Radiopharmaceutical Therapy (RPT) is an emergent therapeutic approach for the treatment of different types of cancer. Unlike more traditional radiotherapy, cytotoxic radiation does not penetrate the body through external beams, but it is delivered into cancer cells or in their microenvironment by the administration of a drug. The latter allows the accumulation of a therapeutic radionuclide in the tumor site through physiological mechanisms, or by an appropriate delivery system selective for the target site. Radionuclides defined as α emitters can be exploited to eradicate malignant cells, since the emission of α particles due to their decay can break both strands of DNA within a range of some cell diameters. 223Ra is an α emitter used for about a decade as radium chloride ([223Ra]RaCl2) for the palliative therapy of symptomatic bone metastases in patients with castration-resistant prostate cancer. The clinical success of this radiopharmaceutical, branded as Xofigo®, has aroused the interest of the researchers in the application of 223Ra to treat other forms of cancer. The development of 223Ra-based radiopharmaceuticals for the treatment of non-osseous tumors involves the use of an appropriate drug delivery system, by which the incorporated radionuclide can be directed to a specific target site in the organism and prevented from being released in vivo. For this purpose, the structure of the radiopharmaceutical must include a suitable bifunctional chelator capable of effectively complexing [223Ra]Ra2+, a linker and a directional molecule. The studies carried out to date on the research of potential chelating agents for Ra2+ complexation have had only limited success. To achieve Ra2+ complexes that are both thermodynamically stable and kinetically inert while using radiopharmaceuticals, further studies are needed, with the aim of investigating the complexing properties of other chelating agents and identifying the most promising chelator. Since all the isotopes of Ra2+ are unstable, the characterization of metal-chelator complexes is initially carried out using non-radioactive substitute Ba2+. In this thesis work the complexation equilibria of Ba2+ with three macrocyclic chelating agents were studied. The characterization of the Ba2+-chelator complexes was carried out by appropriate potentiometric and 1H-NMR spectroscopy analyses in order to determine the formation constants (logβ) of the complexes. Since the formation of complexes is influenced by competition with the acid-base equilibria of the chelator, in a first phase of this work the acid dissociation constants (pKa) of the three compounds under study were determined (again by potentiometry and 1H-NMR spectroscopy) in order to know the effective stability of the complexes at physiological pH, that is the real condition of use of the radiopharmaceutical. The results obtained in this work were used to compare the three macrocyclic chelators and other chelating agents previously characterized in the literature, in order to evaluate their ability to form stable complexes with the metal cation.
La Radiopharmaceutical Therapy (RPT) è un approccio terapeutico emergente per il trattamento di diverse forme di cancro. Diversamente dalla più tradizionale radioterapia, la radiazione citotossica non penetra l’organismo attraverso fasci esterni, ma viene veicolata nelle cellule tumorali o nel loro microambiente mediante la somministrazione di un farmaco. Quest’ultimo permette l’accumulo di un radionuclide terapeutico nel sito tumorale attraverso meccanismi fisiologici, oppure mediante un opportuno sistema di delivery selettivo per il sito bersaglio. I radionuclidi definiti emettitori α possono essere sfruttati per eradicare cellule maligne, in quanto l’emissione di particelle α dovuta al loro decadimento provoca la rottura di entrambi i filamenti di DNA all’interno di un raggio d’azione di alcuni diametri cellulari. Il 223Ra è un emettitore α impiegato da circa un decennio come cloruro di radio ([223Ra]RaCl2) nella terapia palliativa di metastasi ossee sintomatiche in pazienti colpiti da tumore prostatico resistente alla castrazione. Il successo clinico di questo radiofarmaco, commercializzato con il nome Xofigo®, ha stimolato l’interesse della ricerca per l’applicazione del 223Ra nel trattamento di altre forme di cancro. Lo sviluppo di radiofarmaci a base di 223Ra per la terapia di tumori non ossei prevede l’impiego di un opportuno sistema di drug delivery, con il quale è possibile indirizzare il radionuclide ad esso incorporato verso uno specifico sito target nell’organismo ed evitarne il rilascio in vivo. A tale scopo, la struttura del radiofarmaco deve includere un opportuno chelante bifunzionale in grado di complessare efficacemente il [223Ra]Ra2+, un linker e una molecola direzionante. Gli studi condotti fino ad oggi sulla ricerca di potenziali chelanti per il complessamento del