-227, thorium-228, and thorium-229 nuclei, then this would be an example of a process where “at least 0.1% of reaction-product nuclei present result from two or more neutron captures by the same reactant nucleus.”

In at least one example, the total neutron flux experienced by any of the reactant nuclei is greater than approximately IxlO ¹² neutrons/cm ² /s.

In at least one example, the temperature control may include the use of a cryogenic fluid.

In at least one example, the pluralities are arranged in one or more approximately parallel layers, at least one layer being distinct from another layer on the basis of elemental composition, concentration of chemical species, density, or temperature.

In at least one example, a target is configured to emit neutrons when impacted by accelerated particles. The target includes nuclides selected from a group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen- 15, oxygen, fluorine, neon- 20, neon-22, tantalum, tungsten, lead, mercury, thallium, thorium, uranium, neptunium, and other transuranics. The accelerated particles enter the system via an access channel configured to accept greater than 50 percent of the accelerated particles that impinge upon the access channel. The access channel here is any effective path for the particle of interest to impinge upon a target with minimal energy loss.

In some examples, cooling at least one region of the reactant nuclei and/or the moderating nuclei to less than approximately 75 degrees Kelvin, less than approximately 50 degrees Kelvin, less than approximately 30 degrees Kelvin, or less than approximately 3 degrees Kelvin is performed.

In at least one example, the cryogenic fluid is selected from the group consisting of liquid helium, liquid hydrogen, liquid oxygen, liquid neon, and liquid nitrogen.

According to at least one embodiment, a process for producing reaction-product nuclei from reactant nuclei includes generating neutrons, and preparing reactant nuclei. It also includes preparing a collection of nuclides consisting of those nuclides whose nuclei capture at least 0.2% of all emitted neutrons from the neutron source and which are not reactant nuclei, wherein at least one of the nuclides from the collection of nuclides has a microscopic thermal neutron capture cross-section that is lower than the microscopic thermal neutron capture cross-section of any reactant nuclei. It also involves combining the reactant nuclei and the collection of nuclides. It also includes cooling at least one region of the reactant nuclei and/or the collection to a temperature below 250 degrees Kelvin. The pluralities are irradiated with neutrons such that a reaction product is generated when the neutrons are captured by the reactant nuclei, wherein the reaction-product nuclei comprise reaction-product nuclei that result from two or more neutron captures by the same reactant nucleus. A reaction product or decay product that is generated by radioactive decay of the reaction-product nuclei is extracted from the reactant nuclei. The total neutron flux experienced by any of the reactant nuclei is greater than approximately IxlO ¹² neutrons/cm ² /s.

In some embodiments, at least 0.1% of the reaction-product nuclei result from two or more neutron captures by the same reactant nucleus.

The referenced neutron generation could occur using a sealed source, an accelerator (e.g. DT production, spallation production, etc.), a subcritical assembly of fissile material, a nuclear reactor, or any other process capable of generating neutrons.

For the purpose of interpreting, the “collection of nuclides consisting of those nuclides whose nuclei capture at least 0.2% of all generated neutrons. ..” should be understood to imply “for the neutron generation configuration being utilized.” There may be many ways to configure neutron generation so as to alter the isotopes within the collection of nuclides, but the particular configuration being used to produce reaction-product nuclei is the configuration to which the claims apply.

Also for the purposes of interpreting, the “collection of nuclides consisting of those nuclides whose nuclei capture at least 0.2% of all emitted neutrons from the neutron source. ..” can be understood via the following example: if a collection included one type of reactant nuclide - calcium-46; and four types of non-reactant nuclides - oxygen- 16, carbon- 12, manganese-55, and cobalt-59; and they respectively capture 0.1%, 5%, 10%, and 20% of the total emitted neutrons, then the collection of nuclides would consist of carbon- 12, manganese- 55, and cobalt-59, but not oxygen-16, as 0.1% is lower than 0.2%. In this specific example, the carbon- 12 would meet the criterion of having a lower microscopic thermal cross-section than the microscopic thermal neutron capture cross-section of any reactant nuclei, because all calcium-46 nuclei have thermal neutron capture cross-sections higher than those of carbon- 12 nuclei but lower than those of both manganese-55 and cobalt-59 nuclei. In an example where the four named non-reactant nuclei above were retained, but where the reactant nuclei comprised radium-226 and actinium-227 instead of calcium-46, all three of carbon-12, manganese-55, and cobalt-59 would meet the criterion of having a lower microscopic thermal cross-section than the microscopic thermal neutron capture cross-section of any reactant nuclei, because all carbon- 12, manganese-55 and cobalt-59 nuclei have lower thermal neutron capture cross-sections than those of actinium-227 nuclei. In these examples, “thermal” is meant to be interpreted in the typical sense that nuclear engineering nuclide charts present it, which is at approximately 300 degrees Kelvin if using temperature, or approximately 0.026 eV if using energy.

Cooling at least one region of the reactant nuclei and/or the collection to a temperature below 250 degrees Kelvin allows for the possibility that a portion of the reactant nuclei only is cooled below 250 degrees Kelvin, or that a portion of the collection only is cooled. Both a portion of the collection and reactant nuclei could be cooled. All of either or both could be cooled. The nuclei cooled may comprise moderating nuclei, understood in the art to mean nuclei with effective neutron moderating properties, such as carbon, oxygen, deuterium, beryllium, and others.

In at least one example, the reactant nuclei comprise radium-226.

In at least one example, the total mass of radium-226 is greater than approximately 10 milligrams.

In at least one example, the reactant nuclei comprise radium-226, and the reaction-product nuclei comprise actinium-227, thorium-228, or thorium-229 nuclei.

In at least one example, the reactant nuclei comprise radium-226, the reaction-product nuclei comprise actinium-227, thorium-228, or thorium-229, and the decay-product nuclei comprises actinium-225.

In at least one example, the collection of nuclei comprises nuclides that are selected from a group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen-15, oxygen, fluorine, neon-20, neon-22, and lead-208.

In at least one example, the temperature control comprises the use of a cryogenic fluid.

In at least one example, a target is configured to emit neutrons when impacted by accelerated particles, and the target includes nuclides selected from a group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen- 15, oxygen, fluorine, neon- 20, neon-22, tantalum, tungsten, lead, mercury, thallium, thorium, uranium, neptunium, and other transuranics. The accelerated particles enter the system via an access channel configured to accept greater than 50 percent of the accelerated particles that impinge upon the access channel. The access channel here is any effective path for the particle of interest to impinge upon a target with minimal energy loss.

For the purpose of interpreting, “at least 0.1% of reaction-product nuclei present result from two or more neutron captures by the same reactant nucleus” can be understood to mean that at least 0.1% of all reaction-product nuclei present have undergone more than one neutron capture due to the process, regardless of whether radioactive decay has occurred between or after neutron captures. These reaction-product nuclei result when a reactant nucleus captures a neutron, becoming a reaction-product nucleus, and then further captures one or more neutrons. As an example, if the reactant nuclei comprise radium-226, actinium-227, thorium-228, and if the combined population of produced thorium-228 and thorium-229 nuclei sum to 0.12% of the combined population of actinium-227, thorium-228, and thorium-229 nuclei, then this would be an example of a process where “at least 0.1% of reaction-product nuclei present result from two or more neutron captures by the same reactant nucleus.”

In at least one example, the pluralities are arranged in one or more approximately parallel layers, at least one layer being distinct from another layer on the basis of elemental composition, concentration of chemical species, density, or temperature.

In at least one example, the cryogenic fluid is selected from the group consisting of liquid helium, liquid hydrogen, liquid oxygen, liquid neon, and liquid nitrogen.

In some examples, cooling at least one region of the reactant nuclei and/or the collection to less than approximately 75 degrees Kelvin, less than approximately 50 degrees Kelvin, less than approximately 30 degrees Kelvin, or less than approximately 3 degrees Kelvin is performed.

IV. Pharmaceutical Compositions

The radionuclides described herein, and various forms of targeting molecule-chelator combinations and charged versions thereof described herein, are referred to herein as active ingredients. Active ingredients also include prodrugs, salts, analogs, and/or derivatives of the targeting molecule-chelator combinations, by themselves, or when complexed to one or more radionuclides.

Any composition disclosed herein can advantageously include any other pharmaceutically acceptable carriers that include those that do not produce significantly adverse, allergic, or other untoward reactions that outweigh the benefit of administration. Exemplary pharmaceutically acceptable carriers and formulations are disclosed in Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990. Moreover, formulations can be prepared to meet sterility, pyrogenicity, general safety, and purity standards as required by U.S. FDA Office of Biological Standards and/or other relevant foreign regulatory agencies.

In some embodiments, the cationic form of ²²⁵ Ac and/or ²¹³ Bi is chelated. In some aspects of these embodiments, the chelating agent is a molecule that includes both a targeting moiety and a chelating moiety, and, optionally, a linker moiety between the targeting moiety and the chelating moiety.

Where the ²²⁵ Ac and/or ²¹³ Bi ions are combined with a compound that includes a chelating moiety, a targeting moiety, and, optionally, a linker between the chelating moiety and the targeting moiety. The chelating moiety chelates the ²²⁵ Ac/ ²¹³ Bi, and the targeting moiety targets the chelated ²²⁵ Ac/ ²¹³ Bi to a tumor.

In one aspect of this embodiment, the ²²⁵ Ac/ ²¹³ Bi ions, optionally in a chelated form, are encapsulated in nanoparticles, such as small unilamellar vesicles (SUVs), sized to be trapped in capillary beds surrounding tumors.

In some aspects of this embodiment, the targeting moieties are small molecules, for example, agonists, antagonists, partial agonists, inverse agonists, or allosteric inhibitors/modulators, which bind to receptors overexpressed by cancer cells. In other aspects, the targeting moieties are antibodies, peptides, proteins, or nucleic acids that bind to cancer cells, or to receptors overexpressed by the cancer cells.

Receptors Over-Expressed by Cancer Cells

In some embodiments, targeted drug delivery can be achieved by binding an antibody or small molecule that binds to a target on the cancer cell. In some aspects of this embodiment, the antibody or small molecule binds to receptors which are overexpressed in cancer cells relative to normal cells. The following receptors are overexpressed in certain cancer cells:

BnR, bombesin receptor; BR, biotin receptor; c(RGD-K), cyclic {Arginine-Glycine- Aspartic acid (RGD)} containing peptide; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ETRB, endothelin receptor B; FA, folic acid; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; FR, folate receptor; FSH, follicle stimulating hormone; FSHR, follicle stimulating hormone receptor; Nrp-1, neuropilin receptor-1; PEG, SIR, sigma receptor 1; S2R, sigma receptor 2; SRs, sigma receptors; SSTRs, somatostatin receptors; Tf, transferrin; TfR, transferrin receptor

Antibodies, small molecules, and other compounds which bind to these receptors can be used to target radionuclides to the cancer cells.

The G protein-coupled KISSI receptor is overexpressed in triple negative breast cancer (Blake, et al., Sci Rep 7, 46525 (2017).

Triple-negative breast cancer (TNBC) accounts for 20% of breast cancer in women and lacks an effective targeted therapy. The G protein-coupled receptor (GPCR) GPR161 is overexpressed in TNBC (Feigin et al., Proc Natl Acad Sci U S A. 2014 Mar 18; 111(11): 4191-4196).

The non-classic opioid receptor, nociceptin receptor (NOP), is overexpressed in non-small cell lung cancer (Wang et al., Front. Oncol., 05 April 2019).

EphB3 is also overexpressed in non-small-cell lung cancer (Ji et al., Tumor and Stem Cell Biology, February 2011, Vol. 71, Issue 3, DOI: 10.1158/0008-5472).

The receptor tyrosine kinase RET is overexpressed in a subset of ER-positive breast cancers (Morandi et al., Trends in Molecular Medicine, Volume 17, Issue 3, P149-157, March 01, 2011).

The farnesoid X receptor is overexpressed in pancreatic cancer (Lee, et al., Farnesoid X receptor, overexpressed in pancreatic cancer with lymph node metastasis promotes cell migration and invasion. Br J Cancer 104, 1027-1037 (2011) doi: 10.1038/bjc.2011.37). Molecules which bind to this receptor include the FXR antagonist guggulsterone and the FXR agonist GW4064, which has the following formula:

GW 0S4

The carboxylic acid moiety on GW4064 allows for attachment of a linker, subsequent attachment of a chelator, and subsequent chelation of a desired radionuclide.

