Department of Chemistry, Aarhus University, Aarhus, Denmark.
iNano Interdisciplinary Nanosciece Centre, Aarhus University, Aarhus, Denmark.
Angew Chem Int Ed Engl. 2020 May 4;59(19):7390-7396. doi: 10.1002/anie.201916124. Epub 2020 Mar 11.
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.
在这项工作中，通过利用肿瘤本身的酶谱，在肿瘤体积内进行局部药物合成，对肿瘤生长进行干预。为了取得整体成功，针对一种强效毒素单甲基奥瑞他汀 E（MMAE），设计了分子、大分子和超分子型葡萄糖醛酸前药。先导候选物的前药与药物之间的毒性差异倍数为 175，具有增强可递送至肿瘤的有效载荷的工程化机制，并且包含一种强效毒素，以至于只有少数几个前药分子的生物转化就产生了足够高的 MMAE 浓度，从而有效地抑制肿瘤生长。这些要点都非常重要，共同提供了一种安全、选择性的抗癌措施，使肿瘤靶向葡萄糖醛酸苷成为转化医学的热门选择。
