Techniques for obtaining terbium-161 and related systems and methods

Abstract

The inventors have developed technology to improve the generation of daughter isotopes for clinical treatments. The technology includes systems and methods for using a liquid target to deliver parent isotopes to a reactor for neutron bombardment and subsequently separating desired daughter isotopes from the liquid target. According to an aspect of the technology described herein, a method of obtaining desired daughter isotopes comprises pumping a liquid target solution comprising a parent isotope through a fluid path that includes a first portion that passes through a fission reactor, a second portion that passes through a pump, and a third portion that passes through an isotope capture device.

Description

Attorney Docket No. S2302.70007WO00 TECHNIQUES FOR OBTAINING TERBIUM-161 AND RELATED SYSTEMS AND METHODS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 63 / 644,860 filed May 9, 2025, titled “TECHNIQUES FOR OBTAINING TERBIUM-161 AND RELATED SYSTEMS AND METHODS,” which is herein incorporated by reference in its entirety. BACKGROUND

[0002] Nuclear medicine offers a highly effective, non-invasive approach to deliver targeted radiation to tumor cells, ensuring maximum therapeutic efficacy while sparing surrounding healthy tissues. Radiotherapeutic drugs are notably advantageous in scenarios where antibody-drug conjugates (ADCs) may not achieve desired outcomes due to drug resistance or insufficient intracellular drug release. As such, radiotherapeutics can deliver enhanced therapeutic efficacy with fewer side effects, compared to traditional radiation therapy, while facilitating real-time visualization of drug distribution and tumor response. Examples include Lutetium-177 labeled radiotherapeutic drugs, such as Lutathera (2018) and Pluvicto (2021), which have provided novel treatment options for tens of thousands of patients across the US to date. Notably, metastatic castration-resistant prostate cancer (mCRPC) and neuroendocrine tumors (NETs) are the two primary diseases targeted for Pluvicto and Lutathera, respectively. SUMMARY

[0003] According to some aspects of the presently disclosed technology, a method of obtaining desired daughter isotopes comprises: pumping a liquid target solution comprising a parent isotope through a fluid path that includes a first portion that passesAttorney Docket No. S2302.70007WO00 through a fission reactor, a second portion that passes through a pump that pumps the liquid target solution through the fluid path, and a third portion that passes through an isotope capture device, and wherein the second portion and the third portion are located outside of the fission reactor; irradiating the liquid target solution with a neutron flux, as the liquid target solution passes through the fission reactor; and purifying a desired daughter isotope from the liquid target solution at least in part through using the isotope capture device.

[0004] In some embodiments, the purifying step comprises capturing the desired daughter isotope from the liquid target solution using the isotope capture device.

[0005] In some embodiments, the method further comprises eluting the desired daughter isotope captured by the isotope capture device from the isotope capture device.

[0006] In some embodiments, the fluid path is a closed loop.

[0007] In some embodiments, the fluid path is an open path.

[0008] In some embodiments, irradiating the liquid target solution with the neutron flux directly generates the desired daughter isotope.

[0009] In some embodiments, irradiating the liquid target solution with the neutron flux generates an intermediate isotope, and the desired daughter isotope is produced from decay of the intermediate isotope.

[0010] In some embodiments, the intermediate isotope is a first intermediate isotope and irradiating the liquid target solution with the neutron flux generates two or more intermediate isotopes from the liquid target solution, the two or more intermediate isotopes comprising a second intermediate isotope.

[0011] In some embodiments, the second intermediate isotope has a longer half-life than the first intermediate isotope, and the desired daughter isotope is separated from the liquid target solution by: capturing the desired daughter isotope in the isotope capture device; monitoring the liquid target solution for a contaminant isotope, wherein the contaminant isotope is formed from the decay of the second intermediate isotope; and when a concentration of the contaminant isotope increases to a predetermined level, removing the isotope capture device from the fluid path.

[0012] In some embodiments, the second intermediate isotope has a shorter half- life than the first intermediate isotope, and wherein the desired daughter isotope isAttorney Docket No. S2302.70007WO00 separated from the liquid target solution by: capturing a contaminant isotope produced by the decay of the second intermediate isotope using the isotope capture device; after waiting for a first decay period, based on a half-life of the first intermediate isotope, diverting the liquid target solution so it is no longer circulating through the fission reactor; and capturing the desired daughter isotope from the diverted liquid target solution using a second isotope capture device.

[0013] In some embodiments, the parent isotope comprises a plurality of isotopes, and the plurality of isotopes are naturally occurring gadolinium comprising at least gadolinium-158 and gadolinium-160.

[0014] In some embodiments, the parent isotope comprises enriched gadolinium- 160.

[0015] In some embodiments, the desired daughter isotope is terbium-161.

[0016] In some embodiments, purifying terbium-161 comprises using a filter to capture terbium isotopes from the liquid target solution.

[0017] In some embodiments, the filter comprises a chromatography column.

[0018] In some embodiments, the isotope capture device comprises a filter having a capture efficiency between 2% and 50%.

[0019] In some embodiments, the capture efficiency of the filter is between 2% and 25%.

[0020] In some embodiments, the capture efficiency of the filter is between 5% and 10%.

[0021] In some embodiments, the isotope capture device comprises a zirconium oxide filter.

[0022] In some embodiments, the zirconium oxide filter is a chromatography column comprising a zirconium oxide stationary phase.

[0023] In some embodiments, the first portion of the fluid path is between 50% and 95% of a volume of the fluid path.

[0024] In some embodiments, the first portion of the fluid path is between 70% and 95% of the volume of the fluid path.

[0025] In some embodiments, the first portion of the fluid path is between 85% and 95% of the volume of the fluid path.Attorney Docket No. S2302.70007WO00

[0026] In some embodiments, pumping the liquid target solution comprises pumping the liquid target solution until a terbium-159 concentration exceeds a predetermined cutoff concentration.

[0027] In some embodiments, the method further comprises, monitoring for terbium-159 to detect a preselected threshold of terbium-159 in the liquid target solution.

[0028] In some embodiments, the liquid target solution comprises GdCl3and / or Gd(NO3)3.

[0029] In some embodiments, the parent isotope comprises radium-226.

[0030] In some embodiments, the desired daughter isotope is actinium-225.

[0031] In some embodiments, purifying the actinium-225 comprises using a first isotope capture device to capture actinium-225 and actinium-227 isotopes from the liquid target solution and, after a waiting period, using a second isotope capture device to capture actinium-225 isotopes from the liquid target solution.

[0032] In some embodiments, the waiting period is approximately 8 hours.

[0033] In some embodiments, the liquid target solution comprises radium chloride in a hydrochloric acid solution.

[0034] In some embodiments, the liquid target solution comprises radium nitrate in a nitric acid solution.

[0035] According to some aspects of the presently disclosed technology, a system for obtaining desired isotopes comprises: a radiation chamber configured to contain a fuel source for generating a neutron flux; a processing chamber that includes a radiation shield configured to shield contents of the processing chamber from the radiation chamber; a pump configured to control flow of a liquid target between a processing chamber and the radiation chamber; and an isotope capture device that preferentially captures a first isotope from with respect to a second isotope in the liquid target.

[0036] According to some aspects of the presently disclosed technology, a method of obtaining Actinium-225 comprises: pumping a target solution comprising radium through a fluid path, wherein the fluid path includes a first portion that passes through a fission reactor, a second portion that passes through a pump that pumps the target solution through the fluid loop, and a third portion that passes through a first actinium capture device located outside of the fission reactor; producing radium-225 and radium-Attorney Docket No. S2302.70007WO00 227 in the target solution through exposure irradiation of the target solution to neutrons in the fission reactor; and operating the first actinium capture device to capture actinium- 227 from the target solution after exposure to neutrons in the fission reactor by passing the irradiated target solution through the first actinium capture device for an accumulation period; after the accumulation period, diverting the target solution such that it does not pass through the fission reactor; and operating a second actinium capture device to capture actinium-225 from the diverted target solution by passing the diverted target solution through the second actinium capture device. BRIEF DESCRIPTION OF DRAWINGS

[0037] FIG. 1A shows the processes through which naturally occurring gadolinium is used as a precursor to Terbium-161, in accordance with some embodiments.

[0038] FIG. 1B shows the decay of Gd-159 and Gd-161 into terbium isotopes, in accordance with some embodiments.

[0039] FIG. 1C is a schematic of a process of producing Ac-225, according to some embodiments.

[0040] FIG. 2A shows an example of a system 200 for producing and capturing isotopes from an irradiated liquid target, in accordance with some embodiments.

