Local Production of the Alpha-Emitting Radioi-sotope Actinium 225 with Low Impurities for Targeted Alpha Ther-apy by a Compact Neutron Generator System
Main Article Content
Abstract
Alpha-particle emitting radioisotope Actinium225 (225Ac) is of great interest for use in Targeted Alpha Therapy (TAT) treatments of e.g., brain tumors, bladder cancer, neuroendocrine tumors and leukemia. A suitable 225 Ac radioligand is also potentially resolutive for the treatment of advanced and metastatic Castration-Resistant Prostate Cancers (mCRPCs). The mCRPC has a mean survival rate of 9-36 months and encompasses a heterogeneous ample range of molecular cancer behavior with a high risk of progression.
Global demand for the 225 Ac has spurred several production efforts including extraction from 233U, high energy protons or photon irradiation of 226Ra or spallation of 232Th by, at least, 100 MeV protons. Instead of using accelerators systems such as cyclotrons or LINACs, a Compact Neutron Generator (CNG) system has been developed. A 400kV-10 mA DC (D_7Li) CNG potentially able to produce substantial amount of 225Ac with low 227Ac impurities is here presented. Exploiting the high flux of 10 and 13 MeV energy neutrons generated by the (D_7Li) reactions to bombard a thin target layer of 226Ra, 225Ra/225Ac is produced via the 226Ra(n,2n)225Ra nuclear reaction. By irradiating a 5 mm thick 226Ra layer for 100 hours, about 11-13 mCi of 225Ac can be produced – corresponding to the TAT treatment of about 65 oncological patients – with an estimated 227Ac contamination of about one percent, which is below the acceptable limit for clinical use. This 225Ac production scheme by a suitable CNG should allow to adopt a local/regional approach avoiding the shipment costs of 225Ac.
The aim of this paper is to inform the production chain of radioisotopes to be used in medical field and the medical community involved in the application of radiopharmaceuticals for the cure of cancer, that a new technology based on Compact Neutron Generators (CNG) is in a R&D phase and will allow to produce the necessary quantity of radioisotopes for clinical and research purpose. This will be essential in treatment advanced metastatic cancer as for instance the metastatic Castration – Resistant Prostate Cancer.
Article Details
How to Cite
MARTELLINI, Maurizio et al.
Local Production of the Alpha-Emitting Radioi-sotope Actinium 225 with Low Impurities for Targeted Alpha Ther-apy by a Compact Neutron Generator System.
Medical Research Archives, [S.l.], v. 11, n. 9, sep. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4409>. Date accessed: 21 dec. 2024.
doi: https://doi.org/10.18103/mra.v11i9.4409.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Milenic DE, Brechbiel MW. Targeting of radio-isotopes for cancer therapy. Cancer Biology & Therapy. 2004;3:361–370. [PubMed] [Google Scholar]
2. Friesen C, Glatting G, Koop B, Schwarz K, Morgenstern A, Apostolidis C, Debatin KM, Reske SN. Breaking chemoresistance and ra-dioresistance with [213Bi]anti-CD45 antibod-ies in leukemia cells. Cancer Re-search. 2007;67:1950–1958. [PubMed] [Google Scholar]
3. McDevitt MR, Ma D, Lai LT, Simon J, Borchardt P, Frank RK, Wu K, Pellegrini V, Curcio MJ, Miederer M, Bander NH, Scheinberg DA. Tu-mor therapy with targeted atomic nanogener-ators. Science. 2001;294:1537–1540. [PubMed] [Google Scholar]
4. McDevitt MR, Barendswaard E, Ma D, Lai L, Curcio MJ, Sgouros G, Ballangrud AM, Yang WH, Finn RD, Pellegrini V, Geerlings MW, Jr, Lee M, Brechbiel MW, Bander NH, Cordon-Cardo C, Scheinberg DA. An alpha-particle emitting antibody ([213Bi]J591) for radioim-munotherapy of prostate cancer. Cancer Re-search. 2000;60:6095–6100. [PubMed] [Google Scholar]
5. Jurcic JG, Larson SM, Sgouros G, McDevitt MR, Finn RD, Divgi CR, Ballangrud AM, Hamacher KA, Ma D, Humm JL, Brechbiel MW, Molinet R, Scheinberg DA. Targeted alpha particle immunotherapy for myeloid leuke-mia. Blood. 2002;100:1233–1239. [PubMed] [Google Scholar]
6. Jurcic JG, McDevitt MR, Pandit-Taskar N, Divgi CR, Finn RD, Sgouros G, Apostolidis C, Chanel S, Larson SM, Scheinberg DA. Alpha-particle immunotherapy for acute myeloid leukemia (AML) with Bismuth-213 and Actini-um-225. Cancer Biotherapy and Radiopharma-ceuticals. 2006;21(4):396. [Google Scholar]
7. Kennel S.J., Chappell L.L., Dadachova K., Brechbiel M.W., Lankford T.K., Davis I.A., Sta-bin M., Mirzadeh S. Evaluation of 225 Ac for Vascular Targeted Radioimmunotherapy of Lung Tumors. Cancer Biother. Radiopharm. 2000;15:235–244. doi: 10.1089/108497800414329. - DOI - PubMed
8. Adloff JP. Radiochim Acta. 2000. The cen-tenary of a controversial discovery: actinium; pp. 123–127. [Google Scholar]
9. Mirzadeh S. Generator-produced alpha-emitters. Appl Radiat Isot. 1998;49:345–349. [Google Scholar]
10. Geerlings MW, Kaspersen FM, Apostolidis C, van der Hout R. The feasibility of 225Ac as a source of alpha-particles in radioimmuno-therapy. Nuclear Medicine Communica-tions. 1993;14:121–125. [PubMed] [Google Scholar]
11. Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, Tagawa ST, Nordquist LT, Vaishampayan N, El-Haddad G, Park CH, Beer TM, Armour A, Pérez-Contreras WJ, DeSilvio M, Kpamegan E, Gericke G, Messmann RA, Morris MJ, Krause BJ; VISION Investigators. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021 Sep 16;385(12):1091-1103. doi: 10.1056/NEJMoa2107322. Epub 2021 Jun 23. PMID: 34161051; PMCID: PMC8446332.
12. Kratochwil C, Haberkorn U, Giesel FL. 225Ac-PSMA-617 for Therapy of Prostate Cancer. Semin Nucl Med. 2020 Mar;50(2):133-140. doi: 10.1053/j.semnuclmed.2020.02.004. Epub 2020 Feb 14. PMID: 32172798.
13. Sathekge M, Bruchertseifer F, Knoesen O, Reyneke F, Lawal I, Lengana T, Davis C, Ma-hapane J, Corbett C, Vorster M, Morgenstern A. 225Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pi-lot study. Eur J Nucl Med Mol Imaging. 2019 Jan;46(1):129-138. doi: 10.1007/s00259-018-4167-0. Epub 2018 Sep 19. Erratum in: Eur J Nucl Med Mol Imaging. 2019 Jun 26;: PMID: 30232539; PMCID: PMC6267694.
14. Lawal IO, Morgenstern A, Vorster M, Knoesen O, Mahapane J, Hlongwa KN, Maserumule LC, Ndlovu H, Reed JD, Popoola GO, Mokoa-la KMG, Mdlophane A, Bruchertseifer F, Sathekge MM. Hematologic toxicity profile and efficacy of [225Ac]Ac-PSMA-617 α-radioligand therapy of patients with exten-sive skeletal metastases of castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2022 Aug;49(10):3581-3592. doi: 10.1007/s00259-022-05778-w. Epub 2022 Apr 6. PMID: 35384462.
