
==== Front
Semin Nucl Med
Semin Nucl Med
Seminars in Nuclear Medicine
0001-2998 1558-4623 W.B. Saunders 

S0001-2998(20)30004-0
10.1053/j.semnuclmed.2020.02.003
Article
Supply and Clinical Application of Actinium-225 and Bismuth-213
Morgenstern Alfred christopher58@example.net⁎ Apostolidis Christos PhD Bruchertseifer Frank PhD European Commission, Joint Research Centre, Directorate for Nuclear Safety and Security, Karlsruhe, Germany
⁎ Address reprint requests to Alfred Morgenstern, PhD, European Commission, Joint Research Centre, Directorate for Nuclear Safety and Security, Karlsruhe, Germany. christopher58@example.net
1 3 2020 
3 2020 
50 2 119 123
© 2020 The Authors2020This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).The recent development of 225Ac-PSMA617 for therapy of prostate cancer has strikingly demonstrated the clinical potential of targeted alpha therapy. Further promising applications of the alpha emitters 225Actinium and its daughter nuclide 213Bismuth include the therapy of brain tumors, bladder cancer, neuroendocrine tumors, and leukemia. This paper will provide a brief overview on the current status of the clinical development of compounds labelled with 225Ac or 213Bi and describe the various production routes that are in place or are under development to meet the increasing demand for these radionuclides.
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Introduction
The concept of applying 225Actinium and its daughter nuclide 213Bismuth for targeted alpha therapy (TAT) of cancer was described by Geerlings et al in 1993.1 Although the nuclides were hardly accessible at that time, the authors recognized their potential for medical application, given their favorable decay characteristics and chemical properties combined with the inherent advantages of alpha radiation of high energy and short-range in human tissue. For two decades thereafter, extensive research was performed, including the development of methods for production of 225Ac and 213Bi, numerous preclinical studies and several clinical investigations. Early pioneering clinical work focused on treatment of leukemia,2,3 non-Hodgkins lymphoma (NHL),4 malignant melanoma,5, 6, 7 brain tumors,8, 9, 10, 11 neuroendocrine tumors,12,13 and bladder cancer.14 In 2013, 20 years after the initial work of Geerlings et al, the compound 225Ac-PSMA617 was first synthesized and investigated at Joint Research Centre (JRC) Karlsruhe. The remarkable efficacy of this novel compound manifested already in early patient studies conducted in collaboration of JRC and University Hospital Heidelberg and was first reported by Kratochwil et al in 2016.15 While the clinical application of 225Ac-PSMA617 was further developed in collaboration of JRC with hospitals in Heidelberg,16,17 Pretoria,18, 19, 20 and Munich,21 the remarkable benefit observed clinically in an increasing number of patients stimulated worldwide interest in applying 225Ac in TAT. Consequently, an increasing number of novel 225Ac-labeled compounds are currently under development, and production facilities to meet the increasing demand for the nuclide have been set up or are under construction. This paper will summarize important clinical investigations with 225Ac- and 213Bi-labelled compounds just briefly, as they will be described in much detail in other contributions in this issue. Furthermore, the current status of production of 225Ac will be reviewed.

Clinical Experience With 225Ac and 213Bi
The current state of clinical investigation of 225Ac- and 213Bi-labelled compounds is summarized in Table 1. The early studies on TAT of leukemia, NHL, malignant melanoma, and the more recent pilot trial on bladder cancer investigated 213Bi- or 225Ac-labeled antibodies. While the combination of short-lived 213Bi (T1/2) = 46 minutes and full antibodies holds promise for the targeting of rapidly accessible, blood-associated cancers such as leukemia2,3 or NHL,4 the 213Bi-labelled anti-MCSP-antibody investigated for the treatment of malignant melanoma5, 6, 7 probably failed to deliver sufficient tumor dose due to the slower pharmacokinetics of the construct. In contrast, the intravesical application of 213Bi-anti-EGFR-mAb for therapy of carcinoma in situ14 is an excellent approach that facilitates rapid and very selective targeting and minimizes toxicity to other organs.Table 1 Overview of Current Clinical Experience With 225Ac- and 213Bi-Labeled Compounds

Table 1Cancer Type	Radioconjugate	Patients	Reference	
Leukemia	213Bi-anti-CD33-mAb	49	2,3	
	225Ac-anti-CD33-mAb	76	22	
Lymphoma	213Bi-anti-CD20-mAb	12	4	
Melanoma	213Bi-anti-MCSP-mAb	54	5, 6, 7	
Bladder cancer	213Bi-anti-EGFR-mAb	12	14	
Glioma	213Bi-Substance P	68	8, 9, 10, 11	
	225Ac-Substance P	20	23	
Neuroendocrine tumors	213Bi-DOTATOC	25	12	
	225Ac-DOTATOC	39	13	
Prostate cancer	225Ac-PSMA617	>400	15, 16, 17, 18, 19, 20, 21	