[0041] FIG. 2B shows another example of system 220 for capturing isotopes from an irradiated liquid target where, instead of fluid loop, system 220 includes an open fluid path 222, in accordance with some embodiments.

[0042] FIG. 3 is an example of system 300 for capturing daughter isotopes based on a liquid target that includes additional system components for cooling and isotope detection, in accordance with some embodiments.

[0043] FIG. 4 shows the growth of the number of atoms of Gd-159 (400) and Gd- 161 (402) during irradiation, in accordance with some embodiments.

[0044] FIG. 5 shows the theoretical capture efficiency of the isotope capture device, showing that there is a minimal decline in the total mols of Tb-161 collected if capture is performed on a continuous cycle, in accordance with some embodiments.Attorney Docket No. S2302.70007WO00

[0045] FIG. 6A shows an example liquid target reservoir in a nuclear reactor with a gadolinium liquid target, in accordance with some embodiments.

[0046] FIG. 6B shows a diagram of an example of isotope capture device 210 for capturing Tb-161 isotope, in accordance with some embodiments.

[0047] FIG. 6C shows a diagram of the same isotope capture device of FIG. 6B after additional time has passed, in accordance with some embodiments.

[0048] FIG. 7A shows an example liquid target reservoir in a nuclear reactor with a radium-226 liquid target, in accordance with some embodiments.

[0049] FIG. 7B shows a diagram of an example of isotope capture device 210 for capturing actinium isotopes, in accordance with some embodiments.

[0050] FIG. 7C shows a diagram of the same isotope capture device of FIG. 7B after additional time has passed, in accordance with some embodiments.

[0051] FIG. 8 is a flowchart of a process 800 of obtaining desired daughter isotopes, in accordance with some embodiments. DETAILED DESCRIPTION

[0052] The inventors have developed technology to improve the generation of daughter isotopes for clinical treatments. The technology includes systems and methods for using a liquid target to deliver parent isotopes to a reactor for neutron bombardment and subsequently separating desired daughter isotopes from the liquid target.

[0053] Many radiotherapeutic isotope generation techniques are limited by the complexity of purifying the precursor material (parent isotopes) and / or purifying the produced isotopes (daughter isotopes). The inventors have recognized and appreciated that liquid targets in a flow system enable the generation and separation of daughter isotopes from parent isotopes for the radiotherapeutic isotope production (e.g., the production of a desired isotope that may be used in a radiotherapeutic drug), in certain embodiments in a continuous or semi-continuous manner. Selection of appropriate ion capture devices (e.g. comprising chromatography columns) and other aspects of systemAttorney Docket No. S2302.70007WO00 design may reduce the complexity of purification and increase the conversion efficiency of parent isotopes. In particular, configuring an isotope capture and separation system such that pure or relatively pure concentrations of desired isotopes can be collected within specific time windows can improve the efficiency of desired isotope generation by removing the need for more complex purification schemes. Additionally, the liquid target approach disclosed herein may reduce time spent transferring solid targets between radiation chambers and processing chambers, opening and sealing of such targets, etc., thereby achieving higher conversion ratios of parent isotopes into daughter isotopes.

[0054] The inventors have recognized that terbium, actinium, and other daughter isotopes that may be used in radiotherapeutic treatments or which otherwise provide economic value – which may otherwise be difficult to generate and / or purify – may be advantageously produced using the systems and methods described herein. For example, a method of obtaining desired daughter isotopes includes pumping a liquid target solution, that includes a parent isotope, through a fluid path, which in certain embodiments is a closed loop, the fluid path includes a first portion that passes through a fission reactor, a second portion that passes through a pump that pumps the liquid target solution through the fluid path, and a third portion that passes through an isotope capture device, where the second portion and the third portion are located outside the fission reactor; irradiating the liquid target solution with a neutron flux, as the liquid target solution passes through the fission reactor; and capturing an isotope from the liquid target solution using the isotope capture device – for example capturing preferentially a desirable daughter isotope for recovery from the isotope capture device in a purified form.

[0055] As described above, lutetium-177 is an FDA-approved, beta-emitting radionuclide, that has already garnered significant attention in targeted radionuclide therapies for cancer. Lutetium-177 has distinctive decay properties, including a relatively short half-life of 6.7 days and a maximum beta-particle emission energy of 0.5 MeV. This makes it advantageous for Lutetium-177 to be used across a wide range of therapeutic applications when coupled with specific targeting agents (e.g., peptides, antibodies) to deliver cytotoxic radiation directly to tumor sites. However, it has been reported that Lutetium-177 is challenging for promising targets characterized by highAttorney Docket No. S2302.70007WO00 selectivity but limited expression in primary and metastatic lesions. Targets with superior selectivity are predominantly expressed on cancer cells, minimizing off-target effects on healthy tissues. Yet, when these targets are present in suboptimal quantities, it can impede the binding efficiency of Lutetium-177 conjugated drugs, potentially diminishing the therapeutic absorbed radiation dose delivered to the tumor. A prime example is DLL3, which is exceptionally selective but expressed in less than 5,000 copies per tumor cell (for comparison, PSMA and SSTR2 are expressed at 45,000 and 36,000 copies per tumor cell). Furthermore, the inherent heterogeneity of tumors can result in uneven distribution of the Lutetium-177 labeled radiotherapeutic drugs, leading to disparate radiation doses across different tumor regions. This variability poses challenges not only in achieving consistent therapeutic outcomes but also in monitoring treatment efficacy through imaging.

[0056] According to some aspects of the present disclosure, techniques are described herein for producing and capturing Terbium-161, which are motivated by the possibility that Terbium-161 could serve as an alternative to Lutetium-177 as a standard radiotherapeutic isotope. The Auger-component of Terbium-161 may unlock further, precision-targeted cytotoxic effects, further improving the already impressive therapeutic breadth of radiotherapeutics.

[0057] Terbium-161 is a high linear energy transfer (LET) emitter and combines higher energy beta emissions with low energy (<30 keV) extremely-short-range (<500 nm) Auger emissions. This dual-emission profile leads to a more pronounced and localized therapeutic effect, making it suitable for targets with varying or low expression levels. Consequently, Terbium-161’s increased energy deposition leads to more substantial and localized DNA damage within cancer cells. Its Auger emissions are also beneficial since Auger electrons have a very short range in biological material and are highly localized. This causes significant damage within a tiny radius (e.g., on the order of a nanometer to micrometer distance) around the decay site which is advantageous to ensure that the therapeutic impact is concentrated precisely at the tumor site, sparing neighboring healthy tissues. For these reasons, developing Terbium-161 based therapies would be ideal for targeting cancer cells with varying or low antigen expression levels.Attorney Docket No. S2302.70007WO00

[0058] Another drawback of Lutetium-177 is its suboptimal gamma emission for imaging, making post-therapeutic dosimetry and treatment monitoring less precise. In contrast, Terbium-161 (with little gamma) offers a more favorable decay profile with both therapeutic beta emissions and diagnostic gamma emissions, facilitating enhanced imaging capabilities and more accurate dosimetry. The shorter range of beta particles from Terbium-161 also provides a more confined radiation dose, minimizing damage to surrounding healthy tissues, which is advantageous when treating smaller metastases or disseminated diseases, and limits the exposure of clinical personnel to an unnecessary radiation dose. Terbium-161 also does not have any daughter isotopes which could cause long-term off-target toxicity. This is in contrast to other radionuclides where daughter isotopes can migrate from the initial site, cause off-target toxicity, and pose long-term safety concerns. With Terbium-161, the generation of non-carrier added material is possible, further underscoring its potential to ensure higher specific activity and thereby enhancing its therapeutic efficacy.

[0059] Finally, Terbium-161 also has a favorable activity profile, with a half-life of ~6.89 days. This allows sufficient time for the isotope to be produced, formulated into a therapeutic agent, and shipped to treatment centers, even internationally, while still retaining a significant portion of its radioactivity. Therapeutically, its half-life ensures that Terbium-161 remains active within the patient's body for an adequate duration to exert its therapeutic effect, while minimizing radiation exposure risks. This half-life aligns well with typical biological processes (e.g., cellular uptake and tumor targeting), optimizing the therapeutic window wherein the radionuclide can act effectively against cancer cells. Additionally, a cleaner daughter profile also allows an easier handling of doses and radioactive waste in medical infrastructures.