Ra2+ hanno portato solamente dei successi limitati. Per ottenere dei complessi del Ra2+ che risultino termodinamicamente stabili e cineticamente inerti nelle condizioni di impiego del radiofarmaco sono dunque necessari ulteriori studi che, indagando le proprietà complessanti di altri agenti chelanti, permettano di individuare quello più promettente. Poiché tutti gli isotopi del Ra2+ sono instabili, la caratterizzazione dei complessi metallo-chelante viene inizialmente condotta utilizzando come sostituto non radioattivo il Ba2+. Nel presente lavoro di tesi sono stati studiati gli equilibri di complessamento nei confronti del Ba2+ di tre chelanti macrociclici. La caratterizzazione dei complessi Ba2+-chelante è stata condotta mediante opportune analisi potenziometriche e di spettroscopia 1H-NMR, con l’obbiettivo di determinare le costanti di formazione (logβ) dei complessi. Poiché la formazione dei complessi metallo-legante è influenzata dalla competizione con gli equilibri acido-base del chelante, in una prima fase del presente lavoro sono state determinate (sempre mediante potenziometria e spettroscopia 1H-NMR) le costanti di dissociazione acida (pKa) dei tre composti in studio, con le quali è possibile determinare l’effettiva stabilità dei complessi a pH fisiologico, ossia nelle reali condizioni d’impiego del radiofarmaco. Attraverso i risultati ottenuti in questo lavoro, i tre chelanti macrociclici sono stati comparati tra loro e con altri sistemi precedentemente caratterizzati in letteratura, al fine di valutarli in base alla loro capacità di formare complessi stabili con il catione metallico.
Formazione di complessi tra bario(II) e chelanti macrociclici di interesse radiofarmaceutico
VOLPATO, FRANCESCA
2023/2024
Abstract
Radiopharmaceutical Therapy (RPT) is an emergent therapeutic approach for the treatment of different types of cancer. Unlike more traditional radiotherapy, cytotoxic radiation does not penetrate the body through external beams, but it is delivered into cancer cells or in their microenvironment by the administration of a drug. The latter allows the accumulation of a therapeutic radionuclide in the tumor site through physiological mechanisms, or by an appropriate delivery system selective for the target site. Radionuclides defined as α emitters can be exploited to eradicate malignant cells, since the emission of α particles due to their decay can break both strands of DNA within a range of some cell diameters. 223Ra is an α emitter used for about a decade as radium chloride ([223Ra]RaCl2) for the palliative therapy of symptomatic bone metastases in patients with castration-resistant prostate cancer. The clinical success of this radiopharmaceutical, branded as Xofigo®, has aroused the interest of the researchers in the application of 223Ra to treat other forms of cancer. The development of 223Ra-based radiopharmaceuticals for the treatment of non-osseous tumors involves the use of an appropriate drug delivery system, by which the incorporated radionuclide can be directed to a specific target site in the organism and prevented from being released in vivo. For this purpose, the structure of the radiopharmaceutical must include a suitable bifunctional chelator capable of effectively complexing [223Ra]Ra2+, a linker and a directional molecule. The studies carried out to date on the research of potential chelating agents for Ra2+ complexation have had only limited success. To achieve Ra2+ complexes that are both thermodynamically stable and kinetically inert while using radiopharmaceuticals, further studies are needed, with the aim of investigating the complexing properties of other chelating agents and identifying the most promising chelator. Since all the isotopes of Ra2+ are unstable, the characterization of metal-chelator complexes is initially carried out using non-radioactive substitute Ba2+. In this thesis work the complexation equilibria of Ba2+ with three macrocyclic chelating agents were studied. The characterization of the Ba2+-chelator complexes was carried out by appropriate potentiometric and 1H-NMR spectroscopy analyses in order to determine the formation constants (logβ) of the complexes. Since the formation of complexes is influenced by competition with the acid-base equilibria of the chelator, in a first phase of this work the acid dissociation constants (pKa) of the three compounds under study were determined (again by potentiometry and 1H-NMR spectroscopy) in order to know the effective stability of the complexes at physiological pH, that is the real condition of use of the radiopharmaceutical. The results obtained in this work were used to compare the three macrocyclic chelators and other chelating agents previously characterized in the literature, in order to evaluate their ability to form stable complexes with the metal cation.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12608/80641