Production of 230Pa by proton irradiation of 232Th at the LANL isotope production facility: Precursor of 230U for targeted alpha therapy

Friend, Mitchell T.; Mastren, Tara; Parker, T. Gannon; Vermeulen, C.; Brugh, Mark; Birnbaum, Eva R.; Nortier, F.M.; Fassbender, Michael E.

doi:10.1016/j.apradiso.2019.108973

Cited by 19 publications

(11 citation statements)

References 18 publications

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“… , A potential advantage of 230 U with respect to other α emitters is that its decay proceeds through a series of short-lived radionuclides, a feature that should minimize the translocation of these daughters from the target site after α recoil. Furthermore, promising production and purification strategies for 230 U have been reported, − suggesting that its widespread availability for sustaining preclinical and clinical studies may be achievable.…”

Section: Introductionmentioning

confidence: 99%

Stable Chelation of the Uranyl Ion by Acyclic Hexadentate Ligands: Potential Applications for ²³⁰U Targeted α-Therapy

et al. 2022

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Uranium-230 is an α-emitting radionuclide with favorable properties for use in targeted α-therapy (TAT), a type of nuclear medicine that harnesses α particles to eradicate cancer cells. To successfully implement this radionuclide for TAT, a bifunctional chelator that can stably bind uranium in vivo is required. To address this need, we investigated the acyclic ligands H 2 dedpa, H 2 CHXdedpa, H 2 hox, and H 2 CHXhox as uranium chelators. The stability constants of these ligands with UO 2 2+ were measured via spectrophotometric titrations, revealing log β ML values that are greater than 18 and 26 for the "pa" and "hox" chelators, respectively, signifying that the resulting complexes are exceedingly stable. In addition, the UO 2 2+ complexes were structurally characterized by NMR spectroscopy and X-ray crystallography. Crystallographic studies reveal that all six donor atoms of the four ligands span the equatorial plane of the UO 2 2+ ion, giving rise to coordinatively saturated complexes that exclude solvent molecules. To further understand the enhanced thermodynamic stabilities of the "hox" chelators over the "pa" chelators, density functional theory (DFT) calculations were employed. The use of the quantum theory of atoms in molecules revealed that the extent of covalency between all four ligands and UO 2 2+ was similar. Analysis of the DFT-computed ligand strain energy suggested that this factor was the major driving force for the higher thermodynamic stability of the "hox" ligands. To assess the suitability of these ligands for use with 230 U TAT in vivo, their kinetic stabilities were probed by challenging the UO 2 2+ complexes with the bone model hydroxyapatite (HAP) and human plasma. All four complexes were >95% stable in human plasma for 14 days, whereas in the presence of HAP, only the complexes of H 2 CHXdedpa and H 2 hox remained >80% intact over the same period. As a final validation of the suitability of these ligands for radiotherapy applications, the in vivo biodistribution of their UO 2 2+ complexes was determined in mice in comparison to unchelated [UO 2 (NO 3 ) 2 ]. In contrast to [UO 2 (NO 3 ) 2 ], which displays significant bone uptake, all four ligand complexes do not accumulate in the skeletal system, indicating that they remain stable in vivo. Collectively, these studies suggest that the equatorial-spanning ligands H 2 dedpa, H 2 CHXdedpa, H 2 hox, and H 2 CHXhox are highly promising candidates for use in 230 U TAT.

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Section: Introductionmentioning

confidence: 99%

Stable Chelation of the Uranyl Ion by Acyclic Hexadentate Ligands: Potential Applications for ²³⁰U Targeted α-Therapy

et al. 2022

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“…attractive for the first 226 Th-labeling experiments. Although 226 Th is not readily available, a 230 U/ 226 Th generator developed at Los Alamos National Laboratory 36 was obtained for some preliminary chelation studies. A 2.59-MBq (70 μCi) quantity of 230 U was obtained, and a column-based 230 U/ 226 Th generator was prepared 37 and eluted at the time of the chelation studies.…”