[0060] Conventionally, to produce Terbium-161, enriched Gadolinium-160 is used as a starting seed material. Gadolinium is isotopically enriched to predominantly contain Gadolinium-160, then upon irradiation in a nuclear reactor, the enriched Gadolinium-160 absorbs neutrons and undergoes a nuclear reaction to form Terbium-161. The enrichment process is critical to ensure a higher concentration of the Gadolinium-160 isotope, thereby maximizing the yield of Terbium-161 upon irradiation. Following the irradiation, a series of radiochemical separation procedures are employed to isolate Terbium-161Attorney Docket No. S2302.70007WO00 from the irradiated Gadolinium and any other by-products, ensuring a final product of high radionuclide purity. This standard method offers enhanced predictability and control over the production yield and quality of Terbium-161, making it a preferred strategy for many producers in the field of targeted radionuclide therapy. However, there are challenges within today’s production and enrichment processes, which motivate the exploration of alternative, innovative production strategies. In particular, the enrichment process is resource-intensive and complex.

[0061] The inventors have recognized and appreciated techniques for synthesizing Terbium-161 without relying on the need to enrich isotopes. Rather, the techniques described herein utilize naturally occurring isotopes, such as naturally occurring isotopes of Gadolinium.

[0062] The naturally occurring Gadolinium isotopes include Gd-152 (0.2%), Gd- 154 (2.18%), Gd-155 (14.8%), Gd-156 (20.47%), Gd-157 (15.65%), Gd-158 (24.84%), and Gd-160 (21.86%), where the abundance is listed in the brackets. All these Gadolinium isotopes are stable, except for Gd-152 which has a half-life on the order of 1014years, and therefore can be considered stable for the purposes of this disclosure. The most abundant isotopes in naturally occurring Gadolinium are Gd-158 and Gd-160.

[0063] FIG. 1A and 1B show the processes through which naturally occurring gadolinium is used as a precursor to terbium-161, in accordance with some embodiments of the technology described herein. Tb-161 is produced through the decay of Gd-161. Samples of naturally occurring gadolinium include multiple gadolinium isotopes, as described above. FIG. 1 shows a sample of naturally occurring gadolinium 100, that includes multiple gadolinium isotopes including Gd-158 (102), Gd-160 (106), Gd-157 (110), Gd-156 (112), Gd-155 (114), Gd-152 (116), and Gd-154 (118).

[0064] According to some embodiments, naturally occurring Gadolinium (100) is bombarded with neutrons 103 to produce gadolinium isotopes (104) and (108), which correspond to Gd-159 and Gd-161, which are non-stable isotopes with half-lives of 18.48 hours and 3.65 minutes, respectively. FIG. 1B shows the decay of Gd-159 and Gd-161 into terbium isotopes, in accordance with some embodiments described herein. Gd-159 decays via beta decay to Tb-159 (which is stable), and Gd-161 decays via beta decay toAttorney Docket No. S2302.70007WO00 Tb-161, which has a half-life of 6.89 days, and as noted above may be a valuable radiotherapeutic isotope. Accordingly, gadolinium isotopes (108) and (104) which are produced through irradiation decay into gadolinium isotopes (120) [Tb-161] and 121 [Tb-159].

[0065] According to some embodiments, a target material comprising Gadolinium may be arranged within an environment in which there are free neutrons, such as within a fission reactor. Neutrons 103 incident on the Gadolinium may produce Gd-159 from neutron capture of naturally occurring Gd-158 and may produce Gd-161 from neutron capture of naturally occurring Gd-160. As noted above, Gd-158 and Gd-160 are stable and represent almost 50% of naturally occurring Gadolinium.

[0066] According to another aspect of the technology, techniques are described herein for producing and capturing actinium-225. FIG. 1C is a schematic of a process of producing Ac-225, according to some embodiments. In the example of FIG. 1C, two different isotopes may result when neutrons 103 are incident on atoms of Ra-226 (122) are shown. The first type of interaction is an (n, 2n) reaction that converts Ra-226 into Ra-225 (123) and neutrons 124. The threshold kinetic energy of the neutron 103 for this reaction to occur is 6.4 MeV.

[0067] The second type of interaction is an (n, ^) reaction that produces radium- 227 (Ra-227) (126) through neutron capture. The two types of interactions may both take place in an environment rich in neutrons, such as a fission reactor, which contains neutrons of various different energies. It may be noted that the production of Ra-227 (126) through neutron capture more readily occurs with thermal neutrons at lower neutron kinetic energies, whereas the production of Ra-225 (123) requires a fast neutron with kinetic energy above 6.4MeV. However, both of these types of neutrons may generally be present in a fission reactor where a sample of Ra-226 (122) is placed, and as a result Ra-225 and Ra-227 may both be produced in such an environment.

[0068] In the example of FIG. 1C, when Ra-225 (123) with a half-life of 14.9 days is produced, it beta decays to Ac-225 (125). The Ac-225 product has a half-life of 9.92 days. Alternatively, when Ra-227 (126) with a half-life of 42 minutes is produced, it undergoes beta decay to Ac-227 (127). The Ac-227 product has a half-life of 21.8 years.Attorney Docket No. S2302.70007WO00

[0069] One of the challenges with producing Ac-225 in a fission reactor is that both Ac-227 and Ac-225 are produced, yet it is desirable to obtain a purified sample of Ac-225 for medical uses. In this situation, however, Ac-225 cannot be initially obtained through milking because milking does not distinguish between isotopes of actinium; milking only distinguishes between different elements, such as actinium and radium. "Milking" radioisotopes refers to a process where a desired short-lived daughter nuclide is separated from its longer-lived parent nuclide in a radioactive generator. This process is akin to milking a cow, where a product (in this case, the daughter nuclide) is extracted from a source (the parent nuclide). Accordingly, milking of a sample for actinium after removal from an environment in which both Ra-225 and Ra-227 were produced will yield a mixture of Ac-225 and Ac-227. Since Ac-227 has a much longer half-life than Ac-225, waiting for it to decay is also not a suitable solution for producing a purified sample of Ac-225. However, since Ra-227 decays to Ac-227 with a 42 minute half-life, Ra-227 concentrations will not accumulate at the same rate as Ra-225 concentrations in a liquid target solution.

[0070] According to yet other aspects of the technology described herein, the techniques described herein for producing terbium-161 and actinium-225 may also be used to produce other isotopes useful for therapeutic treatments. For example, the techniques described herein may be used to produce lutetium-177, copper-64, copper-66, actinium-227, or molybdenum-99.

[0071] As discussed above, the inventors have recognized and appreciated that a limiting factor in many processes for generating therapeutic isotopes using nuclear reactions is obtaining a high purity starting material and separating the resulting byproducts of the radioactive decay processes to produce a purified desired therapeutic radioisotope(s). The starting materials can be very rare (e.g., only one or two global suppliers). Therefore, maximizing conversion of a starting material to the desired isotope(s) may be critical in practical generation of the therapeutic isotope(s). The conversion efficiency of the starting material may be dependent on how much time the starting material is irradiated. With longer irradiation, a greater number of the isotopes in the starting material undergo a nuclear reaction to produce the desired isotope. Accordingly, time spent taking a target out of the reactor can decrease the conversionAttorney Docket No. S2302.70007WO00 efficiency and the overall production of the desired isotope. The inventors have further recognized and appreciated that the use of a liquid target would enable a flow system to be used that would minimize the time spent transferring the starting material into and out of a reactor, thus improving the conversion ratio.

[0072] FIG. 2A shows an example of a system 200 for producing and capturing isotopes from an irradiated liquid target, in accordance with some embodiments of the technology described herein. System 200 irradiates a liquid target containing a parent radioisotope that is circulated through a radiation chamber with a neutron flux to generate daughter isotopes from the liquid target which are subsequently captured and separated or otherwise further processed to ultimately produce a desired purified therapeutic radioisotope. To generate the neutron flux that facilitates nuclear reactions of the isotopes in the liquid target, system 200 includes a nuclear reactor 202 that uses a controlled fission reaction to generate a neutron flux. The nuclear reactor 202 is immersed in a reactor pool 204 to cool and shield the reactor. A liquid target reservoir 206 is disposed within the nuclear reactor such that the contents of the reservoir are subjected to the neutron flux of the reactor. Irradiation of the liquid target in the reservoir initiates nuclear reactions of at least some of the isotopes in the liquid target. To extract the products of the nuclear reactions, a fluid loop 212, which is connected to a pump 208, is used to move the target solution from the liquid target reservoir 206 in the nuclear reactor 202 to an isotope capture device 210, that is located externally from the nuclear reactor pool 204.

