Polymeric Persulfide Prodrugs: Mitigating Oxidative Stress through Controlled Delivery of Reactive Sulfur Species

Related biologically to the known gasotransmitter hydrogen sulfide (H 2 S), 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 (PLE), resulting in pseudo-first-order persulfide release half-lives of 1.6 ± 0.3 and 36.0 ± 0.6 h, respectively. In cell experiments, slow-releasing poly(EDP-NAC) rescued H9C2 cardiomyocytes more effectively than EDP-NAC when the 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.