15. Khalkin VA, Tsoupka-Sitnikoz VV, Zaitseva NG. Radionuclides for radiotherapy. Proper-ties, preparation and application of Actinium-225. Radiochemistry. 1997;39:483–492. [Google Scholar]
16. Kirby HW. The discovery of actini-um. Isis 1971;62:290 [Google Scholar]
17. Fry C, Thoennessen M. Discovery of actinium, thorium, protactinium, and uranium iso-topes. At Data Nucl Data Ta-bles 2013;99:345 [Google Scholar]
18. ENSDF, Evaluated Nuclear Structure Data File. Maintained by the National Nuclear Da-ta Center at Brookhaven National Lab. Online document at www.nndc.bnl.gov/ensdf Accessed on March17, 2018
19. Yamana H, Mitsugashira T, Shiokawa Y, et al.. Possibility of the existence of divalent ac-tinium in aqueous solution. J Radioanal Chem 1983;76:19 [Google Scholar]
20. Malý J. The amalgamation behavior of heavy elements—III Extraction of radium, lead and the actinides by sodium amalgam from acetate solutions. J Inorg Nucl Chem 1969;31:1007 [Google Scholar]
21. Nugent LJ, Baybarz RD, Burnett JL, et al.. Electron-transfer and f-d absorption bands of some lanthanide and actinide com-plexes and the standard (II-III) oxidation po-tential for each member of the lanthanide and actinide series. J Phys Chem 1973;77:1528 [Google Scholar]
22. Bratsch SG, Lagowski JJ. Actinide thermody-namic predictions. 3. Thermodynamics of compounds and aquo ions of the 2+, 3+, and 4+ oxidation states and standard electrode potentials at 298.15 K. J Phys Chem 1986;90:307 [Google Scholar]
23. Shannon RD. Revised effective ionic radii and systematic studies of interatomic distances in halides and chalcogenides. Acta Cryst A 1976;32:751 [Google Scholar]
24. Ziv DM, Shestakova IA. Investigation of the solubility of certain actinium compounds. II. Determination of the solubility and evaluation of the relative basicity of actinium hydrox-ide. Sov Radiochem 1965;7:176 [Google Scholar]
25. Baes CF, Mesmer RE. The Hydrolysis of Cati-ons. New York: Wiley, 1976 [Google Schol-ar]
26. Kulikov E, Novgorodov A, Schumann D. Hydrolysis of 225Actinium trace quantities. J Radioanal Nucl Chem 1992;164:103 [Google Scholar]
27. Miederer M, Scheinberg DA, McDevitt MR. Realizing the potential of the Actinium-225 radionuclide generator in targeted alpha-particle therapy applications. Advanced Drug Delivery Reviews. 2008;60:1371–1382. [PMC free article] [PubMed] [Google Scholar]
28. McDevitt MR, Finn RD, Sgouros G, Ma D, Scheinberg DA. An 225Ac/213Bi generator system for therapeutic clinical applications: construction and operation. Appl Radiat Isot. 1999;50:895–904. [PubMed] [Google Scholar]
29. Engle J.W. The Production of Ac-225. Curr. Radiopharm. 2018;11:173–179. doi: 10.2174/1874471011666180418141357. - DOI - PubMed
30. Bruchertseifer F., Kellerbauer A., Malmbeck R., Morgenstern A. Targeted Alpha Therapy with Bismuth-213 and Actinium-225: Meeting Future Demand. J. Label. Compd. Radio-pharm. 2019;62:794–802. doi: 10.1002/jlcr.3792. - DOI - PubMed
31. Griswold J.R., Medvedev D.G., Engle J.W., Copping R., Fitzsimmons J.M., Radchenko V., Cooley J.C., Fassbender M.E., Denton D.L., Murphy K.E., et al. Large Scale Accelerator Production of 225Ac: Effective Cross Sections for 78–192 MeV Protons Incident on 232Th Targets. Appl. Radiat. Isot. 2016;118:366–374. doi: 10.1016/j.apradiso.2016.09.026. - DOI - PubMed
32. Boll R.A., Malkemus D., Mirzadeh S. Produc-tion of Actinium-225 for Alpha Particle Me-diated Radioimmunotherapy. Appl. Radiat. Isot. 2005;62:667–679. doi: 10.1016/j.apradiso.2004.12.003. - DOI - PubMed
33. Apostolidis C, Molinet R, Rasmussen G, Mor-genstern A. Production of Ac-225 from Th-229 for targeted alpha therapy. Analytical chemistry. 2005;77:6288–6291. [PubMed] [Google Scholar]
34. Weidner J.W., Mashnik S.G., John K.D., Bal-lard B., Birnbaum E.R., Bitteker L.J., Couture A., Fassbender M.E., Goff G.S., Gritzo R., et al. 225Ac and 223Ra Production via 800MeV Proton Irradiation of Natural Thori-um Targets. Appl. Radiat. Isot. 2012;70:2590–2595. doi: 10.1016/j.apradiso.2012.07.003. - DOI - PubMed
35. Engle J.W., Mashnik S.G., Weidner J.W., Wolfsberg L.E., Fassbender M.E., Jackman K., Couture A., Bitteker L.J., Ullmann J.L., Gulley M.S., et al. Cross Sections from Proton Irra-diation of Thorium at 800 MeV. Phys. Rev. C. 2013;88:014604. doi: 10.1103/PhysRevC.88.014604. - DOI -PubMed
36. Lambrecht RM, Tomiyoshi K, Sekine T. Radio-nuclide Generators. Radiochimica Ac-ta. 1997;77:103–123. [Google Scholar]
37. Apostolidis C, Molinet R, McGinley J, Abbas K, Mollenbeck J, Morgenstern A. Cyclotron production of Ac-225 for targeted alpha therapy. Appl Radiat Isot. 2005;62:383–387. [PubMed] [Google Scholar]
38. Apostolidis C., Molinet R., Rasmussen G., Morgenstern A. Production of Ac-225 from Th-229 for Targeted α Therapy. Anal. Chem. 2005;77:6288–6291. doi: 10.1021/ac0580114. - DOI - PubMed
39. Hogle S., Boll R.A., Murphy K., Denton D., Owens A., Haverlock T.J., Garland M., Mir-zadeh S. Reactor Production of Thorium-229. Appl. Radiat. Isot. 2016;114:19–27. doi: 10.1016/j.apradiso.2016.05.002. - DOI - PubMed
40. Apostolidis C., Molinet R., McGinley J., Abbas K., Möllenbeck J., Morgenstern A. Cyclotron Production of Ac-225 for Targeted Alpha Therapy11Dedicated to Prof. Dr. Franz Baumgärtner on the Occasion of His 75th Birthday. Appl. Radiat. Isot. 2005;62:383–387. doi: 10.1016/j.apradiso.2004.06.013. - DOI - PubMed
41. Nikula TK, McDevitt MR, Finn RD, Wu C, Kozak RW, Garmestani K, Brechbiel MW, Curcio MJ, Pippin CG, Tiffany-Jones L, Geer-lings MW, Sr, Apostolidis C, Molinet R, Geer-lings MW, Jr, Gansow OA, Scheinberg DA. Alpha-emitting bismuth cyclohexylbenzyl DTPA constructs of recombinant humanized anti-CD33 antibodies: pharmacokinetics, bio-activity, toxicity and chemistry. J Nucl Med. 1999;40:166–176. [PubMed] [Google Scholar]
42. Weast RC. 66th Edition of the CRC Handbook of Chemistry and Physics. CRC Press, Inc; Boca Raton, FL: 1985. [Google Scholar]
43. Poty S., Francesconi L.C., McDevitt M.R., Mor-ris M.J., Lewis J.S. α-Emitters for Radiothera-py: From Basic Radiochemistry to Clinical Studies—Part 1. J. Nucl. Med. 2018;59:878–884. doi: 10.2967/jnumed.116.186338. - DOI - PMC - PubMed
44. Poty S., Francesconi L.C., McDevitt M.R., Mor-ris M.J., Lewis J.S. α-Emitters for Radiothera-py: From Basic Radiochemistry to Clinical Studies—Part 2. J. Nucl. Med. 2018;59:1020–1027. doi: 10.2967/jnumed.117.204651. - DOI - PMC - PubMed
45. Kotovskii A.A., Nerozin N.A., Prokof’ev I.V., Shapovalov V.V., Yakovshchits Y.A., Bolonkin A.S., Dunin A.V. Isolation of Actinium-225 for Medical Purposes. Radiochemistry. 2015;57:285–291.
doi: 10.1134/S1066362215030091. DOI -PubMed
46. Poty S., Carter L.M., Mandleywala K., Mem-breno R., Abdel-Atti D., Ragupathi A., Scholz W.W., Zeglis B.M., Lewis J.S. Leveraging Bioorthogonal Click Chemistry to Improve 225 Ac-Radioimmunotherapy of Pancreatic Ductal Adenocarcinoma. Clin. Cancer Res. 2019;25:868–880. doi: 10.1158/1078-0432.CCR-18-1650. - DOI - PMC - PubMed
47. Ramogida C.F., Robertson A.K.H., Jermilova U., Zhang C., Yang H., Kunz P., Lassen J., Bra-tanovic I., Brown V., Southcott L., et al. Evalu-ation of Polydentate Picolinic Acid Chelating Ligands and an α-Melanocyte-Stimulating Hormone Derivative for Targeted Alpha Therapy Using ISOL-Produced 225Ac. EJNMMI Radiopharm. Chem. 2019;4:21. doi: 10.1186/s41181-019-0072-5. - DOI - PMC - PubMed
48. Chappell L.L., Deal K.A., Dadachova E., Brechbiel M.W. Synthesis, Conjugation, and Radiolabeling of a Novel Bifunctional Chelat-ing Agent for 225 Ac Radioimmunotherapy Applications. Bioconjug. Chem. 2000;11:510–519. doi: 10.1021/bc990153f. - DOI - PubMed
49. Yang H., Zhang C., Yuan Z., Rodriguez-Rodriguez C., Robertson A., Radchenko V., Perron R., Gendron D., Causey P., Gao F., et al. Synthesis and Evaluation of a Macrocyclic Actinium-225 Chelator, Quality Control and In Vivo Evaluation of 225 Ac-crown-αMSH Peptide. Chem. Eur. J. 2020;26:11435–11440. doi: 10.1002/chem.202002999. - DOI - PubMed
50. Pouget J.-P., Georgakilas A.G., Ravanat J.-L. Targeted and Off-Target (Bystander and Ab-scopal) Effects of Radiation Therapy: Redox Mechanisms and Risk/Benefit Analysis. Anti-oxid. Redox Signal. 2018;29:1447–1487. doi: 10.1089/ars.2017.7267. - DOI - PMC - PubMed
51. 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., et al. MIRD Pam-phlet No. 22 (Abridged): Radiobiology and Dosimetry of -Particle Emitters for Targeted Radionuclide Therapy. J. Nucl. Med. 2010;51:311–328. doi: 10.2967/jnumed.108.058651. - DOI - PMC - PubMed
52. Baidoo K.E., Yong K., Brechbiel M.W. Mo-lecular Pathways: Targeted-Particle Radia-tion Therapy. Clin. Cancer Res. 2013;19:530–537. doi: 10.1158/1078-0432.CCR-12-0298. - DOI - PMC - PubMed
53. Aghevlian S., Boyle A.J., Reilly R.M. Radio-immunotherapy of Cancer with High Linear Energy Transfer (LET) Radiation Delivered by Radionuclides Emitting α-Particles or Auger Electrons. Adv. Drug Deliv. Rev. 2017;109:102–118.
