Elsevier

Applied Radiation and Isotopes

Volume 118, December 2016, Pages 366-374
Applied Radiation and Isotopes

Large scale accelerator production of 225Ac: Effective cross sections for 78–192 MeV protons incident on 232Th targets

https://doi.org/10.1016/j.apradiso.2016.09.026Get rights and content

Highlights

  • Natural thorium targets were irradiated with 78–192 MeV protons.

  • Effective cross sections are measured for 225Ac, 226Ac, 227Ac, 227Th, and 228Th.

  • Effective cross sections for 99Mo, 140Ba, and four Ce isotopes are measured.

  • Curie quantities of 225Ac can be produced in a ten-day irradiation of a 5 g cm−2 Th target at either LANL-IPF or BNL-BLIP.

Abstract

Actinium-225 and 213Bi have been used successfully in targeted alpha therapy (TAT) in preclinical and clinical research. This paper is a continuation of research activities aiming to expand the availability of 225Ac. The high-energy proton spallation reaction on natural thorium metal targets has been utilized to produce millicurie quantities of 225Ac. The results of sixteen irradiation experiments of thorium metal at beam energies between 78 and 192 MeV are summarized in this work. Irradiations have been conducted at Brookhaven National Laboratory (BNL) and Los Alamos National Laboratory (LANL), while target dissolution and processing was carried out at Oak Ridge National Laboratory (ORNL). Excitation functions for actinium and thorium isotopes, as well as for some of the fission products, are presented. The cross sections for production of 225Ac range from 3.6 to 16.7 mb in the incident proton energy range of 78–192 MeV. Based on these data, production of curie quantities of 225Ac is possible by irradiating a 5.0 g cm−2 232Th target for 10 days in either BNL or LANL proton irradiation facilities.

Introduction

The scientific community has produced many new diagnostic and therapeutic applications for the field of nuclear medicine over the last few decades. One of these therapeutic applications, targeted alpha radioimmunotherapy (also referred to targeted alpha therapy or TAT), is one of the most promising and effective new methods of treating various forms of oncologic diseases (Essler et al., 2012). This technique involves delivering selected alpha-emitting radionuclides to cancerous sites within the body. Among possible α-emitting radionuclides, currently there is a great interest in the use and application of 213Bi. Results of clinical trials with 213Bi (in the decay chain of 225Ac) eluted from a generator have shown progress in treating several different types of malignant diseases including acute myeloid leukemia (Jurcic and Rosenblat, 2014).

In addition to the generator mode, there have been some investigations focusing on the direct in vivo administration of 225Ac (McDevitt et al., 2001). The four α-particle emission decay chain of 225Ac results in an integrated dose that is about 1000 times larger than the dose from an equivalent quantity of 213Bi, which only decays with the emission of a single α-particle (Mirzadeh, 1998, Brechbiel, 2007). Despite the potential complications associated with the decay products leaving the tumor volume and damaging healthy tissue, this mode of therapy utilizing 225Ac remains attractive due to its potency. Hence, there is a continuous effort to develop approaches designed to overcome this issue (McLaughlin et al., 2013, Mulvey et al., 2013, Rojas et al., 2015), and a recent review is available (de Kruijff et al., 2015). Whether used via the direct application or as a generator for 213Bi, the efficacy in early clinical trials has greatly increased the demand for 225Ac.

Currently, the only method of generating 225Ac for clinical studies is through the decay of long-lived 229Th (t1/2=7880 y) (Boll et al., 2005). Using this technique, 225Ac and its direct parent 225Ra (t1/2=14.9 d) are routinely “milked” from the “cow” (229Th) every few weeks. At present, there are three main sources of 229Th worldwide that are large enough to produce relevant quantities of 225Ac. Each of these sources has been chemically separated from the fissile precursor 233U (Fig. S1). Since 1997, ORNL has been supplying up to 720 mCi per year of high-purity 225Ac. A similar quantity is reported to be available from the Institute of Physics and Power Engineering, in Obninsk, Russia. The Institute for Transuranium Elements in Karlsruhe, Germany (ITU) maintains a smaller 229Th source that is capable of producing up to 350 mCi of 225Ac per year (IAEA, 2013). Demand, even to support a few limited clinical trials, is much larger than the combined international inventory.

