Apparatus for production of actinium-225 from radium-226 and uses thereof

Abstract

The present application relates to an apparatus for manufacturing a material containing radium-225 from a material containing radium-226, by which apparatus a starting material containing radium-226 is subjected to neutron irradiation from a nuclear reactor to cause 226 Ra to be converted into radium-225, thereby providing a material containing radium-225, characterized in that the neutron irradiation of the starting material containing radium-226 is carried out in a moderated nuclear reactor; and the starting material containing radium-226 is shielded with a thermal neutron absorption shield.

Description

TECHNICAL FIELD

[0001] The present invention relates to an apparatus for the production of the actinium-225 ( 226 Ra) isotope from radium-226 ( 225 Ac). More specifically, the present invention relates to an apparatus for the production of radium-225 ( 225 Ra) and its subsequent conversion to actinium-225 by decay. BACKGROUND

[0002] Actinium-225 ( 225 Ac) is an alpha-emitting isotope with a half-life of approximately 10 days that is showing great promise for medical applications. The use of 225 Ac is particularly foreseeable in targeted alpha therapy (TAT). In targeted alpha therapy (TAT), the isotope can be attached to various biological molecules or targeting compounds. The various biological molecules or targeting compounds specifically bind to, for example, cancer cells. The alpha decay of the isotope targeted at the cells destroys the cancer cells by alpha-decay. In the case of sufficiently specific targeting agents, the present application can offer the opportunity for a treatment in which the malignant cells are locally treated and effectively destroyed. By using local and targeted therapy, it is possible to minimize negative side effects. This is more advantageous compared to more commonly used treatments, such as chemotherapy or hormone therapy, in which the entire patient is affected by the treatment and can have severe side effects. The development of targeted alpha therapy (TAT) is rapidly progressing. This rapid development increases the need for alpha-emitting isotopes of suitable quality and quantity to be used in TAT, such as 225 Ac.

[0003] Furthermore, 225 Ac, one of the daughter isotopes of 213 Bi (bismuth-213). 213 Bi has a half-life of 45 minutes and can also be suitable for alpha-emitter-based therapy. When 225 Ac is produced, the 213 Bi isotope is also produced indirectly.

[0004] High-purity 225 Ac is difficult to produce. Therefore, to date, only small amounts of 229 Th (thorium-229) sources have been available. 229 Th generates 225 Ac by decay via 225 Ra. However, due to the only small amounts of 229 Th available, these approaches can only support small-scale applications. Irradiation of 226 Ra in a thermal spectrum by multiple neutron capture enables the creation of a source for the production of 225 Ac.229 Th source. Unfortunately, this pathway also produces unwanted isotopes, such as 228 Th, which generates high-energy gamma flux. Such as from 228 The high energy gamma flux of Th leads to difficulties in handling and radiation protection over a period of 10-20 years.

[0005] produce 225 Another way to obtain Ac is through induction by high-energy (fast) neutrons. 226 The Ra(n,2n) reaction directly produces 225 Ra.

[0006] Some existing publications describe 226 Ra is converted to 225 Ra and further transformation 225 Ac's equipment.

[0007] EP0752710 describes the conversion of radium-226 to actinium-225 in a fast-spectrum nuclear reactor using high-energy neutrons in the (n,2n)- reaction, and focuses on the chemical separation of the desired isotope after the decay of the unwanted radium-227 isotope, followed by the separation of actinium-225.

[0008] US20140226774 describes 226 Ra to 227 The conversion of Ac utilizes thermal shielding for protection. 227 Ac is protected from thermal neutrons and shapes the spectrum so that 226 Ra nuclei are exposed to neutrons in a higher hyperthermal group with energies between 20 eV and 1 keV.

[0009] US20070092051 describes a method of irradiating a fast neutron reactor (FNR) with a high fast neutron flux using neutrons. 226 Ra is used to produce actinium-225. Fast neutrons have neutron energies of about 0.1-5 MeV to about 20 MeV. Irradiating radium-226 with neutrons having neutron energies of about 0.1 MeV, preferably 5 MeV to about 20 MeV will produce actinium-225. 225 Ra. Caused by the emission of β particles. 225 The natural decay of Ra is transformed into 225 Ac. Based on theoretical calculations, the potential yield in US20070092051 is estimated to be 5 mCi (0.185 GBq) of radium-225 per gram of radium-226.