doi:10.1016/j.addr.2015.12.003. DOI - PubMed
54. Sathekge M, Bruchertseifer F, Vorster M, Lawal IO, Mokoala K, Reed J, Maseremule L, Ndlovu H, Hlongwa K, Maes A, Morgenstern A, Van de Wiele C. 225Ac-PSMA-617 radi-oligand therapy of de novo metastatic hor-mone-sensitive prostate carcinoma (mHSPC): preliminary clinical findings. Eur J Nucl Med Mol Imaging. 2023 Jun;50(7):2210-2218. doi: 10.1007/s00259-023-06165-9. Epub 2023 Mar 3. PMID: 36864360; PMCID: PMC1019987.
55. Sidaway. 177Lu-PSMA-PET extends Survival. P.Nat Rev Clin Oncol. 2021 Sep;18(9):542. doi: 10.1038/s41571-021-00543-8.PMID: 34262157.
56. Hadaschik B, Herrmann K.Eur. Lutetium-177-PSMA-617 for Metastatic Castration- Re-sistant Prostate Cancer. Urol. 2021 Oct;80(4):520-521. doi: 10.1016/j.eururo.2021.07.006. Epub 2021 Jul 24.PMID: 34312019.
57. Deal K.A., Davis I.A., Mirzadeh S., Kennel S.J., Brechbiel M.W. Improved in Vivo Stabil-ity of Actinium-225 Macrocyclic Complexes. J. Med. Chem. 1999;42:2988–2992. doi: 10.1021/jm990141f. - DOI - PubMed
58. McDevitt M.R., Ma D., Simon J., Frank R.K., Scheinberg D.A. Design and Synthesis of 225Ac Radioimmunopharmaceuticals. Appl. Radiat. Isot. 2002;57:841–847. doi: 10.1016/S0969-8043(02)00167-7. - DOI - PubMed
59. Antczak C., Jaggi J.S., LeFave C.V., Curcio M.J., McDevitt M.R., Scheinberg D.A. Influ-ence of the Linker on the Biodistribution and Catabolism of Actinium-225 Self-Immolative Tumor-Targeted Isotope Generators. Biocon-jug. Chem. 2006;17:1551–1560. doi: 10.1021/bc060156+. - DOI - PMC - PubMed
60. Maguire W.F., McDevitt M.R., Smith-Jones P.M., Scheinberg D.A. Efficient 1-Step Radio-labeling of Monoclonal Antibodies to High Specific Activity with 225Ac for α-Particle Radioimmunotherapy of Cancer. J. Nucl. Med. 2014;55:1492–1498. doi: 10.2967/jnumed.114.138347. - DOI - PMC - PubMed
61. Beyer G.J., Bergmann R., Schomäcker K., Rösch F., Schäfer G., Kulikov E.V., Novgo-rodov A.F. Comparison of the Biodistribution of 225Ac and Radio-Lanthanides as Citrate Complexes. Isot. Environ. Health Stud. 1990;26:111–114. doi: 10.1080/10256019008624245. - DOI
62. Poty S., Membreno R., Glaser J.M., Ragupathi A., Scholz W.W., Zeglis B.M., Lewis J.S. The Inverse Electron-Demand Diels–Alder Reac-tion as a New Methodology for the Synthesis of 225 Ac-Labelled Radioimmunoconjugates. Chem. Commun. 2018;54:2599–2602. doi: 10.1039/C7CC09129J. - DOI - PMC - PubMed
63. ClinicalTrials.gov Identifier: NCT04597411 Recruiting Status: Recruiting, First Posted: Oc-tober 22,2020 Last Update: November 25, 2022
64. ClinicalTrials.gov Identifier: NCT05219500 Recruiting Status: Recruiting, First Posted: February 2, 2022, Last Update Posted: March 27, 2023
65. Davis I.A., Glowienka K.A., Boll R.A., Deal K.A., Brechbiel M.W., Stabin M., Bochsler P.N., Mirzadeh S., Kennel S.J. Comparison of 225actinium Chelates: Tissue Distribution and Radiotoxicity. Nucl. Med. Biol. 1999;26:581–589. doi: 10.1016/S0969-8051(99)00024-4. - DOI - PubMed
66. Comba P., Jermilova U., Orvig C., Patrick B.O., Ramogida C.F., Rück K., Schneider C., Starke M. Octadentate Picolinic Acid-Based Bispidine Ligand for Radiometal Ions. Chem. Eur. J. 2017;23:15945–15956. doi: 10.1002/chem.201702284. - DOI - PubMed
67. Thiele N.A., Brown V., Kelly J.M., Amor-Coarasa A., Jermilova U., MacMillan S.N., Nikolopoulou A., Ponnala S., Ramogida C.F., Robertson A.K.H., et al. An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy. Angew. Chem. Int. Ed. 2017;56:14712–14717. doi: 10.1002/anie.201709532. - DOI - PubMed
68. Zielińska B, Bilewicz A. The hydrolysis of ac-tinium. J Radioanal Nucl Chem 2004;261:195 [Google Scholar]
69. Pearson RG. Hard and soft acids and bases. J Am Chem Soc 1963;85:3533 [Google Schol-ar]
70. Parr RG, Pearson RG. Absolute hardness: Companion parameter to absolute electro-negativity. J Am Chem Soc 1983;105:7512 [Google Scholar]
71. Pearson RG. Absolute electronegativity and hardness: Application to inorganic chemis-try. Inorg Chem 1988;27:734 [Google Scholar]
72. Cotton S. Introduction to the actinides. In: Cot-ton S. (ed.), Lanthanide and Actinide Chemis-try. Chichester: John Wiley & Sons, Ltd, 2006;145 [Google Scholar]
73. Drago RS, Vogel GC, Needham TE. A four-parameter equation for predicting enthalpies of adduct formation. J Am Chem Soc 1971;93:6014 [Google Scholar]
74. Hancock RD, Marsicano F. Parametric corre-lation of formation constants in aqueous solu-tion. 1. Ligands with small donor atoms. Inorg Chem 1978;17:560 [Google Scholar]
75. Hancock RD, Marsicano F. Parametric corre-lation of formation constants in aqueous solu-tion. 2. Ligands with large donor atoms. Inorg Chem 1980;19:2709 [Google Scholar]
76. Aziz A, Lyle SJ. Complexes of lanthanum and actinium with fluoride, oxalate and sulphate in aqueous solutions. J Inorg Nucl Chem 1970;32:1925 [Google Scholar]
77. Shahani CJ, Mathew KA, Rao CL, et al.. Chemistry of actinium. I. Stability con-stants of chloride, bromide, nitrate and sul-phate complexes. Radiochim Ac-ta 1968;10:165 [Google Scholar]
78. Rao CL, Shahani CJ, Mathew KA. Chemistry of actinium—II Stability constants of thiocya-nate complexes of actinium and lantha-num. Inorg Nucl Chem Lett 1968;4:655 [Google Scholar]
79. Sekine T, Sakairi M. Studies of actinium(III) in various solutions. III. Actinium (III) complexes with oxalate, sulfate, chloride, and thiocya-nate ions in perchlorate media. Bull Chem Soc Jpn 1969;42:2712 [Google Scholar]
80. Rao VK, Shahani CJ, Rao CL. Studies on the phosphate complexes of actinium and lan-thanum. Radiochim Acta 1970;14:31 [Google Scholar]
81. Alleluia IB, Eberle SH, Keller C, Kirby HW. Gmelin Handbook of Inorganic Chemis-try, Actinium, 8th ed., In: Kugler HK, Keller C. (eds.), system no. 40 suppl. vol. 1 Berlin: Springer-Verlag, 1981. [Google Scholar]
82. Makarova TP, Sinitsyna GS, Stepanov AV, et al.. Complex formation of actinium. I. Deter-mination of the stability constants of eth-ylenediaminetetraacetate complexes of ac-tinium and its separation from lanthanum in solutions of EDTA by the method of elec-tromigration. Sov Radi-ochem 1972;14:555 [Google Scholar]
83. Smith RM, Martell AE. Iminodiacetic Acid De-rivatives. In: Martell AE, Smith RM. (eds.), Critical Stability Constants: Second Supplement. Boston: Springer, 1989;67 [Google Scholar]
84. Smith RM, Martell AE. Carboxylic acids. In: Martell AE, Smith RM. (eds.), Critical Stability Constants: Second Supplement. Boston: Springer, 1989;299 [Google Scholar]
85. Fried S, Hagemann F, Zachariasen WH. The preparation and identification of some pure actinium compounds. J Am Chem Soc 1950;72:771 [Google Scholar]
86. 225Actinium DOE User Meeting July 28, 2020 Introduction Ekaterina (Kate) Dadachova, PhD Chair in Radiopharmacy, Fedoruk Center for Nuclear Innovation Pro-fessor, College of Pharmacy and Nutrition University of Saskatchewan, Canada
87. Ac-225 User Group: Production Effort to Pro-vide Accelerator-Produced 225Ac for Radio-therapy Cathy S. Cutler, Brookhaven Nation-al Laboratory Kevin John, Los Alamos Na-tional Laboratory, Project Manager, U.S. DOE Tri-Lab
88. Actinium-225 (Ac-225) Radiopharmaceuticals FDA Perspective – Chemistry, Manufacturing and Controls (CMC) Ravi Kasliwal, Ph.D. Of-fice of New Drug Products DNDC-3, Branch-6 Office of Pharmaceutical Quality CDER/FDA
89. Actinium-225 & Bismuth-213: Two Important Alpha Emitters for the Future of Therapeutics Kevin Allen, PhD July 28th, 2020 Actinium-225 DOE Users Meeting Actinium Pharmaceu-ticals, Inc. This research is supported by the U.S. Department of Energy Isotope Program
90. Engle JW. The Production of Ac-225. Curr Radiopharm. 2018;11(3):173-179. doi: 10.2174/1874471011666180418141357. PMID: 29669509.