The combination of short-lived 213Bi and low molecular weight, rapidly diffusing peptides, such as DOTATOC and Substance P analogues, showed promising results for the treatment of neuroendocrine tumors12,13 and gliomas,8, 9, 10, 11 in particular after locoregional administration for improved tumor uptake. In collaboration of JRC Karlsruhe and University Hospital Heidelberg 25 patients with multiresistant neuroendocrine tumors refractory to therapy with beta emitter labeled 90Y-/177Lu-DOTATOC were treated with 213Bi-DOTATOC. Although patients presented in clinically challenging situations and had developed resistance against therapy with beta emitters, TAT with 213Bi-DOTATOC resulted in a high number of long-lasting antitumor responses, including one complete remission. Hematotoxicity was dose-limiting, and potential long-term renal toxicity has to be considered and closely monitored.

Locoregional application of 213Bi-[Thi8,Met(O2)11]-substance P for treatment of gliomas has been found safe after injection of doses of 2 GBq in 2-month interval up to cumulative doses of 11.2 GBq with only mild and transient adverse reactions. The median overall survival after recurrence of 10.9 months observed in a cohort of 20 patients with recurrent glioblastoma (GBM) compares favorably to available alternative treatments.11 Also in a small cohort of nine patients suffering from secondary GBM, treatment with 213Bi-[Thi8,Met(O2)11]-substance P was well tolerated and resulted in median overall survival of 18.6 months after conversion of the primary low grade glioma to grade IV GBM.10 Two out of nine patients with secondary GBM were still alive 39 and 51 months after initiation of locoregional alpha therapy.

While the combination of low molecular weight, rapidly diffusing peptides with local modes of administration holds promise for therapeutic application of short-lived 213Bi, the high cost and currently still limited supply of high activity 225Ac/213Bi generators required for preparation of patient doses in the multiple GBq range still poses considerable limitations for clinical application of these treatment approaches. These limitations can be overcome to some extent through application of 225Ac with its longer half-live of 9.9 days and its higher cytotoxicity associated with the multiple alpha particles generated in its decay chain.

The first in human clinical investigation of a 225Ac-labeled small molecule was started in 2011 in collaboration of JRC Karlsruhe and University Hospital Heidelberg for therapy of patients with neuroendocrine tumors using 225Ac-DOTATOC.13 In a group of 39 patients, the treatment was found to be safe with activities of 18.5 MBq given in 2-month interval up to a cumulative dose of 75 MBq. The MTD of a single dose was determined as 40 MBq. Although several of patient responses were observed, further investigations are needed to improve patient selection and fractionation regimes.

The development of 225Ac-PSMA617 for therapy of prostate cancer can be considered a milestone in the evolution of TAT. The pharmacokinetics of PSMA617, in particular its rapid tumor uptake within a few hours, its extended tumor retention as well as its rapid renal clearance of unbound compound provide an excellent match to the decay characteristics of long-lived 225Ac. In particular the high degree of internalization of PSMA617 allows intracellular capture of the decay daughters of 225Ac and utilizing their cytotoxicity for tumor cell kill, while minimizing toxicity of errant daughters. Following the development and in vitro characterization of 225Ac-PSMA617 at JRC Karlsruhe in 2013/2014, clinical testing was started initially in collaboration of JRC Karlsruhe with University Hospital Heidelberg, and subsequently extended to Steve Biko Academic Hospital Pretoria and Technical University Munich.

For initial clinical application of 225Ac-PSMA617, a standardized protocol was developed based on a dosimetry estimate and retrospective evaluation of the efficacy and tolerability of salvage therapies performed in 14 advanced stage metastatic castration-resistant prostate cancer patients, consisting of a treatment activity of 100 kBq/kg of 225Ac-PSMA617 per cycle repeated twice every 8 weeks.16 In a cohort of 40 advanced stage patients the protocol demonstrated remarkable antitumor efficacy, while xerostomia (dry mouth syndrome) was observed as main adverse effect leading to discontinuation of treatment in 10% of patients.17 In subsequent clinical investigations, 225Ac-PSMA617 was administered in fixed activities of 8 MBq for the first cycle (corresponding to 100 kBq/kg body weight in a typical patient of 80 kg) for reasons of standardization and simplification of procedures. In addition, to minimize damage to salivary glands, administered activities in subsequent cycles were de-escalated to 7-4 MBq as function of patient response.18 An analysis of 73 patients treated with 225Ac-PSMA617 at Steve Biko Academic Hospital in Pretoria demonstrated excellent therapeutic efficacy and increased tolerability of this de-escalation approach, showing a Prostate specific antigen (PSA) decline of ≥50% in 70% of patients, while 83% of patients had any PSA decline and 0% of patients discontinued treatment.19 Another promising approach for maintaining high therapeutic efficacy while minimizing toxicity to salivary glands is the combination of alpha- and beta emitter labelled PSMA617. An interim analysis of a first group of 17 patients with advanced metastatic castration-resistant prostate cancer treated with a combination of 4 MBq 225Ac-PSMA617 and 4 GBq 177Lu-PSMA617 demonstrated improved tolerability with a response rate of 76% (PSA decline >50%).24 Notably, therapy with 225Ac-PSMA617 was also found to be effective for brain metastases in advanced prostate cancer patients.20

