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

Drug safety and efficacy due to premature drug release in the bloodstream and poor biodistribution remain challenging issues despite seminal advances in the field. To circumvent these limitations, we report a directed-macrocylization as a dual lock for camptothecin (CPT), a small molecule anticancer drug. In this way, the activity is “locked” within the cyclic structure by the redox responsive disulfide and pH-responsive boronic acid-salicylhydroxamate and turned on only in the presence of acidic pH and glutathione through traceless release. Notably the dual-responsive CPT is more active (100-fold) compared to the non-cleavable (closed) analogue. We further include bioorthogonal handle in the cyclic backbone for subsequent functionalization to generate cell-targeting peptide-macrocyclic and protein-macrocyclic CPTs for targeted, traceless drug release in triple negative metastatic breast cancer cells to inhibit cell growth in the low nanomolar concentration.