Solvent Extraction and Ion Exchange Isolation of ...

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Isolation of Medicine-Applicable Actinium-225 from Thorium Targets Irradiated by Medium-Energy Protons a

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a

a

R. A. Aliev , S. V. Ermolaev , A. N. Vasiliev , V. S. Ostapenko , E. b

b

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V. Lapshina , B. L. Zhuikov , N. V. Zakharov , V. V. Pozdeev , V. M. b

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Kokhanyuk , B. F. Myasoedov & S. N. Kalmykov a

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Lomonosov Moscow State University, Moscow, Russia

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Institute for Nuclear Research of Russian Academy of Sciences, Moscow-Troitsk, Russia c

Obninsk Branch of Karpov Institute of Physical Chemistry, Obninsk, Russia d

Frumkin Institute of Physical Chemistry and Electrochemistry of Russian Academy of Sciences, Moscow, Russia Accepted author version posted online: 07 Mar 2014.Published online: 06 Jun 2014.

To cite this article: R. A. Aliev, S. V. Ermolaev, A. N. Vasiliev, V. S. Ostapenko, E. V. Lapshina, B. L. Zhuikov, N. V. Zakharov, V. V. Pozdeev, V. M. Kokhanyuk, B. F. Myasoedov & S. N. Kalmykov (2014) Isolation of Medicine-Applicable Actinium-225 from Thorium Targets Irradiated by Medium-Energy Protons, Solvent Extraction and Ion Exchange, 32:5, 468-477, DOI: 10.1080/07366299.2014.896582 To link to this article: http://dx.doi.org/10.1080/07366299.2014.896582

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Solvent Extraction and Ion Exchange, 32: 468–477, 2014 Copyright © Taylor & Francis Group, LLC ISSN: 0736-6299 print / 1532-2262 online DOI: 10.1080/07366299.2014.896582

ISOLATION OF MEDICINE-APPLICABLE ACTINIUM-225 FROM THORIUM TARGETS IRRADIATED BY MEDIUM-ENERGY PROTONS


R. A. Aliev1 , S. V. Ermolaev2 , A. N. Vasiliev1 , V. S. Ostapenko1 , E. V. Lapshina2 , B. L. Zhuikov2 , N. V. Zakharov3 , V. V. Pozdeev3 , V. M. Kokhanyuk2 , B. F. Myasoedov4 , and S. N. Kalmykov1,4 1

Lomonosov Moscow State University, Moscow, Russia Institute for Nuclear Research of Russian Academy of Sciences, Moscow-Troitsk, Russia 3 Obninsk Branch of Karpov Institute of Physical Chemistry, Obninsk, Russia 4 Frumkin Institute of Physical Chemistry and Electrochemistry of Russian Academy of Sciences, Moscow, Russia 2

A method of isolation of actinium-225 for nuclear medical applications from thorium targets irradiated by protons is presented. It comprises liquid extraction and extraction chromatography separations. The method demonstrates high (> 85%) chemical yield and radionuclide purity of the final product. An impurity of 227 Ac (0.1% at the end of bombardment) does not hinder 225 Ac from being used for medical 225 Ac/213 Bi generators. Keywords: 225 Ac, proton irradiation, thorium target, actinium isolation, extraction chromatography

INTRODUCTION Alpha-emitters are promising for targeted radiotherapy of cancer due to their high linear energy transfer (LET) of about 100 keV/µm and the low range of alpha particles of about 50-100 μm in biological tissue. It has been shown that only a few single alpha particle exposures are sufficient to induce cell death.[1,2] If the alpha-emitter is delivered inside the cell nucleus, their cytotoxic activity is increased due to the geometry factors and additional effect is caused by the recoil nuclei.[3] The number of potential alpha-emitters that could be used in medical applications is limited by the requirements of half-life, availability of these alpha-emitters, and difficulties in their separation. The most promising candidates for clinical applications are 211 At, 212 Bi, 213 Bi, 223 Ra, and 225 Ac. 225 Ac may be used either directly for preparation of radioimmunoconjugates[4] or as a mother radionuclide in 213 Bi isotope generator.[5] However, wide application of 225 Ac and 213 Bi is limited by the low availability of these radionuclides. Address correspondence to S. N. Kalmykov, Lomonosov Moscow State University, Leninskie Gory, 119991, Moscow, Russia. E-mail: [email protected] Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsei

