Molecular, Macromolecular, and Supramolecular Glucuronide Prodrugs: Lead Identified for Anticancer Prodrug Monotherapy

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, mo...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2020-05, Vol.59 (19), p.7390-7396
Main Authors: Jarlstad Olesen, Morten T., Walther, Raoul, Poier, Pier Paolo, Dagnæs‐Hansen, Frederik, Zelikin, Alexander N.
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacokinetics
Bioconversion
Cancer
Cell Line, Tumor
Chemical compounds
Chromatography, High Pressure Liquid
drug delivery
Drug Delivery Systems
Drugs
enzymes
glucuronides
Glucuronides - chemical synthesis
Glucuronides - pharmacokinetics
Humans
Indicators and Reagents
Macromolecular Substances
Macromolecules
Mice
Models, Molecular
Molecular Docking Simulation
Neoplasms - drug therapy
Neoplasms - metabolism
Oligopeptides - chemical synthesis
Oligopeptides - pharmacology
Prodrugs
Prodrugs - chemical synthesis
Prodrugs - pharmacokinetics
Toxicity
Toxins
Translational Medical Research
Tumors
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201916124