Trisulfide-Bearing PEG Brush Polymers Donate Hydrogen Sulfide and Ameliorate Cellular Oxidative Stress

A potential approach to combat cellular dysfunction is to manipulate cell communication and signaling pathways to restore physiological functions while protecting unaffected cells. For instance, delivering the signaling molecule H₂S to certain cells has been shown to restore cell viability and re-normalize cell behavior. We have previously demonstrated the ability to incorporate a trisulfide-based H₂S-donating moiety into linear polymers with good in vitro releasing profiles and demonstrated their potential for ameliorating oxidative stress. Herein, we report two novel series of brush polymers decorated with higher numbers of H₂S-releasing segments. These materials contain two trisulfide-based monomers co-polymerized with oligo(ethylene glycol methyl ether methacrylate) via reversible addition-fragmentation chain-transfer polymerization. The macromolecules were characterized to have a range of trisulfide densities with similar, well-defined molecular weight distribution, good H₂S-releasing profiles, and high cellular tolerance. Using an amperometric technique, the H₂S liberated and total sulfide release were found to depend on concentrations and chemical nature of triggering molecules (glutathione and cysteine) and, importantly, the position of reactive groups within the brush structure. Notably, when introduced to cells at well-tolerated doses, two macromolecular donors which have the same proportion as of the H₂S-donating monomer (30%) but differ in releasing moiety location show similar cellular H₂S-releasing kinetics. These donors can restore reactive oxygen species levels to baseline values, when polymer pretreated cells are exposed to exogenous oxidants (H₂O₂). Our work opens up a new aspect in preparing H₂S macromolecule donors and their application to arresting cellular oxidative cascades.