Elsevier

Journal of Chromatography A

Volume 1380, 6 February 2015, Pages 55-63
Journal of Chromatography A

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

https://doi.org/10.1016/j.chroma.2014.12.045Get rights and content

Highlights

  • Actinium-225 (t1/2 = 9.92 d) is an α-emitting radionuclide for use in targeted alpha therapy.

  • During proton irradiation of thorium metal, long-lived 227Ac (t1/2 = 21.8 a) is co-produced.

  • An efficient Ac/Th separation procedure is required for rapid 225Ac/227Ac ratio determination.

  • For Ac isolation, a sequence of cation exchange and extraction chromatography was implemented.

  • Ac is isolated from Th and then purified from fission lanthanides via extraction chromatography.

Abstract

Actinium-225 (t1/2 = 9.92 d) is an α-emitting radionuclide with nuclear properties well-suited for use in targeted alpha therapy (TAT), a powerful treatment method for malignant tumors. Actinium-225 can also be utilized as a generator for 213Bi (t1/2 45.6 min), which is another valuable candidate for TAT. Actinium-225 can be produced via proton irradiation of thorium metal; however, long-lived 227Ac (t1/2 = 21.8 a, 99% β, 1% α) is co-produced during this process and will impact the quality of the final product. Thus, accurate assays are needed to determine the 225Ac/227Ac ratio, which is dependent on beam energy, irradiation time and target design. Accurate actinium assays, in turn, require efficient separation of actinium isotopes from both the Th matrix and highly radioactive activation by-products, especially radiolanthanides formed from proton-induced fission. In this study, we introduce a novel, selective chromatographic technique for the recovery and purification of actinium isotopes from irradiated Th matrices. A two-step sequence of cation exchange and extraction chromatography was implemented. Radiolanthanides were quantitatively removed from Ac, and no non-Ac radionuclidic impurities were detected in the final Ac fraction. An 225Ac spike added prior to separation was recovered at ≥98%, and Ac decontamination from Th was found to be ≥106. The purified actinium fraction allowed for highly accurate 227Ac determination at analytical scales, i.e., at 227Ac activities of 1–100 kBq (27 nCi to 2.7 μCi).

Introduction

Nuclear medicine has great utility for both diagnostic and therapeutic applications [1], [2], [3]. Attachment of diagnostic or therapeutic radionuclides to selective biomolecules (peptides, antibody fragments and intact antibodies) allows for the delivery of imaging or therapeutic doses to in vivo target sites (tumors or other tissues). Targeted alpha therapy (TAT) is a fast growing area which utilizes α-emitting radionuclides for the selective delivery of cell killing α-radiation doses to the tumor location [4], [5]. The low penetration range (50–90 μm) and high linear energy transfer of α-particles (tens to hundreds of keV/μm) enables maximum cancer cell destruction with minimal damage to surrounding healthy tissue. An α-emitting radionuclide has to meet several important criteria in order to be useful for TAT purposes: (1) the nuclide should have a physical half-life matching the biological kinetics of the targeting ligand; (2) the nuclide should have high α-decay ratio; (3) the effective half-life, i.e., half-life resulting from both physical half-life and biological elimination half-time, should correspond to the time required for the therapy course; (4) the decay chain of the radionuclide should not include long-lived intermediates that may cause radiation damage to healthy tissues, (5) the nuclide should form in vivo stable complexes or compounds with biomolecules and finally, (6) the nuclide should be regularly available and affordable. Table 1 lists several radionuclides potentially suitable for targeted α-therapy.

Actinium-225 (t1/2 = 9.92 d) has significant potential as a TAT radionuclide owing to its favorable half-life and a decay cascade that includes multiple short-lived α-emitters [7], [8]. It can be utilized directly for therapy when conjugated to biological targeting vectors or as a generator parent for daughter nuclide 213Bi (t1/2 = 45.6 min), which, in turn, can be chelated or complexed for in vivo use. Currently, the main source of 225Ac is the generator parent 229Th (t1/2 = 7340 a), which was previously obtained from reactor-bred 233U material [9]. The current global supply of decay-generated 225Ac is limited to ≤63 GBq (1.7 Ci) per year [10]. The current demand for 225Ac already exceeds the amount that can be generated from the global feedstock of 229Th. Alternative methods to produce 225Ac have therefore been evaluated by different groups including Los Alamos National Laboratory (LANL) in recent years [11], [12], [13]. One of the most promising routes involves activation of 232Th with medium to high-energy (>70 MeV) protons via 232Th(p,x) nuclear pathways.