91. Ju, K., Kim, Y. Feasibility of a novel photo-production of 225Ac and 227Th with natural thorium target. Sci Rep 12, 372 (2022). https://doi.org/10.1038/s41598-021-04339-9103.
92. Scheinberg DA, McDevitt MR. Actinium-225 in targeted alpha-particle therapeutic applica-tions. Curr Radiopharm. 2011 Oct;4(4):306-20. doi: 10.2174/1874471011104040306. PMID: 22202153; PMCID: PMC5565267.
93. K. N. Leung, J. K. Leung, and G. Melville, “Feasibility Study on Medical Isotope Produc-tion Using a Compact Neutron Generator,” Appl. Radiat. Isot., 137C, 23 (2018). DOI: 10.1016/j.apradiso.2018.02.026
94. J. Ishikawa, “Appl. Of Accelerators in Re-search and Industry,” J. L. Duggan and I. L. Morgan, Eds., AIP Press, New York (1977).
95. K. N. Leung and K. W. Ehlers, “Self-extraction negative ion source,” Rev. Sci. Instrum. 53(6) Jun. (1982) 803-809. FERMILAB-PUB-05-094-AD
96. Robertson A.K.H., McNeil B.L., Yang H., Gen-dron D., Perron R., Radchenko V., Zeisler S., Causey P., Schaffer P. 232Th-Spallation-Produced 225 Ac with Reduced 227 Ac Con-tent. Inorg. Chem. 2020;59:12156–12165. doi: 10.1021/acs.inorgchem.0c01081. - DOI - PubMed
97. de Kruijff R., Wolterbeek H., Denkova A. A Critical Review of Alpha Radionuclide Thera-py—How to Deal with Recoiling Daughters? Pharmaceuticals. 2015;8:321–336. doi: 10.3390/ph8020321. - DOI - PMC - PubMed
98. Singh Jaggi J., Kappel B.J., McDevitt M.R., Sgouros G., Flombaum C.D., Cabassa C., Scheinberg D.A. Efforts to Control the Errant Products of a Targeted In Vivo Generator. Cancer Res. 2005;65:4888–4895. doi: 10.1158/0008-5472.CAN-04-3096. - DOI - PubMed
99. JRC SCIENCE FOR POLICY REPORT “Study on sustainable and resilient supply of medical radioisotopes in the EU- Therapeutic Radionu-clides”, Ligvoet, Scholten, Davé, King, Petro-sova, Chiti, Goulard De Medeiros, Joerger, 2021, EUR 30690 EN.
100. Radiopharmaceutical Quality Control Consid-erations for Accelerator-Produced Actinium Therapies”, Abou, Zerkel, Robben, McLaugh-lin, Hazlehurst, Morse, Wadas, Pandaya, Oyama, Gaehle, Nickels, Thorek, Cancer Bio-therapy and Radiopharmaceuticals, Vol. 27, Number 5, 2022. Doi: 10.1089/cbr.2022.0010.
101. The supply of Medical Isotopes, an economic diagnosis and possible solutions, OECD, NEA Nuclear Energy Agency.
102. IAEA – Report on Joint IAEA-JRC Workshop “Supply of Actinium-225”, IAEA, Vienna, 2018
103. Sgouros G., Bodei L., McDevitt M.R., Nedrow J.R. Radiopharmaceutical Therapy in Cancer: Clinical Advances and Challenges. Nat. Rev. Drug Discov. 2020;19:589–608. doi: 10.1038/s41573-020-0073-9. - DOI - PMC - PubMed
104. Kassis A.I., Adelstein S.J. Radiobiologic Prin-ciples in Radionuclide Therapy. J. Nucl. Med. 2005;46:4S. - PubMed
105. Tafreshi N.K., Doligalski M.L., Tichacek C.J., Pandya D.N., Budzevich M.M., El-Haddad G., Khushalani N.I., Moros E.G., McLaughlin M.L., Wadas T.J., et al. Development of Targeted Alpha Particle Therapy for Solid Tumors. Molecules. 2019;24:4314. doi: 10.3390/molecules24234314. - DOI - PMC - PubMed
106. Robertson A.K.H., Ramogida C.F., Schaffer P., Radchenko V. Development of225 Ac Radio-pharmaceuticals: TRIUMF Perspectives and Experiences. Curr. Radiopharm. 2018;11:156–172. doi: 10.2174/1874471011666180416161908. - DOI - PMC - PubMed
107. Jurcic J.G. Targeted Alpha-Particle Therapy for Hematologic Malignancies. Semin. Nucl. Med. 2020;50:152–161. doi: 10.1053/j.semnuclmed.2019.09.002. - DOI - PubMed
108. Huclier-Markai S., Alliot C., Varmenot N., Cut-ler S.C., Barbet J. Alpha-Emitters for Immuno-Therapy: A Review of Recent Developments from Chemistry to Clinics. Curr. Top. Med. Chem. 2013;12:2642–2654. doi: 10.2174/1568026611212230002. - DOI - PubMed
109. Makvandi M., Dupis E., Engle J.W., Nortier F.M., Fassbender M.E., Simon S., Birnbaum E.R., Atcher R.W., John K.D., Rixe O., et al. Alpha-Emitters and Targeted Alpha Therapy in Oncology: From Basic Science to Clinical Investigations. Target. Oncol. 2018;13:189–203. doi: 10.1007/s11523-018-0550-9. - DOI - PubMed
110. Morgenstern A., Apostolidis C., Kratochwil C., Sathekge M., Krolicki L., Bruchertseifer F. An Overview of Targeted Alpha Therapy with 225 Actinium and 213 Bismuth. Curr. Radio-pharm. 2018;11:200–208. doi: 10.2174/1874471011666180502104524. - DOI - PMC - PubMed
111. “Guideline on current good radiopharmacy practice (cGRPP) for the small-scale prepara-tion of radiopharmaceuticals”, Gillings, Hjels-tuen, Ballinger, Behe, Decristoforo, Elsinga, Ferrari, Paitl, Koziorowsi, Laverman, Mindt, Neels, Ocak, Patt, Todde, EJNMMI Radio-pharmacy and Chemistry, 2021, Springer Open. https://doi.org/10.1186/s41181-021-00123-2
112. Treatment Planning For Molecular Radiother-apy: Potential and Prospects, European Asso-ciation of Nuclear Medicine, www.eanm.org
113. Pouget J.-P., Lozza C., Deshayes E., Boudousq V., Navarro-Teulon I. Introduction to Radiobi-ology of Targeted Radionuclide Therapy. Front. Med. 2015;2 doi: 10.3389/fmed.2015.00012. - DOI - PMC - PubMed
114. Li L., Rousseau J., de Guadalupe Jara-quemada-Peláez M., Wang X., Robertson A., Radchenko V., Schaffer P., Lin K.-S., Bénard F., Orvig C. 225Ac-H4 Py4pa for Targeted Alpha Therapy. Bioconjug. Chem. 2020 doi: 10.1021/acs.bioconjchem.0c00171. - DOI - PubMed
115. Kirby HW, Morss LR. Actinium. In: Morss LR, Edelstein NM, Fuger J. (eds.), The Chemistry of the Actinide and Transactinide Elements. Dordrecht: Springer Netherlands, 2006;18 [Google Scholar]
116. Martellini, Sarotto, Leung, Gherardi, “A Compact Neutron Generator for the Niort® Treatment of Severe Solid Cancers”, Medical Research Archives, ESMED, March 2023, https://doi.org/10.18103/mra.v11i3.3799
117. McDevitt MR, Sgouros G, Finn RD, Humm JL, Jurcic JG, Larson SM, Scheinberg DA. Radio-immunotherapy with alpha-emitting nu-clides. European Journal of Nuclear Medi-cine. 1998;25:1341–1351. [PubMed] [Google Scholar]
118. ITU Annual Report 1995-(EUR 16368)-Basic Actinide Research. 1995. Methods for the production of Ac-225 and Bi-213 for alpha immunotherapy; pp. 55–56. [Google Schol-ar]
119. Koch L, Apostolidis C, Molinet R, Nicolaou G, Janssens W, Schweikert H. Production of Bi-213 and Ac-225, Alpha-Immuno-97 Sympo-sium; Karlsruhe, Germany. 1997. [Google Scholar]
120. Boll RA, Malkemus D, Mirzadeh S. Production of actinium-225 for alpha particle mediated radioimmunotherapy. Appl Radiat Isot. 2005;62:667–679. [PubMed] [Google Scholar]
121. Boll RA, Mirzadeh S, Kennel SJ, DePaoli DW, Webb OF. Bi-213 for alpha particle mediat-ed radioimmunotherapy. J Label Compds and Radiopharm. 1997;40:341–343. [Google Scholar]
