H2S is a biologically relevant signaling gas that is endogenously produced throughout the body. The (patho)physiological roles of H2S have led researchers to develop various compounds that decompose to release H2S (H2S donors) for exogenous H2S administration. However, many small molecule H2S donors suffer from poor solubility, low stability, and lack of control over H2S release rates. As a result, there has been an increasing interest in utilizing supramolecular materials for exogenous H2S delivery.

With growing potential applications of supramolecular H2S-releasing materials, it is important to explore their properties, e.g., solubility and stability under physiological conditions. We investigated the hydrolytic stability over a range of pH conditions of a series of peptides containing H2S-releasing S-aroylthiooximes (SATOs). The SATO-peptides showed structure–reactivity relationships with SATO ring substituents playing a crucial role in hydrolysis rates. Electron-donating substituents accelerate the rate of hydrolysis while electron-withdrawing substituents slows it down. We also explored their hydrolysis mechanisms at different pH values.

SATO-peptides were then used to form hydrogels at 1 wt.% triggered by Ca2+. Hydrogels can be applied directly at a site of interest, potentially improving the efficacy of H2S compared with small molecule donors that diffuse away. We developed a H2S-releasing hydrogel capable of slowly releasing H2S locally to test its efficacy on intimal hyperplasia. The hydrogel delivered H2S over the period of several hours and inhibited the proliferation of human vascular smooth muscle cells (VSMCs) significantly better than fast-releasing NaSH salts. This study shows a promising application of supramolecular H2S-releasing materials over widely used sulfide salts.

The macroscopic properties of peptide hydrogels could be further modulated to achieve additional control over the H2S release properties. We synthesized a series of peptide hydrogels incorporating different linker segments to study their effects on hydrogelation properties. Most peptides formed hydrogels but with significantly different rheological behavior. We found that peptides with flexible linkers such as ethyl, substituted O-methylene, and others, formed stronger hydrogels compared to those with more rigid linkers. Interestingly, we found that stiffer hydrogels released H2S over longer periods than softer ones by retarding the diffusion of a thiol trigger, likely due to bulk degradation of the soft gels but surface erosion of the stiff gels as they release H2S.