Epidermal growth factor receptor (EGFR) is overexpressed in anaplastic thyroid cancer (Schiff et al., Epidermal growth factor receptor (EGFR) is overexpressed in anaplastic thyroid cancer, and the EGFR inhibitor gefitinib inhibits the growth of anaplastic thyroid cancer. Clin Cancer Res 2004;10:8594-602). Compounds which bind to this receptor include gefitinib, which has the formula:

The amine moiety on this molecule can be used to conjugate a linker moiety, which can then be used to conjugate a chelator, which can then be used to chelate a radionuclide.

The folate receptor, a glycosylphosphatidylinositol-anchored cell surface receptor, is overexpressed on the vast majority of cancer tissues, while its expression is limited in healthy tissues and organs (Zwicke, Grant L et al. “Utilizing the folate receptor for active targeting of cancer nanotherapeutics.” Nano reviews vol. 3 (2012): 10.3402/nano.v3i0.18496. doi: 10.3402/nano.v3i0.18496). For example, folate receptors are highly expressed in epithelial, ovarian, cervical, breast, lung, kidney, colorectal, and brain tumors.

Folic acid has the following formula:

Folic acid can be conjugated to a chelating agent, such as the one shown below, and complexed to a radionuclide, such as the one shown below ( ^99m Tc).

Targeting Domains

In particular embodiments, the compounds disclosed herein include a targeting domain. Targeting domains can direct radionuclides to imaging or therapeutic areas of interest. In particular embodiments, the targeting domains direct the radionuclides to a region of the body that will be imaged using nuclear medicine diagnostic techniques. In particular embodiments, the targeting domains direct the radionuclides to a cell type that is targeted for radiotherapy.

In particular embodiments, targeting domains can be derived from whole proteins or protein fragments with an affinity for particular tissues and/or cell types of interest. In particular embodiments, targeting domains can be derived from whole antibodies or binding fragments of an antibody, e.g., Fv, Fab, Fab', F(ab')2, Fc, and single chain Fv fragments (scFvs) or any biologically effective fragments of an immunoglobulin that bind specifically to, for example, a cancer antigen epitope. Antibodies or antigen binding fragments include all or a portion of polyclonal antibodies, monoclonal antibodies, human antibodies, humanized antibodies, synthetic antibodies, chimeric antibodies, bispecific antibodies, mini bodies, and linear antibodies.

Targeting domains from human origin or humanized antibodies have lowered or no immunogenicity in humans and have a lower number of non-immunogenic epitopes compared to non-human antibodies. Antibodies and their fragments will generally be selected to have a reduced level or no antigenicity in human subjects. Targeting domains can particularly include any peptide that specifically binds a selected unwanted cell epitope. Sources of targeting domains include antibody variable regions from various species (which can be in the form of antibodies, sFvs, scFvs, Fabs, scFv-based grababody, or soluble VH domain or domain antibodies). These antibodies can form antigen-binding regions using only a heavy chain variable region, i.e., these functional antibodies are homodimers of heavy chains only (referred to as "heavy chain antibodies") (Jespers et al., Nat. Biotechnol. 22: 1161, 2004; Cortez-Retamozo et al., Cancer Res. 64:2853, 2004; Baral et al., Nature Med. 12:580, 2006; and Barthelemy et al., J. Biol. Chem. 283:3639, 2008).

Phage display libraries of partially or fully synthetic antibodies are available and can be screened for an antibody or fragment thereof that can bind a selected epitope. For example, targeting domains may be identified by screening a Fab phage library for Fab fragments that specifically bind to a target of interest (see Hoet et al., Nat. Biotechnol. 23:344, 2005). Phage display libraries of human antibodies are also available. Additionally, traditional strategies for hybridoma development using a target of interest as an immunogen in convenient systems (e.g., mice, HuMAb Mouse. RTM., TC Mouse. TM., KM-Mouse®, llamas, chicken, rats, hamsters, rabbits, etc.) can be used to develop targeting domains.

In particular embodiments, antibodies specifically bind to selected epitopes expressed by targeted cells and do not cross react with nonspecific components or unrelated targets. Once identified, the amino acid sequence or polynucleotide sequence coding for the antibody can be isolated and/or determined.

An alternative source of targeting domains includes sequences that encode random peptide libraries or sequences that encode an engineered diversity of amino acids in loop regions of alternative non-antibody scaffolds, such as scTCR (see, e.g., Lake et al., Int. Immunol. 11 :745, 1999; Maynard et al., J. Immunol. Methods 306:51, 2005; U.S. Pat. No. 8,361,794), mAb2 or Fcab.TM. (see, e.g., PCT Patent Application Publication Nos. WO 2007/098934; WO 2006/072620), affibody, avimers, fynomers, cytotoxic T-lymphocyte associated protein-4 (Weidle et al., Cancer Gen. Proteo. 10: 155, 2013), or the like (Nord et al., Protein Eng. 8:601, 1995; Nord et al., Nat. Biotechnol. 15:772, 1997; Nord et al., Euro. J. Biochem. 268:4269, 2001; Binz et al., Nat. Biotechnol. 23: 1257, 2005; Boersma and Pluckthun, Curr. Opin. Biotechnol. 22:849, 2011).

In particular embodiments, an antibody fragment is used as the targeting domain of a SCC. An "antibody fragment" denotes a portion of a complete or full length antibody that retains the ability to bind to an epitope. Examples of antibody fragments include Fv, scFv, Fab, Fab', Fab'- SH, F(ab')2; diabodies; and linear antibodies.

A single chain variable fragment (scFv) is a fusion protein of the variable regions of the heavy and light chains of immunoglobulins connected with a short linker peptide. Fv fragments include the VL and VH domains of a single arm of an antibody. Although the two domains of the Fv fragment, VL and VH, are coded by separate genes, they can be joined, using, for example, recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (single chain Fv (scFv)). For additional information regarding Fv and scFv, see e.g., Bird, et al., Science 242 (1988) 423-426; Huston, et al., Proc. Natl. Acad. Sci. USA 85 (1988) 5879-5883; Plueckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore (eds.), Springer- Verlag, New York), (1994) 269-315; WO1993/16185; U.S. Pat. Nos. 5,571,894; and 5,587,458.

A Fab fragment is a monovalent antibody fragment including VL, VH, CL and CHI domains. A F(ab')2 fragment is a bivalent fragment including two Fab fragments linked by a disulfide bridge at the hinge region. For discussion of Fab and F(ab')2 fragments having increased in vivo half-life, see U.S. Pat. No. 5,869,046. Diabodies include two epitope-binding sites that may be bivalent. See, for example, EP 0404097; WO1993/01161; and Holliger, et al., Proc. Natl. Acad. Sci. USA 90 (1993) 6444-6448. Dual affinity retargeting antibodies (DART™; based on the diabody format but featuring a C-terminal disulfide bridge for additional stabilization (Moore et al., Blood 117, 4542-51 (2011))) can also be used. Antibody fragments can also include isolated CDRs. For a review of antibody fragments, see Hudson, et al., Nat. Med. 9 (2003) 129-134.

Antibody fragments can be made by various techniques, including proteolytic digestion of an intact antibody as well as production by recombinant host-cells (e.g. E. coli or phage), as described herein. Antibody fragments can be screened for their binding properties in the same manner as intact antibodies.

In particular embodiments, targeting domains can also include a natural receptor or ligand for an epitope. For example, if a target for binding includes PD-L1, the binding domain can include PD-1 (including, e.g., a PD-l/antiCD3 fusion). One example of a receptor fusion for binding is Enbrel.RTM. (Immunex). Natural receptors or ligands can also be modified to enhance binding. For example, betalacept is a modified version of abatacept. Binding can also be enhanced through increasing avidity. Any screening method known in the art can be used to identify increased avidity to an antigen epitope.

As used herein, an epitope denotes the binding site on a protein target bound by a corresponding targeting domain. The targeting domain either binds to a linear epitope, (e.g., an epitope including a stretch of 5 to 12 consecutive amino acids), or the targeting domains binds to a three-dimensional structure formed by the spatial arrangement of several short stretches of the protein target. Three-dimensional epitopes recognized by a targeting domain, e.g. by the epitope recognition site or paratope of an antibody or antibody fragment, can be thought of as three- dimensional surface features of an epitope molecule. These features fit precisely (in)to the corresponding binding site of the targeting domains and thereby binding between the targeting domains and its target protein is facilitated.

"Bind" means that the targeting domain associates with its target epitope with a dissociation constant (1(D) of 10-8 M or less, in one embodiment of from 10' ⁵ M to 10' ¹³ M, in one embodiment of from 10' ⁵ M to IO' ¹⁰ M, in one embodiment of from 10' ⁵ M to 10' ⁷ M, in one embodiment of from 10' ⁸ M to 10' ¹³ M, or in one embodiment of from 10' ⁹ M to 10' ¹³ M. The term can be further used to indicate that the targeting domains does not bind to other biomolecules present, (e.g., it binds to other biomolecules with a dissociation constant (KD) of 10-4 M or more, in one embodiment of from 10' ⁴ M to 1 M.

In particular embodiments, targeting domains of SCCs can be designed to target cancer cell antigens. Cancer cell antigens are preferentially expressed by cancer cells. "Preferentially expressed" means that a cancer cell antigen is found at higher levels on cancer cells as compared to other cell types. The difference in expression level is significant enough that, within sound medical judgment, administration of therapeutics selectively targeting the cancer cells based on the presence of the cancer antigen outweighs the risk of collateral killing of other non-cancer cells that may also express the marker to a lesser degree. In some instances, a cancer antigen is only expressed by the targeted cancer cell type. In other instances, the cancer antigen is expressed on the targeted cancer cell type at least 25%, 35%, 45%, 55%, 65%, 75%, 85%, 95%, 96%, 97%, 98%, 99%, or 100% more than on non-targeted cells.

The following table provides examples of particular cancer antigens that can be targeted.

TABLE 1 Targeted Cancer Cancer Antigens

Leukemia/Lymphoma CD 19, CD20, CD22, ROR1, CD33, WT-1

Multiple Myeloma B-cell maturation antigen (BCMA)

Prostate Cancer PSMA, WT1, Prostate Stem Cell antigen (PSCA), SV40 T

Breast Cancer HER2, ERBB2, ROR1 Stem Cell Cancer CD 133

Ovarian Cancer LI -CAM, extracellular domain of MUC16 (MUC-CD), folate binding protein (folate receptor), Lewis Y, ROR1, mesothelin, WT-1

Mesothelioma mesothelin

Renal Cell Carcinoma carboxy-anhydrase-IX (CAIX)

Melanoma GD2

Pancreatic Cancer mesothelin, CEA, CD24, ROR1

Lung Cancer ROR1

Linkers

Any suitable linker can be used which couples a chelating moiety to a targeting moiety. Representative examples include alkylene linkers, polyethylene glycol/oxoethylene linkers, and peptide linkers.

PEG and oxoethylene linkers can be used to space the targeting moiety and the chelating agent, and increase the overall hydrophilicity of the molecule, which can improves exposure of certain targeting moieties away from the liposome surface, when bound in liposomes, and provide lower clearance of the complexes and/or liposomes through the reticulo-endothelial system (RES).

