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

Here, we report a general workflow for the facile microwave-assisted synthesis of kinetically inert platinum(II)-metallacages (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, an integrin-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. Beyond synthetic flexibility, we demonstrate that these Pt(II) MCgs can encapsulate chemotherapeutic agents, facilitate cellular imaging, and modulate biological responses. Targeted cages enhanced the intracellular delivery and cytotoxicity of doxorubicin in integrin-expressing cancer cells, while DOTA-functionalized cages were successfully radiolabeled with gallium-68 and lutetium-177, with high radiochemical purity (RCP). Overall, our work expands the synthetic accessibility and functional scope of Pt(II) MCgs, paving the way for their application in drug delivery, imaging, supramolecular radiotheranostics, and beyond.