A Platinum(IV) ProdrugPerfluoroaryl Macrocyclic Peptide Conjugate Enhances Platinum Uptake in the Brain

Effective delivery to the brain limits the development of novel glioblastoma therapies. Here, we introduce conjugation between platinum­(IV) prodrugs of cisplatin and perfluoroaryl peptide macrocycles to increase brain uptake. We demonstrate that one such conjugate shows efficacy against glioma stem...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2020-07, Vol.63 (13), p.6741-6747
Main Authors: Fadzen, Colin M, Wolfe, Justin M, Zhou, Wen, Cho, Choi-Fong, von Spreckelsen, Niklas, Hutchinson, Kathryn T, Lee, Yen-Chun, Chiocca, E. Antonio, Lawler, Sean E, Yilmaz, Omer H, Lippard, Stephen J, Pentelute, Bradley L
Format: Article
Language:English
Subjects:
Biological Transport
Brain - metabolism
Cell Line
Humans
Macrocyclic Compounds - chemistry
Peptides - chemistry
Platinum - chemistry
Platinum - metabolism
Prodrugs - metabolism
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Summary:Effective delivery to the brain limits the development of novel glioblastoma therapies. Here, we introduce conjugation between platinum­(IV) prodrugs of cisplatin and perfluoroaryl peptide macrocycles to increase brain uptake. We demonstrate that one such conjugate shows efficacy against glioma stem-like cells. We investigate the pharmacokinetics of this conjugate in mice and show that the amount of platinum in the brain after treatment with the conjugate is 15-fold greater than with cisplatin after 5 h.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c00022