Chelating Moieties

Moieties which chelate radioactive ions are known to those of skill in the art. In various embodiments, the chelating moiety is selected from the group consisting of S-2-(4-Nitrobenzyl)- 1 ,4,7, 10-tetraazacyclododecane; 1 ,4,7, 10-T etraazacyclododecane- 1 ,4,7-tri(carbamoylmethyl)- 10- acetic acid; S-2-(4-Nitrobenzyl)- 1,4, 7,10-tetraazacyclododecane tetraacetic acid; S-2-(4- Aminobenzyl)- 1,4, 7,10-tetraazacyclododecane tetraacetic acid; S-2-(4- Aminobenzyl)- 1,4,7,10- tetraazacyclododecane tetra-tert-butylacetate; S-2-(4-Isothiocyanatobenzyl)-l,4,7, 10- tetraazacyclododecane tetraacetic acid; l,4,7,10-Tetraazacyclododecane-l,4,7-tris-tert-butyl acetate- 10-acetic acid; l,4,7,10-Tetraazacyclododecane-l,4,7-tris-tert-butyl acetate-10- succinimidyl acetate; l,4,7,10-Tetraazacyclododecane-l,4,7-tris-tert-butyl acetate-10- maleimidoethylacetamide; 1,4,7, 10-Tetraazacyclododecane-l,4,7-tris-acetic acid-10- maleimidoethylacetamide; 1,4,7, 10-Tetraazacyclododecane-l,4,7-tris-tert-butyl acetate- 10-(N-a- Fmoc-N-e-acetamido-L-lysine); 1,4,7, 10-Tetraazacyclododecane-l,4,7-tris(t-butyl acetate)-10- (3 -butynylacetamide); 1 ,4,7, 10-T etraazacyclododecane- 1 ,4,7-tris(t-butyl-acetate)- 10-

(aminoethyl- acetamide); acetate- 10-(azidopropyl ethylacetamide); 1,4,7,10- Tetraazacyclododecane-l,4,7-tris(t-butyl acetate)- 10-(4-aminobutyl)acetamide; 1,4,7,10- Tetraazacyclododecane-l,4,7,10-tetraacetic acid mono-N-hydroxysuccinimide ester; 1,4,7,10- Tetraazacyclododecane-l,4,7-tris(acetic acid)-10-(2-thioethyl)acetamide or other variation of DOTA; S-2-(4-Aminobenzyl)-diethylenetriamine pentaacetic acid or other variation of DTPA; 3 , 6, 9, 15 -T etraazabicyclo [9.3.1] pentadeca- 1(15), 11, 13 -triene-4- S-(4-aminobenzyl)-3 ,6,9- triacetic acid or other variation on this pentadeca macrocycle; l-Oxa-4,7,10- tetraazacyclododecane-5-S-(4-aminobenzyl)-4,7,10-triacetic acid or other variation on oxosub stituted macrocycle; 2- S-(4-Isothiocyanatobenzyl)- 1,4,7 -triazacyclononane- 1,4,7 -triacetic acid or other variation on this cyclononane; and 1 l-(4-isothiocyanatophenyl)-3-[6,17-dihydroxy- 7,10,18,21-tetraoxo-27-(N-a- cetylhydroxylamino)-6, 11,17,22-tetraazaheptaeicosine] thiourea or other variation on deferoxamine.

In one embodiment, the chelator includes a nitrogen ring structure including a tetraazacyclododecane, atriazacyclononane, and/or a tetraazabicyclo [6.6.2] hexadecanederivative.

One example of a suitable chelating agent is DOTA (tetraxetan), an organic compound with the formula (CH2CH2NCH2CO2H)4. The molecule consists of a central 12-membered tetraaza (i.e., containing four nitrogen atoms) ring. DOTA is used as a complexing agent, and its complexes have medical applications as contrast agents and cancer treatments. The formula is shown below:

DOTA can be directly conjugated to monoclonal antibodies, without using a linker, for example, by attaching one of the four carboxyl groups to an amine on the antibody to form an amide. The remaining three carboxylate anions are available for binding to the radioactive ions. The modified antibody accumulates in the tumor cells, concentrating the effects of the radioactivity of the chelated radioactive ion. Drugs containing this module receive an International Nonproprietary Name ending in tetraxetan.

DOTA can also be linked to small molecules that have affinity for various structures, for example, small molecules which bind to receptors which are overexpressed in cancer cells. The resulting compounds can be used to chelate radioisotopes for use in cancer therapy and/or diagnosis (for example in positron emission tomography).

By way of example, some DOTA analogs have affinity for somatostatin receptors, which are found on neuroendocrine tumors:

DOTATOC, DOTA-(Tyr3)-octreotide or edotreotide

DOTA-TATE or DOTA-(Tyr3)-octreotate

DOTA can also be linked to the proteins streptavidin and avidin, which can be targeted at tumors by using monoclonal antibodies (i.e., DOTA-biotin). Other chelating agents can be used in a similar manner.

In some embodiments, the ²²⁵ Ac is present in the form of a radioimmunoconjugate that includes a humanized monoclonal antibody directed against prostate specific membrane antigen (PSMA). This type of radioimmunoconjugate can be used to not only diagnose prostate cancer, but also to treat prostate cancer (i.e., the radioimmunoconjugate is a theranostic agent).

Methods of Synthesizing Chelators

In some embodiments, compositions of chelators described herein can be synthesized using techniques that are simpler and less harsh than conventional techniques. In particular, the use of dichlorophenylmethane improves the synthesis of natural siderophores and analogs, such as 3,4,3- LI(CAM), by minimizing the use of harsh, toxic substances in the synthesis of siderophores and siderophore-like ligands. Additionally, the reaction conditions are improved when dichlorophenylmethane is used in the synthesis of siderophores and siderophore-like ligands.

Methods of Making Chelator/ Antibody Combinations

In particular embodiments, chelator/antibody combinations can be made by contacting one or more targeting proteins/antibodies with chelators and allowing complexes between the two molecules to form.

Methods of Charging Chelators with Radionuclides

In particular embodiments, chelators can be charged with radionuclides by contacting the chelators with metallic radioisotopes and allowing complexes between the two molecules to form.

Methods of Making Antibody-Chelator-Radionuclide Complexes

In particular embodiments, antibody-chelator-metal complexes can be made by contacting antibody-chelator complexes with metallic radioisotopes and allowing complexes between the molecules to form.

In other embodiments, complexes can be made by contacting chelator-metal combinations with antibodies, and allowing complexes between the molecules to form

CD33 or Siglec-3 (sialic acid binding Ig-like lectin 3, SIGLEC3, SIGLEC-3, gp67, p67) is a transmembrane receptor expressed on cells of myeloid lineage. It is usually considered myeloid- specific, but it can also be found on some lymphoid cells. Antibodies to this receptor, or other molecules which specifically bind to this receptor, can be used to target the radioisotopes to myeloid cancer cells, as well as some lymphoid cancer cells. Thus, where the ²²⁵ Ac or ²¹³ Bi is complexed to/chelated by a moiety including a chelating agent and an antibody which binds to the CD33 receptor, the complex can be used to treat leukemias, myelomas, certain lymphomas, and other plasma cell dyscrasias. Actinium Pharmaceuticals, Inc. has several clinical trials underway using antibodies to the CD33 receptor, combined with ²²⁵ Ac, for treating AML, multiple myeloma, and myelodysplastic syndrome (MDS). Other therapies using ²²⁵ Ac for treating leukemia are disclosed, for example, in Jurcic et al. “Targeted alpha particle immunotherapy for myeloid leukemia,” Blood. 2002;100(4): 1233-1239.

Prostate specific membrane antigen (PSMA) is expressed in prostate tumor cells. Complexation of the ²²⁵ Ac with a moiety including a chelating agent and an antibody to PSMA can be used to diagnose and/or treat prostate cancer.

Certain breast cancers can be targeted with antibodies, depending on the type of breast cancer. Other antibodies bind to markers associated with breast cancer. Specific targets/markers for breast cancer, and antibodies against those targets/markers, are provided below.

One antibody which binds to the HER2 receptor is the HER2 Antibody LS-B2133 (LS Bio). One antibody which binds to ER1, an estrogen receptor, is LS-B 10527 (LS Bio). One antibody which binds to the progesterone receptor is LS-B2983 (LS Bio). One antibody which binds to TP53 is LS-C172956 (LS Bio). One antibody which binds to EGFR is LS-B2914 (LS Bio). One antibody which binds to BRCA1 is LS-B3772 (LS Bio). One antibody which binds to APOBEC is LS-B12051 (LS Bio). One antibody which binds to Ki67 is LS-B3321 (LS Bio). One antibody which binds to CNN1 (calponin) is LS-B4304 (LS Bio). One antibody which binds to smooth muscle actin (SMA) is LS-B7351 (LS Bio). One antibody which binds to SMMHC (smooth muscle myosin heavy chain / MYH11) is LS-B5148 (LS Bio). One antibody which binds to CK5 (KRT5) is LS-B3359 (LS Bio). One antibody which binds to CK7 (KRT7) is LS-B7164 (LS Bio). One antibody which binds to CK14 (KRT14) is LS-B3916 (LS Bio). One antibody which binds to CK20 is LS-B10488 (LS Bio). One antibody which binds to E-cadherin (CDH1) is LS-B4674 (LS Bio). One antibody which binds to pl20 (CTNND1) is LS-B14422 (LS Bio). One antibody which binds to FOXA1 is LS-B4356 (LS Bio). One antibody which binds to GAT A3 is LS-B4163 (LS Bio). Other antibodies for these targets/markers can also be used. These antibodies can be conjugated with a chelating agent, and complexed with ²²⁵ Ac, to form diagnostic, therapeutic, and/or theranostic agents.

Libraries of Complexes Which Target Different Cancer Types In another embodiment, a library of compounds with appropriate chelating moieties and targeting moieties can be prepared. By including a number of different targeting moieties, once a patient’s tumor type has been identified, a custom anti-cancer drug, complete with isotopically- pure ²²⁵ Ac/ ²¹³ Bi, and a targeting moiety optimized for the patient’s cancer type, can be prepared. In this embodiment, not only is the patient’s specific type of cancer targeted, but also, the ²²⁵ Ac/ ²¹³ Bi that is delivered is more isotopically pure than ²²⁵ Ac/ ²¹³ Bi prepared by conventional processes, so is less likely to result in unwanted toxicity as a result of undesired isotopes, such as would be produced by procedures such as high energy spallation of ²³² Th, which produces unwanted and unavoidable quantities of ²²⁷ Ac.

Appropriate chelating, linker, and targeting moieties are discussed in more detail elsewhere herein.

To facilitate rapid production of appropriate targeted radiopharmaceuticals, these libraries of compounds capable of chelating the isolated ²²⁵ Ac/ ²¹³ Bi ions, and targeting the isolated ²²⁵ Ac/ ²¹³ Bi ions to specific cancers, can be created. Then, as the isolated ²²⁵ Ac/ ²¹³ Bi ions are formed, and a patient is genetically screened to identify the type of cancer to be treated, a specific treatment regimen can be created for this patient by complexing the isolated ²²⁵ Ac/ ²¹³ Bi ions with a molecule specifically designed to target the patient’s particular form of cancer.

Thus, using the processes described herein, a personalized medicine approach can be provided, for each type of cancer patient, using a robust process for preparing ²²⁵ Ac/ ²¹³ Bi, where the ²²⁵ Ac/ ²¹³ Bi has minimal isotopic impurities. By maximizing the efficiency of neutron capture, one can provide commercial quantities of ²²⁵ Ac/ ²¹³ Bi. By minimizing unwanted reactions, such as the (n,2n) reaction, one can provide isotopically-pure ²²⁵ Ac/ ²¹³ Bi, which is safer than ²²⁵ Ac/ ²¹³ Bi which includes higher quantities of unwanted isotopes. Finally, by custom synthesis of therapeutics that chelate the ²²⁵ Ac/ ²¹³ Bi and target a patient’s specific cancer type, patients can be efficiently treated for their specific cancer types.

V. Combination Therapy

Combination therapy using the radioactive ions/complexes described herein in combination with other anticancer drugs are also disclosed. The ions/complexes can be administered in combination or alternation with other types of anticancer agents. Representative additional anti-cancer agents are discussed below. Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP- 9 (matrix-metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, can be used in conjunction with a compound of formula 1 and pharmaceutical compositions described herein. Examples of useful COX-II inhibitors include CELEBREX. TM. (alecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published Oct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European Patent Application No. 97304971.1 (filed Jul. 8, 1997), European Patent Application No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (published Feb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918 (published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO 98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16, 1998), European Patent Publication 606,046 (published Jul. 13, 1994), European Patent Publication 931,788 (published Jul. 28, 1999), WO 90/05719 (published May 331, 1990), WO 99/52910 (published Oct. 21, 1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (published Jun. 17, 1999), PCT International Application No. PCT/IB98/01113 (filed Jul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar. 25, 1999), Great Britain patent application number 9912961.1 (filed Jun. 3, 1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12, 1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861,510 (issued Jan. 19, 1999), and European Patent Publication 780,386 (published Jun. 25, 1997), all of which are incorporated herein in their entireties by reference. Preferred MMP inhibitors are those that do not demonstrate arthralgia. More preferred are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrixmetalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP- 12, and MMP- 13).

The compounds described herein can also be used with signal transduction inhibitors, such as agents that can inhibit EGFR (epidermal growth factor receptor) responses, such as EGFR antibodies, EGF antibodies, and molecules that are EGFR inhibitors; VEGF (vascular endothelial growth factor) inhibitors, such as VEGF receptors and molecules that can inhibit VEGF; and erbB2 receptor inhibitors, such as organic molecules or antibodies that bind to the erbB2 receptor, for example, HERCEPTIN™ (Genentech, Inc. of South San Francisco, Calif., USA).