[0073] Fluid loop 212 in this exemplary embodiment is a closed loop system for circulating a liquid target between the nuclear reactor 202 and the isotope capture device. Accordingly, isotopes generated by nuclear reactions in the nuclear reactor 202 may be continuously captured as the liquid target circulates through the isotope capture device 210. Depending on the half-life of the desired isotope relative to half-lives of any contaminating isotopes, the isotope capture device 210 can be used either to capture the desired isotope or the contaminating isotopes. Contaminating isotopes are other isotopes of the same element as the therapeutic isotope, which themselves are not suitable for therapeutic treatments. Contaminating isotopes may be produced as byproducts of the nuclear reactions that occur during, or in parallel to, the generation of the desired isotope,Attorney Docket No. S2302.70007WO00 or a parent isotope of the desired isotope which subsequently decays into the desired isotope.

[0074] In some embodiments, where the isotope capture device is used to capture the desired isotope, the captured desired isotopes can be removed in purified form by eluting the desired isotopes from the isotope capture device 210. For example, if the isotope capture device 210 is a chromatography column, the column may be removed from the fluid loop 212 to permit the desired isotope to be eluted from the column.

[0075] In some embodiments, where the isotope capture device is used to capture a contaminating isotope, the desired isotope can be removed by transferring at least a portion of the liquid target collected downstream of the isotope capture device after removal of the contaminating isotope out of the fluid loop and then separating the desired isotope from the rest of the liquid target through a further separation technique. A chromatography column may be used for the further separation technique.

[0076] As discussed above, the amount of time the starting material spends in the nuclear reactor 202 has an impact on the conversion efficiency. Therefore, in some embodiments, the volume of the liquid target reservoir is designed to be a significant volume of the volume of the entire flow path system. For example, the volume of the liquid reservoir and the portion of the fluid loop 212 that is in the nuclear reactor 202 is between 50% and 95% of the volume of the whole fluid loop 212. As another example, the volume of the liquid reservoir and the portion of the fluid loop 212 that is in the nuclear reactor 202 is between 70% and 95% of the volume of the whole fluid loop 212. As yet another example, the volume of the liquid reservoir and the portion of the fluid loop 212 that is in the nuclear reactor 202 is between 85% and 95% of the volume of the whole fluid loop 212.

[0077] In some embodiments, the liquid target reservoir is designed to have a high surface area. For example, gadolinium has a high absorption coefficient for neutrons. Accordingly, the penetration depth of neutron flux is very shallow for a gadolinium sample. Therefore, to increase the efficiency of irradiating the gadolinium, the liquid target reservoir may be designed to have thinner pipes that increase the surface area ofAttorney Docket No. S2302.70007WO00 the liquid target such that more gadolinium is exposed to the neutron flux, resulting in an increase of the conversion efficiency of gadolinium to terbium.

[0078] Although system 200 is shown as having a single pump 208 configured along fluid loop 212, the position of pump 208 is not limited to being configured between the outflow of the liquid target reservoir 206 and the isotope capture device 210. Rather, pump 208 may be configured anywhere along fluid loop 212. Additionally, system 200 is not limited to having a single pump. An additional pump or pump(s) may be included at other positions of fluid loop 212.

[0079] Isotope capture device 210 may be implemented using any suitable device. In some embodiments, the isotope capture device is a high-throughput filtration device containing a solid phase media capable of selectively binding one or more types of isotopes. For example, the isotope capture device may be a low-efficiency filter, such as a filter having a filter (i.e., capture) efficiency between 2% and 50%, a filter efficiency between 2% and 25%, or a filter efficiency between 5% and 10%.

[0080] In some embodiments, the isotope capture device comprises a chromatography column. In some embodiments, the isotope capture device uses a zirconium oxide solid phase media as a filter. For example, a zirconium oxide on a resin carrier may be used as filter media in the isotope capture device.

[0081] In some embodiments, the pump 208 is a peristaltic or diaphragm pump. In other embodiments, other types of pumps may be used, as aspects of the technology described herein are not limited in this respect.

[0082] Although described as a continuously circulating configuration, in some embodiments, the system of FIG. 2A may be used to pump-in and pump-out liquid target to / from the nuclear reactor 202. Accordingly, the liquid target may be pumped in to be irradiated for a period of time and then the irradiated liquid target is pumped to the isotope capture device 210. Subsequent to the isotope capture device 210, the liquid target may be pumped back into the nuclear reactor 202 for further irradiation.

[0083] The system 200 shown in FIG. 2A is an example of an embodiment of the technology described herein that uses a closed fluid loop. However, aspects of theAttorney Docket No. S2302.70007WO00 technology described herein are not limited to a closed fluid loop system. FIG. 2B shows another example of system 220 for capturing isotopes from an irradiated liquid target where, instead of a closed fluid loop, system 220 includes an open fluid path 222, in accordance with some embodiments of the technology described herein. The open fluid path system includes the same components as described above in connection with FIG. 2A. However, system 220 of FIG. 2B differs from system 200 of FIG. 2A in that the fluid path is an open loop. Accordingly, rather than circulating the liquid target between the isotope capture device 210 and the nuclear reactor 202, the liquid target is pumped through the system in a single pass. In another embodiment of system 220, the pump may alternate the direction of flow of the liquid target. For example, the pump may pump the liquid target into the reactor in a first direction and, upon switch directions, may pump the liquid target out of the reactor and back into a loading tank.

[0084] System 220 includes liquid target loading tank 214. Tank 214 is used to contain the volume of the liquid target before irradiation. Pump 208 is used to pump the liquid target from the liquid target loading tank 214 to the liquid target reservoir 206 in the nuclear reactor 202. After passing through the liquid target reservoir 206, the liquid target is pumped from the liquid target reservoir 206 to the isotope capture device 210. The remaining liquid target solution which has passed through the isotope capture device may be collected and subjected to further processes to extract additional quantities of the desired isotope, to purify the solution prior to a subsequent cycle or irradiation, or to extract other isotopes which may have therapeutic or commercial value.

[0085] Although FIG. 2B shows a single pump 208 that is configured between liquid target loading tank 214 and the nuclear reactor pool 204, pump 208 may be configured in other positions along fluid path 222. Additionally, system 220 is not limited to a single pump. An additional pump may be positioned between the nuclear reactor pool 204 and the isotope capture device 210.

[0086] According to some aspects of the technology described herein, additional components may be included with the system. In some embodiments, a cooling device is included to cool the temperature of the liquid target as if exits the nuclear reactor. Additionally, or alternatively, an isotope detector may be included with the system toAttorney Docket No. S2302.70007WO00 monitor for concentrations of the isotopes in the liquid target. For example, the isotope detector may be used to monitor for a concentration of a contaminant isotope so that once the concentration of the contaminant isotope reaches unacceptable concentrations for the collection of desired isotopes, the system may be stopped and the liquid target solution replaced with a fresh liquid target.

[0087] FIG. 3 is an example of system 300 for capturing daughter isotopes based on a liquid target that includes additional system components for cooling and isotope detection, in accordance with some embodiments. System 300 may be configured the same as the closed loop system 200 of FIG. 2A or the open loop system 220 of FIG. 2B. In the illustrated example of FIG. 3, system 300 is shown as a closed loop system. In addition to the components of system 200, described above, system 300 also includes a cooling device 302 and isotope detectors 304.

[0088] The cooling device 302 in the exemplary illustrated embodiment is configured between the outflow of the liquid target from the nuclear reactor 202 and the pump 208. The cooling device dissipates heat from the liquid target to ensure that the circulating liquid target does not get too hot. Any suitable cooling device may be used for cooling device 302. For example, cooling device 302 may be a forced air cooling system. The cooling system may flow a coolant over a portion of the fluid loop between the reactor pool 204 and the pump 208. The coolant may be air or a liquid coolant, as aspects of the technology described herein are not limited in this respect. The coolant may use a counterflow, crossflow, straight flow, or some combination thereof.

[0089] As shown in FIG. 3, isotope detectors 304 are configured before and after the isotope capture device. The isotope detectors can detect the concentration of isotopes circulating in the fluid loop 212 to determine the concentration of the desired isotope to contaminant isotopes. In some embodiments, the isotope detector 304a configured before the isotope capture device may monitor the fluid loop for the concentration of contaminant isotopes that are accumulating as the liquid target circulates through the nuclear reactor 202. If the isotope detector 304a determines that the contaminant isotope concentration increases past a predetermined level, the flow to the isotope capture device 210 can be stopped so as to not introduce additional contaminant isotopes into theAttorney Docket No. S2302.70007WO00 isotope capture device. Then, the target isotope can be extracted and the liquid target can be replaced.