[0010] Therefore, via 225 Ra(n,2n) route generation 225 Ac has become possible. However, given the growing attention, in generating...225 Raand by 225 Ra 225 There is a correlation between the higher efficiency, the more convenient and the more productive routes for the production of

[0011] A drawback of existing routes based on FNRs such as described in US20070092051 is that FNRs are not readily available and difficult to operate in a commercially reasonable way. Worldwide there are about 20 FNRs available. These FNRs are typically not used or usable for the production of medical isotopes. Introduction and retrieval of targets in such FNRs is often complex and for 225 The flexibility and operational days of these systems are limited for the convenient production of SUMMARY

[0012] The inventors of the present application have come up with an improved apparatus and in particular an apparatus capable of producing the desired radium-225 and actinium-225 isotopes from radium-226 in a more efficient way, with higher yields and selectivity and making use of a nuclear infrastructure that is more readily available and more suitable for the production purpose.

[0013] The inventors of the present application have found that radium-225 and actinium-225 can be produced in high yield and selectivity when using a "normal" moderated material test reactor instead of an internal FNR.

[0014] The moderated material test reactor is producing a neutron flux containing fast neutrons (with energies in the MeV spectrum) and (epi-)thermal neutrons (with energies in the < KeV spectrum). In the neutron spectrum of the moderated material test reactor, the presence of thermal neutrons is in 225 There is a problem in the efficient production of 225 Ra, thus complicating the processing of the desired isotope product and burning up 225 Ra starting material, i.e. reducing the desired 225 yield of

[0015] From initial experiments at the High Flux Reactor Petten (HFR) it was found that the production of 226 Ra(n,2n) from 225 The rate of production of 225 Ac is higher than hitherto known production rates. This offers the opportunity to use the fast neutron part of the neutron flux in a "normal" moderated material test reactor (like the HFR) for the production of 225 Ra as a source of 226 Ac. Common moderated material test reactors (like the HFR) typically have a lower fast neutron flux than most FNRs, but the 226Post-irradiation experiments on Ra show that the fast flux in the material testing reactor is sufficient to produce a significant amount of 225 Ac.

[0016] The inventors of the present invention realized that, by 226 manufacturing 225 Ac, an efficient way is to use only the fast neutron part of the neutron flux and (essentially) eliminate the thermal neutron activation. The inventors realized that this can be achieved by making use of a surrounding thermal neutron absorbing shield and preferably a Radium-226 target.

[0017] The shield absorbs (most of) the thermal neutrons and enables most of the fast neutrons to pass through the target material ( 226 Ra) and interact with it.

[0018] Preferably, the thermal shield is formed such that the spectrum is shaped such that only neutrons with the required energy to convert 226 Ra into 225 Ra are not absorbed and interact with the target material. The preferred neutron energy window for the conversion of 226 Ra into 225 Ra lies in the range from 0.1 MeV to 20 MeV, preferably 5 MeV to 20 MeV.

[0019] The present invention thus relates to the manufacture of Radium-225 containing material from Radium-226 containing material by subjecting the Radium-226 containing starting material to neutron irradiation from a moderated nuclear reactor (internally or in the vicinity) to convert the Radium-226 into Radium-225 to provide the Radium-225 containing material, characterized in that:

[0020] - the neutron irradiation of the Radium-226 containing starting material is performed in a moderated nuclear reactor; and

[0021] - the Radium-226 containing starting material is shielded with a thermal neutron absorbing shield.

[0022] It was found that the use of a thermal neutron absorbing shield during the irradiation of Radium-226 provides the following benefits:

[0023] - the amount and kind of high radioactive isotopes produced by thermal neutron activation of Radium-226 is reduced. Some of the high radioactive isotopes produce high energy gamma radiation which is difficult to shield and complicate the post-irradiation handling and processing. This thermal neutron shield effectively reduces the formation of these specific isotopes and thereby greatly facilitates the feasibility of the handling, processing and purification of the target material after irradiation.

[0024] - the amount and kind of isotopes produced by thermal neutron activation of Ra-226 is reduced. This reduces the production of unwanted isotopes by thermal neutron activation, which can end up in the final product (improved product quality) and reduces the waste stream and the complexity of the separation process (improved process quality). This is especially true for isotopes with a very long lifetime 227 Ac, which should be eliminated from the final product as much as possible, but cannot be separated from the desired isotopes 225 Ac chemical separation.