122. McDevitt MR, Finn RD, Ma D, Larson SM, Scheinberg DA. Preparation of alpha-emitting 213Bi-labeled antibody constructs for clinical use. J Nucl Med. 1999;40:1722–1727. [PubMed] [Google Scholar]
2. Friesen C, Glatting G, Koop B, Schwarz K, Morgenstern A, Apostolidis C, Debatin KM, Reske SN. Breaking chemoresistance and ra-dioresistance with [213Bi]anti-CD45 antibod-ies in leukemia cells. Cancer Re-search. 2007;67:1950–1958. [PubMed] [Google Scholar]
3. McDevitt MR, Ma D, Lai LT, Simon J, Borchardt P, Frank RK, Wu K, Pellegrini V, Curcio MJ, Miederer M, Bander NH, Scheinberg DA. Tu-mor therapy with targeted atomic nanogener-ators. Science. 2001;294:1537–1540. [PubMed] [Google Scholar]
4. McDevitt MR, Barendswaard E, Ma D, Lai L, Curcio MJ, Sgouros G, Ballangrud AM, Yang WH, Finn RD, Pellegrini V, Geerlings MW, Jr, Lee M, Brechbiel MW, Bander NH, Cordon-Cardo C, Scheinberg DA. An alpha-particle emitting antibody ([213Bi]J591) for radioim-munotherapy of prostate cancer. Cancer Re-search. 2000;60:6095–6100. [PubMed] [Google Scholar]
5. Jurcic JG, Larson SM, Sgouros G, McDevitt MR, Finn RD, Divgi CR, Ballangrud AM, Hamacher KA, Ma D, Humm JL, Brechbiel MW, Molinet R, Scheinberg DA. Targeted alpha particle immunotherapy for myeloid leuke-mia. Blood. 2002;100:1233–1239. [PubMed] [Google Scholar]
6. Jurcic JG, McDevitt MR, Pandit-Taskar N, Divgi CR, Finn RD, Sgouros G, Apostolidis C, Chanel S, Larson SM, Scheinberg DA. Alpha-particle immunotherapy for acute myeloid leukemia (AML) with Bismuth-213 and Actini-um-225. Cancer Biotherapy and Radiopharma-ceuticals. 2006;21(4):396. [Google Scholar]
7. Kennel S.J., Chappell L.L., Dadachova K., Brechbiel M.W., Lankford T.K., Davis I.A., Sta-bin M., Mirzadeh S. Evaluation of 225 Ac for Vascular Targeted Radioimmunotherapy of Lung Tumors. Cancer Biother. Radiopharm. 2000;15:235–244. doi: 10.1089/108497800414329. - DOI - PubMed
8. Adloff JP. Radiochim Acta. 2000. The cen-tenary of a controversial discovery: actinium; pp. 123–127. [Google Scholar]
9. Mirzadeh S. Generator-produced alpha-emitters. Appl Radiat Isot. 1998;49:345–349. [Google Scholar]
10. Geerlings MW, Kaspersen FM, Apostolidis C, van der Hout R. The feasibility of 225Ac as a source of alpha-particles in radioimmuno-therapy. Nuclear Medicine Communica-tions. 1993;14:121–125. [PubMed] [Google Scholar]
11. Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, Tagawa ST, Nordquist LT, Vaishampayan N, El-Haddad G, Park CH, Beer TM, Armour A, Pérez-Contreras WJ, DeSilvio M, Kpamegan E, Gericke G, Messmann RA, Morris MJ, Krause BJ; VISION Investigators. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021 Sep 16;385(12):1091-1103. doi: 10.1056/NEJMoa2107322. Epub 2021 Jun 23. PMID: 34161051; PMCID: PMC8446332.
12. Kratochwil C, Haberkorn U, Giesel FL. 225Ac-PSMA-617 for Therapy of Prostate Cancer. Semin Nucl Med. 2020 Mar;50(2):133-140. doi: 10.1053/j.semnuclmed.2020.02.004. Epub 2020 Feb 14. PMID: 32172798.
13. Sathekge M, Bruchertseifer F, Knoesen O, Reyneke F, Lawal I, Lengana T, Davis C, Ma-hapane J, Corbett C, Vorster M, Morgenstern A. 225Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pi-lot study. Eur J Nucl Med Mol Imaging. 2019 Jan;46(1):129-138. doi: 10.1007/s00259-018-4167-0. Epub 2018 Sep 19. Erratum in: Eur J Nucl Med Mol Imaging. 2019 Jun 26;: PMID: 30232539; PMCID: PMC6267694.
14. Lawal IO, Morgenstern A, Vorster M, Knoesen O, Mahapane J, Hlongwa KN, Maserumule LC, Ndlovu H, Reed JD, Popoola GO, Mokoa-la KMG, Mdlophane A, Bruchertseifer F, Sathekge MM. Hematologic toxicity profile and efficacy of [225Ac]Ac-PSMA-617 α-radioligand therapy of patients with exten-sive skeletal metastases of castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2022 Aug;49(10):3581-3592. doi: 10.1007/s00259-022-05778-w. Epub 2022 Apr 6. PMID: 35384462.
15. Khalkin VA, Tsoupka-Sitnikoz VV, Zaitseva NG. Radionuclides for radiotherapy. Proper-ties, preparation and application of Actinium-225. Radiochemistry. 1997;39:483–492. [Google Scholar]
16. Kirby HW. The discovery of actini-um. Isis 1971;62:290 [Google Scholar]
17. Fry C, Thoennessen M. Discovery of actinium, thorium, protactinium, and uranium iso-topes. At Data Nucl Data Ta-bles 2013;99:345 [Google Scholar]
18. ENSDF, Evaluated Nuclear Structure Data File. Maintained by the National Nuclear Da-ta Center at Brookhaven National Lab. Online document at www.nndc.bnl.gov/ensdf Accessed on March17, 2018
19. Yamana H, Mitsugashira T, Shiokawa Y, et al.. Possibility of the existence of divalent ac-tinium in aqueous solution. J Radioanal Chem 1983;76:19 [Google Scholar]
20. Malý J. The amalgamation behavior of heavy elements—III Extraction of radium, lead and the actinides by sodium amalgam from acetate solutions. J Inorg Nucl Chem 1969;31:1007 [Google Scholar]
21. Nugent LJ, Baybarz RD, Burnett JL, et al.. Electron-transfer and f-d absorption bands of some lanthanide and actinide com-plexes and the standard (II-III) oxidation po-tential for each member of the lanthanide and actinide series. J Phys Chem 1973;77:1528 [Google Scholar]
22. Bratsch SG, Lagowski JJ. Actinide thermody-namic predictions. 3. Thermodynamics of compounds and aquo ions of the 2+, 3+, and 4+ oxidation states and standard electrode potentials at 298.15 K. J Phys Chem 1986;90:307 [Google Scholar]
23. Shannon RD. Revised effective ionic radii and systematic studies of interatomic distances in halides and chalcogenides. Acta Cryst A 1976;32:751 [Google Scholar]
24. Ziv DM, Shestakova IA. Investigation of the solubility of certain actinium compounds. II. Determination of the solubility and evaluation of the relative basicity of actinium hydrox-ide. Sov Radiochem 1965;7:176 [Google Scholar]
25. Baes CF, Mesmer RE. The Hydrolysis of Cati-ons. New York: Wiley, 1976 [Google Schol-ar]
26. Kulikov E, Novgorodov A, Schumann D. Hydrolysis of 225Actinium trace quantities. J Radioanal Nucl Chem 1992;164:103 [Google Scholar]
27. Miederer M, Scheinberg DA, McDevitt MR. Realizing the potential of the Actinium-225 radionuclide generator in targeted alpha-particle therapy applications. Advanced Drug Delivery Reviews. 2008;60:1371–1382. [PMC free article] [PubMed] [Google Scholar]
28. McDevitt MR, Finn RD, Sgouros G, Ma D, Scheinberg DA. An 225Ac/213Bi generator system for therapeutic clinical applications: construction and operation. Appl Radiat Isot. 1999;50:895–904. [PubMed] [Google Scholar]
29. Engle J.W. The Production of Ac-225. Curr. Radiopharm. 2018;11:173–179. doi: 10.2174/1874471011666180418141357. - DOI - PubMed
