Linker-Regulated H₂S Release from Aromatic Peptide Amphiphile Hydrogels

Controlled release is an essential requirement for delivery of hydrogen sulfide (H₂S) because of its reactive nature, short half-life in biological fluids, and toxicity at high concentrations. In this context, H₂S delivery via hydrogels may be beneficial as they can deliver H₂S locally at the site of interest. Herein, we employed hydrogels based on aromatic peptide amphiphiles (APAs) with tunable mechanical properties to modulate the rates of H₂S release. The APAs contained an aromatic S-aroylthiooxime (SATO) H₂S donor attached with a linker to a short IAVEEE hexapeptide. Linker units included carbonyl, substituted O-methylenes, alkenyl, and alkyl segments with the goal of evaluating the role of linker structure on self-assembly, capacity for hydrogelation, and H₂S release rate. We studied each peptide by transmission electron microscopy, circular dichroism spectroscopy, and rheology, and we measured H₂S release rates from each gel, triggering SATO decomposition and release of H₂S by addition of cysteine (Cys). Using an H₂S-selective electrode probe as well as a turn-on fluorescent H₂S probe in the presence of H9C2 cardiomyocytes, we found that the rate of H₂S release from the hydrogels depended on the rate of Cys penetration into the nanofiber core with stiffer gels showing longer overall release.