[0025] - the burn-up of Ra by thermal neutron activation is reduced, thus reducing the production of the desired 226 Ra. 226 The amount of Ra is reduced. 226 Ra is scarce.

[0026] - the burn-up of Ra by thermal neutron absorption ("deactivation") of Ra to 225 Ra is reduced, thus optimizing the production of Ra. 226 Ra. 225 The amount of Ra is reduced. 225 The production of Ra is optimized.

[0027] - the yield of Ra production per weight unit (gr) 226 Ra is increased. 225 The yield of Ra production is increased.

[0028] - the yield of Ac production per weight unit (gr) 226 Ra is increased. 225 The yield of Ac production is increased.

[0029] - the amount of waste produced (such as unwanted isotopes) is reduced.

[0030] The device of the invention can make use of existing and readily available irradiation infrastructure, whereby the device for producing actinium isotopes with a wide applicability in the medical field can be implemented relatively quickly and cost-effectively. Since irradiation infrastructure such as a moderated material test reactor can irradiate large volumes, a larger yield can be produced. 225 The half-life of Ac is 10 days, a relatively long half-life that makes it possible to distribute it worldwide without losing too much effectiveness, which makes it possible to concentrate the production. The use of alternative 225 Ac production techniques brings significant economic benefits.

[0031] In another aspect of the invention, it is found that irradiating Ra in a thermal neutron absorption shield 226Ra, i.e. all radium isotopes in the target, can be separated from the other elements in the target within a few days after irradiation to eliminate unwanted impurities present in the target or unwanted impurities generated by decay. The time period between the end of irradiation and the first purification should be at least sufficient to allow 227 Ra (half-life 42.2 min) to decay. 227 Ac is an especially unwanted isotope with a half-life of 21.8 years that should be avoided to be introduced into the patient and the environment and that can still be present in the irradiated material in unacceptable amounts even though its production is largely avoided in the device of the present invention by employing a thermal neutron absorption shield.

[0032] This treatment, i.e. the separation of the desired isotope, can be performed in different ways.

[0033] In one embodiment, the actinium isotopes are chemically extracted (or eluted) from the irradiated 226 Ra to remove actinium ( 227 Ac and 225 Ac) both). The separation is performed within a few hours or days after irradiation, since all other actinium isotopes that can impair the quality of the product have been removed before the production of 225 Ac. A sufficient amount of 225 Ra can be retained to produce a sufficient amount of new 225 Ac in purified form.

[0034] In another embodiment, this treatment can be performed by extracting (or eluting) the radium isotopes from the irradiated 226 Ra and subsequently allowing 225 Ra in the separation to decay into 225 Ac.

[0035] The thermal neutron shield in the device of the present invention can be established by encapsulating the radium-226 starting material in a (closed) thermal neutron shield. The thermal neutron shield is made of a material having a high thermal neutron cross section. The thermal neutron shielding material is preferably selected from the group of elements with a high thermal neutron absorption cross section consisting of boron, cadmium, gadolinium, hafnium and mixtures thereof. A gadolinium shield is preferred.

[0036] The starting 226 Ra material can be provided in the desired chemical form, such as a metal, an oxide, a salt or mixtures thereof. The starting material can also be provided as a powder and / or in combination with other elements, such as Al. The starting material can be sintered and / or granulated. The starting material is placed in a container, preferably forming a closed container, such as a closed ampoule, which can be made of a metal, quartz or ceramic material and can be closed to form the container.

[0037] The ampoule is preferably placed in a cylinder which consists of a material with a high thermal neutron absorption cross section and with a low absorption cross section for high energy neutrons, such as preferably gadolinium. The thermal neutron shield can also be considered to form a closed container. In addition or alternatively, the target material in the ampoule can be mixed with a thermal neutron absorber material. The construction is placed in a second container, which is typically a metal cylinder closed with (welded) end caps. The container is cooled from the outside by the reactor coolant.

[0038] Between the shield and the outer container, a filler of low density and high thermal conductivity can be added as required to transport the heat generated in all materials and components to the coolant without high thermal gradients, to avoid overheating and to reduce thermal gradients and thereby thermal stresses, melting, decomposition in the various materials and components.

