Dataset Information

Photonuclear production, chemistry, and in vitro evaluation of the theranostic radionuclide ⁴⁷Sc.

ABSTRACT:

Background

In molecular imaging and nuclear medicine, theranostic agents that integrate radionuclide pairs are successfully being used for individualized care, which has led to rapidly growing interest in their continued development. These compounds, which are radiolabeled with one radionuclide for imaging and a chemically identical or similar radionuclide for therapy, may improve patient-specific treatment and outcomes by matching the properties of different radionuclides with a targeting vector for a particular tumor type. One proposed theranostic radionuclide is scandium-47 (⁴⁷Sc, T_1/2?=?3.35 days), which can be used for targeted radiotherapy and may be paired with the positron emitting radionuclides, ⁴³Sc (T_1/2?=?3.89 h) and ⁴⁴Sc (T_1/2?=?3.97 h) for imaging. The aim of this study was to investigate the photonuclear production of ⁴⁷Sc via the ⁴⁸Ti(?,p)⁴⁷Sc reaction using an electron linear accelerator (eLINAC), separation and purification of ⁴⁷Sc, the radiolabeling of somatostatin receptor-targeting peptide DOTATOC with ⁴⁷Sc, and in vitro receptor-mediated binding of [⁴⁷Sc]Sc-DOTATOC in AR42J somatostatin receptor subtype two (SSTR2) expressing rat pancreatic tumor cells.

Results

The rate of ⁴⁷Sc production in a stack of natural titanium foils (n?=?39) was 8?×?10⁷ Bq/mA·h (n?=?3). Irradiated target foils were dissolved in 2.0 M H₂SO₄ under reflux. After dissolution, trivalent ⁴⁷Sc ions were separated from natural Ti using AG MP-50 cation exchange resin. The recovered ⁴⁷Sc was then purified using CHELEX 100 ion exchange resin. The average decay-corrected two-step ⁴⁷Sc recovery (n?=?9) was (77?±?7)%. A radiolabeling yield of >?99.9% of [⁴⁷Sc]Sc-DOTATOC (0.384 mg in 0.3 mL) was achieved using 1.7 MBq of ⁴⁷Sc. Blocking studies using Octreotide illustrated receptor-mediated uptake of [⁴⁷Sc]Sc-DOTATOC in AR42J cells.

Conclusions

⁴⁷Sc can be produced via the ⁴⁸Ti(?,p)⁴⁷Sc reaction and separated from natural Ti targets with a yield and radiochemical purity suitable for radiolabeling of peptides for in vitro studies. The data in this work supports the potential use of eLINACs for studies of photonuclear production of medical radionuclides and the future development of high-intensity eLINAC facilities capable of producing relevant quantities of carrier-free radionuclides currently inaccessible via routine production pathways or limited due to costly enriched targets.

SUBMITTER: Loveless CS

PROVIDER: S-EPMC6522578 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

Photonuclear production, chemistry, and in vitro evaluation of the theranostic radionuclide <sup>47</sup>Sc.

Loveless C Shaun CS Radford Lauren L LL Ferran Samuel J SJ Queern Stacy L SL Shepherd Matthew R MR Lapi Suzanne E SE

EJNMMI research 20190516 1

<h4>Background</h4>In molecular imaging and nuclear medicine, theranostic agents that integrate radionuclide pairs are successfully being used for individualized care, which has led to rapidly growing interest in their continued development. These compounds, which are radiolabeled with one radionuclide for imaging and a chemically identical or similar radionuclide for therapy, may improve patient-specific treatment and outcomes by matching the properties of different radionuclides with a targeti ...[more]

PMID: 31098710

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Project description:BackgroundRadiotheragnostics makes use of the same molecular targeting vectors, labeled either with a diagnostic or therapeutic radionuclide, ideally of the same chemical element. The matched pair of scandium radionuclides, 44Sc and 47Sc, satisfies the desired physical aspects for PET imaging and radionuclide therapy, respectively. While the production and application of 44Sc was extensively studied, 47Sc is still in its infancy. The aim of the present study was, therefore, to investigate and compare two different methods of 47Sc production, based on the neutron irradiation of enriched 46Ca and 47Ti targets, respectively.Methods47Sc was produced by thermal neutron irradiation of enriched 46Ca targets via the 46Ca(n,γ)47Ca → 47Sc nuclear reaction and by fast neutron irradiation of 47Ti targets via the 47Ti(n,p)47Sc nuclear reaction, respectively. The product was compared with regard to yield and radionuclidic purity. The chemical separation of 47Sc was optimized in order to obtain a product of sufficient quality determined by labeling experiments using DOTANOC. Finally, preclinical SPECT/CT experiments were performed in tumor-bearing mice and compared with the PET image of the 44Sc labeled counterpart.ResultsUp to 2 GBq 47Sc was produced by thermal neutron irradiation of enriched 46Ca targets. The optimized chemical isolation of 47Sc from the target material allowed formulation of up to 1.5 GBq 47Sc with high radionuclidic purity (>99.99%) in a small volume (~700 μL) useful for labeling purposes. Three consecutive separations were possible by isolating the in-grown 47Sc from the 46/47Ca-containing fraction. 47Sc produced by fast neutron irradiated 47Ti targets resulted in a reduced radionuclidic purity (99.95-88.5%). The chemical purity of the separated 47Sc was determined by radiolabeling experiments using DOTANOC achievable at specific activities of 10 MBq/nmol. In vivo the 47Sc-DOTANOC performed equal to 44Sc-DOTANOC as determined by nuclear imaging.ConclusionThe production of 47Sc via the 46Ca(n,γ)47Ca nuclear reaction demonstrated significant advantages over the 47Ti production route, as it provided higher quantities of a radionuclidically pure product. The subsequent decay of 47Ca enabled the repeated separation of the 47Sc daughter nuclide from the 47Ca parent nuclide. Based on the results obtained from this work, 47Sc shows potential to be produced in suitable quality for clinical application.

