Supramolecular Tuning of H₂S Release from Aromatic Peptide Amphiphile Gels: Effect of Core Unit Substituents

H₂S is a gasotransmitter with several physiological roles, but its reactivity and short half-life in biological media make its controlled delivery difficult. For biological applications of the gas, hydrogels have the potential to deliver H₂S with several advantages over other donor systems, including localized delivery, controlled release rates, biodegradation, and variable mechanical properties. In this study, we designed and evaluated peptide-based H₂S-releasing hydrogels with controllable H₂S delivery. The hydrogels were prepared from short, self-assembling aromatic peptide amphiphiles (APAs), functionalized on their N-terminus with S-aroylthiooximes (SATOs), which release H₂S in response to a thiol trigger. The APAs were studied both in solution and in gel forms, with gelation initiated by addition of CaCl₂. Various substituents were included on the SATO component of the APAs in order to evaluate their effects on self-assembled morphology and H₂S release rate in both the solution and gel phases. Transmission electron microscopy (TEM) images confirmed that all H₂S-releasing APAs self-assembled into nanofibers above a critical aggregation concentration (CAC) of ∼0.5 mg/mL. Below the CAC, substituents on the SATO group affected H₂S release rates predictably in line with electronic effects (Hammett σ values) according to a linear free energy relationship. Above the CAC, circular dichroism, infrared, and fluorescence spectroscopies demonstrated that substituents influenced the self-assembled structures by affecting hydrogen bonding (β-sheet formation) and π- π stacking. At these concentrations, electronic control over release rates diminished, both in solution and in the gel form. Rather, the release rate depended primarily on the degree of organization in the β-sheets and the amount of π- π stacking. This supramolecular control over release rate may enable the evaluation of H₂S-releasing hydrogels with different release rates in biological applications.