EGFR inhibitors are described in, for example in WO 95/19970 (published Jul. 27, 1995), WO 98/14451 (published Apr. 9, 1998), WO 98/02434 (published Jan. 22, 1998), and U.S. Pat. No. 5,747,498 (issued May 5, 1998), and such substances can be used in the present invention as described herein. EGFR-inhibiting agents include, but are not limited to, the monoclonal antibodies C225 and anti-EGFR 22Mab (ImClone Systems Incorporated of New York, N.Y., USA), ABX-EGF (Abgenix/Cell Genesys), EMD-7200 (Merck KgaA), EMD-5590 (Merck KgaA), MDX-447/H-477 (Medarex Inc. of Annandale, N.J., USA and Merck KgaA), and the compounds ZD-1834, ZD-1838 and ZD-1839 (AstraZeneca), PKI-166 (Novartis), PKI-166/CGP- 75166 (Novartis), PTK 787 (Novartis), CP 701 (Cephalon), leflunomide (Pharmacia/Sugen), CI- 1033 (Warner Lambert Parke Davis), CI-1033/PD 183,805 (Warner Lambert Parke Davis), CL- 387,785 (Wyeth- Ayerst), BBR-1611 (Boehringer Mannheim GmbH/Roche), Naamidine A (Bristol Myers Squibb), RC-3940-11 (Pharmacia), BIBX-1382 (Boehringer Ingelheim), OLX-103 (Merck & Co. of Whitehouse Station, N.J., USA), VRCTC-310 (Ventech Research), EGF fusion toxin (Seragen Inc. of Hopkinton, Mass.), DAB-389 (Seragen/Lilgand), ZM-252808 (Imperical Cancer Research Fund), RG-50864 (INSERM), LFM-A12 (Parker Hughes Cancer Center), WHL P97 (Parker Hughes Cancer Center), GW-282974 (Glaxo), KT-8391 (Kyowa Hakko) and EGFR Vaccine (York Medical/Centro de Immunologia Molecular (CIM)). These and other EGFR- inhibiting agents can be used in the present invention.

VEGF inhibitors, for example CP-547,632 (Pfizer Inc., N.Y.), AG-13736 (Agouron Pharmceuticals, Inc. a Pfizer Company), SU-5416 and SU-6668 (Sugen Inc. of South San Francisco, Calif, USA), and SH-268 (Schering) can also be combined with the compound of the present invention. VEGF inhibitors are described in, for example in WO 99/24440 (published May 20, 1999), PCT International Application PCT/IB99/00797 (filed May 3, 1999), in WO 95/21613 (published Aug. 17, 1995), WO 99/61422 (published Dec. 2, 1999), U.S. Pat. No. 5,834,504 (issued Nov. 10, 1998), WO 98/50356 (published Nov. 12, 1998), U.S. Pat. No. 5,883,113 (issued Mar. 16, 1999), U.S. Pat. No. 5,886,020 (issued Mar. 23, 1999), U.S. Pat. No. 5,792,783 (issued Aug. 11, 1998), WO 99/10349 (published Mar. 4, 1999), WO 97/32856 (published Sep. 12, 1997), WO 97/22596 (published Jun. 26, 1997), WO 98/54093 (published Dec. 3, 1998), WO 98/02438 (published Jan. 22, 1998), WO 99/16755 (published Apr. 8, 1999), and WO 98/02437 (published Jan. 22, 1998), all of which are incorporated herein in their entireties by reference. Other examples of some specific VEGF inhibitors useful in the present invention are IM862 (Cytran Inc. of Kirkland, Wash., USA); anti- VEGF monoclonal antibody of Genentech, Inc. of South San Francisco, Calif ; and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colo.) and Chiron (Emeryville, Calif.). These and other VEGF inhibitors can be used in the present invention as described herein.

ErbB2 receptor inhibitors, such as CP-358,774 (OSI-774) (Tarceva) (OSI Pharmaceuticals, Inc.), GW-282974 (Glaxo Wellcome pic), and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Tex., USA) and 2B-1 (Chiron), can furthermore be combined with the compound of the invention, for example those indicated in WO 98/02434 (published Jan. 22, 1998), WO 99/35146 (published Jul. 15, 1999), WO 99/35132 (published Jul. 15, 1999), WO 98/02437 (published Jan. 22, 1998), WO 97/13760 (published Apr. 17, 1997), WO 95/19970 (published Jul. 27, 1995), U.S. Pat. No. 5,587,458 (issued Dec. 24, 1996), and U.S. Pat. No. 5,877,305 (issued Mar. 2, 1999), which are all hereby incorporated herein in their entireties by reference. ErbB2 receptor inhibitors useful in the present invention are also described in U.S. Provisional Application No. 60/117,341, filed Jan. 27, 1999, and in U.S. Provisional Application No. 60/117,346, filed Jan. 27, 1999, both of which are incorporated in their entireties herein by reference. The erbB2 receptor inhibitor compounds and substance described in the aforementioned PCT applications, U.S. patents, and U.S. provisional applications, as well as other compounds and substances that inhibit the erbB2 receptor, can be used with the compounds described herein in accordance with the present invention.

The compounds can also be used with other agents useful in treating abnormal cellular proliferation or cancer, including, but not limited to, agents capable of enhancing antitumor immune responses, such as CTLA4 (cytotoxic lymphocite antigen 4) antibodies, and other agents capable of blocking CTLA4; and anti-proliferative agents such as other farnesyl protein transferase inhibitors, and the like. Specific CTLA4 antibodies that can be used in the present invention include those described in U.S. Provisional Application 60/113,647 (filed Dec. 23, 1998) which is incorporated by reference in its entirety, however other CTLA4 antibodies can be used in the present invention.

Other anti-angiogenesis agents, including, but not limited to, other COX-II inhibitors, other MMP inhibitors, other anti- VEGF antibodies or inhibitors of other effectors of vascularization can also be used.

Compositions like Neulasta® which help stimulate the growth of white blood cells, can also be used. U.S. Publication No. 20150286796 discloses combination therapy that includes different radiopharma isotopes. Using an analogous approach, one can combine additional radiopharmaceuticals with the ²²⁵ Ac and/or ²¹³ Bi produced by the processes disclosed herein. For example, a treatment plan may be optimized using more than one radiopharmaceutical. Radiopharmaceuticals emitting beta-particles, alpha-particles, or auger electrons, or any combination thereof may be used. Radiopharmaceuticals emitting beta-particles of different energy can be used.

VI. Methods of Treatment

In one embodiment, methods of treating cancer using the isolated ²²⁵ Ac and/or ²¹³ Bi ions are disclosed. In some embodiments, the compositions disclosed herein include in imaging and treatment in the same subject.

A "therapeutic treatment" can include a treatment administered to a subject in need of imaging. The subject can be in need of imaging to aid in diagnosis; to locate a position for a therapeutic intervention; to assess the functioning of a body part; and/or to assess the presence or absence of a condition. The effectiveness of a therapeutic imaging treatment can be confirmed based on the capture of an image sufficient for its intended purpose.

Exemplary types of imaging that utilize nuclear medicine include: positron emission tomography (PET), single photon emission computed tomography, radioisotope renography, and scintigraphy.

A "therapeutic treatment" can also include a treatment administered to a subject with a condition. The therapeutic treatment reduces, controls, or eliminates the condition or a symptom associated with the condition. Conditions treated with nuclear medicine include those associated with the proliferation of unwanted cells.

The compositions described herein are useful for treating cancer. Representative types of cancer that can be treated and/or imaged using the methods described herein include adrenal cancer, bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, carcinoma, cervical cancer, colon cancer, colorectal cancer, corpus uterine cancer, ear, nose and throat (ENT) cancer, endometrial cancer, esophageal cancer, gastrointestinal cancer, head and neck cancer, Hodgkin's disease cancer, intestinal cancer, kidney cancer, larynx cancer, leukemia, liver cancer, lymph node cancer, lymphoma, lung cancer, melanoma, mesothelioma, myeloma, nasopharynx cancer, neuroblastoma, non-Hodgkin's lymphoma, oral cancer, ovarian cancer, pancreatic cancer, penile cancer, pharynx cancer, prostate cancer, rectal cancer, sarcomcancer, seminomcancer, skin cancer, stomach cancer, teratomcancer, testicular cancer, thyroid cancer, uterine cancer, vaginal cancer, vascular tumor cancer, and/or cancer from metastases thereof. Specific examples include breast cancer, a leukemia, a lymphoma, brain cancer, liver cancer, lung cancer, melanoma, ovarian cancer, prostate cancer, pancreatic cancer, or bone cancer.

An "effective amount" is the amount of a composition necessary to result in a desired physiological change in the subject. Effective amounts are often administered for research purposes. Effective amounts disclosed herein can cause a statistically- significant effect in an animal model assessing a use of nuclear medicine.

The actual dose of the compositions described herein which is administered to a particular subject can be determined by a physician, veterinarian (for treating non- human animals), or researcher taking into account parameters such as physical and physiological factors including body weight; severity of condition; previous or concurrent therapeutic interventions; idiopathy of the subject; and route of administration.

In particular embodiments, the total dose of absorbed radiation may include 10' ³ grays (Gy), IO’ ² Gy, 10’ ¹ Gy, 1 Gy, 5 Gy, 10 Gy, 25 Gy, 50 Gy, 75 Gy, 100 Gy, 200 Gy, 300 Gy, 400 Gy, 500 Gy, 600 Gy, 700 Gy, 800 Gy, 900 Gy, or 1000 Gy.

Doses of absorbed radiation can be achieved by delivering an appropriate amount of a composition. Exemplary amounts of compositions can include 0.05 mg/kg to 5.0 mg/kg administered to a subject per day in one or more doses. For certain indications, the total daily dose can be 0.05 mg/kg to 3.0 mg/kg administered intravenously to a subject one to three times a day, including administration of total daily doses of 0.05-3.0, 0.1-3.0, 0.5-3.0, 1.0-3.0, 1.5-3.0, 2.0-3.0, 2.5-3.0, and 0.5-3.0 mg/kg/day of composition using 60-minute QD, BID, or TID intravenous infusion dosing. Additional useful doses can often range from 0.1 to 5 pg/kg or from 0.5 to 1 pg/kg. In other examples, a dose can include 1 pg/kg, 20 pg/kg, 40 pg/kg, 60 pg/kg, 80 pg/kg, 100 pg/kg, 200 pg/kg, 350 pg/kg, 500 pg/kg, 700 pg/kg, 0.1 to 5 mg/kg, or from 0.5 to 1 mg/kg. In other examples, a dose can include 1 mg/kg, 10 mg/kg, 20 mg/kg, 40 mg/kg, 60 mg/kg, 80 mg/kg, 100 mg/kg, 200 mg/kg, 400 mg/kg, 500 mg/kg, 700 mg/kg, 750 mg/kg, 1000 mg/kg, or more. Therapeutically effective amounts can be achieved by administering single or multiple doses during the course of an imaging or treatment regimen (e.g., daily, every other day, every 3 days, every 4 days, every 5 days, every 6 days, weekly, every 2 weeks, every 3 weeks, monthly, every 2 months, every 3 months, every 4 months, every 5 months, every 6 months, every 7 months, every 8 months, every 9 months, every 10 months, every 11 months, or yearly).

Brachytherapy

The radioisotopes discussed herein can be used in both targeted therapy, where drugs are administered systemically and target the tumor cells, and local therapy, such as brachytherapy, there the radioisotopes are administered at or near a tumor site.

Brachytherapy is one form of local, internal radiation therapy in which seeds, ribbons, or capsules that contain a radiation source, such as the radioisotopes described herein, are placed in your body, in or near the tumor. Brachytherapy is a local treatment and treats only a specific part of the patient’s body. Brachytherapy is most commonly used to treat prostate cancer, but can also be used to treat other cancer types, such as gynecologic cancers, like cervical, vaginal, and uterine (endometrial) cancer, breast cancer, lung cancer, rectal cancer, eye cancer, skin cancer, brain cancer, head and neck cancers, and pancreatic cancer.

Targeted Delivery

Ideally, the ²²⁵ Ac and/or ²¹³ Bi ions are delivered using targeted drug delivery approaches. Targeted drug delivery involves delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others.

