Preclinical development of 698ga-labelled aptamers for molecular cancer imaging

This PhD thesis aimed at developing novel aptamer-based radiopharmaceuticals for molecular imaging of HER2-positive cancer at the preclinical level. Aptamers are short, synthetic oligonucleotides that can interact with a specific target through their 3Dstructure. We selected novel HER2 aptamers through the systematic evolution of ligands by exponential enrichment (SELEX) process. Various settings of the SELEX process were investigated in order to obtain HER2 aptamers with high affinity and specificity for the HER2 receptor. Subsequently, the selected HER2 aptamers were developed into radiopharmaceuticals for PET imaging. We established an easy and reliable protocol for the bioconjugation to a chelator (NOTA) and radiolabelling with 68Ga in order to obtain pure and stable products. Finally, we evaluated the 68Garadiolabelled HER2 aptamers in a mouse model bearing HER2-positive and HER2-negative tumours in both hind flanks. Ex vivo biodistribution analysis and PET/MRI scanning revealed high uptake in the tumours and in the main organs, except the brain, which could be overcome by blood perfusion. Our findings suggest that the aptamers bind to blood proteins in a non-specific way. Further research is warranted to achieve decreased blood residence time in order to gain better contrast for imaging. This PhD research was a first step towards the preclinical development of aptamer-based radiopharmaceuticals for molecular cancer imaging.