Project description:Receptor-targeted image-guided Radionuclide Therapy (TRT) is increasingly recognized as a promising approach to cancer treatment. In particular, the potential for clinical translation of receptor-targeted alpha-particle therapy is receiving considerable attention as an approach that can improve outcomes for cancer patients. Higher Linear-energy Transfer (LET) of alpha-particles (compared to beta particles) for this purpose results in an increased incidence of double-strand DNA breaks and improved-localized cancer-cell damage. Recent clinical studies provide compelling evidence that alpha-TRT has the potential to deliver a significantly more potent anti-cancer effect compared with beta-TRT. Generator-produced 212Pb (which decays to alpha emitters 212Bi and 212Po) is a particularly promising radionuclide for receptor-targeted alpha-particle therapy. A second attractive feature that distinguishes 212Pb alpha-TRT from other available radionuclides is the possibility to employ elementallymatched isotope 203Pb as an imaging surrogate in place of the therapeutic radionuclide. As direct non-invasive measurement of alpha-particle emissions cannot be conducted using current medical scanner technology, the imaging surrogate allows for a pharmacologically-inactive determination of the pharmacokinetics and biodistribution of TRT candidate ligands in advance of treatment. Thus, elementally-matched 203Pb labeled radiopharmaceuticals can be used to identify patients who may benefit from 212Pb alpha-TRT and apply appropriate dosimetry and treatment planning in advance of the therapy. In this review, we provide a brief history on the use of these isotopes for cancer therapy; describe the decay and chemical characteristics of 203/212Pb for their use in cancer theranostics and methodologies applied for production and purification of these isotopes for radiopharmaceutical production. In addition, a medical physics and dosimetry perspective is provided that highlights the potential of 212Pb for alpha-TRT and the expected safety for 203Pb surrogate imaging. Recent and current preclinical and clinical studies are presented. The sum of the findings herein and observations presented provide evidence that the 203Pb/212Pb theranostic pair has a promising future for use in radiopharmaceutical theranostic therapies for cancer.

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Project description:BackgroundThe favorable decay properties of 43Sc and 44Sc for PET make them promising candidates for future applications in nuclear medicine. An advantage 43Sc (T1/2 = 3.89 h, Eβ+av = 476 keV [88%]) exhibits over 44Sc, however, is the absence of co-emitted high energy γ-rays. While the production and application of 44Sc has been comprehensively discussed, research concerning 43Sc is still in its infancy. This study aimed at developing two different production routes for 43Sc, based on proton irradiation of enriched 46Ti and 43Ca target material.Results43Sc was produced via the 46Ti(p,α)43Sc and 43Ca(p,n)43Sc nuclear reactions, yielding activities of up to 225 MBq and 480 MBq, respectively. 43Sc was chemically separated from enriched metallic 46Ti (97.0%) and 43CaCO3 (57.9%) targets, using extraction chromatography. In both cases, ~90% of the final activity was eluted in a small volume of 700 μL, thereby, making it suitable for direct radiolabeling. The prepared products were of high radionuclidic purity, i.e. 98.2% 43Sc were achieved from the irradiation of 46Ti, whereas the product isolated from irradiated 43Ca consisted of 66.2% 43Sc and 33.3% 44Sc. A PET phantom study performed with 43Sc, via both nuclear reactions, revealed slightly improved resolution over 44Sc. In order to assess the chemical purity of the separated 43Sc, radiolabeling experiments were performed with DOTANOC, attaining specific activities of 5-8 MBq/nmol, respectively, with a radiochemical yield of >96%.ConclusionsIt was determined that higher 43Sc activities were accessible via the 43Ca production route, with a comparatively less complex target preparation and separation procedure. The product isolated from irradiated 46Ti, however, revealed purer 43Sc with minor radionuclidic impurities. Based on the results obtained herein, the 43Ca route features some advantages (such as higher yields and direct usage of the purchased target material) over the 46Ti path when aiming at 43Sc production on a routine basis.

Dataset Information

Photonuclear production, chemistry, and in vitro evaluation of the theranostic radionuclide ⁴⁷Sc.

Background

Results

Conclusions

Publications

Photonuclear production, chemistry, and in vitro evaluation of the theranostic radionuclide <sup>47</sup>Sc.

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Dataset Information

Photonuclear production, chemistry, and in vitro evaluation of the theranostic radionuclide 47Sc.

Background

Results

Conclusions

Publications

Photonuclear production, chemistry, and in vitro evaluation of the theranostic radionuclide <sup>47</sup>Sc.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Photonuclear production, chemistry, and in vitro evaluation of the theranostic radionuclide ⁴⁷Sc.