Feasibility of a novel photoproduction of 225Ac and 227Th with natural thorium target

We propose an innovative way to produce both 225Ac and 227Th, two precious radioisotopes enabling promising targeted alpha therapy, in a natural thorium target bombarded with a 30–90 MeV electron beam. Bremsstrahlung photons in the target are analyzed by MCNP and in-situ photonuclear transmutation of 232Th is evaluated by using the TENDL nuclear data. In the photo-transmutation analysis, 13 nuclides including 229Th and 231Pa are modelled. Special procedures with chemical separations are also proposed to produce pure 225Ac and 227Th in separate streams. In addition, performance of the new approach is compared with conventional methods in terms of the 225Ac and 227Th yields. After a Th target is bombarded with a 500 kW electron beam for a year, yearly 225Ac yield is ~ 8.47 GBq (semi-permanently) and yearly 227Th yield is ~ 48.9 GBq over 50 years, and their yields are at least doubled in a 2-year irradiation. This work will help increase global supply of the two precious isotopes and would invariably help advance TAT-related researches and developments.

www.nature.com/scientificreports/ options but to produce 227 Ac from the 226 Ra(n,γ) 227 Ra reaction 2,14 , which means that the aforementioned Ra target issue remains unresolved and a costly neutron source is required. In response to the high demand of the 'rarest drugs' 225 Ac and 227 Th, we propose an innovative method to semi-permanently produce the α-emitters with an electron accelerator and natural thorium ( 232 Th) target. The Monte Carlo N-Particle transport (MCNP) version 6.2 code is used to calculate X-ray or photon generation and heat deposition in the Th target 15 . The photo-transmutations of 232 Th into 225 Ac or 227 Th are estimated by using the TALYS-generated Evaluated Nuclear Data Libraries (TENDL) cross-sections for various (γ,xn) photonuclear reactions 16 .

Methods
Photonuclear reactions in thorium target. Figure 1 shows schematic diagram of the proposed Th target system for photo-production of both 225 Ac and 227 Th. A metallic cylindrical Th target is directly bombarded by an electron beam to generate Bremsstrahlung photons and trigger photonuclear reactions. The target should rotate to manage locally-deposited heat during beam irradiation and it is supposed to be equipped with a cooling and radiation protection system as in the TRIUMF Isotope Separator and Accelerator (ISAC) facility 17 . Taking into account target cooling, the electron beam power is set to 500 kW and a relatively large target is considered (radius = 10 cm and thickness = 6 cm) to minimize the photon leakage from the target. To achieve appropriate target cooling, we adopt a beam diameter of 40 mm and a rotational speed of 120 RPM (rotation per minute). Detailed discussion on the heat deposition and removal is provided in Supplementary Information Sect. A. Figure 2 describes major photonuclear reactions and transmutation chains of 13 nuclides in the Th target. Two most significant pathways to generate 225 Ac and 227 Th are highlighted with bold lines respectively: 232 Th(γ ,3n) 229 Th → 225 Ra → 225 Ac and 232 Th(γ,n) 231 Th → 231 Pa → 227 Ac → 227 Th. Isotopic yields involving multiple photonuclear reactions with other thorium isotopes are actually very small. Other actinium isotopes can also be   www.nature.com/scientificreports/ generated from (γ,p) and (γ,np) photonuclear reactions. However, they quickly decay to thorium isotopes except for 229 Th(γ,np) 227 Ac reaction, which is insignificant due to very small (γ,np) cross-section. We also neglect the photo-fission of 232 Th, in spite of noticeable probability, since both fission products and neutrons hardly affect yield of 225 Ac and 227 Th. Meanwhile, the impact of photo-fissions on heat deposition turns out to be noticeable and it is discussed in Supplementary Information Sect. A. In the Th target, many fast neutrons are also generated by the photonuclear reactions including the photo-fissions. When the Th target is bombarded with 500 kW electron beam (70 MeV energy and 7.14 mA current), the neutron production is roughly estimated to be ~ 1.94E + 15 #/s. However, it is found that most of the fast neutrons (> 97%) simply escape the target and cannot contribute to the production of 225 Ac and 227 Th. Measured cross-sections of the photonuclear reactions of the Th and Pa isotopes are unknown except for (γ,n) and (γ,2n) reactions of 232 Th 18 . In order to calculate the photonuclear transmutation rate, the TENDL nuclear data are utilized. Figure 3 shows experimental (γ,xn) and photo-fission cross-sections of 232 Th together with the TENDL data for comparison. Except for overrated TENDL data of (γ,n) cross-section at a high energy tail, most of the experimental data for (γ,n) and (γ,2n) reactions are within one standard deviation of the TENDL data. While nuclear reaction modelling codes including TALYS generally provide rather uncertain parameters for photonuclear reactions, it is known that the parameter of giant dipole resonance (GDR) reactions such as (γ,xn) of heavy nuclides is slowly varying with the atomic mass number and the deviation from one nuclide to another is rather small [19][20][21] . Therefore, a GDR cross-section of a nuclide can be well predicted based on the experimental data of neighboring nuclei. Based on the measured cross-sections and general credibility of the TENDL library as shown in Fig. 3, actual cross-sections of 232 Th(γ,3n) 229 Th and other (γ,xn) reactions with similar mass number such as 231 Pa are expected to be similar to the TENDL data. Impacts of TENDL data uncertainty on the isotopic yields are given in Supplementary Information Sect. E.
As indicated in Fig. 3, high energy (> 6 MeV) photons are required for the photonuclear (γ,xn) reactions of 232 Th and the electron energy should exceed about 30 MeV. The Bremsstrahlung photon source in the Th target is generated by using the well-validated MCNP code. For a given photon source, number density of ' A' nuclide (N A ) is estimated by solving the following balance equations.
where λ Nat is natural decay constant, λ (γ,xn) is an effective decay constant for a (γ,xn) reaction, λ γ is summation of the effective decay constants for all (γ,xn) reactions, and dN γ /dE is the photon spectral density obtained by MCNP 6.2. A space-dependent photon spectral density should be used for accurate evaluation of the isotopic yields. The last two terms in Eq. (1) denote production of 'A' nuclide due to decay or transmutation of other nuclides. Detailed coupled equations for the 13 nuclides in Fig. 2  www.nature.com/scientificreports/ Sect. B. Spatial distribution of the photon source in Eq. (2) is pre-evaluated with MCNP and it is assumed to be constant since transmutation rate of 232 Th is extremely low in the rotating Th target.