There are two main types of targeting - passive and active.

Passive Targeting

In passive targeting, the drug’s success is directly related to circulation time. This is achieved by cloaking the nanoparticle with some sort of coating. Several substances can achieve this, with one of them being polyethylene glycol (PEG). By adding PEG to the surface of the nanoparticle, it is rendered hydrophilic, thus allowing water molecules to bind to the oxygen molecules on PEG via hydrogen bonding. The result of this bond is a film of hydration around the nanoparticle which makes the substance antiphagocytic. The particles obtain this property due to the hydrophobic interactions that are natural to the reticuloendothelial system (RES), thus the drug- loaded nanoparticle is able to stay in circulation for a longer period of time. To work in conjunction with this mechanism of passive targeting, nanoparticles that are between 10 and 100 nanometers in size have been found to circulate systemically for longer periods of time.

Active Targeting

Active targeting of drug-loaded nanoparticles enhances the effects of passive targeting to make the nanoparticle more specific to a target site. There are several ways that active targeting can be accomplished. One way to actively target solely diseased tissue in the body is to know the nature of a receptor on the cell for which the drug will be targeted to. One of skill in the art can use cell- specific ligands that will allow for the nanoparticle to bind specifically to the cell that has the complementary receptor. This form of active targeting was found to be successful when utilizing transferrin as the cell-specific ligand. The transferrin was conjugated to the nanoparticle to target tumor cells that possess transferrin-receptor mediated endocytosis mechanisms on their membrane. This means of targeting was found to increase uptake, as opposed to non-conjugated nanoparticles.

In some embodiments, the targeted drug delivery is accomplished by chelating the radioactive ions with a chelating agent bound, directly or through a linker, to a targeting moiety.

In other embodiments, the targeted drug delivery is accomplished by encapsulating the ions in a drug delivery vehicle sized to get lodged in capillary beds surrounding tumors. In one aspect of this embodiment, the treatment methods can involve targeting the isolated ²²⁵ Ac ions to cancer cells by encapsulating them in nanoparticles that lodge in capillary beds surrounding tumors, such as a small unilammelar vesicle, with a size less than 100 nm in diameter, preferably less than 50 nm in diameter.

In still other embodiments, the targeted drug delivery is accomplished by encapsulating the ions in a drug delivery vehicle that is coupled to a targeting moiety. These targeting moieties nanoparticles are loaded with drugs and targeted to specific parts of the body where there is solely diseased tissue, in this case, tumors, thereby avoiding interaction with healthy tissue.

There are different types of drug delivery vehicles, such as polymeric micelles, liposomes, lipoprotein-based drug carriers, nano-particle drug carriers, dendrimers, etc. Ideally, the drug delivery vehicle is non-toxic, biocompatible, non-immunogenic, biodegradable, and/or avoids recognition by the host's defense mechanisms.

In addition to biological targeting approaches, for example, using antibodies or small molecules which bind to receptors overexpressed in certain cancer types, other proposed cancer drug delivery methods use liposomes, viral nanoparticles, or carbon nanotubes (CNTs). Liposomes are spherical structures composed of an outer lipid bilayer surrounding a central aqueous space. Viral nanoparticles are derived from a variety of viruses, including the cowpea mosaic virus, cowpea chlorotic mottle virus, canine parvovirus, and bacteriophage. An advantage of viral nanoparticles is that recombinant deoxyribonucleic acid (DNA) methods can be used to cause the surface display of the targeting molecules. CNTs, despite that fact that they need modification to make them water-soluble, have the advantage of being able to be conjugated to a wide variety of active molecules such as nucleic acids, peptides, proteins, and other therapeutic compounds. CNTs can even be functionalized with multiple molecules at one time, which make them advantageous for cancer treatment. Fluorescently linked CNTs can also be used to detect cancerous cells. In one in vivo study, drugs bound to CNTs were shown to be more effectively internalized into cells than the free drug.

One limitation associated with using liposomes is their immediate uptake and clearance by the RES system and their relatively low stability. To combat this, polyethylene glycol (PEG) can be added to the surface of the liposomes, for example, in a mole percent of around 4-10%.

VII. Theranostic Treatment

In a “theranostic” application, one can diagnose, and then treat tumors. Theranostics is a combination of the terms therapeutics and diagnostics. In one embodiment, theranostics involves using one radioactive drug to identify (diagnose) and a second radioactive drug to deliver therapy to treat the main tumor and any metastatic tumors. However, one can identify where the actinium or bismuth ions are localized in the body using imaging techniques, so after the drug is delivered, ideally in a targeted way so that it localizes in tumors relative to healthy tissue, one can determine whether the tumor has metastasized, and follow the tumor progression over time. For example, by imaging the tumors, whether in a previously known location, a previously unknown location, or both, one can follow the progression of tumor size over the course of treatment, and know whether the treatment is being effective.

As discussed above, theranostic agents such as radioimmunoconjugates including ²²⁵ Ac and a humanized monoclonal antibody directed against prostate specific membrane antigen (PSMA) can be used to not only diagnose prostate cancer, but also to treat prostate cancer. The same applies for breast cancer, myelomas, leukemias, lymphomas, and other types of cancers.

Using the theranostic methods described herein, one can alternatively validate that a patient tumor is expressing a given target. This can be evidenced by chelating the 225 Ac described herein to a chelating agent/antibody that binds to the given target, and administering the resulting conjugate. Alternatively, one can initially use an imaging (gamma emitting) isotope that is targeted to the given target (such as by conjugation to a targeting moiety), and, once the existence of the tumor is confirmed, the patient can be treated using a therapeutic agent (i.e., 225 Ac or 213Bi produced as described herein, complexed with a chelating agent conjugated to an antibody specific for the given target).

Information obtained from the initial imaging can be used to customize a dosing level or dosing schedule, and follow-up imaging can be used to track the progress of the treatment, i.e., by comparing the size of the tumor at the start of treatment to the size of the tumor at various times after the initial treatment, and any subsequent treatments.

VIII. Kits

Also disclosed herein are kits including one or more containers including one or more of the active ingredients, compositions, antibodies or other targeting molecules, chelators, and/or radionuclides described herein.

In various embodiments, the kits may include one or more containers containing one or more portions of active ingredients and/or compositions to be used in combination with other portions of the active ingredients and/or compositions described herein. Associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use, or sale for human administration.

Optionally, the kits described herein further include instructions for using the kit in the methods disclosed herein. In various embodiments, the kit may include instructions regarding preparation of the active ingredients and/or compositions for administration; administration of the active ingredients and/or compositions; appropriate reference levels to interpret results associated with using the kit; proper disposal of the related waste; and the like. The instructions can be in the form of printed instructions provided within the kit or the instructions can be printed on a portion of the kit itself. Instructions may be in the form of a sheet, pamphlet, brochure, CD-Rom, or computer-readable device, or can provide directions to instructions at a remote location, such as a website. The instructions may be in English and/or in any national or regional language. In various embodiments, possible side effects and contraindications to further use of components of the kit based on a subject's symptoms can be included.

In various embodiments, the kits described herein include some or all of the necessary medical supplies needed to use the kit effectively, thereby eliminating the need to locate and gather such medical supplies. Such medical supplies can include syringes, ampules, tubing, facemasks, protective clothing, a needleless fluid transfer device, an injection cap, sponges, sterile adhesive strips, Chloraprep, gloves, and the like. Variations in contents of any of the kits described herein can be made. Particular kits provide materials to administer compositions through intravenous administration.

The present invention will be better understood with respect to the following non-limiting examples.

Example 1: Exemplary Configurations

For the purpose of interpreting within this disclosure, especially in cases where multiple neutron captures are occurring, decay-product nuclei can still be considered to also be reactionproduct nuclei. Reaction-product nuclei, whether they are also decay-product nuclei or not, may capture further neutrons. The resultant nuclei that result from the second capture (and any subsequent neutron captures beyond the second) are still considered to be reaction-product nuclei. This is true even if further radioactive decay occurs between or after neutron captures.

In the following descriptions, specially designed structures are implemented to cause entering neutrons to be moderated in such a way as to greatly increase their chances of being captured by a given intended reactant nucleus, such as radium-226, actinium-227, thorium-228, radium-228, or thorium-232. Vessels and housings described below are structures that are configured, generally, to minimize neutron leakage and to maximize internal neutron downscattering, analogous to a nuclear reactor’s flux trap, but not in the context or confines of a nuclear reactor. Cooling a volume containing at least some reactant or moderating nuclei, or a portion of a collection of nuclides, for example by using a cryogenic fluid like liquid helium, oxygen, nitrogen, neon, or deuterium, increases the likelihood of neutron capture by an intended reactant nucleus. For the purposes of this description, a reaction chamber is any volume in which reactant nuclei capture neutrons. This definition holds even if the volume comprises other nonreactant nuclei.

The following descriptions refer to reactant nuclei, reaction product nuclei, decay- product nuclei, and moderating nuclei. Unless otherwise expressly stated or implied, such references are made without regard to whether electrons are bound in electron shells about the nuclei or free. These descriptions relate therefore to both ionized and charge-balanced atomic arrangements of the described nuclei, such that the described nuclei may be that of uncharged atoms, ionized atoms, free atoms, and atoms bound in molecular bonds including ionic and covalent bonds. The described nuclei may be present in solid, gas, gel, liquid, or other forms. The reactant and moderating species may be combined as disordered mixtures, regular matrices, and molecular compounds prior to neutron exposure and such arrangements may be maintained, altered, or lost upon, for example, neutron capture reactions leading to subsequent decays. The reactant nuclei may be concentrated in a single location or dispersed throughout the apparatus.

The reactant nuclei may, if in solid form, be concentrated into one or more pellets, or into foils with large surface areas, or into other shapes. The reactant nuclei may be in solution within a solvent, or may be a component in a liquid, or may be in gaseous form.

Modeling simulations indicate that a system including an approximately 2-4 meter diameter vessel (with optional use of spheres and concentric spherical shells to differentiate layers on the basis of composition, temperature, or density) that implements at least to some degree some of the above principles can produce many hard-to-manufacture radioisotopes (“RI”s), including thorium-229 and actinium-225, at neutron efficiencies exceeding the current state of the art, where neutron efficiency is defined as:

Neutron Efficiency = (production rate of reaction-product nuclei) / (neutron production rate)

For this definition, it is understood that the production rates described are those observed during periods of operation, more specifically during the period of operation when neutrons are being produced. For this definition, it is also understood that the neutrons in the denominator’s “neutron production rate” refer to the initially produced neutrons (e.g. by nuclear spallation, DT reactions, from fission) rather than neutrons subsequently produced due to secondary reactions (e.g. such as from (n,xn) reactions) contained within the vessel. Initially produced neutrons, for example, would include both neutrons originating external to the apparatus and then incident upon the apparatus, and also neutrons produced within the apparatus by the action of a charged particle reaction such as a DT reaction, fission, or a spallation reaction. Subsequent neutron multiplication, e.g. (n,xn) reactions, do not contribute towards increasing the denominator. It is also understood, for this definition, that the rates mentioned in the numerator and denominator are considered to be averaged over short time intervals, preferably minutes and more preferably seconds, rather than over long periods of time such as hours, days or more. The rates described should be considered in the context of instantaneous rates rather than averaged rates considered over long time spans such as hours. Monte Carlo N-Particle (hereafter MCNP) simulations indicate that neutron efficiency values of approximately 10 percent and above are achievable upon implementation of one or more of the embodiments described below. Efficiencies above 50% (and in some cases above 100%, e.g. wherever (n,xn) reactions are common) might be realized upon improvement upon one or more of the embodiments by certain improvements in vessel geometry, temperature, and/or elemental composition. These neutron efficiency results can in general be achieved with a much smaller mass of reactant nuclei than can techniques that fail to implement to at least some degree some or all of the principles described above. Several embodiments of a system for the production of at least one isotope are described in the following detailed descriptions and are represented in the drawings.

Modeling simulations indicate that the production of reaction-product nuclei that are intended to capture multiple neutrons, placing at least some reactant nuclei closer to the neutron source at a distance lower than the distance taught in prior art (35-38 cm in U.S. Publication No. 20160042826), e.g. at distances lower than 30 cm, will greatly increase production rate, resulting in neutron efficiencies in the 10-30% range for masses of ²²⁶ Ra in the roughly 0.1 to 1 kg range. Higher efficiencies are achievable if the reactant nuclei also include reaction-product nuclei such as ²²⁷ Ac, ²²⁸ Th, and others. In these simulations, temperature reduction below 250 degrees Kelvin is assumed, most especially in the 4-10 degrees Kelvin range. Other temperatures such as about 75 degrees, about 50 degrees, and about 30 degrees Kelvin are also considered.