30. Bruchertseifer F., Kellerbauer A., Malmbeck R., Morgenstern A. Targeted Alpha Therapy with Bismuth-213 and Actinium-225: Meeting Future Demand. J. Label. Compd. Radio-pharm. 2019;62:794–802. doi: 10.1002/jlcr.3792. - DOI - PubMed
31. Griswold J.R., Medvedev D.G., Engle J.W., Copping R., Fitzsimmons J.M., Radchenko V., Cooley J.C., Fassbender M.E., Denton D.L., Murphy K.E., et al. Large Scale Accelerator Production of 225Ac: Effective Cross Sections for 78–192 MeV Protons Incident on 232Th Targets. Appl. Radiat. Isot. 2016;118:366–374. doi: 10.1016/j.apradiso.2016.09.026. - DOI - PubMed
32. Boll R.A., Malkemus D., Mirzadeh S. Produc-tion of Actinium-225 for Alpha Particle Me-diated Radioimmunotherapy. Appl. Radiat. Isot. 2005;62:667–679. doi: 10.1016/j.apradiso.2004.12.003. - DOI - PubMed
33. Apostolidis C, Molinet R, Rasmussen G, Mor-genstern A. Production of Ac-225 from Th-229 for targeted alpha therapy. Analytical chemistry. 2005;77:6288–6291. [PubMed] [Google Scholar]
34. Weidner J.W., Mashnik S.G., John K.D., Bal-lard B., Birnbaum E.R., Bitteker L.J., Couture A., Fassbender M.E., Goff G.S., Gritzo R., et al. 225Ac and 223Ra Production via 800MeV Proton Irradiation of Natural Thori-um Targets. Appl. Radiat. Isot. 2012;70:2590–2595. doi: 10.1016/j.apradiso.2012.07.003. - DOI - PubMed
35. Engle J.W., Mashnik S.G., Weidner J.W., Wolfsberg L.E., Fassbender M.E., Jackman K., Couture A., Bitteker L.J., Ullmann J.L., Gulley M.S., et al. Cross Sections from Proton Irra-diation of Thorium at 800 MeV. Phys. Rev. C. 2013;88:014604. doi: 10.1103/PhysRevC.88.014604. - DOI -PubMed
36. Lambrecht RM, Tomiyoshi K, Sekine T. Radio-nuclide Generators. Radiochimica Ac-ta. 1997;77:103–123. [Google Scholar]
37. Apostolidis C, Molinet R, McGinley J, Abbas K, Mollenbeck J, Morgenstern A. Cyclotron production of Ac-225 for targeted alpha therapy. Appl Radiat Isot. 2005;62:383–387. [PubMed] [Google Scholar]
38. Apostolidis C., Molinet R., Rasmussen G., Morgenstern A. Production of Ac-225 from Th-229 for Targeted α Therapy. Anal. Chem. 2005;77:6288–6291. doi: 10.1021/ac0580114. - DOI - PubMed
39. Hogle S., Boll R.A., Murphy K., Denton D., Owens A., Haverlock T.J., Garland M., Mir-zadeh S. Reactor Production of Thorium-229. Appl. Radiat. Isot. 2016;114:19–27. doi: 10.1016/j.apradiso.2016.05.002. - DOI - PubMed
40. Apostolidis C., Molinet R., McGinley J., Abbas K., Möllenbeck J., Morgenstern A. Cyclotron Production of Ac-225 for Targeted Alpha Therapy11Dedicated to Prof. Dr. Franz Baumgärtner on the Occasion of His 75th Birthday. Appl. Radiat. Isot. 2005;62:383–387. doi: 10.1016/j.apradiso.2004.06.013. - DOI - PubMed
41. Nikula TK, McDevitt MR, Finn RD, Wu C, Kozak RW, Garmestani K, Brechbiel MW, Curcio MJ, Pippin CG, Tiffany-Jones L, Geer-lings MW, Sr, Apostolidis C, Molinet R, Geer-lings MW, Jr, Gansow OA, Scheinberg DA. Alpha-emitting bismuth cyclohexylbenzyl DTPA constructs of recombinant humanized anti-CD33 antibodies: pharmacokinetics, bio-activity, toxicity and chemistry. J Nucl Med. 1999;40:166–176. [PubMed] [Google Scholar]
42. Weast RC. 66th Edition of the CRC Handbook of Chemistry and Physics. CRC Press, Inc; Boca Raton, FL: 1985. [Google Scholar]
43. Poty S., Francesconi L.C., McDevitt M.R., Mor-ris M.J., Lewis J.S. α-Emitters for Radiothera-py: From Basic Radiochemistry to Clinical Studies—Part 1. J. Nucl. Med. 2018;59:878–884. doi: 10.2967/jnumed.116.186338. - DOI - PMC - PubMed
44. Poty S., Francesconi L.C., McDevitt M.R., Mor-ris M.J., Lewis J.S. α-Emitters for Radiothera-py: From Basic Radiochemistry to Clinical Studies—Part 2. J. Nucl. Med. 2018;59:1020–1027. doi: 10.2967/jnumed.117.204651. - DOI - PMC - PubMed
45. Kotovskii A.A., Nerozin N.A., Prokof’ev I.V., Shapovalov V.V., Yakovshchits Y.A., Bolonkin A.S., Dunin A.V. Isolation of Actinium-225 for Medical Purposes. Radiochemistry. 2015;57:285–291.
doi: 10.1134/S1066362215030091. DOI -PubMed
46. Poty S., Carter L.M., Mandleywala K., Mem-breno R., Abdel-Atti D., Ragupathi A., Scholz W.W., Zeglis B.M., Lewis J.S. Leveraging Bioorthogonal Click Chemistry to Improve 225 Ac-Radioimmunotherapy of Pancreatic Ductal Adenocarcinoma. Clin. Cancer Res. 2019;25:868–880. doi: 10.1158/1078-0432.CCR-18-1650. - DOI - PMC - PubMed
47. Ramogida C.F., Robertson A.K.H., Jermilova U., Zhang C., Yang H., Kunz P., Lassen J., Bra-tanovic I., Brown V., Southcott L., et al. Evalu-ation of Polydentate Picolinic Acid Chelating Ligands and an α-Melanocyte-Stimulating Hormone Derivative for Targeted Alpha Therapy Using ISOL-Produced 225Ac. EJNMMI Radiopharm. Chem. 2019;4:21. doi: 10.1186/s41181-019-0072-5. - DOI - PMC - PubMed
48. Chappell L.L., Deal K.A., Dadachova E., Brechbiel M.W. Synthesis, Conjugation, and Radiolabeling of a Novel Bifunctional Chelat-ing Agent for 225 Ac Radioimmunotherapy Applications. Bioconjug. Chem. 2000;11:510–519. doi: 10.1021/bc990153f. - DOI - PubMed
49. Yang H., Zhang C., Yuan Z., Rodriguez-Rodriguez C., Robertson A., Radchenko V., Perron R., Gendron D., Causey P., Gao F., et al. Synthesis and Evaluation of a Macrocyclic Actinium-225 Chelator, Quality Control and In Vivo Evaluation of 225 Ac-crown-αMSH Peptide. Chem. Eur. J. 2020;26:11435–11440. doi: 10.1002/chem.202002999. - DOI - PubMed
50. Pouget J.-P., Georgakilas A.G., Ravanat J.-L. Targeted and Off-Target (Bystander and Ab-scopal) Effects of Radiation Therapy: Redox Mechanisms and Risk/Benefit Analysis. Anti-oxid. Redox Signal. 2018;29:1447–1487. doi: 10.1089/ars.2017.7267. - DOI - PMC - PubMed
51. 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., et al. MIRD Pam-phlet No. 22 (Abridged): Radiobiology and Dosimetry of -Particle Emitters for Targeted Radionuclide Therapy. J. Nucl. Med. 2010;51:311–328. doi: 10.2967/jnumed.108.058651. - DOI - PMC - PubMed
52. Baidoo K.E., Yong K., Brechbiel M.W. Mo-lecular Pathways: Targeted-Particle Radia-tion Therapy. Clin. Cancer Res. 2013;19:530–537. doi: 10.1158/1078-0432.CCR-12-0298. - DOI - PMC - PubMed
53. Aghevlian S., Boyle A.J., Reilly R.M. Radio-immunotherapy of Cancer with High Linear Energy Transfer (LET) Radiation Delivered by Radionuclides Emitting α-Particles or Auger Electrons. Adv. Drug Deliv. Rev. 2017;109:102–118.
doi:10.1016/j.addr.2015.12.003. DOI - PubMed
54. Sathekge M, Bruchertseifer F, Vorster M, Lawal IO, Mokoala K, Reed J, Maseremule L, Ndlovu H, Hlongwa K, Maes A, Morgenstern A, Van de Wiele C. 225Ac-PSMA-617 radi-oligand therapy of de novo metastatic hor-mone-sensitive prostate carcinoma (mHSPC): preliminary clinical findings. Eur J Nucl Med Mol Imaging. 2023 Jun;50(7):2210-2218. doi: 10.1007/s00259-023-06165-9. Epub 2023 Mar 3. PMID: 36864360; PMCID: PMC1019987.