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Production of 225 Ac is provided by three main suppliers—JRC Institute for Transuranium Elements (JRC ITU) in Karlsruhe, Germany,[6,7] Oak Ridge National Laboratory (ORNL) in USA,[8] and The Institute of Physics and Power Engineering (IPPE) in Obninsk, Russia.[9] The current worldwide production of 225 Ac is approximately 63 GBq (1.7 Ci) per year that corresponds to only 100-200 patients that could be treated annually.[10] Several methods have been proposed for 225 Ac production. The most common approach is separation from mother 229 Th (T1/2 = 7880 y).[7,8] Irradiation of 226 Ra with protons in a cyclotron could be used as well.[6] Both methods have some practical limitations to be applied routinely. Mother isotope 229 Th is separated from aged 233 U. However, its stocks are limited due to the non-proliferation policy, and the accumulation rate of 229 Th does not enable to meet the growing demand for 225 Ac. Production of Ci-amounts 225 Ac using a cyclotron requires gram quantities of 226 Ra for target preparation. In addition, 226 Ra regeneration from irradiated targets faces significant technical problems, in particular those associated with high radioactivity of 226 Ra and evolving gaseous 222 Rn. The reported[6] yield of 225 Ac upon irradiation of 30 mg 226 Ra by 16 MeV protons is only 13.1 mCi at 50 μA beam current during 45.3 h. Other methods of 225 Ac production, for example, irradiation of 226 Ra by Bremsstrahlung photons[11,12] or neutrons in high flux reactors (via 229 Th)[13,14] are currently far from practical routine applications. 225 Ac can be also produced by irradiation of natural thorium with medium energy protons. 225 Ac is generated via several nuclear channels (Fig.1). Precise cumulative cross sections of 225 Ac, 227 Ac, 227 Th, 228 Th formations have been obtained recently.[15−18] Lindner and Osborne[20] were the first who studied generation of 225 Ac and other radionuclides in nuclear reactions of 232 Th with middle energy protons ( 99.9%) at the Research Institute of Atomic Reactors (RIAR), Dimitrovgrad, Russia. The targets in the form of foil (45-69 μm thick) or plate (2.6-3.0 mm thick, 9-18 g) encapsulated into graphite shell, were irradiated during about 10 hours at a linear accelerator of Institute for Nuclear Research of Russian Academy of Sciences (INR RAS), Troitsk, Russia. Initial proton energy on thorium targets varied from 141 to 90 MeV. A beam current reached 50 μA in case of thorium plates. The irradiation technique was described in detail earlier.[16,26] Radionuclide analysis was performed with a gamma-spectrometer with a high pure Ge detector GR 3818 and an alpha-spectrometer with a silicon PIPS detector. Both instruments, as well as software Genie 2000 for spectrum processing, were produced by Canberra Ind. Nuclear data from the BNL database[27] were used for radionuclide identification and activity calculation. 225 Ac was determined via its decay products 221 Fr (T1/2 = 4.9 min, Eγ = 218.2 keV, 11.6%) and 213 Bi (T1/2 = 45.6 min, Eγ = 440.5 keV, 26.1%) after attaining secular equilibrium. The thorium amount was measured by gamma-spectrometry through 227 Th (T1/2 = 18.7 d, Eγ = 236.0 keV, 12.3%; 256.3 keV, 7%) and by atomic emission spectrometry ICP-AES (Optima 2100 DV, Perkin-Elmer). An irradiated target was dissolved in a solution containing 8 M HNO3 and 0.004 M HF. Thorium concentration after dissolution did not exceed 0.4 M and HNO3 concentration did not decrease below 4 M. The main quantity of thorium was separated by two sequential extractions with a solution of di(2-ethylhexyl)orthophoshoric acid (HDEHP) in toluene (1:1 by volume) which was preliminarily equilibrated with 6 M HNO3 . The volume of the organic phase doubled the volume of the aqueous one. Extraction was done in a separation funnel with intensive bubbling of air for phase mixing and equilibration. The equilibration time was c.a. 30 min. No solvent yellowing, third phase formation, or solid precipitation was observed. The aqueous phase was rinsed with toluene twice to ensure complete separation. The aqueous phase (100-150 mL) containing actinium, Ra-225, and most fission products was then loaded onto a column (V = 2 mL, Ø = 6 mm) filled with extractionchromatographic sorbent DGA Resin (Triskem Int.) with 100-150 μm particle size having N,N,N`,N`tetroctyldiglicolamide as an extracting phase. The retention and elution of actinium and other elements was studied by collecting eluate solution after the column. After washing the column with 20 mL of 6 M HNO3 solution, the actinium fraction together with rare earth elements was stripped off with a small amount (∼3 mL) of 0.01 M HNO3 solution. To test the performance of DGA Resin for 225 Ac uptake as a function of HNO3 concentration, batch sorption tests were done by shaking 1 mL of solution with 50 mg of