[0090] In some embodiments, the isotope detector 304b is configured after the isotope capture device may monitor the fluid loop for the concentration of the target isotope for capture. For example, the isotope capture device 210 may have a limited efficiency in capturing isotopes as they pass through the device. However, since the system is a circulating loop, target isotopes which were not captured by the isotope capture device 210 on a first pass may then be captured on a second, third, fourth, or other subsequent pass through the isotope capture device 210. Accordingly, isotope detector 304b may monitor for the concentration of target isotope circulating in the fluid loop 212 after the isotope capture device. The concentration of the target isotope may be used to determine when to stop the process. As an example, if the target isotope is the desired isotope or a parent isotope which will decay into the desired isotope, then the captured target isotope may be eluted from the isotope capture device when the concentration circulating in the fluid loop decreases to a predetermined level. As another example, if the target isotope is the contaminant isotope, then the liquid target – that includes the desired isotope or a parent isotope of the desired isotope – may be extracted from the system once the contaminant isotope concentration drops below a predetermined threshold.

[0091] Although FIG. 3 shows two separate isotope detectors 304a and 304b, the system may include a single isotope detector which may be positioned anywhere along the fluid loop and may provide the functionality of either or both of isotope detectors 304a and 304b.

[0092] In some embodiments, the isotope detectors are radiation detectors configured to detect radiation signatures of specific isotopes. For example, the isotope detectors may be radiation spectrometers configured to detect an energy of radiation received by the detector.

[0093] The systems 200, 220, and 300 described above in connection with FIGs. 2A, 2B, and 3, respectively, may be used to implement methods to obtain desired daughter isotopes, such as the methods described below in connection with FIG. 4-8.Attorney Docket No. S2302.70007WO00

[0094] The systems described herein may in certain embodiments be used or adapted to efficiently obtain high purity Tb-161 from naturally occurring gadolinium. Tb-161 purity may be enhanced by operating the system to capture the Tb-161 before accumulation of Tb-159 in the liquid target solution. For example, due to the large differences between the half-lives of Gd-159 and Gd-161 (18.48 hours versus 3.65 minutes, respectively), Tb-161 will be produced more quickly from the resulting isotopes than Tb-159. As a result, by capturing and eluting Terbium from the target material promptly after exposure to neutrons, the vast majority of Terbium yielded will be Tb- 161. Isotopic evolution of Gd-161 and Gd-159 during this process is shown in FIG. 4.

[0095] FIG. 4 shows the growth of the number of atoms of Gd-159 (400) and Gd- 161 (402) during irradiation, in accordance with some embodiments of the technology described herein. The ratio of the number of atoms of Gd-161 to Gd-159 is plotted as 404. Plot 404 shows that the ratio of Gd-161 to Gd-159 decreases rapidly as Gd-159 decays into Tb-161.

[0096] As shown in FIG. 4, during irradiation of a target material comprising Gadolinium, the amounts of Gd-159 and Gd-161 increase, then once irradiation ends, the amount of Gd-161 drops rapidly due to Gd-161’s comparatively short half-life (producing Tb-161), whereas the amount of Gd-159 drops very slowly in comparison.

[0097] According to some embodiments, Terbium may be captured from a target material comprising Gadolinium during irradiation of the target material with neutrons. Since decay of Gd-161 to Tb-161 is so rapid, there may be a benefit to extract Terbium from the target material prior to irradiation concluding. For instance, it may not be possible to remove a capsule of target material from within a fission reactor and extract Terbium from the target material sufficiently rapidly to ensure that the yield of Terbium is pure Tb-161 (or substantially pure Tb-161, or a yield consisting essentially of Tb-161), since given enough time, the Gd-159 will decay to Tb-159.

[0098] According to some embodiments, Terbium is captured from a target material comprising Gadolinium (e.g., natural Gadolinium) during irradiation by cycling the target material through the reactor and extracting Terbium from the target material during irradiation. For instance, the target material may be a solution of Gadolinium thatAttorney Docket No. S2302.70007WO00 is pumped through a loop that includes a region of the loop within a fission reactor, and that includes device to capture Terbium within the loop. With this setup, pure Tb-161 (or substantially pure Tb-161, or a yield consisting essentially of Tb-161) can be captured during irradiation until too much Tb-159 is detected in the target material, at which point irradiation and capture of Terbium may end and the process initiated again with a new target material comprising Gadolinium (e.g., naturally occurring Gadolinium). The initial target material comprises Gd-159, but since the half-life of this isotope is 18.48 hours, after a week or two the initial target material will no longer contain any Gd-159 (or contains a negligible and non-meaningful amount) and can be re- used in a new process of cycling through the reactor as described above. An illustrative example of an apparatus for such a process is shown in FIG. 2A-3.

[0099] According to some embodiments, the solution of Gadolinium may comprise one or more Gadolinium compounds soluble in water, such as but not limited to, GdCl3, Gd(NO3)3, gadofullerides, gadolinium metallofullerenols, or combinations thereof.

[0100] According to some embodiments, the isotope capture device to capture Terbium may be a resin bed / column separator, comprising a resin tuned for Terbium separation from Gadolinium. According to some embodiments, the isotope capture device to capture Terbium may be a resin column separation device, such as an extraction chromatographic resin device, or a strong acid cation exchange resin device. One illustrative example of a suitable device to capture Terbium from a solution is described in Kazakov, A. G., et al., “Separation of radioisotopes of terbium from a europium target irradiated by 27 MeV ^-particles,” Radiochimica Acta, 106(2), 135–140 (2018). Another illustrative device is described in Dash, A., et al., “Production of 177Lu for Radionuclide Therapy: Available Options,” Nucl. Med. Mol. Imaging, 49, 85-107 (2015).

[0101] According to some embodiments, the pump may comprise a peristaltic pump and / or a diaphragm pump.

[0102] The theoretical filter efficiency (i.e., capture efficiency) of the separator (isotope capture device) is shown in FIG. 5, showing that there is a minimal decline in the total mols of Tb-161 collected if capture is performed on a continuous cycle.Attorney Docket No. S2302.70007WO00

[0103] As referred to herein, “naturally occurring Gadolinium” refers to Gadolinium that has not been isotopically enriched, or has not been meaningfully isotopically enriched, such that the balance of isotopes in the naturally occurring Gadolinium is at or close to that described above (i.e., Gd-152 (0.2%), Gd-154 (2.18%), Gd-155 (14.8%), Gd-156 (20.47%), Gd-157 (15.65%), Gd-158 (24.84%), and Gd-160 (21.86%)).

[0104] FIG. 6A shows an example liquid target reservoir in a nuclear reactor with a gadolinium liquid target, in accordance with some embodiments of the technology described herein. Nuclear reactor 202 includes liquid target reservoir 206 for containing a liquid target for irradiation by a flux of neutrons 203 from the reactor. The liquid target reservoir 206 has inflow and outflow through fluid path 212. As shown in FIG. 6A, the naturally occurring gadolinium target 600 enters the liquid target reservoir 206 where the neutron bombardment initiates nuclear reactions to form Gd-161 and Gd-159, as described in connection with FIG. 1A-1B above.

[0105] FIG. 6B shows a diagram of an example of isotope capture device 210 for capturing Tb-161 isotope, in accordance with some embodiments of the technology described herein. The isotope capture device 210 is configured to capture terbium isotopes. Tb-161 is useful as a radiotherapeutic isotope, but Tb-159 which is a byproduct of irradiating Gd-159 (a component of naturally occurring gadolinium) is not generally considered useful as a radiotherapeutic isotope. Accordingly, samples of Tb-161 should contain no measurable quantity or very low quantities of Gd-159. Following the irradiation shown in FIG. 6A, quantities of Gd-161 and Gd-159 are produced. Given the shorter half-life of Gd-161, described above, the concentration of Tb-161 starts to increase much faster than that of Tb-159. Accordingly, FIG. 6B shows the capture of Tb- 161 at early times after the beginning of the irradiation of the liquid target.

[0106] FIG. 6C shows a diagram of the same isotope capture device of FIG. 6B after additional time has passed. Tb-161 accumulates in the isotope capture device without appreciable contamination from Tb-159 because of the difference in half-life between the two. Once the system detects a concentration of Tb-159 exceeding aAttorney Docket No. S2302.70007WO00 predetermined threshold, the flow to the isotope capture device is stopped and the Tb- 161 is eluted from the isotope capture device.

[0107] FIG. 7A shows an example liquid target reservoir in a nuclear reactor with a radium-226 liquid target, in accordance with some embodiments of the technology described herein. The configuration of nuclear reactor 202 shown in FIG. 7A is the same as the configuration shown in FIG. 6A, but FIG. 7A includes a radium-226-containing liquid target. The radium-226-containing target 700 enters the liquid target reservoir 206 where the neutron bombardment initiates nuclear reactions to form Ra-225 and Ra-227, as described in connection with FIG. 1C above.

