Cross-sections of the reaction 232Th(p,3n)230Pa for production of 230U for targeted alpha therapy

https://doi.org/10.1016/j.apradiso.2008.02.066Get rights and content

Abstract

230U/226Th is a promising novel alpha-emitter system for application in targeted alpha therapy of cancer. The therapeutic nuclides can be produced by proton irradiation of natural 232Th according to the reaction 232Th(p,3n)230Pa, followed by subsequent beta decay of 230Pa to 230U. In this study, the experimental excitation function for the 232Th(p,3n)230Pa reaction up to 34 MeV proton energy has been measured using the stacked-foil technique. The proton energies in the various foils were calculated with the SRIM 2003 code and gamma-ray spectrometry was used to measure the activities of the various radioisotopes produced. The measured cross-sections are in good agreement with selected literature values and with model calculations using the EMPIRE II code. The reaction 232Th(p,3n)230Pa allows the production of carrier-free 230U in clinically relevant levels.

Introduction

Targeted alpha therapy (TAT) is based on the coupling of alpha-particle-emitting radionuclides to target-selective carrier molecules. Due to the short range (<100 μm) and high linear energy transfer (LET≈100 keV/μm) of alpha particles in human tissue, TAT offers the potential of delivering a highly cytotoxic dose to targeted cells while minimizing damage to the surrounding healthy tissue. The efficacy and safety of TAT has been demonstrated in a number of pre-clinical studies and in clinical trials of leukemia (Jurcic et al., 2002), malignant melanoma (Allen et al., 2005; Raja et al., 2007), lymphoma (Schmidt et al., 2004), glioblastoma (Kneifel et al., 2006; Zalutsky et al., 2008) and skeletal metastases (Bruland et al., 2006).

Unfortunately, only few alpha-emitting radionuclides have physical and chemical properties that allow their application in radio-immunotherapy and are also available in sufficient quantities (Mulford et al., 2005). Currently, clinical studies using the isotope 213Bi (T1/2=46 min) that can be made available to hospitals via a radionuclide generator loaded with its mother nuclide 225Ac (T1/2=10 d) (Apostolidis et al., 2005) are the most advanced. However, the very limited availability of 225Ac/213Bi worldwide, currently sufficient for the treatment of approximately 100 patients per year, remains the main impediment for the widespread application.

We have identified the novel alpha cascade emitter system 230U/226Th as a new option for TAT. 230U is a pure alpha emitter (T1/2=20.8 d) decaying through a rapid cascade of four further alpha-emitting daughter isotopes with half-lives of 164 μs–31 min to long-lived 210Pb (T1/2=22.3 yr) (Fig. 1). Overall the decay of 230U is generating five alpha particles with a cumulative energy of 33.5 MeV, delivering a highly cytotoxic dose to targeted cells. Due to its relatively long half-life, 230U can be applied as therapeutic nuclide for the targeting of slowly accessible tumors, e.g. when coupled to monoclonal antibodies. Alternatively, 230U can be loaded on a 230U/226Th radionuclide generator to provide short-lived 226Th (T1/2=31 min) as a therapeutic nuclide for rapidly accessible tumors using fast diffusible peptidic vectors or for locoregional applications. Due to the very short half-lives of the 226Th daughter nuclides of 164 μs–38 s, their dislocation from the target sites is minimised, thus limiting toxicity caused by unspecific irradiation of healthy tissue.

The production of 230U/226Th in clinically relevant amounts is a main prerequisite for the introduction of the novel alpha emitters into pre-clinical and clinical testing. 230U can be produced in cyclotrons by proton irradiation of natural 232Th according to the reaction 232Th(p,3n)230Pa. Following the beta-decay of 230Pa (8.4% branching), carrier-free 230U can be isolated from the irradiated target 27–28 d after the end of beam with a maximum activity of 2.82% relative to the activity of 230Pa initially produced. Following a similar approach, Koua Aka et al. (1995) have reported the production of 30 MBq 230U by proton irradiation of 232Th using a proton beam of 34 MeV and a charge of 800 μA h. For the optimization of the production parameters, reliable data on the activation cross-sections for the (p,3n) reaction on 232Th reaction are required. Several authors have reported cross-sections in the energy range from 13 to 344 MeV (Tewes and James, 1952; Tewes, 1955; Meinke et al., 1956; Lefort et al., 1961; Brun and Simonoff, 1962; Celler et al., 1981; Kudo et al., 1982; Chu and Zhou, 1983; Roshchin et al., 1997). The literature data available in the low-to-medium energy region from 10 to 50 MeV are summarized in Fig. 2. The data of Meinke et al. (1956) have been excluded due to a significant shift of the proton energies of approx. 50 MeV as reported by the authors themselves. As shown in Fig. 2, the available literature data are in relatively good agreement in the energy region below 20 MeV, however, at higher energies the data vary significantly between different authors. The variation of the literature values indicate that a more thorough measurement of the proton-induced cross-section on 232Th is desirable in the energy range from 16 to 34 MeV which is most relevant for the production of 230Pa and 230U. The cross-sections have been measured by irradiation of thin targets in a conventional stacked-foil technique using copper foils as beam monitors and thick target yields have been calculated.

