Cross-sections of the reaction 232Th(p,3n)230Pa for production of 230U for targeted alpha therapy
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.
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2020, Nuclear Instruments and Methods in Physics Research, Section B: Beam Interactions with Materials and AtomsProduction 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 IsotopesCitation 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 IsotopesCitation 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).