Metallodrugs for therapy and imaging: investigation of their mechanism of action

PhD Ceremony: Sarah Spreckelmeyer, 23 februari, Faculty of Science and Engineering

Thesis: Metallodrugs for therapy and imaging: investigation of their mechanism of action

In the thesis of Sara Spreckelmeyer metallodrugs were designed and characterized in order to be used for cancer therapy and diagnosis. The first aim was to synthesize new drugs that incorporate a radiometal (resulting in a so-called radiopharmaceutical) for diagnostic or therapeutic application for the treatment of cancer. Secondly, the toxicity and mechanisms of transport of metallodrugs like cisplatin (a widely used anti-cancer metallodrug containing platinum) and novel gold containing drugs were investigated. Different techniques were used, like basic organic chemistry, in vitro cell experiments and biological assays, drug transporter competition experiments using cimetidine or CuCl2 as inhibitors or competitors, radiolabeling procedures, ex vivo precision cut tissue slicing and in vivo mice experiments. Transport mechanisms via the organic cation transporter 2 (OCT2)/multi drug extrusion protein (MATE) and copper transporter 1 (CTR1) and ATP7A/B were investigated in vitro and ex vivo.We synthesized and characterized successfully a novel molecule (called H4neunpa) that can bind to several radiometals, like 111In (used in imaging for diagnosis), 225Ac and 213Bi (used for therapy). This molecule is stable in vitro and in vivo and further experiments are currently ongoing to test its application in vivo. Furthermore, we found that gold containing drugs can be as potent as cisplatin against cancer cells in vitro, although their mechanism of action is different, but they are also toxic for healthy kidney tissue. Slight structural modifications in a gold containing molecule can change its transport behavior and beside OCT2, MATE, CTR1 and ATP7A/B, other transporters might be involved in their mechanisms of action.