Schauenburg, Dominik;
Gao, Bingjie;
Rochet, Léa NC;
Schüler, Darijan;
Coelho, Jaime AS;
Ng, David YW;
Chudasama, Vijay;
... Weil, Tanja; + view all
(2024)
Macrocyclic Dual-Locked “Turn-On” Drug for Selective and Traceless Release in Cancer Cells.
Angewandte Chemie International Edition
, Article e202314143. 10.1002/anie.202314143.
(In press).
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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.
| Type: | Article |
|---|---|
| Title: | Macrocyclic Dual-Locked “Turn-On” Drug for Selective and Traceless Release in Cancer Cells |
| Location: | Germany |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/anie.202314143 |
| Publisher version: | http://dx.doi.org/10.1002/anie.202314143 |
| Language: | English |
| Additional information: | Copyright © 2024 The Authors. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
| Keywords: | drug delivery, dual-responsive chemotherapeutics, macrocyclic drug, traceless release |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10185375 |
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