Modeling simulations indicate that during the production of reaction-product nuclei where the capture of only a single neutron is desired, placing at least some reactant nuclei further from the neutron source than the distance taught in prior art (35-38 cm in U.S. Publication No. 20160042826) will reduce the rate of unwanted (n,2n) reactions, reducing the production of e.g. unwanted ²³² U. In these simulations, temperature reduction below 250 degrees Kelvin is assumed, most especially in the 4-10 degrees Kelvin range. Other temperatures such as about 75 degrees, about 50 degrees, and about 30 degrees Kelvin are also considered.

In at least one such embodiment, the production of isotopes includes a reaction chamber in which reactant nuclei and moderating nuclei or a collection of nuclides are present. Temperature control capable of bringing at least some reactant nuclei or moderating nuclei or a portion of a collection of nuclides to temperatures below 250 degrees Kelvin is present. Neutrons for neutron capture reactions are introduced into the reaction chamber from an external neutron source, or are produced locally, for example via spallation when a spallation target inside of or nearby the reaction chamber is impacted by accelerated particles.

An apparatus 300 for producing reaction-product nuclei from reactant nuclei is shown in cross-sectional view in FIG. 1. Following the prior art, within a reaction chamber 304, neutrons 320 are preferably captured by reactant nuclei 322 to produce desired reaction product nuclei 324. Moderating nuclei or the collection of nuclides 326 are also present in the reaction chamber 304 in the illustrated embodiment. The moderating nuclei or the collection of nuclides scatter neutrons, thermalizing them to the local temperature of the moderating nuclei. In at least one embodiment, the apparatus contains temperature control capable of cooling at least some of the reactant nuclei and the moderating nuclei or a portion of a collection of nuclides to temperatures below 250 degrees Kelvin, preferentially below 50 degrees Kelvin. Reaction chamber walls 306 and 312 serve as structural support, and are preferably made of low cross-section material consistent with low temperature operation. The neutron source 316 is in proximity to the reactant nuclei sufficient to produce reaction-product nuclei. Cryogenic fluids may be present that assist with achieving the temperatures below 250 degrees Kelvin.

In at least one embodiment, the reaction-product nuclei 324 includes thorium-229 nuclei produced via multiple neutron capture upon radium-226 reaction-product nuclei 324 by neutron capture reactions. Due to the radioactive decay of thorium-229 nuclei, actinium-225 decay-product nuclei may also be present.

In at least one embodiment, the reaction-product nuclei 324 includes uranium-233 nuclei produced via single neutron capture upon thorium-232 reaction-product nuclei 324 by neutron capture reactions. Due to the radioactive decay of uranium-233 nuclei, thorium-229 decay-product nuclei may also be present.

In at least one embodiment, the reaction-product nuclei 324 includes thorium-229 nuclei produced via single neutron capture upon radium-228 reaction-product nuclei 324 by neutron capture reactions. Due to the radioactive decay of thorium-229 nuclei, actinium-225 decay-product nuclei may also be present.

In at least one embodiment, the moderating nuclei or the collection of nuclides 326 include nuclides that are chosen from a group consisting of deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen- 15, oxygen, fluorine, neon-20, and neon-22.

The neutron source 316 diagrammatically represents many types of neutron sources. Suitable examples include neutron emitters, neutron generators, nuclear reactors, subcritical assemblies of fissile material (sometimes called “piles”), sealed sources, DT generators, spallation neutron targets, and other neutron production devices. In at least one embodiment, the illustrated neutron source 316 represents a neutron generator with a neutron emission that is greater than 1 * 10 ¹⁴ neutrons per second, preferentially in the range of 1x10 ¹⁶ neutrons per second. The neutron generator may include a proton, deuteron, or helium-ion accelerator with a projectile energy greater than 8 MeV (much lower for DT neutron-producing reactions) and beam current typically in the range of a milliamp or higher, although systems may be designed with beam current in the range of microamps to hundreds of microamps. Thus, in various embodiments, neutrons 320 are provided by the neutron source 316, and the neutrons irradiate the reactant nuclei 322 such that the reaction product nuclei 324 are generated when the neutrons 320 are captured by the reactant nuclei 322. The system 300 in at least one embodiment is utilized to produce a particular nuclear species in a staged process that includes one or more induced neutron captures followed by one or more stages of radioactive decay resulting in production of the particular nuclear species. In at least one example, reactant nuclei 322 are exposed to neutrons 320 to produce, through neutron capture, reaction-product nuclei 324. Natural radioactive decays of the reaction-product nuclei 324 then subsequently produce decay-product nuclei 328 of a desired particular nuclear species. In a particular example, the reactant nuclei 322 in FIG. 1 represent thorium-228 nuclei that capture neutrons 320 to produce thorium-229 nuclei, which are represented by reaction-product nuclei 324.

Continuing that particular example, the decay-product nuclei 328 can represent a desired nuclear species, actinium-225, produced by the radioactive decay of thorium-229 followed by the decay of radium-225. It should be understood that FIG. 1 represents many other particular examples in which a desired nuclear species is created by a decay chain in which one or more radioactive decays occur following the production of the reaction-product nuclei 324 by neutron capture reactions induced by irradiating reactant nuclei 322 with neutrons 320. While thorium-229 produces actinium-225 in a double series of radioactive decay following neutron capture by thorium-228, these descriptions relate as well to various other decay sequences in which additional stages of decay occur, or where only one does. Multiple neutron captures can also occur upon the same reactant nuclei 322.

Generally, the apparatus 300 directs neutrons 320 into a volume where neutrons are captured by the reactant nuclei 322, instead of by other nuclei (e.g. 326, moderating nuclei or the collection of nuclides) or structure outside of reaction chambers, in a ratio that is significantly higher than in systems that lack strong thermalization, high moderating ratios, or low temperature utilization. As such, the apparatus 300 reduces neutron leakage, and allows the neutrons 320 emitted from the neutron source to be captured by the desired reactant nuclei at a meaningfully higher rate per mass of reactant nuclei, i.e., with many fewer neutrons 320 leaking out or being captured by nuclei other than reactant nuclei, and thus being wasted. The result is that the efficiency of capturing neutrons on the desired reactant nuclei in the apparatus 300 is high, (e.g. between 5 and 50%) and generally described by the following previously described relationship:

Following the prior art, a system 700 for producing reaction-product nuclei from reactant nuclei according to at least one embodiment is represented in FIG. 2. The system includes approximately spherical walls separating approximately spherical volumes, although forms such as cubes, rectangular prisms, and other compact shapes or compromises between them are possible. An external wall 702 defines the extent of the vessel. The vessel contains volumes (e.g. 706, 710, 712, 714, 716, 718) that may be or may comprise reactant nuclei, moderating nuclei, or the collection of nuclides. The volumes may be reaction chambers. In the embodiment shown in system 700, the volume 714 is denoted with hash marks as an example reaction chamber, although other configurations are possible in other embodiments. An access channel 732 defined through each of the walls and volumes permits access for accelerated particles to a central spherical target 706. A spherical shell-shaped reaction chamber 714 at least partially surrounds the target 706, although reaction chamber forms such as cubes, rectangular prisms, and other compact shapes or compromises between them are possible. The various volumes within the vessel may surround the target 706 concentrically. The target 706 is configured to emit neutrons when impacted by accelerated particles that reach the target through the access channel 732. The target 706 may be constructed of such materials as deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen- 15, oxygen, fluorine, neon-20, neon-22, tantalum, tungsten, lead, mercury, thallium, thorium, uranium, neptunium, and other transuranics. The access channel configured to accept greater than 50 percent of the accelerated particles that impinge upon the access channel.

Like the walls of the reaction chamber 304 of FIG. 1, and following the prior art, the walls (702, 720, 722, 724, 726) of FIG. 2 serve as a structural element with minimal neutron absorbing tendencies (e.g. a relatively low microscopic thermal neutron capture cross-section). Moderating nuclei or a collection of nuclides, which may comprise portions of regions 706, 710, 712, 714, 716, and 718, return at least some of the neutrons which scatter into their volumes back to the reaction chamber 714, which contains higher densities of reactant nuclei, to increase the likelihood that each neutron will be captured by reactant nuclei. The walls may include moderating nuclei, such that the wall is composed of high moderating ratio material having a low neutron capture cross section. For example, the walls may include beryllium and/or carbon. In at least one embodiment, a volume 718 external to the reaction chamber 714, may serve as a reflector, returning neutrons to inner volumes. Following the prior art, the reflector, in terms of thickness, in at least one embodiment, is greater than approximately 20 centimeters and less than approximately 15 meters. In some embodiments, thickness values between one and three meters are used. Other structural elements, not pictured, may be present, consistent with previously enumerated operating principles. As shown in FIG. 3, a particle accelerator (800) directs a high-energy beam 802 of particles into the access channel 732 of the system 700 (FIG. 2.) The target 706 within the path of the beam 802 produces neutrons as the beam of particles strike the target. The particle accelerator 800 may provide, for example, a high-energy beam of protons, deuterons, tritons, helium, or other particles. The particle accelerator 800 and target 732 together constitute a neutron source in at least one embodiment.

In at least one embodiment, neutrons produced at the target 706 are emitted in a fully or partially isotropic fashion. It is thought that neutron spallation produces a partially isotropic neutron emission distribution. Thus, putting the neutron emitting target at the center of the approximately spherical reaction chamber facilitates an acceptably uniform distribution of neutrons in that volume of the reaction chamber 714 where intended reactant nuclei await the emitted nuclei. Nonetheless, in embodiments where neutrons are provided or emitted anisotropically or directionally, the target 706 may be constructed and placed, for example non- concentrically with the wall 702, at any location within or relative to the reaction chamber 714 to maximize neutron efficiency with regard to capture by intended reactant nuclei in the chamber.

In one embodiment relating the concepts depicted in FIGS. 3. and 7., the reaction chamber 300 shown in cross-sectional format in FIG. 1. has its full volume shown 714 in FIG. 2. In this embodiment, all previous descriptions of processes occurring within FIG. 1 related to neutron capture, reaction-products and decay-products apply to volume 714.

The neutron capture target, which is composed of reactant nuclei, can exist in a variety of forms, such as pure metal, oxide, fluoride, or in general any form that makes radiochemistry straightforward and which does not introduce nuclei that would unduly compete with the reactant nuclei for neutron absorption. The phase of matter of the reactant nuclei, either pure or in whatever compound it is located in, can vary consistent with the intent of the previous sentence. In lower temperature systems, solid targets are thought to be more likely.

A system 700 for the production of desired nuclear species is represented in FIG. 2 according to at least one embodiment. The system 700 includes an at least partially spherical assembly within an outer wall 702. The system 700 is supported by a base 704, represented as a trapezoidal pedestal for exemplary purposes. The base 704 supports the weight of the system 700 without interfering with practical operation. Within the outer wall 702, multiple spherical shell layers surround a central target 706 in a concentric arrangement. The central target 706 emits neutrons when a beam 802 of particles is incident upon the target. The neutrons are emitted into the spherical shell layers surrounding the central target 706, at least some of the neutrons passing from the inner- most layer 710 to more outer layers. At least one of the spherical shell layers serves as a neutron capture reaction volume, having nuclei intended for neutron capture reactions present. Other layers serve as moderating and/or reflective layers to increase the likelihood that neutrons emitted from the central target 706 are captured by intended nuclei.

Although five spherical shell layers are illustrated in FIG. 2, these descriptions relate to layered structures having less than and more than five spherical shell layers. For purposes of example, the spherical shell reaction chamber layers illustrated in FIG. 2 are described herein, in increasing radial size from the central spherical target 706 to the outer wall 702, as: a first layer 710; a second layer 712; a third layer 714; a fourth layer 716; and a fifth layer 718, in which their numbered order corresponds to their radially ordered positions in the layered structure.

In FIG. 2, four spherical radially intermediary boundaries are illustrated in cross- section as: a first boundary 720 between the first layer 710 and second layer 712; a second boundary 722 between the second layer 712 and third layer 714; a third boundary 724 between the third layer 714 and fourth layer 716; and a fourth boundary 726 between the fourth layer 716 and fifth layer 718.