[0108] FIG. 7B shows a diagram of an example of isotope capture device 210 for capturing actinium isotopes, in accordance with some embodiments of the technology described herein. The isotope capture device 210 is configured to capture actinium isotopes. Ac-225 is useful as a radiotherapeutic isotope, but Ac-227 which is a byproduct of irradiating Ra-226 is not ideal for use as a radiotherapeutic isotope. Accordingly, samples of Ac-225 should contain no measurable quantity or very low quantities of Ac- 227. Following the irradiation shown in FIG. 7A, quantities of Ra-225 and Ra-227 are produced. Ra-225 and Ra-227 decay into Ac-225 and Ac-227, respectively. Given the shorter half-life of Ra-227, described above, the accumulation of Ac-227 occurs on a much faster time than the accumulation of Ac-225. Accordingly, FIG. 6B shows the capture of Ac-227 at early times after the beginning of the irradiation of the liquid target.

[0109] FIG. 7C shows a diagram of the same isotope capture device of FIG. 7B after additional time has passed, in accordance with some embodiments of the technology described herein. Ac-227 accumulates in the isotope capture device before Ra-225 has had the chance to decay because of the difference in half-life between the Ra-225 and Ra-227. Thus, while the isotope capture device may capture some Ac-225, it will predominately have captured Ac-227 until such a time that the Ra-225 decays.

[0110] In more detail, prior to the beginning of irradiation of a fresh liquid target, Ra-226 is present in the solution with no expected quantities of Ra-227, Ra-225, Ac-227, or Ra-225. Shortly after irradiation begins, the concentrations of Ra-227 and Ra-225 will slowly start to accumulate in solution. However, as irradiation continues, the Ra-225Attorney Docket No. S2302.70007WO00 concentration would be expected to accumulate faster than the Ra-227 concentration. This can be understood by comparing the half-lives of each isotope. The rate of accumulation will depend on the rate of the nuclear reaction that produces the isotope and on the half-life of that isotope. Since Ra-227 has a substantially shorter half-live (e.g., a half-life on the order of minutes rather than a half-life on the order of days) the rate of accumulation of Ra-227 will be much smaller than that of Ra-225. In other words, the Ra-227 that is produced by irradiating Ra-226 will decay into Ac-227 at such a rate that it will prevent the Ra-227 from accumulating at the same rate as Ra-225 (which has a half-live of approximately 15 days). Therefore, as Ra-227 decays, Ac-227 would accumulate in the liquid target solution. Absent isotope removal, over the course of several days, the concentration of Ac-227 and Ra-225 would both be steadily increasing in solution. However, by using an isotope capture device that preferentially captures actinium, the Ac-227 will be captured from the solution preventing its accumulation, while the Ra-225 concentration accumulates. Once a desired quantity of Ra-225 has been generated, the solution can be diverted such that it does not pass through the reactor. By diverting the solution, Ra-227 will cease to be generated from the remaining Ra-226. Thus, once diverted, the solution may have some quantity of Ra-227 which has not yet fully decayed into Ac-227, but the solution will predominantly be comprised of Ra-225. As the Ra-225 decays into Ac-225, the Ac-225 can be effectively captured from the solution with trace or no quantities of Ac-227.

[0111] Accordingly, after Ra-225 has accumulated to a predetermined threshold in the circulating liquid target, the liquid target solution may be removed from the fluid loop. The removed fluid may have trace quantities of Ra-227 generated from the irradiation prior to removing the fluid but the Ra-227 will be in trace quantities relative to the Ra-225. Thus, the liquid target solution can be milked to obtain Ac-225 in pure or near pure quantities.

[0112] FIG. 8 is a flowchart of a process 800 of obtaining desired daughter isotopes, in accordance with some embodiments of the technology described herein. Process 800 may be performed using any suitable sample, as described herein, in addition to a suitable fission reactor.Attorney Docket No. S2302.70007WO00

[0113] Process 800 begins at act 802 by pumping a liquid target solution comprising a parent isotope through a fluid path (e.g., a fluid loop) that passes through a fission reactor and an isotope capture device, in accordance with some embodiments described herein. The fluid path includes a first portion that passes through a fission reactor. As the liquid target solution passes through the first portion of the fluid path, neutron flux generated by the fission reactor initiates nuclear reactions, as described herein in connection with FIGs. 1A-1C.

[0114] After the first portion, the second portion of the fluid path passes through a pump. Unlike the first portion of the fluid path, the second portion of the fluid path is outside the fission reactor. The pump through which the second portion of the fluid path passes controls the flow of the liquid target through the fluid path. In some embodiments, the pump is a peristaltic or diaphragm pump.

[0115] After the second portion, the third portion of the fluid path passes through an isotope capture device. The third portion of the fluid path is outside the fission reactor and terminates at the beginning of the first portion. Thus, after the liquid target passes through the third portion of the fluid path, in certain embodiments in which the fluid path is a closed loop, it enters the first portion of the fluid path to be irradiated again. In some embodiments, the isotope capture device is a chromatography column, as described herein.

[0116] In some embodiments, the liquid target solution includes a salt form of the parent isotope. In some embodiments, the liquid target solution comprises a hydrochloric acid or other strong acid solution. For example, a liquid target solution may comprise radium nitrate (in a nitric acid solution having a concentration of approximately 6 molar). In some embodiments, the liquid target solution is a nitric acid solution.

[0117] Next, process 800 continues at act 804 by irradiating the liquid target solution with a neutron flux, in accordance with some embodiments described herein. In some embodiments, irradiating the liquid target solution directly generates the desired daughter isotope. In other embodiments, irradiating the liquid target solution generates an intermediate isotope that decays into the desired daughter isotopes. For example, toAttorney Docket No. S2302.70007WO00 obtain Tb-161, Gd-160 is irradiated by neutron flux to generate Gd-161 (e.g., an intermediate isotope) that subsequently decays into Tb-161, as described herein.

[0118] Next, process 800 continues at act 806 by purifying a desired daughter isotope from the liquid target solution, in accordance with some embodiments described herein.

[0119] In some embodiments, irradiating the liquid target solution at act 804 generates multiple intermediate isotopes. In the example of irradiating naturally occurring gadolinium, Gd-161and Gd-159 will both be produced as intermediate isotopes. In the example of irradiating Ra-226, both Ra-225 and Ra-227 will both be produced as intermediate isotopes. Accordingly, one of the intermediate isotopes decays into the desired daughter isotope while the other intermediate isotope decays into a contaminant isotope.

[0120] In some embodiments, such as in the production of Tb-161, when the intermediate isotope that decays into the contaminant isotope has a longer half-life than the first intermediate isotope, then the desired daughter isotope may be captured directly by the isotope capture device, thus purifying the desired daughter isotope. In some embodiments, once the desired daughter isotope is extracted from the isotope capture device, the desired daughter isotope will have a purity such that no more than 1% of the contaminant isotope activity is present relative to the desired daughter isotope. For example, for the production of Tb-161, the Tb-161 sample will have no more than a 1% activity of Tb-159. Similarly, in the example of Ac-225 included below, the Ac-225 sample will have no more than a 1% activity of Ac-227.

[0121] Additionally, in some embodiments, capturing the desired daughter isotope may further include monitoring the liquid target solution for the contaminant isotope. When the concentration of the contaminant isotope increases to a predetermined level, the capturing process is stopped so as to prevent contamination of the desired daughter isotope by the contaminant isotope. For example, when obtaining Tb-161, the concentration of the contaminant isotope Tb-159 is monitored in liquid target solution. When the concentration of Tb-159 exceeds a predetermined cutoff concentration, the pump and / or a valve stop the flow through the isotope collection device. The cutoffAttorney Docket No. S2302.70007WO00 concentration is a concentration that is set based on the particular application of the desired isotope and the purity required. Additionally or alternatively, the concentration of the desired isotope may be monitored.

[0122] In some embodiments, when the intermediate isotope that decays into the contaminant isotope has a shorter half-life than the first intermediate isotope, then the contaminant isotope is captured directly by the isotope capture device and the desired daughter isotope remains circulating in the liquid target solution. Accordingly, once the desired daughter isotope has accumulated to a sufficient quantity, the desired daughter isotope may be separated and purified from the liquid target solution using a second isotope capture device. In the example of Ra-225 and Ra-227, Ra-227 has a much shorter half-life than Ra-225. However, the Ac-227 produced from the decay of Ra-227 is not ideal for use as a radiotherapeutic isotope. As described above, the first isotope capture device will capture Ac-227 as Ra-225 accumulates in the liquid target solution. Once Ra- 225 has accumulated to a predetermined quantity, the liquid target solution is diverted such that it no longer passes through the nuclear reactor and then the liquid target solution is filtered using a chromatography column (e.g., a second isotope capture device). The chromatography column may retain the Ac-225 which may be eluted off after capture and separation from non-captured Ra-225.