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resin in a plastic tube at ambient temperature. Equilibration time was 15 minutes, then the solution was filtered through a Whatman filter and the radioactivity remaining in solution was measured. Mass distribution ratios (Dm ) were calculated using the following equation:


Dm = (Ao -As ) /m (As /V), where Ao and As are the aqueous phase actinium activity before and after equilibration, m is the weight of resin in grams, and V is the volume of the aqueous phase in milliliters. The capacity factor k used in chromatography may be obtained by using the following equation: k = Dm ·0.57.[28] Further, to separate Ac(III) from rare earth elements the solution after DGA Resin was adjusted to 3 M HNO3 by adding the required amount of concentrated nitric acid and passed through a column (V = 0.8 mL, Ø = 4 mm) filled with extractionchromatographic sorbent TRU Resin (100–150 μm, Triskem Int.) with octyl(phenyl)N,N-di-isobutylcarbomoylmethylphosphine oxide (CMPO) dissolved in tributylphosphate (TBP) as an extracting phase. Finally, a pure actinium fraction was eluted with 30 mL of 3 M HNO3 solution. The scheme of 225 Ac isolation is presented in Fig. 2. Th target

Th, Ac, Pa, Ra, REE, Tc, Mo, Ru, Te, Sb, Ba, Cd, Ag, Zr, Nb etc.

Dissolution HNO3+HF

LLX 2xHDEHP

I, RIG

Th, Pa, Cd, Zr, Nb

DGA

Ra, Ru, Cs,Mo Ba, Te, Ag, Nb, Sb

Ac, La, Ce, Nd, Pm

TRU

225Ac

Figure 2 Scheme of 225 Ac isolation from the irradiated thorium target.

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Besides actinium isotopes (225, 226, 227 Ac), other spallation and fission products are generated in irradiation of natural thorium with medium-energy protons. A number of fission radionuclides 95, 97 Zr, 95, 96 Nb, 99 Mo, 103 Ru, 105 Rh, 115 Cd, 122, 126, 127 Sb, 131m, 132 Te, 130, 131, 133 136 I, Cs, 140 Ba, 140 La, 141, 143, 144 Ce, 147 Nd, 148m Pm as well as spallation prod227, 228 Th,229, 230, 233 Pa, 223, 224, 225 Ra and their decay products have been detected with ucts gamma-spectrometry in the irradiated targets. The spectra were obtained for different decay times after the end of bombardment (EOB) (see an example in Fig. 3). Earlier,[16,17] the 225 Ra amount produced was estimated to be more than an order of magnitude less than the 225 Ac. However, it is still significant and could be utilized as a source of pure 225 Ac. Isolation of pure actinium fraction is a complicated problem. 225 Ac-activity in the irradiated target does not exceed few per cent and it is to be isolated from a large amount of thorium (tens grams). Moreover, actinium should be quantitatively separated from chemically similar elements such as lanthanum and other rare earth elements. Some elements, for example, ruthenium, exist in various chemical states and cause additional difficulties when the pure actinium fraction is recovered. Thus, the actinium isolation comprises three main steps: (1) separation from macroamounts of thorium; (2) pre-concentration and separation of the fraction containing actinium and rare earth elements from other elements; (3) separation of actinium from rare earth elements. First, low-irradiated thorium foils were used for development of radiochemical procedures so that they could be applicable for hot cell conditions. Then the method

