Post-assembly modification of Pt(II) metallacages: an open door to medicinal applications

Metallacages (MCgs) have emerged as highly tunable modular – multicomponent and multifunctional – platforms with promising applications in catalysis, sensing, and medicine. Strategies for the synthesis of MCgs have been developed over the last decades, supplying several remarkable structures with striking varieties of size, shapes, and functions. Yet the efficient formation of systems with increased complexity and functionality remains a significant challenge towards their translation into practice. In particular, the transition of MCgs to medicine as next generation ‘theranostic’ agents requires not only the generation of robust structures, but also the development of tailored strategies towards the integration of different bioactive components. In this context, this work presents a general workflow for the facile microwave-assisted synthesis of kinetically inert platinum(II)-MCgs and their post-assembly modification (PAM) via amide coupling and copper-catalyzed click chemistry. This approach enables the incorporation of diverse functional groups under mild conditions, including a fluorescent rhodamine label for optical imaging, a targeting cyclo(RGDfK) peptide, and a DOTA-derived chelator for complexation of radioactive isotopes, demonstrating the versatility and compatibility of the method with biologically relevant functionalities. Overall, our work expands the synthetic accessibility and functional scope of Pt(II)-MCgs, paving the way to their application in drug delivery, imaging, supramolecular radiotheranostics, and beyond.