Abstract:
Prostate cancer is the most frequently diagnosed cancer type for men and also shows a high mortality. The current treatment of prostate cancer involves active surveillance, radical prostatectomy, radiotherapy, hormone therapy and chemotherapy. However, all these approaches involve several side effects and the loss of quality of life. Targeted therapy is the new hope for prostate cancer treatment. In this new approach, a target binding structure is conjugated to an effector. Consequently, this increases the concentration at the target site which also leads to fewer side effects. The prostate- specific membrane antigen (PSMA) is an enzyme that is overexpressed in prostate cancer cells and is therefore a suitable target for Prostate cancer therapy. The urea-based binding motif Lys-NH-CO-NH-Glu has shown to bind to PSMA with high affinity, while lipophilic linkers further optimize binding properties. The goal of this work was to optimize the drug load of this PSMA binding motif. As a consequence, the drug concentration at the tumor site can be increased specifically. Different numbers of DOTA, a chelator used for endoradiotherapy, were conjugated to the PSMA binding motif via a lysine multimer. DOTA I, DOTA II and DOTA IV were synthesized with 1, 2 and 4 DOTA molecules respectively. The compounds synthesized were evaluated in internalization experiments and PET scans of an LNCaP mouse. The results were compared to the properties of MB17, a promising compound in clinical trials. The PET scans showed specific enrichment in the tumor for the compounds with up to two DOTA molecules. Furthermore, the clearance of the molecules synthesized from the tumor was slower when compared to MB17. The internalization ratio for DOTA I (15.7%) and II (13.4%) were much higher than the one for MB17 (9%), even though one hydrophobic linker was not present in the molecules synthesized. Based on these results, further optimization of the molecules synthesized presents a great potential for the drug load-optimized targeted therapy of prostate cancer.