are described in Supplementary Information
Procedures to retrieve pure 227 Th and 225 Ac. To produce pure 225 Ac and 227 Th from the irradiated target, their parent nuclides, 229 Th and 227 Ac, should be separated in order to avoid the 227 Ac contamination. There have been a few experimental validations for extraction of 225 Ac from 233 U or 229 Th stockpiles 22,23 . For the same purpose, we propose a simple strategy and chemical processings for periodic milking of the α-emitters, as shown in Fig. 4. Purpose of the cooling phase is to let 231 Th (progenitor of 227 Ac) completely decay out. After irradiation, the target should be cooled for a certain time to minimize the 227 Ac impurity for pure 225 Ac extraction. Once 231 Th disappears by its natural decay, all remaining Th isotopes are chemically separated from the others, then 225 Ac is purely produced by decay of 229 Th and this chemical extraction of 225 Ac can be near permanent due to long halflife of 229 Th. It should be noted that 226 Ra can be also produced due to decay of 230 Th in the separated Th stream and it can be used as the target material for other accelerated-based 225 Ac production methods.
Meanwhile, pure 227 Th can be chemically extracted from the separated irradiation byproducts, which are basically Ra, Ac, and Pa isotopes, i.e., 231 Pa slowly decays to 227 Ac decaying again to 227 Th with a half-life of ~ 22 years. If 227 Th is directly extracted from the separated byproducts without any additional chemical partitionings, the 227 Th can be blended with 230 Th generated by a natural decay of 230 Pa, which may cause an unwanted hazard induced by its daughter nuclides. For the purity of 227 Th, we chemically partition the byproducts into three parts: Ra, Ac, and Pa isotopes (blue lines in the non-Th products in Fig. 4). Then, 227 Ac is extracted from the separated Pa and moved to the actinium part where pure 227 Th can be purely extracted periodically. It is important to note that 227 Th production is quite semi-permanent (over 50 years) since half-life of 227 Ac is about 22 years. All chemical procedures in Fig. 4 are very analogous with ones used in the current 225 Ac extraction from natural thorium target bombarded by proton beam 24,25 , and they are considered to be readily available. It is also obvious that the 225 Ac and 227 Th yields should increase if the amount of 229 Th and 231 Pa in the target is increased with a prolonged beam irradiation and/or higher electron current.

