PUB - Publikationen an der Universität Bielefeld

The cure of cancer represents an ultimate challenge for scientists from different fields. Cancer complexity and diversity hamper the discovery of a broadly applicable treatment, and consequently, cancer represents the second cause of premature death worldwide. Despite the continuous approval of new drugs, the cancer burden keeps increasing due to different factors and leaves a vast number of patients helpless. Conventional chemotherapy still represents the backbone of cancer medical care. However, these agents are not able to selectively accumulate at the disease site which limits their efficacy and cause severe side effects. In the last years, targeted therapy has appeared as an innovative approach to overcome the drawbacks shown by traditional chemotherapeutics. In this approach, a cytotoxic agent is directed to the tumor site through the covalent conjugation to homing devices (e.g. antibodies, small molecules). Cryptophycins are cyclic depsipeptides with natural origin that present high cytotoxicity against several cell lines. Although cryptophycins cannot be used as stand-alone agent due to their side effects, they hold great potential as cytotoxic agent for tumor targeted therapy. Therefore, the discovery of new cryptophycins that can be conjugated to homing devices and their vectorization could be translated in a significant therapeutic activity. In the first part (chapter 3), the discovery of new cryptophycin analogues that retain the high cytotoxicity of the parent compound and present a functional group that can be used for conjugation to a delivery vehicle was described. Moreover, the usage of molecular dynamics to predict the biological activity of new analogues was explored. The second part (chapters 4 and 5), describes the usage of cryptophycin-55 glycinate as payload in small molecule-drug conjugates (SMDCs). In chapter 4, the payload was conjugated to a ligand capable to target the carbonic anhydrase IX, a transmembrane enzyme that is widely overexpressed in tumors. The cytotoxic activity of the resulting conjugate was studied in vitro, and the therapeutic activity was investigated in mice. In chapter 5, the payload was further explored by coupling it to a cyclic peptide targeting the somatostatin receptor 2, a marker which is commonly overexpressed in neuroendocrine tumors. The cytotoxicity of the conjugates was evaluated in a cell-based assay. In this case, further investigations in their targeting properties and stability were performed. Finally, the antitumor activity of the lead compound was investigated in vivo.