Tunable Radiolabelled Agents based on Molecular Cages for Theranostics

Objective

Prostate cancer (PC) is the second most commonly diagnosed cancer in men and a leading cause of mortality. Current systemic therapies, particularly chemotherapy, often suffer from high toxicity and limited specificity. Theranostic agents, which combine diagnostic and therapeutic functions in a single platform, enable targeted imaging and treatment when equipped with units that recognize specific biomarkers, offering a promising alternative to conventional approaches. In PC, the prostate-specific membrane antigen (PSMA) is a validated target, with PSMA-617 already in clinical use. However, its rigid molecular design hinders multimodal integration, requiring separate administration of diagnostic and therapeutic agents. TRACE proposes an ambitious and ground-breaking strategy to overcome these limitations through the design of multifunctional molecular cages (MCs) as next-generation theranostic agents. This project will pioneer a modular post-functionalization strategy to introduce multiple units of PSMA target ligands, DOTA macrocycle chelators, therapeutic radionuclides (^177Lu), imaging radionuclides (^64Cu), and fluorescent probes within a single and robust MC architecture. This innovative MC design will allow precise control over multifunctionality, enhanced binding affinity, synergistic therapy, multimodal imaging, and superior biological stability. Importantly, the intrinsic coordination properties of the MCs will allow confinement and stabilization of imaging radionuclides in biological media, improving diagnostic accuracy. TRACE will deliver the first family of covalent MC-based theranostic agents for PC, providing superior selectivity, stability, and therapeutic efficacy. Beyond prostate cancer, this versatile supramolecular platform will pave the way for personalized cancer treatment.