8000

99mTc+ 99Mo

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4000 97

Zr

2000 133

I 122 Sb

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126Sb

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RESULTS AND DISCUSSION

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0 150

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Figure 3 Gamma-spectrum of irradiated thorium target (5 days after EOB).

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was tested twice in a hot cell with thick thorium plates irradiated with the proton beam current up to 50 μA. The dissolution of irradiated metallic thorium plates lasted about 6 hours. Radioactive gases released along with thorium dissolution were entrapped in solution of sodium hydroxide and then in activated carbon. The macro-amounts of thorium were removed from the solution by liquid-liquid extraction. HDEHP dissolved in toluene (1:1) was used as an extracting agent. Other extracting agents such as neat TBP, 1:1 TBP dissolved in toluene, and tri-noctylphosphine oxide (TOPO) dissolved in toluene were also tested. TBP is known to be effective for the separation of tetra- and hexavalent actinides from rare earth elements and most fission products in the nuclear fuel cycle. TBP displays high capacity and reasonable radiation resistance. However, our experiments demonstrated that full removal of thorium from concentrated solutions (up to 0.4 M of Th) could not be achieved even after 5 extraction steps with neat TBP or TBP in toluene. Upon the increase of Th concentration up to 0.4 M the separation was constant and reaches the value of 95 ± 5% while for Th concentration of 0.8 M Th extraction dropped down to about 80%. The distribution coefficient K D , which was as high as ∼5 for the first extraction step, dropped down to 1 for the fifth extraction step. The aqueous phase was attempted and failed to be purified completely from the residual thorium by anion exchange (AG1 × 8 resin, BioRad) and extraction chromatography (TEVA resin, Triskem Int.). One of the possible reasons is the formation of water-soluble complexes of TBP with thorium. The other tested extracting agent was TOPO dissolved in toluene. It showed relatively high distribution coefficient for extraction of thorium from diluted solutions (K D ∼ 30; aqueous phase: C (HNO3 ) = 7 M, C (Th) = 0.07 M; organic phase: C (TOPO) = 0.2 M). However, it could not be used for thorium solutions of higher concentration due to its low extractive capacity. HDEHP dissolved in toluene quantitatively extracted Th, Zr, Mo(VI), and Pa, and partially Nb from 6 M HNO3 solution. The distribution coefficient for thorium exceeded 2·103 when the initial thorium concentration was 0.4 M. Actinium was not extracted under these conditions, as well as mono-, divalent, and rare earth elements. After two extraction steps the aqueous phase contained less than 0.01% of thorium and up to 100% of actinium. Further pre-concentration of the fraction containing actinium and rare earth elements was performed by extraction chromatography. DGA Resin was used because it demonstrates the highest capacity factor k for trivalent elements among the commercially available sorbents. For example, k for Am and Y reaches 5·104 and k (Ce) = 4·103 in 6 M HNO3 solution. Adsorption of thorium is also high (k = 5·103 ). While the HNO3 concentration is decreased down to 0.01 M, trivalent elements are easily stripped off the resin whereas k for Th still remains about 60[28] that enables to separate the remaining tracer amounts of Th form solution. The capacity factor k for Ac as a function of HNO3 concentration has been measured in the batch sorption test as presented in Fig. 4. The reported values are in good agreement with the earlier reported data by Zielinska et al.[29] By using the presented capacity factors of Ac on DGA resin the procedure to separate it from most of the other elements except rare earth elements have been developed based on the Ac sorption from 4–8 M HNO3 and its further elution by diluted nitric acid. Figure 5a demonstrates the pre-concentration of the fraction containing actinium and rare earth elements using DGA Resin. The final isolation of actinium from lanthanides was implemented on extractionchromatographic sorbent TRU Resin. It was determined that actinium was adsorbed

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k`

1000

100

10

This work Zielinska et al.

