Samenvatting
In the past decade, radioligand therapy (RLT) has gained interest as a promising cancer treatment, effectively delivering locally a radiation dose while sparing healthy tissues. While several betaemitting-based radiopharmaceuticals have already been approved as treatment modalities in the clinic, targeted alpha therapy (TAT) is exploring the effectiveness of alpha-emitting radionuclides. Alpha particles have the advantage of providing a high energy delivered in a very short range. However,
among all α-emitting radionuclides, only few α-emitting radionuclides exhibit the necessary properties for TAT, also listed as ‘the hopeful eight’ from which three potential candidates which are present in most early phase 1 or phase 1 clinical trials in TAT are: 225Ac, 212Pb and 211At. Despite their clinical potential, their availability is a common obstacle hindering quick advancement for all α-emitting radionuclides.
Compared to 225Ac and 212Pb, 211At is characterised by 100% α-emission radionuclide per decay. It has a half-life of 7.2h, no generation of toxic daughters, and is more straightforwardly produced by cyclotrons through irradiation natural bismuth with an α-particle beam. Despite this, 211At is scarcely available due to (i) only few cyclotrons worldwide (two located in Europe) can produce relevant quantities of 211At and (ii) the common practice of restricting the energy of the incident α-particle
beam to limit the co-production of 210At (half-life 8.1h) which predominantly decays into 210Po, a 100% α-emitter with a long half-life of 138 days and is difficult to detect via gamma spectrometry due to its weak gamma emission.
The limited number of cyclotrons is currently being tackled in Europe by the installation and the commissioning at other sites (Polatom, Warsaw and Forschungszentrum, Jülich), which will be an addition to the already existing production centres: Rigshospitalet in Copenhagen and Arronax in Nantes. In addition, targets are being fabricated to withstand higher beam currents, resulting in higher produced activities at the end of bombardment (EOB). Contemporaneously increasing the incident αparticle beam energy on the target can help tackle the problem of the availability of 211At, however, at the cost of producing elevated levels of 210At/210Po. Before adopting this approach, it is crucial to ensure that the 210Po is effectively managed during target processing and radiochemical separation and assessed in vivo to protect the staff, the environment, and the patient. The various chapters in this thesis aim to address the challenges introduced at higher incident energy irradiation.
Chapter 1 provides a broad overview of nuclear medicine's role in cancer diagnostics and therapies. It follows with a short discussion of 225Ac, 212Pb, and 211At. 211At is discussed in more depth, with additional state-of-the-art radiochemical separation modalities.
Chapter 2 discusses the outline and research objectives, which are each described in the subsequent chapters: (i) the establishment of dedicated measurement protocols, (ii) the characterisation of irradiated bismuth targets, (iii) destructive target characterisation and activity balance of 211At, 210At and 210Po during radiochemical separation and (iv) assessment of the impact of 210At/210Po in-vivo using astatine labelled anti-HER2 single domain antibodies (sdAbs).
Chapter 3 describes the establishment of dedicated measurement protocols employing different αdetection techniques (α-spectrometer, α-camera, and liquid scintillation counting). It describes each modality, its characteristics, the reported efficiencies for detecting 210Po, and its advantages and disadvantages.
In Chapter 4, the total 210Po on an irradiated target (i.e., the 210Po source term) is non-destructively determined by implementing a specific target model combined with Monte Carlo simulations and detector-specific calibrations.
This non-destructive 210Po source term is subsequently verified destructively by dissolution of the target, after which radiochemical separation is performed using extraction chromatography (chapter 5). Here, the isolation capability of 210Po from the extracted 211At is assessed using this novel technique.
Chapter 6 focuses on the potential migration of the contaminants 210At/210Po in a preclinical in-vivo setting, employing [210At/211At]At-AGMB-antiHER2 sdAbs to evaluate not only the biodistribution of 210Po in this specific setting but also the dosimetric impact.
