I radiofarmaci sono una classe di farmaci divenuti indispensabili nell'attuale medicina nucleare in quanto possono servire sia per scopi terapeutici che diagnostici. Questi farmaci contengono un isotopo radioattivo il quale viene legato ad una macromolecola in grado di accumularsi, in maniera selettiva, in specifici tessuti permettendo un trattamento molto focalizzato, nel caso di trattementi terapeutici o un imaging preciso nel caso di pratiche diagnostiche. La ricerca nel campo dei radiofarmaci riguarda, da un lato, lo sviluppo di nuovi ligandi per specifici bersagli cellulari e, dall'altro, l'identificazione delle possibili applicazioni mediche dei radionuclidi innovativi. Tuttavia, la produzione di radionuclidi medicinali innovativi è talvolta ostacolata dall'assenza di un'adeguata procedura di produzione che possa garantire la purezza radionuclidica o un'attività specifica adatta alla marcatura di un farmaco. Accanto allo sviluppo dei metodi di produzione convenzionali, che sono per lo più basati su acceleratori o reattori, stanno emergendo nuovi approcci, come MEDICIS al CERN e ISOLPHARM all'INFN-LNL, entrambi basati su separatori di massa elettromagnetici per aumentare la purezza radionuclidica ottenibile.Tutte le attività presentate in questa tesi sono inserite nell'ambito del progetto ISOLPHARM (ISOL technique for radioPHARMaceuticals). ISOLPHARM è un progetto dedicato alla scoperta e allo sviluppo di radiofarmaci ad alta purezza sfruttando i radionuclidi producibili con la futura facility ISOL (Isotope Separation On-Line) SPES dei Laboratori Nazionali di Legnaro dell'INFN. In particolare, ISOLPHARM può essere in grado di fornire nuclidi mai studiati prima con caratteristiche di decadimento importanti dal punto di vista medico, come 111-Ag. Quest’ultimo è un radionuclide molto promettente per l’uso terapeutico grazie alle sue interessanti caratteristiche di decadimento, decadendo tramite decadimento beta- con una vita media di 7.45 giorni; inoltre, emette due gamma a bassa energia adatti all'imaging SPECT. Questo lavoro è collegato all'esperimento ISOLPHARM_EIRA, incentrato sulla caratterizzazione della produzione di 111-Ag mediante l'irraggiamento di campioni di palladio arricchito 110-Pd presso il reattore Triga del LENA di Pavia, che sarà utilizzato negli anni successivi per fornire un primo flusso stabile di 111-Ag, essenziale per dare impulso alle attività di ricerca preclinica con questo radionuclide innovativo in attesa dell'entrata in funzione dell'impianto SPES. I risultati riportati in questa tesi hanno permesso di pianificare il programma di irraggiamento necessario per ottenere una quantità sufficiente di radionuclidi per la radiomarcatura di radiofarmaci di nuova concezione. Inoltre, viene presentato il progetto di un gamma-counter economico e portatile basato su uno scintillatore inorganico in Lantanio BromoCloro (LBC). Questo dispositivo è stato progettato per essere utilizzato nell'ambito dell'esperimento ISOLPHARM_EIRA per la misurazione della biodistribuzione in vivo di molecole innovative. Il rivelatore è stato progettato e caratterizzato valutando le sue prestazioni e le misure sperimentali sono state confrontate con una simulazione GEANT4 del setup. Inoltre, la risposta del sistema è stata confrontata con un calibratore di dose commerciale dell'Ospedale Cannizzaro di Catania. Infine, il dispositivo è stato utilizzato per valutare la biodistribuzione in vivo di un chelante innovativo basato sulla molecola DO2A2S radiomarcata con 64-Cu. In conclusione, il setup spettroscopico basato su LBC è stato aggiornato per essere accoppiato con il dispositivo ISOLPHARM Radionuclide Implantation Station (IRIS) allo scopo di caratterizzare il bersaglio irradiato con RIB alla SPES. Infine, lo strumento è stato utilizzato per la misurazione di campioni di palladio naturale e arricchito e anche per le misure degli eluati della separazione chimica tra 111-Ag e il target di palladio.