Section: Thorium-226 Chelation Studiesmentioning

confidence: 99%

Thorium chelators for targeted alpha therapy: Rapid chelation of thorium‐226

Ferrier

Chyan

et al. 2020

Labelled Comp Radiopharmac

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One of the main challenges in targeted alpha therapy is assuring delivery of the α‐particle dose to the targeted cells. Thus, it is critical to identify ligands for α‐emitting radiometals that will form complexes that are very stable, both in vitro and in vivo. In this investigation, thorium‐227 (t1/2 = 18.70 days) chelation of ligands containing hydroxypyridinonate (HOPO) or picolinic acid (pa) moieties and the stability of the resultant complexes were studied. Chelation reactions were followed by reversed‐phased HPLC and gamma spectroscopy. Studies revealed that high 227Th chelation yields could be obtained within 2.5 h or less with ligands containing four Me‐3,2‐HOPO moieties, 1 (83%) and 2 (65%), and also with ligands containing pa moieties, H4octapa 3 (65%) and H4py4pa 6 (87%). No reaction occurred with H4neunpa‐p‐Bn‐NO2 4, and the chelation reaction with another pa ligand H4pypa 5 gave inconsistent yields with a very broad radio‐HPLC peak. The ligands spermine‐(Me‐3,2‐HOPO)4 1, H4octapa 3, and H4py4pa 6 had high stability (i.e., 87% of 227Th still bound to the ligand) in phosphate‐buffered saline at room temperature over a 6‐day period. Preliminary studies with ligand 6 demonstrated efficient chelation of thorium‐226 (t1/2 = 30.57 min) when heated to 80°C for 5 min.

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“…Scientific organizations worldwide are actively developing the production of 230 U through irradiation of 232 Th with protons [10][11][12][13][14]. This method has proven to be the most effective in terms of product yield compared with the reactions with deuterons [15,16].…”

Section: Introductionmentioning

confidence: 99%

Rapid EElution of 226Th from a Two-Column 230U/226Th Generator with Diluted and Buffer Solutions

Ermolaev¹,

Skasyrskaya²,

Vasiliev³

2023

Preprint

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A unique two-column 230U/226Th generator has been developed. The focus was hold on obtaining 226Th of high purity in a solution amenable to further labeling. The first column of the proposed generator filled with TEVA Resin held 230U, from which 226Th was eluted with 7 M HCl solution. UTEVA Resin pretreated with nitric acid solution was used as a sorbent for the second column for thorium retention. 226Th was extracted with 0.01-0.05 M citric buffer solution. One cycle of generator milking took 5-7 minutes and produced > 90% of 226Th in 1.5 ml of eluate, pH 4.5-5.0. The proposed two-column 230U/226Th generator was tested over two months including a second loading of 230U additionally accumulated from 230Pa. The 230U impurity in 226Th eluate was less than 0.01% allowing to use it directly in synthesis of radiopharmaceutical compounds.

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Production of 230Pa by proton irradiation of 232Th at the LANL isotope production facility: Precursor of 230U for targeted alpha therapy

Cited by 19 publications

References 18 publications

Stable Chelation of the Uranyl Ion by Acyclic Hexadentate Ligands: Potential Applications for ²³⁰U Targeted α-Therapy

Stable Chelation of the Uranyl Ion by Acyclic Hexadentate Ligands: Potential Applications for ²³⁰U Targeted α-Therapy

Thorium chelators for targeted alpha therapy: Rapid chelation of thorium‐226

Rapid EElution of <sup>226</sup>Th from a Two-Column <sup>230</sup>U/<sup>226</sup>Th Generator with Diluted and Buffer Solutions

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Production of 230Pa by proton irradiation of 232Th at the LANL isotope production facility: Precursor of 230U for targeted alpha therapy

Cited by 19 publications

References 18 publications

Stable Chelation of the Uranyl Ion by Acyclic Hexadentate Ligands: Potential Applications for 230U Targeted α-Therapy

Stable Chelation of the Uranyl Ion by Acyclic Hexadentate Ligands: Potential Applications for 230U Targeted α-Therapy

Thorium chelators for targeted alpha therapy: Rapid chelation of thorium‐226

Rapid EElution of <sup>226</sup>Th from a Two-Column <sup>230</sup>U/<sup>226</sup>Th Generator with Diluted and Buffer Solutions

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Stable Chelation of the Uranyl Ion by Acyclic Hexadentate Ligands: Potential Applications for ²³⁰U Targeted α-Therapy

Stable Chelation of the Uranyl Ion by Acyclic Hexadentate Ligands: Potential Applications for ²³⁰U Targeted α-Therapy