Intracellular fluorogenic supramolecular assemblies for self-reporting bioorthogonal prodrug activation

A visual drug delivery system (DDS) is urgently needed for precision medicine. DDS-mediated bioorthogonal prodrug activation strategies have demonstrated remarkable advantages in enlarging a therapeutic index via the alleviation of adverse drug reactions. However, the events of bioorthogonal prodrug activation remain inaccessible. Here, we construct a self-reporting bioorthogonal prodrug activation system using fluorescence emission to interpret prodrug activation events. In designed reactive oxygen species (ROS)-instructed supramolecular assemblies, the bioorthogonal reaction handle of tetrazine carries a dual role as fluorescence quencher and prodrug activator. The subsequent inverse-electron-demand Diels-Alder (IEDDA) reaction simultaneously liberates fluorescence and active drugs, which form a linear relationship. Differentiated by their cellular redox status, ROS-instructed supramolecular assemblies form selectively in both tumor cells and cell spheroids. Upon prodrug treatment, the brightness of fluorescence reflects the liberation of active drugs, which further correlates with the cell survival rate. Therefore, a fluorescence-based visualizable DDS (VDDS) for bioorthogonal prodrug activation is demonstrated, which should be useful to elucidate the multi-step processes in drug delivery and determine prodrug activation efficacy.

Automated summary

There is an urgent need for a visual drug delivery system in precision medicine. This study constructs a self-reporting bioorthogonal prodrug activation system that interprets prodrug activation events using fluorescence emission. The system selectively forms in tumor cells and can reflect the release of active drugs through measuring fluorescence brightness.