Vacancies | Laboratory of Cell Biology and Histology

PhD: Metal microanalysis as input for dosimetry of therapeutic radiopharmaceuticals

Over the past years, targeted radionuclide therapy (TRT), has become an attractive approach to treat metastatic cancer because of its unique combination of a targeted vector, which specifically targets tumor cells, and a therapeutic radionuclide, which eradicates the tumor cells by irradiation. [¹⁷⁷Lu]Lu-DOTATATE (Lutathera®) is one of the most well-known TRT for neuroendocrine tumors and has shown promising results in several clinical trials (NETTER-1/2). Recently, the use of terbium-161 (¹⁶¹Tb) as therapeutic radionuclide has been gaining momentum because it emits additional short-range Conversion and Auger electrons in addition to β^--particles and γ-radiation, like lutetium-177. These additional particles provide an increased dose deposition across a very short range, in the nanometer to micrometer range.

The fact that ¹⁶¹Tb is a relatively novel player in the TRT-field underlines the importance of thorough radiobiological and dosimetry research into its fundamental mechanisms of action. Especially for dosimetry, it is essential to acquire information on the location of the decaying radionuclide on a multilevel scale, from organ to sub-tissue and (sub-)cellular level. Yet, by using the established nuclear medicine instrumentation, we lack sensitivity/resolution to analyze the surplus in emitted electrons from ¹⁶¹Tb for dosimetric purposes (e.g. with autoradiography or gamma counting).

Rather than relying on the emitted β^- particles, electrons or γ-irradiation of the parent radionuclide, ¹⁶¹Tb, we hypothesize that electron microscopy (EM) can be utilized to characterize its stable lanthanide daughter, dysprosium (Dy-161), to deliver semi-quantitative input for ¹⁶¹Tb dosimetry on a micro- to nanoscale. Initially, the first task within the project will be to intercompare (EM) modalities to reach an optimal ratio between resolution and sensitivity on different levels, i.e. from a tissue to cellular scale. This will require optimization of several essential steps such as sample preparation, data acquisition and post-processing. A proof-of-concept study will test the feasibility of EM to qualitatively analyze low focal accumulation of lanthanides in biological samples. Upon validation of the EM methodology, it will be utilized for key dosimetry applications, one being the dosimetry of nephron substructures within the kidney, the main dose-limiting organ for peptide-based radioligands. Secondly, we aim to improve the subcellular dosimetry, including dose-deposition in radiosensitive structures such as the cell membrane. Biodistribution experiments with clinically relevant ¹⁶¹Tb-labelled vectors, such as DOTA-TATE, DOTA-LM3 or PSMA I&T will generate the required tissue samples for microscale applications whereas 2D/3D cell culture uptake experiments may be utilized for nanoscale applications. Finally, the Dy-161 metal microanalysis should provide the required qualitative info to improve the currently available micro- and nanoscale dosimetry frameworks.