Production of 225Ac and 213Bi
Radiochemical Extraction of 225Ac From 229Th
The radiochemical extraction of 225Ac from 229Th (T1/2 = 7917 years) sources has been the workhorse for production of 225Ac and 213Bi since the early 1990s. All clinical investigations and virtually all preclinical research with 225Ac and 213Bi-labelled compounds to date have been conducted with radionuclides obtained from 229Th decay. Worldwide three sources of 229Th are available that allow the production of clinically relevant activities of 225Ac/213Bi, located at the Directorate for Nuclear Safety and Security of the JRC of the European Commission in Karlsruhe, Germany (formerly known as Institute for Transuranium Elements),25 Oak Ridge National Laboratory (ORNL), USA26 and at the Institute of Physics and Power Engineering (IPPE) in Obninsk, Russia.27 The 229Th sources have been obtained by separation from aged, fissile 233U originally produced for weapons applications by neutron irradiation of natural 232Th. More recently the preparation of a small scale 229Th source has been also reported from Canadian Nuclear Laboratories.28 Notably, it has been reported that from 2019 onward a very significant increase in availability of 229Th will be generated through extraction of 229Th from legacy wastes stored within the US Department of Energy. The total amount of accessible 229Th has been estimated to up to 45 g, corresponding to a potential increase in 225Ac supply of up to 40 fold compared to current levels.29

The production of 225Ac from 229Th at JRC Karlsruhe is based on a combination of anion exchange and extraction chromatography,25,30 while the process in place at ORNL is utilizing anion and cation exchange.26 JRC has been the first laboratory to prepare 225Ac/213Bi for clinical use in the mid 1990s and has since then produced approximately 13 GBq 225Ac annually for preclinical research and clinical testing performed at JRC Karlsruhe or in collaboration with a wide network of clinical partners. The maximum annual production of 225Ac at ORNL is approximately 33 GBq, while IPPE has reported a production of 22 GBq per year.27 While 225Ac produced at JRC Karlsruhe and ORNL has been extensively applied for patient treatment and found safe for administration to humans, direct clinical application of 225Ac produced at IPPE to our knowledge has not been reported to date.

225Ac can be used directly as therapeutic nuclide or can be loaded on 225Ac/213Bi generators to provide short-lived 213Bi on site. In general 225Ac/213Bi generators based on AG MP-50 cation exchange resin are most established and have been used for all patient studies with 213Bi to date.31 The high activity generator system developed at JRC Karlsruhe allows reliable operation of the generator when loaded with activities up to 4 GBq 225Ac with yields of 213Bi elution exceeding 80% and a low breakthrough of 225Ac parent nuclide of less than 0.2 ppm (activity).32 A key feature during preparation of this generator is the process of loading the parent nuclide, resulting in the distribution of 225Ac activity over approximately two thirds of the generator resin in order to minimize radiolytic degradation of the organic resin and to assure reliable operation over several weeks. The generator has been successfully used clinically for preparation of therapeutic doses of 213Bi-labelled peptides with activities up to 2.3 GBq at time of injection.

