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Jarlstad Olesen, Morten T.; Walther, Raoul; Poier, Pier Paolo; Dagnæs‐Hansen, Frederik; Zelikin, Alexander N.
Angewandte Chemie International Edition, May 4, 2020, Letnik: 59, Številka: 19Journal Article
In this work, a tumor growth intervention by localized drug synthesis within the tumor volume, using the enzymatic repertoire of the tumor itself, is presented. Towards the overall success, molecular, macromolecular, and supramolecular glucuronide prodrugs were designed for a highly potent toxin, monomethyl auristatin E (MMAE). The lead candidate exhibited a fold difference in toxicity between the prodrug and the drug of 175, had an engineered mechanism to enhance the deliverable payload to tumours, and contained a highly potent toxin such that bioconversion of only a few prodrug molecules created a concentration of MMAE sufficient enough for efficient suppression of tumor growth. Each of these points is highly significant and together afford a safe, selective anticancer measure, making tumor‐targeted glucuronides attractive for translational medicine. Targeting tumors: Safe, tumor‐accumulating prodrugs that are specific to the enzymatic repertoire of the tumor comprise an effective anticancer therapy. The lead structure could not be predicted by in vitro/ex vivo screens but was identified through in vivo monitoring.
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