Chapter 7 reflects on the various posed research questions and potential implementation/improvements for future TAT laboratories and clinics and seeks to formulate an
answer to the question resonating throughout the thesis:“Can we increase the yield of 211At at EOB, provided that we can manage the formed 210Po every step of the way, from production to an in-vivo setting?”
among all α-emitting radionuclides, only few α-emitting radionuclides exhibit the necessary properties for TAT, also listed as ‘the hopeful eight’ from which three potential candidates which are present in most early phase 1 or phase 1 clinical trials in TAT are: 225Ac, 212Pb and 211At. Despite their clinical potential, their availability is a common obstacle hindering quick advancement for all α-emitting radionuclides.
Compared to 225Ac and 212Pb, 211At is characterised by 100% α-emission radionuclide per decay. It has a half-life of 7.2h, no generation of toxic daughters, and is more straightforwardly produced by cyclotrons through irradiation natural bismuth with an α-particle beam. Despite this, 211At is scarcely available due to (i) only few cyclotrons worldwide (two located in Europe) can produce relevant quantities of 211At and (ii) the common practice of restricting the energy of the incident α-particle
beam to limit the co-production of 210At (half-life 8.1h) which predominantly decays into 210Po, a 100% α-emitter with a long half-life of 138 days and is difficult to detect via gamma spectrometry due to its weak gamma emission.
The limited number of cyclotrons is currently being tackled in Europe by the installation and the commissioning at other sites (Polatom, Warsaw and Forschungszentrum, Jülich), which will be an addition to the already existing production centres: Rigshospitalet in Copenhagen and Arronax in Nantes. In addition, targets are being fabricated to withstand higher beam currents, resulting in higher produced activities at the end of bombardment (EOB). Contemporaneously increasing the incident αparticle beam energy on the target can help tackle the problem of the availability of 211At, however, at the cost of producing elevated levels of 210At/210Po. Before adopting this approach, it is crucial to ensure that the 210Po is effectively managed during target processing and radiochemical separation and assessed in vivo to protect the staff, the environment, and the patient. The various chapters in this thesis aim to address the challenges introduced at higher incident energy irradiation.
Chapter 1 provides a broad overview of nuclear medicine's role in cancer diagnostics and therapies. It follows with a short discussion of 225Ac, 212Pb, and 211At. 211At is discussed in more depth, with additional state-of-the-art radiochemical separation modalities.
Chapter 2 discusses the outline and research objectives, which are each described in the subsequent chapters: (i) the establishment of dedicated measurement protocols, (ii) the characterisation of irradiated bismuth targets, (iii) destructive target characterisation and activity balance of 211At, 210At and 210Po during radiochemical separation and (iv) assessment of the impact of 210At/210Po in-vivo using astatine labelled anti-HER2 single domain antibodies (sdAbs).
Chapter 3 describes the establishment of dedicated measurement protocols employing different αdetection techniques (α-spectrometer, α-camera, and liquid scintillation counting). It describes each modality, its characteristics, the reported efficiencies for detecting 210Po, and its advantages and disadvantages.
In Chapter 4, the total 210Po on an irradiated target (i.e., the 210Po source term) is non-destructively determined by implementing a specific target model combined with Monte Carlo simulations and detector-specific calibrations.
This non-destructive 210Po source term is subsequently verified destructively by dissolution of the target, after which radiochemical separation is performed using extraction chromatography (chapter 5). Here, the isolation capability of 210Po from the extracted 211At is assessed using this novel technique.
Chapter 6 focuses on the potential migration of the contaminants 210At/210Po in a preclinical in-vivo setting, employing [210At/211At]At-AGMB-antiHER2 sdAbs to evaluate not only the biodistribution of 210Po in this specific setting but also the dosimetric impact.
Chapter 7 reflects on the various posed research questions and potential implementation/improvements for future TAT laboratories and clinics and seeks to formulate an
answer to the question resonating throughout the thesis:“Can we increase the yield of 211At at EOB, provided that we can manage the formed 210Po every step of the way, from production to an in-vivo setting?”
| Originele taal-2 | English |
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| Toekennende instantie |
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| Begeleider(s)/adviseur |
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| Datum van toekenning | 25 nov. 2024 |
| Status | Published - 2024 |