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Chaque ann\u00e9e, le comit\u00e9 des \u00e9tudiants et des jeunes professionnels de l\u2019ACRP organise le concours de communications \u00e9tudiantes Anthony J. MacKay. Le concours est ouvert \u00e0 toutes les \u00e9tudiantes et tous les \u00e9tudiants inscrit(e)s \u00e0 temps plein dans un programme reli\u00e9 aux sciences des rayonnements. De toutes les participations re\u00e7ues, trois finalistes ont \u00e9t\u00e9 retenu(e)s et auront l\u2019occasion de pr\u00e9senter leurs travaux au congr\u00e8s lors d\u2019une s\u00e9ance pl\u00e9ni\u00e8re. Les pr\u00e9sentations seront jug\u00e9es sur place, et le nom de la gagnante ou du gagnant sera annonc\u00e9 pendant le banquet du congr\u00e8s.<\/p>\n
Le gagnant du concours cette ann\u00e9e \u00e9tait Bryce Nelson, candidat au doctorat en oncologie, Universit\u00e9 de l’Alberta. Vous pouvez lire sa soumission ci-dessous.<\/p>\n
Vous pouvez \u00e9galement lire les soumissions des deux autres finalistes dans l’article \u00ab Concours de communications \u00e9tudiantes Anthony J. Mackay 2023 per Contest<\/a> \u00bb qui a \u00e9t\u00e9 publi\u00e9 dans le Bulletin<\/em> du 17 mai 2023.<\/p>\n <\/p>\n Bryce Nelson, PhD candidate in oncology, University of Alberta<\/b><\/p>\n Coauthors<\/p>\n La th\u00e9ranostique en m\u00e9decine nucl\u00e9aire consiste \u00e0 marquer un vecteur de ciblage biologique d\u2019abord par un radionucl\u00e9ide pour de l\u2019imagerie diagnostique, puis par un radionucl\u00e9ide \u00e9metteur de particules pour une th\u00e9rapie cibl\u00e9e par ce radionucl\u00e9ide. Un essai clinique r\u00e9cent utilisant le Pb 212-DOTAMTATE pour traiter des tumeurs neuroendocrines m\u00e9tastatiques a d\u00e9coul\u00e9 en un taux de r\u00e9ponse global de 80 % chez les patients, exc\u00e9dant significativement les traitements standards. Cependant, les examens diagnostics pour suivre la th\u00e9rapie avec le Pb 212 ont \u00e9t\u00e9 effectu\u00e9s avec les radiotraceurs conventionnels fluor 18 et gallium 68. Ceci n\u2019est pas optimal puisque \u00e7a pourrait mener \u00e0 l\u2019irradiation involontaire de tissus sains par des particules alpha. L\u2019objectif de cette \u00e9tude \u00e9tait d\u2019\u00e9laborer une fa\u00e7on de produire un haut rendement de Pb 203 par cyclotron en utilisant le mat\u00e9riau cible enrichi par l\u2019isotope Tl 205 et la r\u00e9action Tl 205(p,3n) Pb 203 comme alternative \u00e0 la production d\u2019une \u00e9nergie plus faible par le biais de la r\u00e9action Tl 203(p,n) Pb 203.<\/p>\n<\/div>\n Nuclear medicine theranostics involves labelling a biological targeting vector first with a radionuclide (radioactive atom) for diagnostic imaging, followed by a particle-emitting radionuclide for targeted radionuclide therapy. Lead-212 (Pb-212, t1\/2<\/sub> = 10.6 h) is a particularly attractive therapeutic radionuclide due to its payload of one alpha and two beta\u2212<\/sup>\u00a0particles in its decay chain and the rapid decay of its progeny to stable Pb-208.<\/p>\n A recent clinical trial (Delpassand et al., 2022<\/a>)\u00a0using [Pb-212]Pb-DOTAMTATE to treat metastatic neuroendocrine tumours resulted in an 80% overall patient response rate, significantly exceeding standard-of-care treatments. However, diagnostic scans to track Pb-212 therapy were performed with conventional fluorine-18 and gallium-68 radiopharmaceuticals. This is suboptimal, as dissimilar chemistries between the diagnostic and therapeutic radionuclides could alter the structural conformation of the radiopharmaceutical and result in different biodistribution between the diagnostic and therapeutic compounds. The differences between the biodistribution observed in diagnostic imaging scans and subsequent biodistribution of the therapeutic radiopharmaceutical could, therefore, result in sub-optimal tumor dosing, or potentially unintended and destructive alpha-irradiation of healthy tissues.<\/p>\n As isotopes of an element are chemically indistinguishable, Pb-212 alpha therapy is ideally paired with the chemically identical lead-203 (Pb-203, t1\/2<\/sub> = 51.9 h) to provide diagnostic SPECT imaging using the 279 keV (81%) gamma-photons emitted during Pb-203 decay. However, worldwide supply of Pb-203 is extremely limited since cyclotron Pb-203 production requires irradiating highly toxic thallium (Tl) material.<\/p>\n Our objectives were to develop a high-yield Pb-203 cyclotron production route on the TR-24 Cyclotron (shown in Figure 1) in Edmonton\u2019s Medical Isotope and Cyclotron Facility. We aimed to use use isotopically enriched Tl-205 target material and the Tl-205(p,3n) Pb-203 reaction as an alternative to lower energy production via the Tl-203(p,n) Pb-203 reaction. A robust cyclotron target and efficient chemical purification process must be designed to maximize Pb-203 yield and purity for research and clinical applications, while maintaining stringent radiation and chemical safety given the significant hazards presented to the operators and cyclotron facility.