1 0,001

0,01

0,1

1

10

Figure 4 Capacity factor k (Ac) on DGA Resin as a function of HNO3 concentration. Data from Zielinska et al.[29] is presented for comparison. a: Sample in 6 M HNO3

6 M HNO3

0.01 M HNO3

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Activity,%

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Figure 5 Isolation of actinium fraction: a) pre-concentration of the fraction containing actinium and rare earth elements on DGA Resin; b) final separation on TRU Resin (3 M HNO3 ).

ISOLATION OF MEDICINE-APPLICABLE ACTINIUM-225 FROM THORIUM TARGETS 217

At

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223

Ra

b) 5000

5500

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7500

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9000


Figure 6 Alpha-spectra of the sample containing actinium isotopes: a) just after the recovery of actinium fraction; b) 70 days after the recovery.

noticeably weaker than lanthanides (Fig. 5b). The separation may be performed in a wide range of HNO3 concentrations (2–4 M). k (Ac) was estimated to be about 12 in 2 M HNO3 solution. Following the developed method of actinium recovery, two thick thorium targets (plates) were processed in hot cell conditions. The cooling time between EOB and start of the separation process was about 5 days. 6 and 16 mCi of 225 Ac (recalculated at EOB) were obtained, respectively. The average chemical yield was 85%; the processing took three working days. Radionuclide impurities in the final actinium fraction were assessed by gamma- and alpha-spectrometric techniques while stable impurities were measured by atomic emission spectrometry, ICP-AES. Thorium concentration was found to be less than the detection limit of about 1 ppm. Special attention was paid to the evaluation of the long-lived 227 Ac as the main isotopic and chemically inseparable impurity in 225 Ac. Actinium isotopes were electrodeposited onto polished stainless steel disk which was then measured at regular time intervals by alpha-spectrometry. Figure 6 demonstrates the alpha-spectrum evolution along with 225 Ac decay. Impurity of 227 Ac was determined as 0.1% of 225 Ac activity calculated at EOB. CONCLUSIONS Irradiation of metallic thorium with medium-energy protons proved to be a prospective way for large-scale production of 225 Ac. The radioisotopic purity of the final product is acceptable for using 225 Ac in 225 Ac/213 Bi generators. Radionuclide purity of 213 Bi needs to be assessed for further medical applications. The developed method demonstrates a number of important advantages in comparison with other production methods: independence from expensive and difficult to recover sources (233 U, 229 Th, 226 Ra); no preparation and regeneration of highly radioactive starting target material 226 Ra. In addition to INR linear accelerator, 225 Ac and 223 Ra may be produced by this method at intensive proton beams of accelerators of Brookhaven National Laboratory, USA (proton energy 200 MeV) and TRIUMF, Canada (120 and 500 MeV). Also, production with a lower yield may be realized at Los Alamos National Laboratory (100 MeV) and proposed installation of KOMAC, South Korea (100 MeV). All these facilities would be able to provide a steady supply of 225 Ac and 223 Ra in the future.

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The method is adapted to hot cell processing and may be up-scaled to obtain multiCurie amounts of 225 Ac per one accelerator irradiation run (7-10 days). However, a design of thorium target reliable at high beam current is necessary. This may require a modification of the radiochemical procedure, in particular, due to the impact of radiation on solutions and resins with increasing target activity. FUNDING The work was supported by the Russian Foundation for Basic Research (project 1303-01304).