Accelerator-Based Routes
Currently the global supply of 225Ac from 229Th is still insufficient for widespread routine application of 225Ac and 213Bi-labelled compounds in hospitals worldwide. Consequently, a variety of alternative methods for large scale production of 225Ac have been investigated, including the spallation of 232Th or natU targets with highly energetic protons and the irradiation of 226Ra targets using protons, deuterons or gamma-rays.33

Among these routes, the production of 225Ac by spallation of 232Th is currently the most advanced. The feasibility of the process has been demonstrated at the Institute for Nuclear Research, Russian Academy of Sciences, in Troitsk, Russia34,35 and at Los Alamos National Laboratory in the US.36,37 In the last years the routine production of 225Ac via spallation of 232Th has been successfully established within the US DoE Tri-Lab (ORNL, BNL, LANL) effort. Irradiations can be performed at Brookhaven National Laboratory (200 MeV at 165 μA) and Los Alamos National Laboratory (100 MeV at 275 μA), while targets are processed and the final product is distributed from ORNL.38 The main limitation of the process is the coproduction of long-lived 227Ac (T1/2 = 21.8 years) at levels of 0.1%-0.2% activity (at EOB). Since 225Ac and 227Ac isotopes cannot be chemically separated, the implications of the 227Ac impurity for the clinical application of the 225Ac product have to be considered. Initial studies indicate that the impact of the 227Ac impurity on patient dosimetry will be negligible.39 However, issues related to licensing, safe handling, and disposal of long lived 227Ac in hospital settings still have to be resolved.

The production of 225Ac by proton irradiation of 226Ra targets in a cyclotron through the reaction 226Ra(p,2n)225Ac offers a number of advantages over the 232Th spallation reaction. The process can be performed with high yields in a cost-effective manner in medium-sized cyclotrons at proton energies below 20 MeV.40 A 24 hour irradiation of 50 mg 226Ra at the maximum of the excitation function at 15-16 MeV with a current of 100 µA protons is expected to yield approximately 5 GBq 225Ac, equivalent to 500 patient doses of 10 MBq 225Ac. Chemical purification of the irradiated targets yields 225Ac of high isotopic purity as no other long-lived actinium isotopes such as 227Ac (T1/2 = 21.8 years) are co-produced. Co-production of impurities of short-lived 226Ac (T1/2 = 29 hours) and 224Ac (T1/2 = 2.9 hours) formed according to the reactions 226Ra(p,n)226Ac and 226Ra(p,3n)224Ac can be minimized through selection of appropriate proton energies. In addition, their activity will further decay to low levels during the time required for target cooling and reprocessing. The main challenges of the process are related to the preparation and handling of targets containing milligram amounts of radioactive 226Ra (T1/2 = 1600 years) and management of its gaseous decay product 222Rn (T1/2 = 3.8 days). Currently research on implementation of this production route is ongoing in facilities in North and South America, Europe, and Asia.

The irradiation of 226Ra with deuterons according to the reaction 226Ra(d,3n)225Ac has been suggested as an improved method for production of 225Ac.33 Cross-sections for the reaction have not been measured experimentally yet, however, model calculations are predicting a maximum cross-section of 864 christopher58@example.net MeV and slightly increased production yields compared to the 226Ra(p,2n)225Ac reaction. However, deuteron irradiation would lead to an enhanced co-production of 226Ac (T1/2 = 29 hours) via the reaction 226Ra(d,2n)226Ac, making an extended cooling time necessary to allow for 226Ac decay. In addition, only few accelerators are available that can provide deuteron beams of sufficient energy.

Another route for production of 225Ac via irradiation of 226Ra is based on the photonuclear reaction 226Ra(γ,n)225Ra and subsequent beta decay of 225Ra to 225Ac. The reaction has a photon energy threshold of 6.4 MeV, experimentally measured cross-section data are not available to date. However, as modeling data predict moderate reaction yields,41 modern accelerators providing high-intensity electron beams are required for commercially viable production. Proof of principle of the process has been demonstrated on laboratory scale at JRC Karlsruhe.42 Betatron irradiation of a zircaloy capsule containing 1 mg 226Ra embedded in 800 mg BaCl2 matrix for 3.5 hours at 52 MeV led to production of 0.24 µCi of 225Ac. Feasibility of the process has also been successfully demonstrated at Joint Institute for Nuclear Research, Dubna, Russia43 and at the Illawarra Cancer Centre, in Wollongong, Australia.44 Maslov et al reported a radiation yield of 550 Bq/(µAh mg 226Ra) at 24 MeV maximal photon energy. The detailed measurement of cross-section data for this reaction is highly desirable for more accurate prediction of production yields. Nevertheless, implementation of the process for large scale production of 225Ac is already underway at several facilities.45

Conclusions
Reports on the remarkable therapeutic efficacy of 225Ac-PSMA617 for therapy of prostate cancer have stimulated significant global interest in applying 225Ac as therapeutic nuclide in TAT of cancer. It is expected that in order to meet the rising future demand for supply of the alpha emitter a variety of production routes will be utilized, including the extraction of additional 229Th stocks from US legacy wastes and the implementation of various accelerator based routes. In this respect common criteria for quality of the 225Ac product need to be established in order to facilitate safe clinical use of the radionuclide independent of its production pathway.
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