<\/p>\n Figure 1:<\/strong> TR-24 cyclotron in Edmonton\u2019s Medical Isotope and Cyclotron Facility.<\/p>\n Our entire process was designed around preserving radiation and chemical safety. To reduce Tl contamination risk, we employed our patent-pending sealed cyclotron target design (shown in Figure 2) \u00a0that is used to produce other radionuclides.<\/p>\n Tl-205 metal (99.9% isotopic enrichment) was pressed using a hardened stainless-steel die.\u00a0High purity aluminum (Al) target discs (99.999%) were machined with a central depression and annulus groove.<\/p>\n A Tl-205 pellet was placed into the central depression of the Al disc, and indium wire was laid in the annulus. An aluminum foil cover was then pressed on, cold welding the cover to the disc via the indium with an airtight bond.<\/p>\n Targets were irradiated at 23.3 MeV for up to 516 minutes on a TR-24 cyclotron at proton currents up to 60 microamps\u00a0to produce Pb-203 via the Tl-205(p,3n)Pb-203 nuclear reaction. Following a period of at least 12 hours to allow decay of Pb-204m (t1\/2<\/sub>\u00a0=\u00a067 min, 899 keV [99%]), the target was removed and Tl-205 was dissolved in HNO3<\/sub>.<\/p>\n A NEPTIS Mosaic-LC synthesis unit performed automated separation using Eichrom Pb resin, and Pb-203 was eluted with hydrochloric acid or ammonium acetate. The waste solution was diverted to a vial for subsequent Tl-205 recovery in an electrolytic cell.<\/p>\n Pb-203 product radionuclidic and elemental purity were assessed by high-purity germanium (HPGe) gamma spectroscopy and inductively coupled plasma optical emission spectroscopy (ICP-OES), respectively. Radiolabelling and blood serum stability studies were performed with PSC, TCMC, and DOTA chelators, and to stably sequester 203Pb for attachment to a biological targeting vector. Pb-203 chelation incorporation was verified by radio-thin layer chromatography (radio-TLC) analysis.<\/p>\n Figure 2:<\/strong> Sealed solid target assembly designed to encapsulate toxic thallium metal for cyclotron irradiation.<\/p>\n Cyclotron irradiations were performed at a 60 microamps proton beam current and 23.3 MeV energy without any observable target degradation or thallium leakage. Automated purification took less than 4 hours, yielding greater than 85% decay-corrected Pb-203 with a radionuclidic purity of over 99.9% (gamma spectrum shown in Figure 3). Purified Pb-203 yields up to 12 GBq were attained, and Pb-203 was successfully chelated and exhibited over 99% incorporation after 120 hours in human serum for each of the PSC, TCMC, and DOTA chelators.<\/p>\n Figure 3:<\/strong> HPGe gamma spectrum of purified Pb-203 product.<\/p>\n Radiation safety implications:<\/b> In over 100 production runs, there were no cyclotron target station or processing equipment contamination incidents.<\/p>\n Targets were irradiated during the afternoon and removed the following morning to permit decay of short-lived impurities. By allowing over 12 hours (over 10 Pb-204m half-lives) prior to target removal, operator dose was minimized.<\/p>\n Utilizing high purity Al target components nearly eliminated long-lived activation products, minimizing operator extremity dose when performing target recycling. When combined with a target retrieval shielding cart, a custom-designed lead-shielded processing castle, and an efficient automated process, the operator radiation dose per full production run is less than 10 \u00b5Sv (measured by electronic personal dosimeter).<\/p>\n Our recently published high-yield Pb-203 production process significantly enhances Pb-203 production capabilities to meet the rapidly growing worldwide preclinical and clinical demand for Pb-203 radiopharmaceuticals alongside Pb-212 alpha particle therapy (Nelson, B. J. B. et al., 2023<\/a>).<\/p>\n Since January 2022, we have successfully shipped over 70 batches of Pb-203 to customers and collaborators in 13 locations across 5 countries for research and diagnostic SPECT imaging clinical trials of metastatic melanoma and neuroendocrine tumours. Although we anticipate continually increasing demand, we are confident that our robust process design will maintain operator radiation dose at a small fraction of the permitted annual limit.<\/p>\n <\/p>\nHigh-yield cyclotron production of Pb-203 using a sealed Tl-205 solid target<\/h1>\n
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\nR\u00e9sum\u00e9 :<\/h4>\n
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Introduction<\/h2>\n
![\"TR-24](\"https:\/\/www.crpa-acrp-bulletin.ca\/wp-content\/uploads\/2023\/08\/Figure-1-TR-24-Cyclotron-1024x689.png\")
<\/p>\nMethods<\/h2>\n
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<\/p>\nResults<\/h2>\n
![\"HPGe](\"https:\/\/www.crpa-acrp-bulletin.ca\/wp-content\/uploads\/2023\/08\/Figure-3-Pb203-gamma-spectrum-2-1024x481.png\")
<\/p>\nConclusion<\/h2>\n
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Bryce Nelson<\/h2>\n