REFERENCES 1. Nikula, T. K.; McDevitt, M. R.; Finn, R. D.; Wu, C.; Kozak, R. W.; Garmestani, K.; Brechbiel, M.W.; Curcio, M. J.; Pippin, C. G.; Tiffany-Jones, L.; Geerlings, Sr., M. W.; Apostolidis, C.; Molinet, R.; Geerlings, Jr., M. W.; Gansow, O. A.; Scheinberg, D. A. Alpha-emitting bismuth cyclohexylbenzyl DTPA constructs of recombinant humanized anti-cd33 antibodies: Pharmacokinetics, bioactivity, toxicity and chemistry. J. Nucl. Med. 1999, 40, 166–176. 2. Sgouros, G.; Roeske, J. C.; McDevitt, M. R.; Palm, S.; Allen, B. J.; Fisher, D. R.; Brill, A. B.; Song, H.; Howell, R. W.; Akabani, G. and in collaboration with the SNM MIRD committee: Wesley, E. B.; Brill, A. B.; Fisher, D. R.; Howell, R. W.; Meredith, R. F.; Sgouros, G; Wossels, B. W. and Zanzonico B. MIRD Pamphlet No. 22 (Abridged): Radiobiology and Dosimetry of α-Particle Emitters for Targeted Radionuclide Therapy. J. Nucl. Med. 2010, 51, 311–328. 3. McDevitt, M. R.; Ma, D.; Lai, L. T.; Simon, J.; Borchardt, P.; Frank, R. K.; Wu, K.; Pellegrini, V.; Curcio, M. J.; Miederer, M.; Bander, N. H.; Scheinberg, D. A. Tumor therapy with targeted atomic nanogenerators. Science 2001, 294(16), 1537–1540. 4. McDevitt, M. R.; Ma, D.; Simon, J.; Frank, R. K.; Scheinberg, D. A. Design and synthesis of 225 Ac radioimmunopharmaceuticals. Appl. Rad. Isot. 2002, 57, 841–847. 5. Wu, B.C.; Brechbiel, M.W.; Gansow, O.A. An improved generator for the production of 213 Bi from 225 Ac. Radiochimica Acta 1997, 79, 141–145. 6. Apostolidis, C.; Molinet, R.; McGinley, J.; Abbas, K.; Möllenbeck, J.; Morgenstern, A. Cyclotron production of Ac-225 for targeted alpha therapy. Appl. Rad. Isot. 2005, 62, 383–387. 7. Apostolidis, C.; Molinet, R.; Rasmussen, G.; Morgenstern, A. Production of Ac-225 from Th229 for Targeted α-Therapy. Anal. Chem. 2005, 77, 6288–6291. 8. Boll, R. A.; Malkemus, D.; Mirzadeh, S. Production of actinium-225 for alpha particle mediated radioimmunotherapy. Appl. Radi.Isot. 2005, 62, 667–679. 9. Nerozin, N.A. Alpha-Emitters for Oncology. In: Abstracts of the 6th Symposium on AlphaEmitting Radionuclides in Therapy. Toronto, Canada, June 13–17, 2009. 10. Morgenstern, A.; Bruchertseifer, F.; Apostolidis, C. Targeted alpha therapy with 213Bi. Current Radiopharmaceut. 2011, 4, 295–305. 11. Melville, G.; Meriarty, H.; Metcalfe, P.; Knittel, T.; Allen, B.J. Production of Ac-225 for cancer therapy by photon-induced transmutation of Ra-226. Appl. Radi. Isot. 2007, 65, 1014–1022. 12. Maslov, O. D.; Sabel’nikov, A. V.; Dmitriev, S. N. Preparation of 225 Ac by 226 Ra (γ ,n) Photonuclear reaction on an electron accelerator, MT-25 Microtron. Radiochem. 2006, 48(2), 195–197. 13. Kuznetsov, R. A.; Butkalyuk, P. S.; Andreev,O. I.; Baranov, A. Yu.; Tarasov, V. A.; Romanov, E. G.; Butkalyuk, I. L.; Tselischev, I. V.; Kupriyanov, V. N. Determination of effective rates of nuclear reactions under irradiation of radium-226 in the high flux reactor SM. Abstracts of the 6th Russian Conference on Radiochemistry, Moscow, Russia, October 12–16, 2009; p 356.