Studies have been conducted to investigate different means of increasing the available supply of either the 229Th parent or 225Ac itself. Producing relevant quantities of 229Th is challenging due to its extremely long half-life. Despite the ~160 mb cross section for the 232Th[p,4n]229Pa reaction at ~30 MeV, dedicated accelerator production of 229Th may not be viable due to long irradiation times and high currents required to produce a substantial quantity of 229Th (Jost et al., 2013). However, substantial 229Th could be generated if 232Th were used as a beam stop for several years at any high-current proton accelerator facility. Reactor production of 229Th is possible through the neutron irradiation of 226Ra (t1/2=1600 y) and is currently under further investigation (Boll et al., 2008). Proton irradiation of 226Ra targets has been carried out at ITU resulting in cross section data for the 226Ra[p,2n]225Ac reaction for the energy range of 8.8–24.8 MeV, with a maximum cross section of 710 mb at 16.8 MeV (Apostolidis et al., 2005). A feasibility study of the 226Ra[γ,n]225Ra reaction for producing the 225Ra, the parent to 225Ac, has revealed that 225Ra yields are insufficient for practical use (Melville et al., 2007).

Actinium-225 can be directly generated through the high-energy proton (78–192 MeV) irradiation of 232Th (Lefort et al., 1961, Gauvin, 1963, Titarenko et al., 2003, Ermolaev et al., 2012, Weidner et al., 2012). The U.S. Department of Energy (DOE) Isotope Program operates two high-current, high-energy linear accelerators capable of producing 225Ac from 232Th in substantial quantities. The primary focus of this study is the practical evaluation of the feasibility of producing 225Ac using DOE operated facilities, and preliminary results are reported in a previous document (Mirzadeh, 2014). The Brookhaven Linac Isotope Producer (BLIP) at BNL, the Isotope Production Facility (IPF) at LANL, and the Medical Radioisotope Program (MRP) at ORNL engaged in distinct and critical roles for this project. IPF and BLIP were responsible for the irradiation of the Th targets, and MRP performed the chemical separations required to isolate 225Ac.

In this paper, we report effective cross section and yield measurement for large-scale production of 225Ac. We also report cross sections for several other radioisotopes including: 226Ac, 227Ac, 227Th, 228Th, 99Mo, 140Ba, 139Ce, 141Ce, 143Ce, and 144Ce. Measurement of yield of the other actinium isotopes relative to 225Ac is crucial since the coproduced actinium isotopes cannot be chemically separated and, hence, they constitute major impurities. The effective cross sections2 and yields of the other radioisotopes are included due to their effect on chemical processing and purity of the 225Ac product, among the most important are isotopes of La (140Ba decays to 140La) and Ce due to their very close chemical resemblance to Ac. The details of the chemical isolation of actinium from fission products and actinides coproduced in the high-energy proton irradiation of natural Th is beyond the scope of this current paper, and it will be reported separately.

Section snippets

Irradiation facilities

The irradiation facilities used in this work differ from each other in proton intensity and energy capabilities. The BNL Linac is capable of generating 130 µA of protons up to 200 MeV for use in the BLIP beam line and target area (Raparia et al., 2014). As part of the LANSCE accelerator system at LANL, IPF is a dedicated proton beam line that can provide up to 250 µA of 100 MeV protons (Lisowski and Schoenberg, 2006).

Irradiations

A total of sixteen irradiations were performed, three at IPF and thirteen at BLIP.

Results

Cross sections of the isotopes of interest are given in Table 3, Table 4 and depicted in Fig. 2, Fig. 3, Fig. 4, Fig. 5. Measured cross sections at 89.6, 128.0, and 191.8 MeV are given as averages with propagated uncertainty since two irradiations at IPF occurred at 89.6 MeV, six irradiations at BLIP occurred at 128.0 MeV, and five additional irradiations at BLIP occurred at 191.8 MeV. Note that the incident proton energy at 191.8 MeV ranges from 190.9 to 192.5 MeV (Table 1). As shown in Fig. 2, Fig.

232Th[p,x]Ac reactions

The data for the 232Th[p,x]225Ac reaction is in close agreement with literature values at Ep <170 MeV but ~25% lower than literature values at Ep=191.8 MeV (Fig. 2). Note that the cross section for this reaction includes a contribution from the β decay of 225Ra, as well as a contribution from the electron capture decay (~10%) of 225Th (t1/2=8.75 m). Earlier measurements showed that the cross section for the 232Th[p,x]225Ra reaction over this energy range is smaller than the 232Th[p,x]225Ac cross

Conclusion and future work

Measured cross sections are reported here for eleven isotopes of Ac, Th, Mo, Ba/La, and Ce This data set validates previously reported measurements for many of these isotopes, and greatly expands the data available for other reaction cross sections such as that for 99Mo. The 232Th[p,f]144Ce reaction cross section between 83 and 190 MeV is reported here for the first time. The data presented here will aid in the development of future irradiations of Th and subsequent chemical purifications of 225