The spherical boundaries represent, in various embodiments, either: structural materials supporting and separating the adjacent layers; or the interface where layers meet without additional structural materials maintaining their separation. That is, the central spherical target 706 and ordered layers 710, 712, 714, 716 and 718 are distinct in various embodiments by their positions, contents and other physical properties such as temperatures with or without intervening material between them at the radially intermediary boundaries. Additional structural members may be used to connect and/or support each layer and boundary.

Structural materials by which the spherical boundaries may be constructed, in at least one embodiment of the system 700 of FIG. 2, include low microscopic thermal neutron capture crosssection materials. For example, silicon carbide, beryllium carbide, carbon, and zirconium may be used. The optimum thickness for structural material layers and their compositions vary among embodiments. Structural layers in various embodiment are thick enough to impart stability but not so thick as to excessively capture neutrons and lower neutron efficiency. In some embodiments, structural materials with average microscopic thermal neutron capture cross sections of less than 300 millibarns, such as zirconium, may be used. In other embodiments, structural material with average microscopic thermal neutron capture cross sections of less than 30 millibarns may be used, such as polymers or plastics containing carbon, deuterium, and oxygen. In some embodiments, materials providing structural support may double as moderating nuclei.

Upon emission of neutrons from the target 706, neutron capture processes occur between the target and an outer wall 702 of the system 700 within one or more of the surrounding layers 710, 712, 714, 716, and 718 to facilitate production of a desired nuclear species. The outer wall 702 is illustrated as a spherical boundary for convenience but may take other form in some embodiments.

An access channel 732 is represented as a cylindrical bore from the outer wall 702 toward the central spherical target 706. The access channel 732 permits a beam 802 of particles to reach the target 706. A radially extending wall 734 defining the access channel 732 is illustrated in FIG. 2 as cylindrically shaped to match the cylindrical bore through the layered structure. In various other examples, the wall 734 and bore have other shapes, for example matching conical shapes with taper, to define the access channel 732. The radially extending wall 734 in at least one embodiment connects the outer wall 702 to the central target 706, isolating the layers 710, 712, 714, 716 and 718 from each other, and from the exterior of the outer wall 702 while permitting access to the central target 706.

The access channel 732 can serve two or more purposes. It allows a particle beam to reach the center of the system 700, where incoming particles such as protons, deuterons, helium nuclei, and other projectiles can produce neutrons, for example by inducing nuclear reactions at a central target. For example, if beryllium is used as the central target 706, incoming high energy particles like e.g. protons can make neutrons via e.g. ⁹ Be(p,n) reactions. The access channel 732 also allows for the entry and exit of cooling fluid to control temperature in the layers of the system 700. For example, liquid helium, oxygen, and/or other coolants might be used to maintain the temperatures of the central spherical target 706 and layers 710-718, each at a particular respective temperature. The cryogenic system has not been illustrated in Figures 1, 2, 3, 5, and 6, for the sake of greater visual clarity of the remaining elements.

In some embodiments of the system 700, temperatures are maintained to preferentially control the moderating ratio and/or to increase the microscopic neutron capture cross-section of a desired reactant nuclide. In some embodiments, temperatures are lowered in some layers to less than about 75, 50, 30, or 10 degrees K, and even to as low as the boiling point of helium, and even lower still.

One or both of these described purposes might be served by the access channel 732 in various embodiments. For example, a neutron generation mechanism might be entirely contained inside the vessel. Furthermore, more than one bore may be present. The shapes, sizes, locations, and numbers of bores can vary without changing the principles above. Some embodiments might not use any bores.

In at least one embodiment, the neutron-emitting target comprises at least 10 grams of nuclei that possess a microscopic thermal neutron capture cross-section greater than that of the reactant nuclei, in a volume where average neutron energy is much higher than thermal energy. Relegating materials with higher than desired microscopic thermal neutron capture cross-sections to central regions, and/or regions where neutron energy is much higher, is thought to minimize parasitic absorptions, while still allowing the material to provide secondary useful purposes, like providing a target for neutron spallation. In at least one embodiment, the neutron-emitting target comprises at least 10 grams of nuclei that possess a microscopic thermal neutron capture crosssection greater than that of the reactant nuclei, and where the neutron-emitting target is configured (e.g. geometrically, thermally) to absorb as few neutrons as possible, for example less than 1, 5, or 10% of all neutrons produced at the target.

In at least one embodiment, an externally delivered beam 802 of particles enters the access channel to create neutrons through nuclear reactions at the target 706. In another example, an RI decay source of neutrons is placed at the target location; for example, AmBe, ²⁵² Cf, PuBe, and other sources may be used.

Because the system is designed to moderate neutrons of high energy (for example, even greater than 8-14 MeV), the system can handle a wide variety of neutron energy input without loss of function. For example, DT neutrons and spallation sources may be used. Various neutron intensities or input rates are also acceptable. An underlying design principle implemented by one or more embodiments described herein is directed to increasing the probability that any one neutron gets captured by a given intended reactant. As a result, the intensity of the neutrons delivered into the vessel should not greatly vary the average neutron efficiency, so long as temperature control can be suitably maintained. There already exist commercial accelerators, that can reach the energies and beam currents necessary to produce approximately the neutrons intensities mentioned previously. For example, particles including protons, deuterium, tritium, helium, and other examples, when incident upon a neutron-producing target, can make between 0.1 and 5 (or more) neutrons per incident particle at energies of tens to a few hundreds of MeV. Different targets yield different neutron yields in a process called nuclear spallation.

In at least one example, a beam of high energy (tens to hundreds MeV) particles are incident on a neutron rich target, generating sufficient neutrons for practical operation. Assuming approximately one neutron is generated per incident nuclear particle, a beam of approximately IxlO ¹⁶ particles per second, or a few milliamps of beam current, is considered useful, although higher or lower beam currents may also be commercially interesting. Beams that can provide a few tens or hundreds of MeV at milliamp beam currents or higher are available in industry research implementations, for example in commercial medical isotope production. Higher or lower beam energies and beam currents may be warranted to reduce cost or to alter neutron production rates over time, in order to alter the rate of neutron-producing-target heating, for example due to heating as the high energy particles decelerate, in which some collisions generate heat instead of (or in addition to) neutrons.

In at least one embodiment, a system 1000 for producing reaction-product nuclei from reactant nuclei is represented in FIG. 5. The system includes approximately spherical walls separating approximately spherical volumes, although forms such as cubes, rectangular prisms, and other compact shapes or compromises between them are possible. An external wall 1002 defines the extent of the vessel. The vessel contains volumes (e.g. 1006, 1010, 1012, 1014, 1016, 1018) that may be or may comprise reactant nuclei, moderating nuclei, or a collection of nuclides. The volumes may be reaction chambers. In the embodiment shown in system 1000, the volume 1014 is denoted with hash marks as an example reaction chamber, although other configurations are possible in other embodiments. An access channel 1032 defined through each of the walls and volumes permits access for accelerated particles to a central spherical target 1006. A spherical shell-shaped reaction chamber 1014 at least partially surrounds the target 1006, although reaction chamber forms such as cubes, rectangular prisms, and other compact shapes or compromises between them are possible. The various volumes within the vessel may surround the target 1006 concentrically. The target 1006 is configured to emit neutrons when impacted by accelerated particles that reach the target through the access channel 1032. The target 1006 may be constructed of such materials as deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen- 15, oxygen, fluorine, neon-20, neon-22, tantalum, tungsten, lead, mercury, thallium, thorium, uranium, neptunium, and other transuranics. The access channel configured to accept greater than 50 percent of the accelerated particles that impinge upon the access channel.

Compared to FIG. 2, FIG. 5. has its reactant nuclei at a distance closer to the source of neutrons, which in this case originate from near or at the center of the spherical vessel. This reduced distance results in a higher total neutron flux in this embodiment for the reaction chamber 1114, which assists with increasing the rate of multiple neutron capture for the reactant nuclei there. In some other respects, the system operates via principles similar to the ones described in previous paragraphs describing Figure 7. However, at closer distances and higher total neutron fluxes, greater heat dissipation may be needed to maintain lowered temperatures. Enhanced cryogenic cooling may be used. In certain embodiments, more than 0.1% of all reactant nuclei may have experienced multiple neutron captures, a result that can be demonstrated using standard nuclear forensics approaches, i.e. approaches which allow one skilled in the art to determine information such as the source, age, and method of nuclear material production. In this context, reactant nuclei are nuclei that the user wishes to experience neutron capture, whether or not further radioactive decays occur. In this context, reaction-product nuclei may serve as further reactant nuclei, as described previously. Reactant nuclei for these embodiments may comprise radium-226, actinium-227, or thorium-228, with the intent of producing thorium-229 and/or actinium-225 and/or radium-225. In this instance, the radium-226 may be original feedstock reactant nuclei, while the actinium-227 are reactant nuclei that may have experienced a single neutron capture and thorium-228 are nuclei that may have experienced double neutron capture. In other instances, actinium-227 may serve as the feedstock material, producing thorium-229 via two neutron captures.

Much more than 0.1% of all nuclei might result from neutron capture, for example, after months or years of operation, more than 1% or more than 10% of all nuclei present may result from multiple neutron capture. Using the high neutron flux geometry embodiment described here for multiple neutron capture should not be construed as precluding its use for single neutron capture applications where high neutron flux operation is critical or enabling for producing sufficient amounts of material, compared to what is taught in the prior art.

In at least one embodiment, a system 1100 for producing reaction-product nuclei from reactant nuclei is represented in FIG. 6. The system includes approximately spherical walls separating approximately spherical volumes, although forms such as cubes, rectangular prisms, and other compact shapes or compromises between them are possible. An external wall 1102 defines the extent of the vessel. The vessel contains volumes (e.g. 1106, 1110, 1112, 1114, 1116, 1118) that may be or may comprise reactant nuclei, moderating nuclei, or a collection of nuclides. The volumes may be reaction chambers. In the embodiment shown in system 1100, the volume 1114 is denoted with hash marks as an example reaction chamber, although other configurations are possible in other embodiments. An access channel 1132 defined through each of the walls and volumes permits access for accelerated particles to a central spherical target 1106. A spherical shell-shaped reaction chamber 1114 at least partially surrounds the target 1106, although reaction chamber forms such as cubes, rectangular prisms, and other compact shapes or compromises between them are possible. The various volumes within the vessel may surround the target 1106 concentrically. The target 1106 is configured to emit neutrons when impacted by accelerated particles that reach the target through the access channel 1132. The target 1106 may be constructed of such materials as deuterium, tritium, helium-4, lithium-7, beryllium, boron-11, carbon, nitrogen- 15, oxygen, fluorine, neon-20, neon-22, tantalum, tungsten, lead, mercury, thallium, thorium, uranium, neptunium, and other transuranics. The access channel configured to accept greater than 50 percent of the accelerated particles that impinge upon the access channel.

Compared to FIG. 2, FIG. 6 has its reactant nuclei at a distance further from the source of neutrons, which in this case originate from at or near the center of the spherical vessel. This results in a lower fast neutron flux (in this case, defined as neutrons with energies greater than 6 MeV) in this embodiment for the reaction chamber 1114, which assists with reducing the rate of unwanted neutron reactions for the reactant or reaction-product nuclei there, e.g. (n,2n) reactions. In other respects, the system operates via principles similar to the ones described in previous paragraphs describing Figure 7. However, at further distances and lower fast neutron fluxes, less heat dissipation may be needed to maintain lowered temperatures. Reduced cryogenic cooling may be used. In certain embodiments, the rate of (n,xn) reactions in the reactant nuclei may be reduced by a factor of lOOx over the rate experienced by the same reactant nuclei operated in the context of the baseline geometry in FIG. 2. In other embodiments, the rate of (n,xn) reactions in the reactant nuclei may be reduced to less than 1 millionth, or even 1 billionth the rate of neutron capture in the reactant nuclei. In this context, reactant nuclei are nuclei that the user wishes to experience neutron capture, whether or not further radioactive decays occur. Reactant nuclei for these embodiments may comprise radium-228 or thorium-232, with the intent of producing thorium-229 and/or actinium-225, and/or radium-225. In some embodiments where thorium-232 reactant nuclei are present, the rate of (n,2n) reactions experienced by uranium-233 reaction-product nuclei might be reduced strongly, resulting in fewer unwanted uranium-232 nuclei, as well as fewer unwanted daughter nuclei, e.g. thorium-228. Using the low fast neutron flux geometry embodiment described here for single neutron capture should not be construed as precluding its use for multiple neutron capture applications where reduced fast neutron flux operation is critical or enabling for producing sufficient amounts of material, compared to what is taught in the prior art.