55. Sidaway. 177Lu-PSMA-PET extends Survival. P.Nat Rev Clin Oncol. 2021 Sep;18(9):542. doi: 10.1038/s41571-021-00543-8.PMID: 34262157.
56. Hadaschik B, Herrmann K.Eur. Lutetium-177-PSMA-617 for Metastatic Castration- Re-sistant Prostate Cancer. Urol. 2021 Oct;80(4):520-521. doi: 10.1016/j.eururo.2021.07.006. Epub 2021 Jul 24.PMID: 34312019.
57. Deal K.A., Davis I.A., Mirzadeh S., Kennel S.J., Brechbiel M.W. Improved in Vivo Stabil-ity of Actinium-225 Macrocyclic Complexes. J. Med. Chem. 1999;42:2988–2992. doi: 10.1021/jm990141f. - DOI - PubMed
58. McDevitt M.R., Ma D., Simon J., Frank R.K., Scheinberg D.A. Design and Synthesis of 225Ac Radioimmunopharmaceuticals. Appl. Radiat. Isot. 2002;57:841–847. doi: 10.1016/S0969-8043(02)00167-7. - DOI - PubMed
59. Antczak C., Jaggi J.S., LeFave C.V., Curcio M.J., McDevitt M.R., Scheinberg D.A. Influ-ence of the Linker on the Biodistribution and Catabolism of Actinium-225 Self-Immolative Tumor-Targeted Isotope Generators. Biocon-jug. Chem. 2006;17:1551–1560. doi: 10.1021/bc060156+. - DOI - PMC - PubMed
60. Maguire W.F., McDevitt M.R., Smith-Jones P.M., Scheinberg D.A. Efficient 1-Step Radio-labeling of Monoclonal Antibodies to High Specific Activity with 225Ac for α-Particle Radioimmunotherapy of Cancer. J. Nucl. Med. 2014;55:1492–1498. doi: 10.2967/jnumed.114.138347. - DOI - PMC - PubMed
61. Beyer G.J., Bergmann R., Schomäcker K., Rösch F., Schäfer G., Kulikov E.V., Novgo-rodov A.F. Comparison of the Biodistribution of 225Ac and Radio-Lanthanides as Citrate Complexes. Isot. Environ. Health Stud. 1990;26:111–114. doi: 10.1080/10256019008624245. - DOI
62. Poty S., Membreno R., Glaser J.M., Ragupathi A., Scholz W.W., Zeglis B.M., Lewis J.S. The Inverse Electron-Demand Diels–Alder Reac-tion as a New Methodology for the Synthesis of 225 Ac-Labelled Radioimmunoconjugates. Chem. Commun. 2018;54:2599–2602. doi: 10.1039/C7CC09129J. - DOI - PMC - PubMed
63. ClinicalTrials.gov Identifier: NCT04597411 Recruiting Status: Recruiting, First Posted: Oc-tober 22,2020 Last Update: November 25, 2022
64. ClinicalTrials.gov Identifier: NCT05219500 Recruiting Status: Recruiting, First Posted: February 2, 2022, Last Update Posted: March 27, 2023
65. Davis I.A., Glowienka K.A., Boll R.A., Deal K.A., Brechbiel M.W., Stabin M., Bochsler P.N., Mirzadeh S., Kennel S.J. Comparison of 225actinium Chelates: Tissue Distribution and Radiotoxicity. Nucl. Med. Biol. 1999;26:581–589. doi: 10.1016/S0969-8051(99)00024-4. - DOI - PubMed
66. Comba P., Jermilova U., Orvig C., Patrick B.O., Ramogida C.F., Rück K., Schneider C., Starke M. Octadentate Picolinic Acid-Based Bispidine Ligand for Radiometal Ions. Chem. Eur. J. 2017;23:15945–15956. doi: 10.1002/chem.201702284. - DOI - PubMed
67. Thiele N.A., Brown V., Kelly J.M., Amor-Coarasa A., Jermilova U., MacMillan S.N., Nikolopoulou A., Ponnala S., Ramogida C.F., Robertson A.K.H., et al. An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy. Angew. Chem. Int. Ed. 2017;56:14712–14717. doi: 10.1002/anie.201709532. - DOI - PubMed
68. Zielińska B, Bilewicz A. The hydrolysis of ac-tinium. J Radioanal Nucl Chem 2004;261:195 [Google Scholar]
69. Pearson RG. Hard and soft acids and bases. J Am Chem Soc 1963;85:3533 [Google Schol-ar]
70. Parr RG, Pearson RG. Absolute hardness: Companion parameter to absolute electro-negativity. J Am Chem Soc 1983;105:7512 [Google Scholar]
71. Pearson RG. Absolute electronegativity and hardness: Application to inorganic chemis-try. Inorg Chem 1988;27:734 [Google Scholar]
72. Cotton S. Introduction to the actinides. In: Cot-ton S. (ed.), Lanthanide and Actinide Chemis-try. Chichester: John Wiley & Sons, Ltd, 2006;145 [Google Scholar]
73. Drago RS, Vogel GC, Needham TE. A four-parameter equation for predicting enthalpies of adduct formation. J Am Chem Soc 1971;93:6014 [Google Scholar]
74. Hancock RD, Marsicano F. Parametric corre-lation of formation constants in aqueous solu-tion. 1. Ligands with small donor atoms. Inorg Chem 1978;17:560 [Google Scholar]
75. Hancock RD, Marsicano F. Parametric corre-lation of formation constants in aqueous solu-tion. 2. Ligands with large donor atoms. Inorg Chem 1980;19:2709 [Google Scholar]
76. Aziz A, Lyle SJ. Complexes of lanthanum and actinium with fluoride, oxalate and sulphate in aqueous solutions. J Inorg Nucl Chem 1970;32:1925 [Google Scholar]
77. Shahani CJ, Mathew KA, Rao CL, et al.. Chemistry of actinium. I. Stability con-stants of chloride, bromide, nitrate and sul-phate complexes. Radiochim Ac-ta 1968;10:165 [Google Scholar]
78. Rao CL, Shahani CJ, Mathew KA. Chemistry of actinium—II Stability constants of thiocya-nate complexes of actinium and lantha-num. Inorg Nucl Chem Lett 1968;4:655 [Google Scholar]
79. Sekine T, Sakairi M. Studies of actinium(III) in various solutions. III. Actinium (III) complexes with oxalate, sulfate, chloride, and thiocya-nate ions in perchlorate media. Bull Chem Soc Jpn 1969;42:2712 [Google Scholar]
80. Rao VK, Shahani CJ, Rao CL. Studies on the phosphate complexes of actinium and lan-thanum. Radiochim Acta 1970;14:31 [Google Scholar]
81. Alleluia IB, Eberle SH, Keller C, Kirby HW. Gmelin Handbook of Inorganic Chemis-try, Actinium, 8th ed., In: Kugler HK, Keller C. (eds.), system no. 40 suppl. vol. 1 Berlin: Springer-Verlag, 1981. [Google Scholar]
82. Makarova TP, Sinitsyna GS, Stepanov AV, et al.. Complex formation of actinium. I. Deter-mination of the stability constants of eth-ylenediaminetetraacetate complexes of ac-tinium and its separation from lanthanum in solutions of EDTA by the method of elec-tromigration. Sov Radi-ochem 1972;14:555 [Google Scholar]
83. Smith RM, Martell AE. Iminodiacetic Acid De-rivatives. In: Martell AE, Smith RM. (eds.), Critical Stability Constants: Second Supplement. Boston: Springer, 1989;67 [Google Scholar]
84. Smith RM, Martell AE. Carboxylic acids. In: Martell AE, Smith RM. (eds.), Critical Stability Constants: Second Supplement. Boston: Springer, 1989;299 [Google Scholar]
85. Fried S, Hagemann F, Zachariasen WH. The preparation and identification of some pure actinium compounds. J Am Chem Soc 1950;72:771 [Google Scholar]
86. 225Actinium DOE User Meeting July 28, 2020 Introduction Ekaterina (Kate) Dadachova, PhD Chair in Radiopharmacy, Fedoruk Center for Nuclear Innovation Pro-fessor, College of Pharmacy and Nutrition University of Saskatchewan, Canada
87. Ac-225 User Group: Production Effort to Pro-vide Accelerator-Produced 225Ac for Radio-therapy Cathy S. Cutler, Brookhaven Nation-al Laboratory Kevin John, Los Alamos Na-tional Laboratory, Project Manager, U.S. DOE Tri-Lab
88. Actinium-225 (Ac-225) Radiopharmaceuticals FDA Perspective – Chemistry, Manufacturing and Controls (CMC) Ravi Kasliwal, Ph.D. Of-fice of New Drug Products DNDC-3, Branch-6 Office of Pharmaceutical Quality CDER/FDA
89. Actinium-225 & Bismuth-213: Two Important Alpha Emitters for the Future of Therapeutics Kevin Allen, PhD July 28th, 2020 Actinium-225 DOE Users Meeting Actinium Pharmaceu-ticals, Inc. This research is supported by the U.S. Department of Energy Isotope Program
90. Engle JW. The Production of Ac-225. Curr Radiopharm. 2018;11(3):173-179. doi: 10.2174/1874471011666180418141357. PMID: 29669509.
