Ontwikkeling van Tb-161 gelabelde nanodeeltjes

Targeted radionuclide therapy (TRT) has emerged as a promising approach for cancer treatment. Its ultimate goal is to selectively deliver a therapeutic radiation dose directly to the tumour site or metastases. This approach effectively offers the potential for selective tumour irradiation while at the same time minimises damage to healthy tissues, potentially overcoming limitations associated with other treatment modalities. In this context, the use of radiolabelled nanomaterials has gained significant attention due to their tunable physicochemical properties, enhanced stability, and potential for multifunctional applications. Over the years, several radiolabelling strategies have been explored, involving different combinations of radionuclides, nanoparticle compositions, and architectures. Achieving optimal stability requires carefully selecting and integrating these components to ensure the formation of robust radiolabelled nanoparticles. Additionally, once the challenging task of obtaining radiolabelled nanoparticles has been reached, they often still require some sort or surface modifications to enable selective tumour targeting. This research focuses on the synthesis, radiolabelling, surface modification, and biological evaluation of lanthanide-based nanomaterials as potential radiopharmaceutical agents. A key aspect of this study is the development of terbium-161 doped nanoparticles. Terbium-161 has a unique advantage over the clinically used lutetium-177, such as the emission of a significantly higher amount of both conversion and Auger electrons. This co-emission of medium and low-energy electrons makes terbium-161 particularly suited to target both small metastases and larger tumour masses and increase the overall dose delivered. Two distinct strategies, based on different precursors, were explored for the synthesis and radiolabelling of NaGdF4 nanoparticles. Following the successful synthesis and terbium-161 labelling, various surface modifications were investigated. While adding a silica shell around the nanoparticles has been shown to be effective at improving biocompatibility, colloidal stability, and enabling further functionalisation, precise control over the thickness of this shell is an important parameter that must be adjusted. Excessive thickness could attenuate the emission of conversion and Auger electrons, diminishing the added benefit of terbium-161. Due to the challenges associated with controlling silica shell thickness, a ligand exchange approach was adopted instead. The nanoparticles were subsequently functionalised with folic acid to target the folate receptor (FRa). The biological evaluation of these nanoparticles included in vitro cell binding and viability assays using SK-OV-3 ovarian cancer cells, chosen for their overexpression of folate receptors. Results indicated that non-radioactive nanoparticles did not significantly affect cell viability, even at high concentrations. This suggests that the observed cytotoxic effects in subsequent studies were primarily caused by the radiation emitted by terbium-161 rather than inherent nanoparticle toxicity. Despite promising radiolabelling results and successful functionalisation, in vivo studies revealed a lack of tumour targeting, necessitating further optimization of the surface functionalisation strategy to improve selective tumour accumulation. In addition to nanoparticles, this research explores the functionalisation of lacunary Keggin-type polyoxometalates (POMs) based terbium complexes. POMs are highly tunable inorganic clusters with unique coordination properties, making them attractive candidates for radiopharmaceutical development. Functionalisation with organic ligands aims to improve their stability, solubility, and potential for biological interactions. Overall, this research contributes to the growing field of radiopharmaceutical nanomaterials by providing insights into the synthesis, radiolabelling, and functionalisation of both nanoparticles and POMs. While the in vivo performance of the developed nanoparticles was not as promising as anticipated, the findings underscore the importance of surface chemistry in nanoparticles-based radiopharmaceutical design. Future studies should focus on optimising functionalisation approaches and evaluating alternative targeting vectors to enhance tumour selectivity and therapeutic efficacy. The continued development of radiolabelled lanthanide-based nanomaterials has the potential to expand the applications of TRT and improve treatment outcomes for various cancers.