Results
Parameter optimization for electron beam. A 500 kW electron beam is considered to evaluate the feasibility and performance of the new photo-production of 225 Ac and 227 Th. In order to find optimal parameters for the 500 kW electron beam, isotopic yield of 229 Th and 231 Pa (parent nuclei of 225 Ac and 227 Th) is evaluated for different beam diameters and electron energies. For accurate evaluation of the photon spatial distribution, the target is subdivided into small zones in both radial and axial directions, which is described in detail in Supplementary Information Sect. C.
For the sensitivity analysis, it is assumed that a 70 MeV beam bombards a fixed target with a 5 cm radius and a 6 cm height. The target size is large enough to minimize the leakage of Bremsstrahlung photons from the target. Figure 5 shows the spatial distribution of isotopic yields with different electron beam sizes (yellow area) after a one-year beam irradiation and cooling of a month. The spatial isotopic yield is evaluated with a different spatial discretization of the target depending on the beam size, as indicated by the dotted lines in Fig. 5. One www.nature.com/scientificreports/ notes that total yield of 229 Th drops by ~ 22% when beam diameter is increased from 15 to 40 mm, whereas the 40 mm beam enhances 231 Pa production slightly. The clearly lower 229 Th yield with the 40 mm beam is because contribution of the 231 Pa(γ,2n) 229 Pa reaction can be noticeably lowered due to lower concentration of 231 Pa with a larger beam diameter. Meanwhile, the slightly higher 231 Pa production for the 40 mm beam is simply due to the slower depletion rate of 232 Th in a bigger irradiated region. It is clear that a smaller beam size is favorable in terms of the 229 Th yield if the integrity of the target is guaranteed during irradiation.
In the actual rotating Th target as shown in Fig. 1, the effective beam size or irradiated area is significantly increased compared with a fixed target. In the Th target with a 120 RPM speed, it is assumed that the spatial photon spectral density is uniform in the azimuthal direction and they are evaluated with a detailed discretization in the radial direction. The isotopic yields of 229 Th and 231 Pa are given in Fig. 6 when the target radius is 10 cm  www.nature.com/scientificreports/ and beam diameter is 40 mm. It is noted that total yield of 229 Th is slightly lower than that of the fixed target due to further dispersion of the electron beam, and production of 231 Pa is slightly increased. The isotopic yields in the rotating target are compared with ones in the fixed target in Table 1. Figure 7a shows MCNP-evaluated zone-wise photon spectral densities for the rotational target in Fig. 6. One clearly notes that the photon flux is highest in the zone A and decreases more quickly in the radial direction due to a localized electron distribution. The highly position-dependent photon density results in the space-dependent yield distribution in Fig. 6. The number of electrons in the MCNP simulation is 8,000,000, leading to accurate photon spectral density in the whole target region. It is mentioned that impact of uncertainty of the photon flux on the α-emitter yield is less than 0.6%. Figure 7b shows the isotopic yield of 229 Th (source of 225 Ac) and 231 Pa (source of 227 Th) in the whole target as a function of the electron energy after a one-year beam irradiation and cooling of a month. The yield for both isotopes converges to an asymptotic value with electron energy since the photonuclear cross-sections of 232 Th are maximized below 30 MeV as indicated in Fig. 3. The optimal energy is about 70 MeV for the 231 Pa, while it is slightly above 90 MeV for 229 Th. This is because 229 Th production is mainly dominated by the (γ,3n) reaction requiring higher electron energy than in the (γ,n)-dominating 231 Pa production. Based on the results, 70 MeV is considered to be near optimal to produce the two isotopes simultaneously as incremental yield of 229 Th is marginal above 70 MeV. Figure 8 shows time-dependent isotope-wise number density in the rotating target and activity of important nuclides in the periodic extractions. The 227 Ac can be less than 10 -8 % in the separated Th stream after 30-day cooling as shown in Fig. 8a. Nuclides inventories in the separated Th and non-Th products for periodic extractions of 225 Ac and 227 Th are shown in Fig. 8b,c. Long-term extraction of both α-emitters can be realized due to a sufficient amount of their parent nuclei and it is clear that extraction of pure 225 Ac and 227 Th is possible in each separated stream. Optimal extraction or milking period for 225 Ac and 227 Th is determined so that accumulated yield should be maximized, as shown in Fig. 8d.

