Macrocyclic Dual-Locked "Turn-On" Drug for Selective and Traceless Release in Cancer Cells.

作者：Dominik Schauenburg, Bingjie Gao, Léa N C Rochet, Darijan Schüler, Jaime A S Coelho, David Y W Ng, V. Chudasama, S. Kuan, Tanja Weil · 发表于：Angewandte Chemie · 年份：2024 · DOI：10.1002/anie.202314143 · 被引用次数：14 · 研究领域：Medicine

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.