91. Ju, K., Kim, Y. Feasibility of a novel photo-production of 225Ac and 227Th with natural thorium target. Sci Rep 12, 372 (2022). https://doi.org/10.1038/s41598-021-04339-9103.
92. Scheinberg DA, McDevitt MR. Actinium-225 in targeted alpha-particle therapeutic applica-tions. Curr Radiopharm. 2011 Oct;4(4):306-20. doi: 10.2174/1874471011104040306. PMID: 22202153; PMCID: PMC5565267.
93. K. N. Leung, J. K. Leung, and G. Melville, “Feasibility Study on Medical Isotope Produc-tion Using a Compact Neutron Generator,” Appl. Radiat. Isot., 137C, 23 (2018). DOI: 10.1016/j.apradiso.2018.02.026
94. J. Ishikawa, “Appl. Of Accelerators in Re-search and Industry,” J. L. Duggan and I. L. Morgan, Eds., AIP Press, New York (1977).
95. K. N. Leung and K. W. Ehlers, “Self-extraction negative ion source,” Rev. Sci. Instrum. 53(6) Jun. (1982) 803-809. FERMILAB-PUB-05-094-AD
96. Robertson A.K.H., McNeil B.L., Yang H., Gen-dron D., Perron R., Radchenko V., Zeisler S., Causey P., Schaffer P. 232Th-Spallation-Produced 225 Ac with Reduced 227 Ac Con-tent. Inorg. Chem. 2020;59:12156–12165. doi: 10.1021/acs.inorgchem.0c01081. - DOI - PubMed
97. de Kruijff R., Wolterbeek H., Denkova A. A Critical Review of Alpha Radionuclide Thera-py—How to Deal with Recoiling Daughters? Pharmaceuticals. 2015;8:321–336. doi: 10.3390/ph8020321. - DOI - PMC - PubMed
98. Singh Jaggi J., Kappel B.J., McDevitt M.R., Sgouros G., Flombaum C.D., Cabassa C., Scheinberg D.A. Efforts to Control the Errant Products of a Targeted In Vivo Generator. Cancer Res. 2005;65:4888–4895. doi: 10.1158/0008-5472.CAN-04-3096. - DOI - PubMed
99. JRC SCIENCE FOR POLICY REPORT “Study on sustainable and resilient supply of medical radioisotopes in the EU- Therapeutic Radionu-clides”, Ligvoet, Scholten, Davé, King, Petro-sova, Chiti, Goulard De Medeiros, Joerger, 2021, EUR 30690 EN.
100. Radiopharmaceutical Quality Control Consid-erations for Accelerator-Produced Actinium Therapies”, Abou, Zerkel, Robben, McLaugh-lin, Hazlehurst, Morse, Wadas, Pandaya, Oyama, Gaehle, Nickels, Thorek, Cancer Bio-therapy and Radiopharmaceuticals, Vol. 27, Number 5, 2022. Doi: 10.1089/cbr.2022.0010.
101. The supply of Medical Isotopes, an economic diagnosis and possible solutions, OECD, NEA Nuclear Energy Agency.
102. IAEA – Report on Joint IAEA-JRC Workshop “Supply of Actinium-225”, IAEA, Vienna, 2018
103. Sgouros G., Bodei L., McDevitt M.R., Nedrow J.R. Radiopharmaceutical Therapy in Cancer: Clinical Advances and Challenges. Nat. Rev. Drug Discov. 2020;19:589–608. doi: 10.1038/s41573-020-0073-9. - DOI - PMC - PubMed
104. Kassis A.I., Adelstein S.J. Radiobiologic Prin-ciples in Radionuclide Therapy. J. Nucl. Med. 2005;46:4S. - PubMed
105. Tafreshi N.K., Doligalski M.L., Tichacek C.J., Pandya D.N., Budzevich M.M., El-Haddad G., Khushalani N.I., Moros E.G., McLaughlin M.L., Wadas T.J., et al. Development of Targeted Alpha Particle Therapy for Solid Tumors. Molecules. 2019;24:4314. doi: 10.3390/molecules24234314. - DOI - PMC - PubMed
106. Robertson A.K.H., Ramogida C.F., Schaffer P., Radchenko V. Development of225 Ac Radio-pharmaceuticals: TRIUMF Perspectives and Experiences. Curr. Radiopharm. 2018;11:156–172. doi: 10.2174/1874471011666180416161908. - DOI - PMC - PubMed
107. Jurcic J.G. Targeted Alpha-Particle Therapy for Hematologic Malignancies. Semin. Nucl. Med. 2020;50:152–161. doi: 10.1053/j.semnuclmed.2019.09.002. - DOI - PubMed
108. Huclier-Markai S., Alliot C., Varmenot N., Cut-ler S.C., Barbet J. Alpha-Emitters for Immuno-Therapy: A Review of Recent Developments from Chemistry to Clinics. Curr. Top. Med. Chem. 2013;12:2642–2654. doi: 10.2174/1568026611212230002. - DOI - PubMed
109. Makvandi M., Dupis E., Engle J.W., Nortier F.M., Fassbender M.E., Simon S., Birnbaum E.R., Atcher R.W., John K.D., Rixe O., et al. Alpha-Emitters and Targeted Alpha Therapy in Oncology: From Basic Science to Clinical Investigations. Target. Oncol. 2018;13:189–203. doi: 10.1007/s11523-018-0550-9. - DOI - PubMed
110. Morgenstern A., Apostolidis C., Kratochwil C., Sathekge M., Krolicki L., Bruchertseifer F. An Overview of Targeted Alpha Therapy with 225 Actinium and 213 Bismuth. Curr. Radio-pharm. 2018;11:200–208. doi: 10.2174/1874471011666180502104524. - DOI - PMC - PubMed
111. “Guideline on current good radiopharmacy practice (cGRPP) for the small-scale prepara-tion of radiopharmaceuticals”, Gillings, Hjels-tuen, Ballinger, Behe, Decristoforo, Elsinga, Ferrari, Paitl, Koziorowsi, Laverman, Mindt, Neels, Ocak, Patt, Todde, EJNMMI Radio-pharmacy and Chemistry, 2021, Springer Open. https://doi.org/10.1186/s41181-021-00123-2
112. Treatment Planning For Molecular Radiother-apy: Potential and Prospects, European Asso-ciation of Nuclear Medicine, www.eanm.org
113. Pouget J.-P., Lozza C., Deshayes E., Boudousq V., Navarro-Teulon I. Introduction to Radiobi-ology of Targeted Radionuclide Therapy. Front. Med. 2015;2 doi: 10.3389/fmed.2015.00012. - DOI - PMC - PubMed
114. Li L., Rousseau J., de Guadalupe Jara-quemada-Peláez M., Wang X., Robertson A., Radchenko V., Schaffer P., Lin K.-S., Bénard F., Orvig C. 225Ac-H4 Py4pa for Targeted Alpha Therapy. Bioconjug. Chem. 2020 doi: 10.1021/acs.bioconjchem.0c00171. - DOI - PubMed
115. Kirby HW, Morss LR. Actinium. In: Morss LR, Edelstein NM, Fuger J. (eds.), The Chemistry of the Actinide and Transactinide Elements. Dordrecht: Springer Netherlands, 2006;18 [Google Scholar]
116. Martellini, Sarotto, Leung, Gherardi, “A Compact Neutron Generator for the Niort® Treatment of Severe Solid Cancers”, Medical Research Archives, ESMED, March 2023, https://doi.org/10.18103/mra.v11i3.3799
117. McDevitt MR, Sgouros G, Finn RD, Humm JL, Jurcic JG, Larson SM, Scheinberg DA. Radio-immunotherapy with alpha-emitting nu-clides. European Journal of Nuclear Medi-cine. 1998;25:1341–1351. [PubMed] [Google Scholar]
118. ITU Annual Report 1995-(EUR 16368)-Basic Actinide Research. 1995. Methods for the production of Ac-225 and Bi-213 for alpha immunotherapy; pp. 55–56. [Google Schol-ar]
119. Koch L, Apostolidis C, Molinet R, Nicolaou G, Janssens W, Schweikert H. Production of Bi-213 and Ac-225, Alpha-Immuno-97 Sympo-sium; Karlsruhe, Germany. 1997. [Google Scholar]
120. Boll RA, Malkemus D, Mirzadeh S. Production of actinium-225 for alpha particle mediated radioimmunotherapy. Appl Radiat Isot. 2005;62:667–679. [PubMed] [Google Scholar]
121. Boll RA, Mirzadeh S, Kennel SJ, DePaoli DW, Webb OF. Bi-213 for alpha particle mediat-ed radioimmunotherapy. J Label Compds and Radiopharm. 1997;40:341–343. [Google Scholar]
122. McDevitt MR, Finn RD, Ma D, Larson SM, Scheinberg DA. Preparation of alpha-emitting 213Bi-labeled antibody constructs for clinical use. J Nucl Med. 1999;40:1722–1727. [PubMed] [Google Scholar]