Periodic yield of 225 Ac and 227 Th.
When 225 Ac is extracted for 50 years after a one-year beam irradiation, its accumulated yield increases until 31-day cooling period and gradually dwindles. Meanwhile, there is no local maximum point of the accumulated 227 Th yield with different extraction periods due to a large difference of half-life between 227 Th and its parent nuclide, and basically the shorter the extraction, the better in terms of the accumulated yield. In this work, we regard 1 day for 227 Th and 31 days for 225 Ac as optimum extraction period. Figure 9 shows the yield of 225 Ac and 227 Th per an extraction for three irradiation periods with a 70 MeV beam over a 50-year operation. One observes in Fig. 8 that 225 Ac yield is almost constant, while the 227 Th yield increases over 30 years and then slowly decreases due to the longer half-life of 227 Ac than that of 225 Ra decaying to 225 Ac, which is the root cause of the low 227 Th yield right after irradiation. If a daily 227 Th yield is too small, a longer extraction period can be adopted in the early operational period (See Supplementary Information Sect. D). www.nature.com/scientificreports/ Discussion. Table 2 compares the proposed method with other approaches using a 226 Ra target to produce 225 Ac and 227 Th. Performances of the new method are based on the mean TENDL data. Their variations due to uncertain TENDL data are discussed in Supplementary Information Sect. E . Regarding the existing methods, an optimistic 225 Ac yield is also evaluated by improving beam and target parameters 13,26,27 . For an optimistic 227 Th yield of the reactor-based approach 14 , an optimal irradiation time and a relatively large target are considered (see Supplementary Information Sect. F).
The new method requires only one 'long' irradiation and 225 Ac can be extracted semi-permanently. However, a 'short' irradiation is always necessary for each production of 225 Ac in the others. In order to compare a yearly yield, it is assumed, based on engineering judgements, that there should be at least 12-h preparation time between  www.nature.com/scientificreports/ irradiations in the conventional methods. The yearly 227 Th yield is averaged over a 50-year operation since it is time-dependent in both new and reactor-based approaches. The optimistic reactor-based 227 Th yield is much higher than that of the new method due to the very favorable target and irradiation conditions. Unfortunately, the nuclear reactor is extremely costly and is not available in many countries. Although the yearly 225 Ac yield of the new method is lower than the optimistic expectation of the others, the following advantages should be recalled: (1) pure 225 Ac can be produced in the new photo-production, while there should be some level of 227 Ac contamination in methods utilizing a Th target bombarded by a proton beam, (2) a semi-permanent source is produced after a single irradiation in a compact electron accelerator, (3) both 225 Ac and 227 Th are simultaneously produced. It is also noteworthy that both yields are rather proportional to the irradiation time since contribution of multiple photonuclear reactions to the yields is quite marginal in the rotational Th target.

Conclusions
The newly proposed 225 Ac and 227 Th photo-production method is deemed to be viable and promising in several aspects. First of all, it can produce pure 225 Ac and 227 Th by irradiating a 'cheap' natural Th target with a 50-70 MeV electron beam and then using the conventional chemical procedures. The electron energy needs to be over 50 MeV and 70 MeV turns out to be optimal for the application. To maximize the 225 Ac and 227 Th yield, a rotational Th target is required and it is shown that yearly yield of 225 Ac and 227 Th can be ~ 8.5 GBq and 49 GBq, respectively, for a 500 kW beam. The required electron accelerator is easily available and the new method can get all counties to benefit from TAT. More importantly 225 Ac production is almost permanent and 227 Th can be produced much over 50 years after a beam irradiation. Yearly 227 Th yield is about four times higher than that of 225 Ac, and the new method is particularly useful for production of emerging 227 Th. We believe that this work will help increase global supply of the two precious isotopes and would invariably help advance TAT-related researches and developments.
Taking into account the photonuclear cross-sections, the expected 227 Th yield seems to be rather reliable while the 225 Ac yield is more uncertain due to absence of measurement data for the governing (γ,3n) cross-section of 232 Th. Therefore, the 232 Th(γ,3n) 229 Th cross-section should be experimentally evaluated for more concrete conclusions.