[0039] The low energy (thermal) neutron flux from the material testing reactor is absorbed by the thermal shielding material, so that there are virtually no low energy (thermal) neutrons in the shielded cavity. The high energy (fast) neutrons (typically about 0.1 MeV, preferably 5 MeV to about 20 MeV) pass relatively undisturbed. Thus, in this configuration a specific fast neutron spectrum is generated in the neutron shield. For the shielded material in the cavity, the following applies: 226 Ra material, 226 The Ra(n,2n) reaction takes place in the fast flux of the material testing reactor, which is largely undisturbed by the shield, but the thermal neutron activation reactions are avoided because the thermal neutrons are effectively absorbed by the shield. DETAILED DESCRIPTION

[0040] The invention can be explained in more detail as follows Figure 1

[0041] ​In the radium starting material containing unit (4) radium starting material (5) is provided (which can be in various chemical forms, such as metal, oxide, carbonate, nitride, etc.). This unit (4) can be an ampoule of radiation resistant material, such as metal, quartz, ceramic. These radium containing starting materials can be placed in a thermal neutron shielding holder (3) which can be closed by an end cap (2). The thermal neutron shielding (4) holder and end cap (3) can be made of a material with a high thermal cross section, such as boron, cadmium, gadolinium. The preferred material for the holder and end cap is gadolinium. Preferably, the holder and end cap are from the same or substantially the same thermal neutron absorbing material. The thermal neutron shielding preferably completely encloses the radium target material, i.e. the radium target material is shielded from the thermal neutrons of the reactor. The thermally shielded radium target material can be placed in a container (7) which is usually made of a metal material which can have a container cap (1). The container and container cap can be sealed closed, for example by welding. The container and container cap are preferably the same or substantially the same material. Between the container and the thermal shielding, a filler material (6) can be provided which is usually a light weight material with good thermal conductivity, for example graphite or aluminium.

[0042] Figure 1 A schematic drawing of one example of a container cylinder containing radium target material with thermal neutron shielding is disclosed.

[0043] Figure 2 During and after irradiation in shielded and unshielded form, 225 Acand 225 Raover time. The unshielded case is based on an actual irradiation of 0.12 mg 226 Ra in a high flux position in the HFR Petten in the Netherlands. The 225 Accontent was measured at three different times and is shown in the figures. From these measurements and supported by calculations, 225 Acprovides the amount of 225 Ra that is produced at the end of the irradiation without thermal neutron absorbing shielding. In case a thermal neutron absorbing shielding is employed, 225 the production rate of 225 Ra is similar or higher because the fast neutrons are neither absorbed nor affected by the thermal neutron absorbing shielding and the thermal neutron absorbing shielding eliminates the burn-up by thermal neutrons of the generated

[0044] The amount of 225 Ra over time based on irradiation and decay is known, it is possible to simulate the process of extracting 225 Ac:

[0045] - after 3 days all actinium is chemically removed, leaving only the radium isotopes 225 Ra and226 Ra. This actinium can contain unacceptable amounts of unwanted 227 Ac isotopes and can be discarded or used for other purposes.

[0046] - from this point in time, 225 Ra continuously produces new 225 Ac, and no other actinium isotopes are formed or present.

[0047] - the produced 225 Ac can be removed repeatedly until 225 most of the 225 Ra has decayed. In the figure an exemplary extraction scheme is shown, where 225 Ac is extracted from the radium after a time period of from 5 to 8 days.

[0048] It is calculated that all radium is extracted and purified three days after the end of irradiation, i.e. 31 + 3 days after the start of irradiation. At this point in time, the extracted and purified radium no longer contains actinium. Subsequently produced 225 Ac is produced by decay of 226 Ra present in the purified radium.

[0049] Figure 2 A graph of the irradiation activation of 226 Ra is shown for both the realized thermal neutron shielded form and the thermal neutron unshielded form (for comparison purposes).

