Polymeric persulfide prodrugs: Mitigating oxidative stress through controlled delivery of reactive sulfur species.

ACS Macro Letters
Kearsley M DillonJohn B Matson

Abstract

Related biologically to the known gasotransmitter hydrogen sulfide (H2S), persulfides (R-SSH) have recently been recognized as native signaling compounds and redox regulators in their own right. Reported here is the synthesis, characterization, and in vitro evaluation of a small molecule persulfide donor and its polymeric counterpart, both of which release N-acetyl cysteine persulfide (NAC-SSH) in response to esterases. The donors, termed EDP-NAC and poly(EDP-NAC), underwent controlled decomposition in response to porcine liver esterase, resulting in pseudo-first-order release half-lives of 1.6 h ± 0.3 h and 36.0 h ± 0.6 h, respectively. In cell experiments, slow-releasing poly(EDP-NAC) rescued H9C2 cardiomyocytes more effectively than EDP-NAC when cells were treated with 5-fluorouricil (5-FU), which induces sustained production of ROS. Neither EDP-NAC nor poly(EDP-NAC) rescued MCF-7 breast cancer cells from 5-FU-induced oxidative stress, suggesting that polymeric persulfide donors could be used as adjuvants to reduce the deleterious cardiotoxic effects of many chemotherapeutics.

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Citations

Sep 6, 2020·International Journal of Molecular Sciences·Gengqi LiuYumiao Zhang
Jun 12, 2021·ACS Chemical Biology·Kearsley M Dillon, John B Matson
Jul 20, 2021·Antioxidants & Redox Signaling·Vinayak S KhodadeJohn P Toscano

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