[0123] In some embodiments, the contaminant isotope may be milked to produce other radiotherapeutic daughter isotopes. For example, Ac-227 which accumulates in the first isotope capture device may then be milked to produce bismuth-213 (Bi-213), thorium-227 (Th-227), and / or radium-223 (Ra-223).

[0124] During (as part of step 806) or following the conclusion of process 800, one or more additional purification step(s) may be performed to further purify the desired isotope to a desired degree of purity. For example, a column separation process that includes a solid phase medium and eluent able to retain undesired (e.g. radium) isotopes on the column while passing / eluting desired (e.g., actinium) isotopes from the column, a DGA resin medium manufactured by Eichrom Technologies Inc. may be employed. The DGA resin may be a N,N,N’,N’-tetra-n-octyldiglycolamide normal resin or a N,N,N’,N’- tetrakis-2-ethylhexyldiglycolamide branched resin. As a second example, the columnAttorney Docket No. S2302.70007WO00 separation process may use a resin based on a mixture of diglycolamide and a phosphine oxide, such as those manufactured by TrisKem International. The diglycolamide and phosphine oxide based resin may be TK-221 or, when based on a branched diglycolamide, TK-222.

[0125] As an exemplary purification process, when TK-221 is used as the column medium, nitric acid or hydrocholoric acid may be used to dissolve Ra-226 targets and load them onto the stationary phase medium. Nitric acid or hydrochloric acid may also be employed to elute various species from the stationary phase medium while retaining others. For example, for Ra-226 targets with lanthanide impurities, the nitric acid or hydrochloric acid may be employed as a mobile phase that retains those impurities as well as iron, polonium, and bismuth impurities. The TK-221 particle size may be between 50-100 microns. A second column may be included downstream that uses a crown-ether resin, such as TK-101. The second column may remove radium, lead, and / or tin as needed.

[0126] A nitric acid and / or hydrochloric acid process may be used with any suitable column media. A typical such separation process may start by dissolving the target in nitric acid. For dissolving typical target materials, nitric acid having a molarity between 2-4 M may be used. The dissolved target is then loaded onto the column.

[0127] Next, the column with the dissolved target may be washed with 4 molar nitric acid to remove radium, barium, lead, and strontium impurities. After washing, 12 molar nitric acid may be used to elute additional radium, actinium, and lanthanides to obtain a dilute eluate.

[0128] Next, the dilute eluate can be loaded onto a column for a second separation. In the second separation, 6 molar nitric acid may be used to rinse the column to remove lanthanides, 10 molar hydrochloric acid may be used to rinse the column to remove bismuth, 0.05 molar nitric acid may be used to rinse the column to remove iron and polonium. Finally, to finish the second separation, 0.05 molar hydrochloric acid may be used to elute the desired radioisotope (e.g., actinium including actinium-225) from the column. The second separation may be repeated two or more times to increase the purity of the desired isotope in the resulting eluate.Attorney Docket No. S2302.70007WO00

[0129] A third separation may be used for further radium, lead, strontium, and bismuth removal. The third separation may load the actinium eluate from the second separation to a column in 0.05 molar hydrochloric acid. As described above, TK-101 resin may be used in the third separation. Once loaded, the column may be washed using 0.05 molar hydrochloric acid to elute the desired product (e.g., actinium). If desired, the further elution of parent elements (e.g., radium) may be eluted from the column using a stronger acid (e.g., 3 molar nitric acid).

[0130] Finally, if nitrates are present, nitrates may be removed as needed using a small anionic resin cartridge.

[0131] Another process which only relies on hydrochloric acid with DGA resin may be used as an alternative to the nitric and hydrochloric acid process for certain separations e.g., to separate radium and actinium). The hydrochloric acid based process dissolves the target in 9 molar hydrochloric acid. To load the dissolved target onto the column, 0.05 molar hydrochloric acid may be used. Next, 9-10 molar hydrochloric acid may be used to rinse the column. During rinsing, a first species (e.g. radium) is eluted from the column. Finally, 0.05 molar hydrochloric acid is used to elute the desired product (e.g., actinium) from the column.

[0132] In certain cases, hydrochloric acid based separation with TK-101 resin may be used. For example, a dissolved target may be loaded onto a column containing the TK-101 resin in 0.05 molar hydrochloric acid. Next, 0.05 molar hydrochloric acid may be used to rinse the column. During rinsing, a first species (e.g., actinium) is eluted from the column. Other (e.g. contaminating) species (e.g., radium) may be retained on the column which can (if desired) be subsequently eluted using 3 molar hydrochloric acid.

[0133] If lanthanides are present and are desired to be removed, a first pass through a TK-221 column may be used. To load the dissolved solution for purification onto the column, 0.05 molar hydrochloric acid may be used. Next, 10 molar hydrochloric acid may be used to rinse the column of bismuth and 0.05 molar nitric acid may be used to rinse the column of iron and polonium. Desired species (e.g., actinium) may be eluted using 0.05 molar hydrochloric acid. This first pass may be repeated as needed to increaseAttorney Docket No. S2302.70007WO00 the purity of the actinium. Additionally, a further TK-101 column may be used to further remove radium, lead, strontium, and barium.

[0134] The flowcharts included herein, such as in FIG. 8, are merely exemplary and other processes or combinations of the processes described herein could be performed for other desired daughter isotopes and initial target content depending on the situation following the teachings of the present disclosure.

[0135] Although the methods and system are described herein as using naturally occurring gadolinium, and that the ability to use naturally occurring gadolinium is an advantage provided by some aspects of the technology described herein. The systems and methods described herein could also be used with enriched starting isotopes. For example, the systems and methods described herein could be used with enriched gadolinium, such as gadolinium-160.

[0136] Having thus described several aspects of at least one embodiment of this invention, it is to be appreciated that various alterations, modifications, and improvements will readily occur to those skilled in the art.

[0137] Such alterations, modifications, and improvements are intended to be part of this disclosure, and are intended to be within the spirit and scope of the invention. Further, though advantages of the present invention are indicated, it should be appreciated that not every embodiment of the technology described herein will include every described advantage. Some embodiments may not implement any features described as advantageous herein and in some instances one or more of the described features may be implemented to achieve further embodiments. Accordingly, the foregoing description and drawings are by way of example only.

[0138] Various aspects of the present invention may be used alone, in combination, or in a variety of arrangements not specifically described in the embodiments described in the foregoing and is therefore not limited in its application to the details and arrangement of components set forth in the foregoing description or illustrated in the drawings. For example, aspects described in one embodiment may be combined in any manner with aspects described in other embodiments.Attorney Docket No. S2302.70007WO00

[0139] Also, the invention may be embodied as a method, of which an example has been provided. The acts performed as part of the method may be ordered in any suitable way. Accordingly, embodiments may be constructed in which acts are performed in an order different than illustrated, which may include performing some acts simultaneously, even though shown as sequential acts in illustrative embodiments.

[0140] Use of ordinal terms such as “first,” “second,” “third,” etc., in the claims to modify a claim element does not by itself connote any priority, precedence, or order of one claim element over another or the temporal order in which acts of a method are performed, but are used merely as labels to distinguish one claim element having a certain name from another element having a same name (but for use of the ordinal term) to distinguish the claim elements.

[0141] The terms “approximately” and “about” may be used to mean within ±20% of a target value in some embodiments, within ±10% of a target value in some embodiments, within ±5% of a target value in some embodiments, and yet within ±2% of a target value in some embodiments. The terms “approximately” and “about” may include the target value. The term “substantially equal” may be used to refer to values that are within ±20% of one another in some embodiments, within ±10% of one another in some embodiments, within ±5% of one another in some embodiments, and yet within ±2% of one another in some embodiments.

[0142] The term “substantially” may be used to refer to values that are within ±20% of a comparative measure in some embodiments, within ±10% in some embodiments, within ±5% in some embodiments, and yet within ±2% in some embodiments. For example, a first direction that is “substantially” perpendicular to a second direction may refer to a first direction that is within ±20% of making a 90° angle with the second direction in some embodiments, within ±10% of making a 90° angle with the second direction in some embodiments, within ±5% of making a 90° angle with the second direction in some embodiments, and yet within ±2% of making a 90° angle with the second direction in some embodiments.

