TY - JOUR
T1 - Molecular, macromolecular, and supramolecular glucuronide prodrugs
T2 - Lead identified for anticancer prodrug monotherapy
AU - Olesen, Morten Tobias Jarlstad
AU - Walther, Raoul
AU - Poier, Pier Paolo
AU - Dagnæs-Hansen, Niels Frederik
AU - Zelikin, Alexander N.
PY - 2020/2
Y1 - 2020/2
N2 - 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.
AB - 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.
KW - cancer
KW - drug delivery
KW - enzymes
KW - glucuronides
KW - prodrugs
UR - https://www.scopus.com/pages/publications/85081307424
U2 - 10.1002/anie.201916124
DO - 10.1002/anie.201916124
M3 - Journal article
C2 - 32073708
SN - 1433-7851
VL - 59
SP - 7390
EP - 7396
JO - Angewandte Chemie International Edition
JF - Angewandte Chemie International Edition
IS - 19
ER -