Section snippets

Target preparation

Thin targets of 232Th were prepared by sputter deposition from a 232Th metal source in an Ar plasma as thin films on high-purity aluminum foils (99.99%, 260 μm thickness, Alfa Aesar) used as support. As typical deposition parameters, a target voltage of 800 V and an ion current of approximately 4 mA was used. During deposition, the aluminum support foils were covered with a hole mask of 9 mm inner diameter to produce circular thorium layers of defined area. The thickness of the layers obtained

Nuclear reaction modelling

The reactions induced by protons on 232Th in the studied energy range occur through the direct, pre-equilibrium and compound nucleus mechanisms. The nuclear data calculations presented here are based on a theoretical analysis with the nuclear modular system EMPIRE II (Herman, 2001; Herman et al., 2007, Herman et al., 2004.) that utilizes the optical and direct reaction models, pre-equilibrium exciton model and the full featured Hauser–Feshbach (HF) model. In this work the direct interaction

Results

The experimentally determined cross-sections for the reaction 232Th(p,3n)230Pa in the energy range from 16.4 to 34.0 MeV are summarized in Table 2 and shown in Fig. 3. The maximum of the 232Th(p,3n)230Pa excitation function (353±14.5 mb) is found at 19.9±0.3 MeV proton energy. Our data are in good agreement with the recent reports of Celler et al. (1981), Kudo et al. (1982) and Roshchin et al. (1997). The cross-sections reported by Tewes et al. (1952) are approximately 20% lower than our results,

Conclusions

This work is providing the cross-section data relevant for the production of 230U via proton irradiation of natural 232Th. The derived thick target yields are sufficient for the production of carrier-free 230U/226Th in clinically relevant levels. The production and handling of targets made of natural 232Th is relatively simple, and irradiations can be performed in medium-energy cyclotrons with proton beams <40 MeV. In summary, the possibility of producing 230U/226Th by proton irradiation of 232

Acknowledgment

The authors want to thank Frank Huber for his support in preparing the 232Th targets.

References (32)

  • J.G. Jurcic et al.

    Targeted α particle immunotherapy for myeloid leukemia

    Blood

    (2002)
  • M. Lefort et al.

    A spallation nuclear reaction on thorium at 150 and 82 MeV proton energies

    Nucl. Phys.

    (1961)
  • W.W. Meinke et al.

    High-energy excitation functions in the heavy region

    J. Inorg. Nucl. Chem.

    (1956)
  • B.J. Allen et al.

    Intralesional targeted alpha therapy for metastatic melanoma

    Cancer Biol. Ther.

    (2005)
  • C. Apostolidis et al.

    Production of 225Ac from 229Th for targeted alpha therapy

    Anal. Chem.

    (2005)
  • T. Belgya et al.

    Handbook for Calculations of Nuclear Reaction Data, RIPL-2. IAEA-TECDOC-1506

    (2006)
  • Ø.S. Bruland et al.

    High-linear energy transfer irradiation targeted to skeletal metastases by the α-emitter 223Ra: adjuvant or alternative to conventional modalities?

    Clin. Cancer Res.

    (2006)
  • C. Brun et al.

    Competition fission-evaporation etude des functions d’excitation dans differents noyaux de protactinium

    J. Phys. Radium

    (1962)
  • Capote, R., Sin, M., Trkov, A., 2006. Evaluation of the neutron induced reactions on 232Th and 231Pa nuclei in the fast...
  • A. Celler et al.

    Cross section of 232Th (p,xn+yn) reactions at energy of protons 6.8–20.2 MeV

    Phys. Scripta

    (1981)
  • Y.Y. Chu et al.

    Comparison of the (p,xn) cross sections from 238U, 235U and 232Th targets irradiated with 200 MeV protons

    IEEE Trans. Nucl. Sci.

    (1983)
  • R.B. Firestone et al.

    Table of Isotopes

    (1998)
  • M. Herman

    EMPIRE-II statistical model code for nuclear reaction calculations

  • Herman, M., Oblozinsky, P., Capote, R., Sin, M., Trkov, A., Ventura, A., Zerkin, V., 2004. Recent development of the...
  • M. Herman et al.

    EMPIRE: nuclear reaction model code system for data evaluation

    Nucl. Data Sheets

    (2007)
  • IAEA, 2007. Charged-particle cross section database for medical radioisotope production, Update March 2007...
  • Cited by (61)

    • Cross section analysis of proton-induced nuclear reactions of thorium

      2020, Nuclear Instruments and Methods in Physics Research, Section B: Beam Interactions with Materials and Atoms
    • Production of <sup>230</sup>Pa by proton irradiation of <sup>232</sup>Th at the LANL isotope production facility: Precursor of <sup>230</sup>U for targeted alpha therapy

      2020, Applied Radiation and Isotopes
      Citation Excerpt :

      Uranium-230 is produced directly from the nuclear reactions in this pathway. The other possible production pathway is by irradiating natural 232Th (t1/2 = 1.40 × 1010 y) metal targets with protons or deuterons (Morgenstern et al., 2008b; Duchemin et al., 2014; Radchenko et al., 2016). Uranium-230 is made indirectly in this method by first producing 230Pa through the reactions 232Th(p,3n)230Pa and 232Th(d,4n)230Pa, which then undergoes β−-decay to 230U with a branching ratio of 7.8% and a 17.4 d half-life.

    • <sup>226</sup>Th nuclear decay data evaluation

      2020, Applied Radiation and Isotopes
      Citation Excerpt :

      The first four daughters of 230U are alpha-particle emitters with short half-lives (maximum 31 minutes), leading to secular equilibrium. The system 230U/226Th can be considered for targeted alpha therapy (TAT), due to the high cumulative energy of the emitted alpha-particles (about 33.5 MeV), having a strong effect on the targeted malignant cells (Morgenstern et al., 2008). The evaluation of 226Th nuclear decay data was carried out using DDEP software tools and computer codes available from the websites of BNL/NNDC (USA) and IAEA (Luca, 2014).

    View all citing articles on Scopus
    View full text