Radiopharmaceuticals are a class of drugs that are indispensable in nuclear medicine, serving both therapeutic and diagnostic purposes. These drugs contain a radioactive nuclide that is bound to a macromolecule that selectively accumulates in a specific tissue, allowing for highly focused treatment or precise imaging of the targeted area. Research in the subject of radiopharmaceuticals entails, on one hand, the development of new ligands for specific cellular targets and, on the other hand, the identification of the possible medical applications of innovative radionuclides. However, the distribution of innovative medical nuclides is sometimes hampered by the absence of a suitable production procedure that can guarantee radionuclidic purity or a specific activity suitable for labeling a pharmaceutical drug. Alongside the development of conventional production methods, which are mostly accelerator- or reactor-based, new approaches are emerging, such as MEDICIS at CERN and ISOLPHARM at INFN-LNL, both of which rely on electromagnetic mass separators to boost the maximum achievable radionuclidic purity. All the activities presented within this thesis are inserted in the framework of the ISOLPHARM (ISOL technique for radioPHARMaceuticals) project. ISOLPHARM is a project dedicated to the discovery and development of high-purity radiopharmaceuticals exploiting the radionuclides producible with the future SPES (Selective Production of Exotic Species) ISOL (Isotope Separation On-Line) facility at the Legnaro National Laboratories (LNL) of the National Institute for Nuclear Physics (INFN). Specifically, ISOLPHARM may be able to produce never-before-studied nuclides with medically relevant decay schemes, such as 111-Ag. Indeed, 111-Ag is an extremely promising radionuclide for targeted radionuclide therapy (TRT) due to its desirable decay characteristics. Specifically, it decays through a beta- decay with an half-life of 7.45 days and emits two low-energy gamma-rays that are suitable for SPECT imaging. In particular, this work is linked with the ISOLPHARM_EIRA experiment: it focuses on characterizing the production of 111-Ag following the irradiation of 110-enriched palladium samples at the LENA Triga Mark II research reactor, which will be used in the following years in order to provide a first stable stream of 111-Ag which is essential for boosting preclinical research activities with this innovative radionuclide while waiting for the SPES facility to be operative. The results reported in this dissertation allowed for the planning of the irradiation schedule required to obtain sufficient radionuclides for radiolabeling newly developed radiopharmaceuticals. Besides, the design of a cost-effective gamma-counter based on a Lanthanum BromoChloride (LBC) inorganic scintillator is presented. This device was designed in order to be used in the framework of the ISOLPHARM_EIRA experiment for the measurements of in-vivo biodistributions of innovative molecules. The detector was designed and characterized, evaluating its performance, and experimental measurements were compared with a GEANT4 Monte Carlo simulation of the setup. Moreover, the system response was benchmarked against a commercial Dose Calibrator at the Cannizzaro Hospital in Catania. Finally, the device was used for evaluating the in-vivo biodistribution of an innovative chelator based on DO2A2S molecule radiolabeled with 64-Cu. In addition, the LBC-based spectroscopic setup was upgraded in order to be coupled with the ISOLPHARM Radionuclide Implantation Station (IRIS) device with the aim of characterizing the RIB irradiated target at SPES. Finally, the instrument was used for the measurement of natural and 110-enriched palladium samples and also for the measurements of the eluates of the chemical separation between 111-Ag and the palladium target.

Production and characterization of 111Ag for radiopharmaceutical applications in the framework of the ISOLPHARM project

MORSELLI, Luca
2023

Abstract

Radiopharmaceuticals are a class of drugs that are indispensable in nuclear medicine, serving both therapeutic and diagnostic purposes. These drugs contain a radioactive nuclide that is bound to a macromolecule that selectively accumulates in a specific tissue, allowing for highly focused treatment or precise imaging of the targeted area. Research in the subject of radiopharmaceuticals entails, on one hand, the development of new ligands for specific cellular targets and, on the other hand, the identification of the possible medical applications of innovative radionuclides. However, the distribution of innovative medical nuclides is sometimes hampered by the absence of a suitable production procedure that can guarantee radionuclidic purity or a specific activity suitable for labeling a pharmaceutical drug. Alongside the development of conventional production methods, which are mostly accelerator- or reactor-based, new approaches are emerging, such as MEDICIS at CERN and ISOLPHARM at INFN-LNL, both of which rely on electromagnetic mass separators to boost the maximum achievable radionuclidic purity. All the activities presented within this thesis are inserted in the framework of the ISOLPHARM (ISOL technique for radioPHARMaceuticals) project. ISOLPHARM is a project dedicated to the discovery and development of high-purity radiopharmaceuticals exploiting the radionuclides producible with the future SPES (Selective Production of Exotic Species) ISOL (Isotope Separation On-Line) facility at the Legnaro National Laboratories (LNL) of the National Institute for Nuclear Physics (INFN). Specifically, ISOLPHARM may be able to produce never-before-studied nuclides with medically relevant decay schemes, such as 111-Ag. Indeed, 111-Ag is an extremely promising radionuclide for targeted radionuclide therapy (TRT) due to its desirable decay characteristics. Specifically, it decays through a beta- decay with an half-life of 7.45 days and emits two low-energy gamma-rays that are suitable for SPECT imaging. In particular, this work is linked with the ISOLPHARM_EIRA experiment: it focuses on characterizing the production of 111-Ag following the irradiation of 110-enriched palladium samples at the LENA Triga Mark II research reactor, which will be used in the following years in order to provide a first stable stream of 111-Ag which is essential for boosting preclinical research activities with this innovative radionuclide while waiting for the SPES facility to be operative. The results reported in this dissertation allowed for the planning of the irradiation schedule required to obtain sufficient radionuclides for radiolabeling newly developed radiopharmaceuticals. Besides, the design of a cost-effective gamma-counter based on a Lanthanum BromoChloride (LBC) inorganic scintillator is presented. This device was designed in order to be used in the framework of the ISOLPHARM_EIRA experiment for the measurements of in-vivo biodistributions of innovative molecules. The detector was designed and characterized, evaluating its performance, and experimental measurements were compared with a GEANT4 Monte Carlo simulation of the setup. Moreover, the system response was benchmarked against a commercial Dose Calibrator at the Cannizzaro Hospital in Catania. Finally, the device was used for evaluating the in-vivo biodistribution of an innovative chelator based on DO2A2S molecule radiolabeled with 64-Cu. In addition, the LBC-based spectroscopic setup was upgraded in order to be coupled with the ISOLPHARM Radionuclide Implantation Station (IRIS) device with the aim of characterizing the RIB irradiated target at SPES. Finally, the instrument was used for the measurement of natural and 110-enriched palladium samples and also for the measurements of the eluates of the chemical separation between 111-Ag and the palladium target.
GUIDI, Vincenzo
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2506195
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