Data acquired at LANL demonstrate that a 10-day, 250 μA, 100 MeV proton irradiation of thorium results in a production of 73.2 GBq (1.98 Ci) of 225Ac [12]. This amount exceeds the yearly accumulation of 225Ac from 229Th presently available to the global research community.

Within the ongoing investigation of accelerator production of 225Ac via 232Th(p,x), an efficient and rapid chemical separation and purification methodology is sought for the following reasons: (1) to validate projected actinium isotope yields, (2) to measure 227Ac/225Ac isotopic ratios and (3) to determine the amounts of non-actinium isotopic impurities. Results will enable additional research efforts and guide the future implementation of reliable production.

While a number of actinium/thorium separation methods have been reported in the literature, the selective chemical recovery of 225Ac from irradiated Th targets poses some challenges. Researchers at Oak Ridge National Laboratory (ORNL) have routinely performed isolation of 225Ac from 229Th using a cascade of anion exchange columns with HCl and HNO3 eluates, followed by 225Ac purification via cation exchange/HNO3 systems [9]. Sani [15] employed co-precipitation with barium and extraction with cupferron to isolate Ra and Ac from bulk thorium amounts. Other reported methods have applied liquid–liquid extraction with tributyl phosphate (TBP) to remove the major thorium mass with subsequent purification of 225Ac via extraction chromatography [16] or cation exchange chromatography [11], [14]. Filosofov et al. [17] used a combination of anion and cation exchange columns to separate Ac and fission products from Th matrices and Ac/Th from each other. The bulk Th amount was first sorbed on an anion exchanger column in nitric acid media. Then, a second anion exchange column was utilized to separate no-carrier-added radionuclides from each other. Chelation methods have been developed as well; such methods create anionic complexes of Th while Ac is retained in cationic form, which was studied with citrate [18] and other reagents [19], [20] as chelators. Reported methods either use liquid–liquid extraction steps involving organic solvents and toxic extractants, or they do not account for efficient fission product removal.

Validation of accelerator production yields requires a fast and simple method to isolate actinium from the thorium matrix as well as lanthanide impurities [21]. The present study introduces a novel procedure for the isolation of Ac from irradiated Th targets. This method has been developed to enable convenient Ac isolation and 225,227Ac assay for quality assurance purposes, as well as to confirm our previous studies on yields of 225/227Ac derived from thin foil studies and other co-produced no-carrier added radionuclides.

Section snippets

Materials and methods

Thorium metal targets were manufactured at the Los Alamos National Laboratory (LANL). Small pieces of Th metal (purity >99% as determined via X-ray fluorescence spectroscopy) were obtained from LANL's internal inventory. The raw material was arc melted and rolled into sheets with mean thickness of 0.50 ± 0.02 mm for the use as proton beam targets.

Target dissolution

The addition of HCl to the Th metal initiated a rapid, vigorous reaction with the formation of a black solid, which could be mostly dissolved after the addition of a catalytic amount of (NH4)2SiF6 solution [19]. Visible black solids (presumably thorium oxide, characterization studies are underway) remained upon reaction completion. Solids could be removed via filtration; the filter residue contained less than 1% of radionuclide activities (0.9% of 103Ru and 0.8% of 95Zr activity). The

Discussion

The irradiation of Th targets with protons generates a complex mixture of radionuclides. We developed a robust and fast separation methodology to allow efficient extraction of Ac isotopes from this mixture on an analytical scale for quality assurance assay purposes and to compare/confirm previous data on production yield of 225/227Ac and other nca radionuclides in proton irradiated Th target.

Table 4 gives a broad overview of published methods aimed at the isolation of Ac from thorium matrices.

Conclusion

An efficient, elegant and convenient chromatographic separation method was developed for the recovery of actinium isotopes from irradiated thorium material. Actnium-227 is co-produced in these irradiations with the desired medical isotope 225Ac (t1/2 = 9.92 d). Although present at comparatively low levels (ratio 227Ac/225Ac  0.1% at the end of proton bombardment), 227Ac is considered an unwanted by-product as it increases internal patient dose. As higher levels of 227Ac impact the quality of 225Ac

Acknowledgments

This material is based upon work supported by the United States Department of Energy, Office of Science, Office of Nuclear Physics, via an award from the Isotope Development and Production for Research and Applications subprogram (under contract number DE-AC52-06NA253996). We are also very thankful for the technical assistance provided by LANL C-IIAC and LANSCE-AOT groups. For help in α-particle spectroscopy we thank the staff of the LANL C-NR counting facility.

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