[0143] Also, the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,”Attorney Docket No. S2302.70007WO00 “comprising,” or “having,” “containing,” “involving,” and variations thereof herein, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

[0144] What is claimed is:

Claims

Attorney Docket No. S2302.70007WO00 CLAIMS 1. A method of obtaining desired daughter isotopes, the method comprising: pumping a liquid target solution comprising a parent isotope through a fluid path that includes a first portion that passes through a fission reactor, a second portion that passes through a pump that pumps the liquid target solution through the fluid path, and a third portion that passes through an isotope capture device, and wherein the second portion and ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ irradiating the liquid target solution with a neutron flux, as the liquid target solution ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ purifying a desired daughter isotope from the liquid target solution at least in part through using the isotope capture device.

2. The method of claim 1, wherein the purifying step comprises capturing the desired daughter isotope from the liquid target solution using the isotope capture device.

3. The method of claim 2, wherein the method further comprises eluting the desired daughter isotope captured by the isotope capture device from the isotope capture device.

4. The method of claim 1, wherein the fluid path is a closed loop.

5. The method of claim 1, wherein the fluid path is an open path.

6. The method of claim 1, wherein irradiating the liquid target solution with the neutron flux directly generates the desired daughter isotope.Attorney Docket No. S2302.70007WO00 7. The method of claim 1, wherein irradiating the liquid target solution with the neutron flux generates an intermediate isotope, and wherein the desired daughter isotope is produced from decay of the intermediate isotope.

8. The method of claim 7, wherein the intermediate isotope is a first intermediate isotope and wherein irradiating the liquid target solution with the neutron flux generates two or more intermediate isotopes from the liquid target solution, the two or more intermediate isotopes comprising a second intermediate isotope.

9. The method of claim 8, wherein the second intermediate isotope has a longer half-life than the first intermediate isotope, and wherein the desired daughter isotope is separated from the liquid target solution by: capturing the desired ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ monitoring the liquid target solution for a contaminant isotope, wherein the ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ and when a concentration of the contaminant isotope increases to a predetermined level, removing the isotope capture device from the fluid path.

10. The method of claim 8, wherein the second intermediate isotope has a shorter half-life than the first intermediate isotope, and wherein the desired daughter isotope is separated from the liquid target solution by: capturing a contaminant isotope produced by the decay of the second ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ after waiting for a first decay period, based on a half-life of the first intermediate isotope, diverting the liquid target solution so it is no longer circulating ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ and capturing the desired daughter isotope from the diverted liquid target solution using a second isotope capture device.Attorney Docket No. S2302.70007WO00 11. The method of claim 1, wherein the parent isotope comprises a plurality of isotopes, and the plurality of isotopes are naturally occurring gadolinium comprising at least gadolinium-158 and gadolinium-160.

12. The method of claim 1, wherein the parent isotope comprises enriched gadolinium-160.

13. The method of claim 11, wherein the desired daughter isotope is terbium-161.

14. The method of claim 13, wherein purifying terbium-161 comprises using a filter to capture terbium isotopes from the liquid target solution.

15. The method of claim 14, wherein the filter comprises a chromatography column.

16. The method of claim 1, wherein the isotope capture device comprises a filter having a capture efficiency between 2% and 50%.

17. The method of claim 16, wherein the capture efficiency of the filter is between 2% and 25%.

18. The method of claim 17, wherein the capture efficiency of the filter is between 5% and 10%.

19. The method of claim 16, wherein the isotope capture device comprises a zirconium oxide filter.

20. The method of claim 19, wherein the zirconium oxide filter is a chromatography column comprising a zirconium oxide stationary phase.

21. The method of claim 1, wherein the first portion of the fluid path is between 50% and 95% of a volume of the fluid path.Attorney Docket No. S2302.70007WO00 22. The method of claim 21, wherein the first portion of the fluid path is between 70% and 95% of the volume of the fluid path.

23. The method of claim 22, wherein the first portion of the fluid path is between 85% and 95% of the volume of the fluid path.

24. The method of claim 11, wherein pumping the liquid target solution comprises pumping the liquid target solution until a terbium-159 concentration exceeds a predetermined cutoff concentration.

25. The method of claim 24, further comprising monitoring for terbium-159 to detect a preselected threshold of terbium-159 in the liquid target solution.

26. The method of claim 1, wherein the liquid target solution comprises GdCl3 and / or Gd(NO3)3.

27. The method of claim 1, wherein the parent isotope comprises radium-226.

28. The method of claim 27, wherein the desired daughter isotope is actinium-225.

29. The method of claim 28, wherein purifying the actinium-225 comprises using a first isotope capture device to capture actinium-225 and actinium-227 isotopes from the liquid target solution and, after a waiting period, using a second isotope capture device to capture actinium-225 isotopes from the liquid target solution.

30. The method of claim 29, wherein the waiting period is approximately 8 hours.

31. The method of claim 27, wherein the liquid target solution comprises radium chloride in a hydrochloric acid solution.Attorney Docket No. S2302.70007WO00 32. The method of claim 23, wherein the liquid target solution comprises radium nitrate in a nitric acid solution.

33. A system for obtaining desired isotopes, the system comprising: ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ a processing chamber that includes a radiation shield configured to shield contents of the processing chamber from the radiation chamber^ a pump configured to control flow of a liquid target between a processing chamber ^^^^^^^^^^^^^^^^^^^^^^^^^^ and an isotope capture device that preferentially captures a first isotope with respect to a second isotope in the liquid target.

34. The system of claim 33, wherein the isotope capture device captures a contaminant isotope formed as a byproduct of irradiating the liquid target.

35. The system of claim 33, wherein the isotope capture device preferentially captures a daughter isotope with respect to a parent isotope in the liquid target.

36. The system of claim 33, further comprising a detector to determine a concentration of isotopes in the liquid target.

37. The system of claim 33, further comprising a cooling device to cool the liquid target after it flows out from the radiation chamber but before the isotope capture device.

38. A method of obtaining terbium-161, the method comprising: pumping a target solution comprising gadolinium through a fluid path, wherein the fluid path includes a first portion that passes through a fission reactor, a second portion that passes through a pump that pumps the target solution through the fluid path, and a third ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^Attorney Docket No. S2302.70007WO00 producing gadolinium-161 in the target solution through exposure of the target ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ operating the terbium capture device to capture terbium-161 produced in the target solution though radioactive decay of the gadolinium-161 produced in the target solution.

39. The method of claim 38, wherein the target solution is a solution of naturally occurring gadolinium.

40. The method of claim 37, wherein the target solution is a solution of enriched gadolinium.

41. The method of claim 39, further comprising producing gadolinium-159 in the target solution in addition to producing the gadolinium-161.

42. The method of claim 38, wherein the fluid path is coupled to a peristaltic or diaphragm pump, which when operated performs said pumping of the target solution through the fluid path.

43. The method of claim 38, wherein the fluid path is a closed loop.

44. The method of any of claims 38-42, wherein the terbium capture device comprises a chromatography column.

45. The method of any of claims 38-42, further comprising detecting an amount of Tb-159 in the target solution, and stopping said pumping of the target solution when a detected amount of Tb-159 is above a preselected threshold.

46. The method of any of claims 38-42, further comprising, subsequent to stopping said pumping of the target solution when a detected amount of Tb-159 is above a preselected threshold, removing the target solution from the fluid path and providing a new target solution comprising gadolinium into the fluid path.Attorney Docket No. S2302.70007WO00 47. The method of claim 38, wherein the target solution comprises aqueous GdCl3 and / or Gd(NO3)3.

48. The method of claim 38-42, wherein operating the terbium capture device captures an isotopically pure sample of terbium-161.

49. The method of claims 38-42 or 47, wherein operating the terbium capture device captures a sample that consists essentially of terbium-161.

50. A method of obtaining Actinium-225, the method comprising: pumping a target solution comprising radium through a fluid path, wherein the fluid path includes a first portion that passes through a fission reactor, a second portion that passes through a pump that pumps the target solution through the fluid path, and a third portion that passes through a first actinium ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ producing radium-225 and radium-227 in the target solution through irradiation of ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ operating the first actinium capture device to capture actinium-227 from the target solution after exposure to neutrons in the fission reactor by passing the irradiated target solution through the first actinium capture device ^^^^^^^^^^^^^^^^^^^^^^^^^^^ after the accumulation period, diverting the target solution such that it does not pass ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ operating a second actinium capture device to capture actinium-225 from the diverted target solution by passing the diverted target solution through the second actinium capture device.

51. The method of claim 50, wherein the first and second actinium capture devices comprise a chromatography column.

52. The method of claim 50, wherein the fluid path is a closed loop.Attorney Docket No. S2302.70007WO00 53. The method of claim 51, wherein during the accumulation period, a concentration of radium-225 increases in the target solution.

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