477

14. Melville, G.; Melvile, P. A theoretical model for the production of Ac-225 for cancer therapy by neutron capture transmutation of Ra-226. Appl. Radi. Isot. http://dx.doi.org/10.1016/j.apradiso. 2012.09.019 15. Zhuikov, B.L.; Kalmykov, S.N.; Ermolaev, S.V.; Aliev, R.A.; Kokhanyuk, V.M. Production of 225 Ac and 223 Ra from thorium irradiated with protons. Radiochem. 2011, 53(1), 66–72. 16. Ermolaev, S.V.; Zhuikov, B.L.; Kokhanyuk, V.M.; Matushko, V.L.; Kalmykov, S.N.; Aliev, R.A.; Tananaev, I.G.; Myasoedov, B.F. Production of actinium, thorium and radium isotopes from natural thorium irradiated with protons up to 141 MeV. Radiochim. Acta. 2012, 100, 1–7. 17. Weidner, J.W.; Mashnik, S.G.; John, K.D. Proton-induced cross sections relevant to production of 225 Ac and 223 Ra in natural thorium targets below 200 MeV. Appl. Radiation Isot. 2012, 70, 2602–2607. 18. Weidner, J.W.; Mashnik, S.G.; John, K.D. 225 Ac and 223 Ra production via 800 MeV proton irradiation of natural thorium targets. Appl. Rad. Isot. 2012, 70, 2590–2595. 19. Pomme, S.; Marouli, M.; Suliman, G.; Dikmen, H.; Van Ammel, R.; Jobbagy, V.; Dirican, A.; Stroh, H.; Paepen, J.; Bruchertseifer, F.; Apostolidis, C.; Morgenrtern, A. Measurement of the 225 Ac half-life. Appl Radiat Isot. 2012, 70, 2608–2614. 20. Lindner, M.; Osborne, R.N. Nonfission inelastic events in uranium and thorium induced by highenergy protons. Phys. Rev. 1956, 103(2), 378–385. 21. Lefort, M.; Simonoff, G.N.; Tarrago, X. Réactions nucléaires de spallation induites sur le thorium par des protons de 150 et 82 MeV. Nucl. Phys. 1961, 25, 216–247. 22. Gauvin, H.; Lefort, M.; Tarrago, X. Èmission d`hélions dans les réactions de spallation. Nucl. Phys. 1962, 39, 447–463. 23. Gauvin, P. H. Réactions (p,2p × n) sur le thorium 232 de 30 a 120 MeV. Le Journal de Physique. 1963, 24, 836–838. 24. Moskvin, L. N.; Tsaritsyna, L. G. Isolation of actinium and radium from thorium target irradiated by 600 MeV protons. Translated from Atomnaya Energiya. 1968, 24(4), 383–384. 25. Harvey, J.; Nolen, J.; Vandegrift, G.; Gomes, I.; Kroc, T.; Horwitz, P.; McAlister, D.; Bowers, D.; Sullivan, V.; Greene, J. Production of Actinium-225 via High Energy Proton Induced Spallation of Thorium-232. Technical Report, USA, DOE/SC0003602-1, December 30, 2011. 26. Zhuikov, B.L.; Kalmykov, S.N.; Aliev, R.A.; Ermolaev, S.V.; Kokhanyuk, V.M.; Kokhanyuk, V.M.; Tananaev, I.G.; Myasoedov, B.F. Method for producing actinium-225 and isotopes of radium and target for implementing same. Patent No. 2373589, Russian Federation, Sept. 23, 2008; Int. Appl. No. PCT/RU2009/000462 (WO/2010/036145), April 1, 2010; US Patent Application 13/120,186, March 22, 2011. 27. National Nuclear Data Center, Brookhaven National Laboratory, USA, http://www.nndc.bnl.gov/ nudat2/. Last accessed 23 April 2014. 28. Horwitz, E. P.; McAlister, D. R.; Bond, A. H.; Barrans, R. E. Novel extraction of chromatographic resins based on tetraalkyldiglycolamides: Characterization and potential applications. Solv. Extr. Ion Exch. 2005, 23(3), 319–344. 29. Zielinska, B.; Apostolidis, C.; Bruchertseifer, F.; Morgenstern, A. An improved method for the production of Ac-225/Bi-213 from Th-229 for targeted alpha therapy. Solv. Extr. Ion Exch. 2007, 25, 339–349.