[0050] It is shown in the figure that from 0.12 mg 225 Ra irradiated in this way in a conventional thermal neutron material testing reactor, like the HFR, it can be extrapolated that approximately a total of 6.9 GBq 226 Ac / g 225 Ra can be produced, which corresponds to a dose for 860 patients, assuming 8 MBq per dose (based on normal PSMA administration of 226 Ac). Therefore, multiple extractions for 100s of patient doses can be made based on the amount of 1 gram 225 Ra. With the thermal neutron absorption shield, similar or higher amounts are provided, while the activity of unwanted isotopes is significantly reduced, which greatly facilitates handling and processing, and reduces the risk of impurities being present in the end product by reducing their formation during irradiation. In the device described in US20070092051, and based on theoretical calculations, the potential yield in a fast neutron reactor was estimated at 5 mCi (0.185 GBq) of radium-225 per gram of radium-226. The present invention provides a significantly higher yield (about 40 times) in a conventional material testing reactor example, like the HFR.

[0051] There are also other known ways of producing 225Ac, but the key benefit of the apparatus claimed in the present invention is that it enables the provision of large quantities of 225 Ac, while simultaneously eliminating the formation of unwanted isotopes that complicate post-irradiation handling, processing and purification. The use of readily available irradiation infrastructure enables relatively rapid and cost-effective implementation. This is important for medical isotopes that are already in high demand and are expected to see a significant increase in demand in the coming years, particularly with respect to the implementation of significant results such as the treatment of castration-resistant prostate cancer in conjunction with PSMA compounds, and the expected efficacy thereof for new medical applications. 225 Ac, while simultaneously eliminating the formation of unwanted isotopes that complicate post-irradiation handling, processing and purification. The use of readily available irradiation infrastructure enables relatively rapid and cost-effective implementation. This is important for medical isotopes that are already in high demand and are expected to see a significant increase in demand in the coming years, particularly with respect to the implementation of significant results such as the treatment of castration-resistant prostate cancer in conjunction with PSMA compounds, and the expected efficacy thereof for new medical applications.

Claims

1. An apparatus for manufacturing a material containing radium-225 from a material containing radium-226, by which the material containing radium-226 is subjected to neutron irradiation in a moderated nuclear reactor, characterized in that: - a radium starting material (5) of radium-226 is subjected to neutron irradiation from a nuclear reactor to convert the radium-226 into radium-225, thereby providing a material containing radium-225, said apparatus comprising: - the container lid (1); the end cap (2); the thermal neutron shielding holder (3); the radium starting material containing unit (4); the radium starting material (5); the filling material (6); and the container (7) are characterized in that: - the neutron irradiation of the radium starting material (5) containing radium-226 is carried out in a moderated nuclear reactor; - the radium starting material (5) containing radium-226 is shielded with the thermal neutron shielding holder (3); - the radium-225 is allowed to decay into actinium-225; and - the actinium-225 is separated from the material containing radium-225.

2. The apparatus according to claim 1, further comprising separating radium isotopes from the material containing radium-225.

3. The apparatus of claim 1 or 2, wherein, The moderated nuclear reactor is a moderated material testing reactor.

4. The apparatus of claim 1, wherein, The moderated nuclear reactor is a moderated high flux reactor.

5. The apparatus of claim 1, wherein, The thermal neutron shielding holder is made of a material comprising boron, cadmium, gadolinium, hafnium or a mixture thereof.

6. The apparatus of claim 1, wherein, The fast neutrons from the moderated nuclear reactor have an energy in the range of 0.1 MeV to 20 MeV.

7. The apparatus of claim 1, wherein, The thermal neutrons have an energy in the range of 20 eV to 1000 eV.

8. The apparatus of claim 1, wherein, The material containing radium-226 is provided as a metal, an oxide, a salt such as a halide, nitrate or carbonate, or a mixture thereof.

9. An apparatus for manufacturing an actinium-225 containing material, by subjecting a radium starting material (5) containing radium-226 to neutron irradiation to convert radium-226 into a material containing radium-225 and actinium-225, the apparatus comprising: The container lid (1); the end cap (2); the thermal neutron shielding holder (3); the radium starting material containing unit (4); the radium starting material (5); the filling material (6); and the container (7) are characterized in that: - the neutron irradiation of the radium starting material (5) containing radium-226 is carried out in a moderated nuclear reactor; and - the radium starting material (5) containing radium-226 is shielded from thermal neutrons with the thermal neutron shielding holder (3); and - the material containing radium-225 is allowed to decay into a material containing actinium-225.

10. The apparatus of claim 9, wherein, Radium isotopes are separated from the material containing radium-225 before decaying into the material containing actinium-225.

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