As shown in FIG. 3, a particle accelerator 800 directs a high-energy beam 802 of particles into the access channel 732 of the system 700 (FIG. 2). In FIG. 3, only the central spherical target 706 is expressly illustrated to represent the layered shell structure more expressly illustrated in FIG. 2. As with FIG. 2, FIG. 3 represents layered structures having any number of approximately spherical shell layers. FIG. 3 illustrates a configuration in which an intended reactant nuclide may be present in any or all layers, and may additionally serve as structural material. Target nuclei 804 within the path of the beam 802 produce neutrons 806 as the beam particles strike. In this diagrammatic representation, a particle accelerator 800, emitting for example protons, deuterons, tritons, helium, or other particles, makes a high energy beam of incident particles or nuclei that enter the system 700 through the access channel 732, hit the target 804, causing neutrons 806 to be emitted. FIGS. 2-3 represent many configurations of materials and geometries that are characterized by a high moderating ratio volume within the system 700. The arrangements represented can be varied within the scope of these descriptions without compromising the high neutron efficiency. For the purpose of interpreting, the target spoken of here, which produces neutrons when struck by accelerated particles, is not the neutron capture target spoken of in other locations in this disclosure.

Many forms of neutron production according to embodiments within the scope of these descriptions cause neutrons to be emitted in a mostly or partially isotropic fashion. Putting the neutron emitting target close to the center of the volume can help distribute isotropically emitted neutrons uniformly into zones rich with nuclei intended for neutron capture to help maximize neutron efficiency. Alternatively, in situations with anisotropy in neutron emission, the neutron emitter location and shape may be varied or optimally selected to improve neutron efficiency.

Heating and/or cooling is provided in various embodiments to maintain a neutronproducing target at a selected stable temperature. Cooling may be used to facilitate enhancement of the neutron capture rate of reactant nuclei by reducing neutron energy and thereby enhancing the microscopic neutron capture cross-section of the intended reactant nuclei, such as ²²⁶ Ra or ²³² Th nuclei. Cooling may include cryogenic cooling, which may include the use of cryogenic fluids. Heating may also be used to reduce neutron capture of non-reactant nuclei by increasing neutron energy. The coolant and any tubing, piping, and casing that carry the coolant within the housings described herein preferably also have small microscopic neutron capture cross-sections, but are able to handle colder-than-room-temperature or cryogenic temperatures without compromising functional integrity. Tubing materials can include, for example: any polymer constructed with carbon, deuterium, oxygen, beryllium, fluorine, and other low microscopic neutron capture cross-section materials; or metals like, for example, zirconium. Sufficient coolant should be applied to remove waste heat created during neutron moderation, and also to remove waste heat created during high-energy photon or electron creation and moderation, e.g. from capture gammas. Coolant may also be used to cool any layers of the vessel and/or reaction chamber down to temperatures below room temperature, for example, down to approximately 100 degrees K, 75 degrees K, 50 degrees K, 30 degrees K, 10 degrees K, or to and even below the boiling point of helium. In some embodiments, the intentional use of heating to raise temperatures above room temperature might also be employed in order to increase neutron energy and thereby reduce microscopic neutron capture cross-sections. A separate cooling loop used to maintain the temperature of the neutron spallation source may also be used. The neutron spallation source may be kept at or below room temperature, or at temperatures above room temperature that are consistent with safe operation of the apparatus as a whole.

Structural material used in constructions should be able to operate at lower-than- roomtemperature and cryogenic temperatures, and also to withstand cycles of temperature between room temperature and lower-than-room-temperature or cryogenic temperature, if lower temperatures are used. Coolant, if used, may enter and leave interior volumes at more than one place. For example, in addition to entering and/or exiting at the bore, coolant might enter or leave at various conduits. Specialty low microscopic thermal neutron capture cross-section variants of commercially available structural materials, pipes, electronic components, heat exchangers, etc. may be used or specifically manufactured for use in this apparatus.

As shown in FIG. 4, an exemplary thermal control system 900 is represented for use with a layered shell vessel 902 that represents layered structures having any number of spherical, cubic, or otherwise compact shell layers 904 concentrically arranged around a central spherical target or cavity 906. A high-energy beam 910 enters the vessel 902 through a bore 912 and a target nucleus 914 within the path of the beam 910 produces neutrons as the beam particles strike the target. FIG. 4 illustrates a configuration in which an intended reactant nuclide may be present in any or all layers, and thus diagrammatically represents thermally maintained implementations of at least the systems illustrated in FIGS. 3, 5, and 6.

The thermal control system 900 includes any number of primary conduits 920 and subconduits 922 and 924 defining send and return fluid paths constituting a branched fluid distribution network implemented in the layered structure of the layered shell vessel 902 such that the shell layers 904 can be thermally maintained independently or together. In at least one embodiment, a standard cryogenic fluid producing device 926 is used to cycle a coolant fluid with low microscopic neutron capture cross-section, and which is sufficiently free of higher microscopic neutron capture cross-section contaminants. In another embodiment, cooling fluid is used to keep at least some reactant nuclei and/or moderating nuclei or a portion of a collection of nuclides between 1 and 250 degrees K. The cooling, whether cryogenic or otherwise, should be done in such a way so as not to interfere with the beam 910 entering the bore.

Particularly within the vessel 902, conduit lines, tubing, enclosures, and the distributed coolant should have low microscopic neutron capture cross-sections so as to minimize neutrons being captured by material within the vessel other than the intended reactant. Various cooling systems and arrangements meeting these conditions are within the scope of these descriptions, as are various methods of lower-than-room-temperature or cryogenic fluid delivery, storage, and production.

In some embodiments, removal of a produced radioisotope may proceed by allowing the various layers to cool or heat up to room temperature naturally, or may occur by removing frozen material, if material is present in frozen form (for example ²²⁶ Ra or thorium in solid D2O, oxygen, etc.). Extraction may involve waiting a certain time period to allow for certain radioactive nuclei present to decay to lower, more acceptable levels of radioactivity. Extraction may involve disassembling certain volumes within the vessel, and removing the reactant nuclei only, or the reactant nuclei and any encapsulation they reside within. It may also involve removing moderating nuclei, or nuclei from a collection of nuclides. It may involve removing all or any of the preceding, plus other kinds of nuclei not strictly defined by reactant or moderating nuclei.

In some embodiments, to extract and ship radioisotopes such as thorium-229 or actinium- 225, existing radiochemical methods and existing or modified supply chain procedures may be followed. In situations where thorium-229 or actinium-225 may not be easily extracted from precursor nuclei, or where such extraction is not warranted or necessary, the mass of thorium-229 may be shipped together, used in thorium generators, and returned to have the thorium extracted for re-use. In some embodiments, altered or improved thorium-229 generators may be used, or the actinium-225 may be shipped directly. Apparatuses according to these descriptions are constructed in such a way that removing or adding reactant nuclei material, such as radium-226, is fast and easy. For example, it may be constructed in such away that the layer or layers containing reactant nuclei material are easily removed, pumped out if liquid, or added back.

The volume or volumes with the intended reactant nuclei for neutron absorption/capture is preferably specially constructed for convenient removal of the activated material after irradiation. Further, enriched material may be used.

Several exemplary configurations are specified in further detail below in Tables 1-6, wherein Tables 1-3 discuss possible configurations of an embodiment where the distance between the neutron capture target and the neutron source is configured in order to increase total neutron flux, and wherein Tables 4-6 discuss possible configurations of an embodiment where the distance between the neutron capture target and the neutron source is configured in order to decrease the high energy neutron flux. In Tables 1-3, densities, materials, temperatures, and dimensions are specified for the central target 1006 and layers 1010 (first layer), 1012 (second layer), 1014 (third layer), 1016 (fourth layer) and 1018 (fifth layer) for the system 1000 of FIG. 5. Of note, an additional layer was added, titled layer la, to reflect the geometry of the exemplary configurations 1-3; this layer would conceptually go between 1010 and 1012 in a hypothetically altered FIG. 5. In Tables 4-6, densities, materials, temperatures, and dimensions are specified for the central target 1106 and layers 1110 (first layer), 1112 (second layer), 1114 (third layer), 1116 (fourth layer) and 1118 (fifth layer) for the system 1100 of FIG. 6. Of note, an additional layer was added, titled layer la, to reflect the geometry of the exemplary configurations 4-6; this layer would conceptually go between 1110 and 1112 in a hypothetically altered FIG. 6.

It should be understood that these configurations are provided as examples without limiting these descriptions to those examples.

Not all conceivable configurations will have a spherical central target and five concentric layers. These are just examples. These exemplary configurations are derived from computer modeling using neutron transport codes. Neutron transport modeling was performed using MCNP5, MCNPX, and Monteburns 2.0, which are known and often used by those of skill in the art. For the sake of simplicity, modeling did not include some structural or thermal control materials or components, but only the geometry considered most relevant to operation. In one instance of computer modeling of the system, summarized below, input neutrons were assumed to be emitted isotropically from the target (either 1006 or 1106) as the result of spallation from a 150 MeV deuteron beam decelerating in the central target, with an energy probability distribution determined by MCNPX, which simulates deuteron spallation. Note that the various materials in the below configurations may be in gas, liquid or solid form depending on temperature. Note that the central target is considered to be a neutron emitting target, whereas the neutron capture target is Layer 3, which is either ²²⁶ Ra or ²³² Th for the examples below.

Tables 1-3 discuss possible configurations of an embodiment where the distance between the neutron capture target and the neutron source is configured in order to increase total neutron flux.

Table 1 - Configuration 1

Table 2 - Configuration 2

Table 3 - Configuration 3 Neutron efficiency, defined as the instantaneous rate of target (in this case ²²⁶ Ra) neutron capture divided by the rate of neutron generation, is predicted to go from about 3.9% to 19% as one transitions from the temperatures (layers 2-4) simulated in configuration 1 to those simulated in configuration 3. This represents production yields that would be commercially competitive ²²⁹ Th production rates if experienced during commercial implementation. MCNP/Monteburns simulations and pen and paper modeling produce highly consistent results, and estimate ²²⁹ Th production at approximately 4-5 grams/year/(kg of target material)/mA of beam current, averaged over a multiyear period.

Tables 4-6 discuss possible configurations of an embodiment where the distance between the neutron capture target and the neutron source is configured in order to decrease the high energy neutron flux.

Table 4 - Configuration 4

Table 5 - Configuration 5

Table 6 - Configuration 6

Neutron efficiency, defined as the instantaneous rate of target (in this case ²³² Th) neutron capture divided by the rate of neutron generation, is predicted to go from about 3.7% to 22% as one transitions from the temperatures (layers 2-4) simulated in configuration 4 to those simulated in configuration 6. MCNP/Monteburns simulations and pen and paper modeling produce highly consistent results, and estimate ²³³ U production at approximately 2.5-3.5 grams/year/(kg of target material)/mA of beam current, averaged over a multiyear period. In turn, this ²³³ U would “in grow” roughly 4 milligrams of ²²⁹ Th per year per kg of ²³³ U. This uranium could be separated from the thorium target at times chosen on the basis of convenience, safety, regulatory compliance, or other factors.

Extra layers could be added, or layers removed, or these principles modified, or geometries or materials added or changed or altered without changing the premise of these descriptions.

Particular embodiments and features have been described with reference to the drawings. It is to be understood that these descriptions are not limited to any single embodiment or any particular set of features, and that similar embodiments and features may arise or modifications and additions may be made without departing from the scope of these descriptions and the spirit of the appended claims.

The frequent use of radium, actinium, thorium, and uranium isotopes in examples throughout this disclosure should not be construed to limit the type or number of isotopes that can be made using the techniques disclosed herein. Additional MCNP simulation results not included above suggest that performing at least some of the techniques disclosed above on different reactant nuclei will result in similarly excellent improvements in reaction-product nuclei production rates and efficiencies. Similarly, reductions in unwanted contaminant isotopes that result from an excess of fast neutron flux are also expected in contexts outside of thorium-232 reactant nuclei and uranium-233, thorium-229, and/or actinium production.

The contents of each reference referred to herein are incorporated herein by reference in their entireties.