Macrocyclic Dual‐Locked “Turn‐On” Drug for Selective and Traceless Release in Cancer Cells

Abstract Drug safety and efficacy due to premature release into the bloodstream and poor biodistribution remains a problem despite seminal advances in this area. To circumvent these limitations, we report drug cyclization based on dynamic covalent linkages to devise a dual lock for the small‐molecule anticancer drug, camptothecin (CPT). Drug activity is “locked” within the cyclic structure by the redox responsive disulfide and pH‐responsive boronic acid‐salicylhydroxamate and turns on only in the presence of acidic pH, reactive oxygen species and glutathione through traceless release. Notably, the dual‐responsive CPT is more active (100‐fold) than the non‐cleavable (permanently closed) analogue. We further include a bioorthogonal handle in the backbone for functionalization to generate cyclic‐locked, cell‐targeting peptide‐ and protein‐CPTs, for targeted delivery of the drug and traceless release in triple negative metastatic breast cancer cells to inhibit cell growth at low nanomolar concentrations.