Enzyme-Triggered Chemodynamic Therapy via a Peptide-H2S Donor Conjugate with Complexed Fe2+

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dc.contributor.authorZhu, Yumengen
dc.contributor.authorArcher, William R.en
dc.contributor.authorMorales, Katlyn F.en
dc.contributor.authorSchulz, Michael D.en
dc.contributor.authorWang, Yinen
dc.contributor.authorMatson, John B.en
dc.date.accessioned2023-08-15T14:43:05Zen
dc.date.available2023-08-15T14:43:05Zen
dc.date.issued2023-04en
dc.description.abstractInducing high levels of reactive oxygen species (ROS) inside tumor cells is a cancer therapy method termed chemodynamic therapy (CDT). Relying on delivery of Fenton reaction promoters such as Fe2+, CDT takes advantage of overproduced ROS in the tumor microenvironment. We developed a peptide-H2S donor conjugate, complexed with Fe2+, termed AAN-PTC-Fe2+. The AAN tripeptide was specifically cleaved by legumain, an enzyme overexpressed in glioma cells, to release carbonyl sulfide (COS). Hydrolysis of COS by carbonic anhydrase formed H2S, an inhibitor of catalase, an enzyme that detoxifies H2O2. Fe2+ and H2S together increased intracellular ROS levels and decreased viability in C6 glioma cells compared with controls lacking either Fe2+, the AAN sequence, or the ability to generate H2S. AAN-PTC-Fe2+ performed better than temezolimide while exhibiting no cytotoxicity toward H9C2 cardiomyocytes. This study provides an H2S-amplified, enzyme-responsive platform for synergistic cancer treatment.en
dc.description.notesAcknowledgments This work was supported by the National Institutes of Health (R01GM123508). The TOC graphic was created with BioRender.com. We thank Professor Andrew Lowell for the use of the plate reader, Professor Rafael Davalos, Dr. Anand Vadlamani, and Barath Udayasuryan for assistance with the C6 glioma cell line; Dr. Willian Keith Ray for assistance with MALDI-TOF experiments; Dr. Jeffery L. Parks for ICP-MS analyses; Professor Emily Mevers and Dr. Carla Menegatti for assistance with LC-MS experiments; and Connor Gallagher for providing helpful information on ITC. Finally, we thank Sarah Swilley, Clark Vu and Dr. Rajnish Kumar for critical reading of the manuscript, and Zhao Li and Kearsley M. Dillon for helpful suggestions.en
dc.description.sponsorshipNational Institutes of Health [R01GM123508]en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1002/anie.202302303en
dc.identifier.eissn1521-3773en
dc.identifier.issn1433-7851en
dc.identifier.pmid37078735en
dc.identifier.urihttp://hdl.handle.net/10919/116042en
dc.language.isoenen
dc.publisherWiley-V C H Verlagen
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectCanceren
dc.subjectDrug Deliveryen
dc.subjectGasotransmitteren
dc.subjectIronen
dc.subjectProdrugsen
dc.titleEnzyme-Triggered Chemodynamic Therapy via a Peptide-H2S Donor Conjugate with Complexed Fe2+en
dc.title.serialAngewandte Chemie-International Editionen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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