Acknowledgements

The authors acknowledge Drs. Tim S. Bigelow and Paul E. Mueller for their critical review of the manuscript. The authors thank the LANL Metallurgy group and the BNL machine shop teams for their efforts related to the fabrication of the targets used in this study. This research is supported by the Isotope Program, Office of Nuclear Physics of the U.S. Department of Energy. ORNL is managed by UT-Battelle, LLC, for the U.S. Department of Energy under contract DE-AC05-00OR22725.

References (46)

  • A. Kumar Jain et al.

    Nuclear data sheets for A=221

    Nucl. Data Sheets

    (2007)
  • M. Lefort et al.

    Spallation reactions of thorium by 150 and 82 MeV protons

    Nucl. Phys.

    (1961)
  • P.W. Lisowski et al.

    The los alamos neutron science center

    Nucl. Instrum. Methods Phys. Res. Sect. A: Accel. Spectrom., Detect. Assoc. Equip.

    (2006)
  • D.G. Medvedev et al.

    Development of a large scale production of 67Cu from 68Zn at the high energy proton accelerator: closing the 68Zn cycle

    Appl. Radiat. Isot.

    (2012)
  • G. Melville et al.

    Production of Ac-225 for cancer therapy by photon-induced transmutation of Ra-226

    Appl. Radiat. Isot.

    (2007)
  • S. Mirzadeh

    Generator-produced alpha-emitters

    Appl. Radiat. Isot.

    (1998)
  • N. Nica

    Nuclear data sheets for A=140

    Nucl. Data Sheets

    (2007)
  • N. Nica

    Nuclear data sheets for A=141

    Nucl. Data Sheets

    (2014)
  • V. Radchenko et al.

    Application of ion exchange and extraction chromatography to the separation of actinium from proton-irradiated thorium metal for analytical purposes

    J. Chromatogr. A

    (2015)
  • J.V. Rojas et al.

    Synthesis and characterization of lanthanum phosphate nanoparticles as carriers for 223Ra and 225Ra for targeted alpha therapy

    Nucl. Med. Biol.

    (2015)
  • S. Singh et al.

    Nuclear data sheets for A=222

    Nucl. Data Sheets

    (2011)
  • A.A. Sonzogni

    Nuclear data sheets for A=144

    Nucl. Data Sheets

    (2001)
  • G.F. Steyn et al.

    Production of 52Fe via proton-induced reactions on manganese and nickel

    Appl. Radiat. Isot.

    (1990)
  • Cited by (72)

    • The investigation of the production of Ac-227, Ra-228, Th-228, and U-232 in thorium by particle accelerators for use in radioisotope power systems and nuclear batteries

      2022, Nuclear Instruments and Methods in Physics Research, Section B: Beam Interactions with Materials and Atoms
    • Transport model predictions of <sup>225</sup>Ac production cross sections via energetic p, d and α irradiation of <sup>232</sup>Th targets

      2021, Applied Radiation and Isotopes
      Citation Excerpt :

      In the energy range below 70 MeV, the calculated cross sections with both models are in excellent agreement with reported experimental data (Duchemin et al., 2015; Ermolaev et al., 2012; Weidner et al., 2012b). Between 70 and 200 MeV, both models were generally a factor of 2–3 higher than the experimental data (Ermolaev et al., 2012; Griswold et al., 2016; Weidner et al., 2012b). MCNP6 model predictions are in good agreement with the data of Weidner et al. (2012a) and Robertson et al. (2019) at incident proton energies >400 MeV, as shown in Fig. 2(a).

    • Progress of <sup>225</sup>Ac-Labelled Radiopharmaceuticals for Cancer Treatment

      2024, He-Huaxue yu Fangshe Huaxue/Journal of Nuclear and Radiochemistry
    View all citing articles on Scopus

    This manuscript has been authored by UT-Battelle, LLC, under Contract No. DE-AC0500OR22725 with the U.S. Department of Energy. The United States Government retains and the publisher, by accepting the article for publication, acknowledges that the United States Government retains a non-exclusive, paid-up, irrevocable, world-wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for the United States Government purposes. The Department of Energy will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan (http://energy.gov/downloads/doe-public-access-plan).

    1

    This work constitutes a portion of JRG's thesis for the Doctor of Philosophy Degree at the University of Tennessee.

    View full text