Design and Synthesis of Polymeric Hydrogen Sulfide Donors

Hydrogen sulfide (H₂S) is a gaseous signaling molecule that has several important biological functions in the human body. Because of the difficulties of handling H₂S gas, small organic compounds that release H₂S under physiological conditions have been developed. The observed bioactivities of these H₂S donors have generally been directly correlated with their H₂S release properties. However, apart from H₂S release, these H₂S donors also exert biological effects by direct interaction with intracellular components within the cytoplasm after passive diffusion across cellular membranes. Here we report polymeric H₂S donors based on ADT–OH which would alter cellular trafficking of ADT–OH to minimize the unfavorable interactions with intracellular components. We designed and synthesized a poly­(ethylene glycol)–ADT (PEG–ADT) conjugate having ADT linked via an ether bond. Whereas ADT–OH significantly reduced cell viability in murine macrophages, the PEG–ADT conjugate did not show obvious cytotoxicity. The PEG–ADT conjugate released H₂S in murine macrophages but not in the presence of serum proteins. The PEG–ADT conjugate was taken up by the cell through the endocytic pathway and stayed inside endolysosomes, which is different from the small amphiphilic donor ADT–OH that can directly enter the cytoplasm. Furthermore, PEG–ADT was capable of potentiating LPS-induced inflammation. This polymeric H₂S donor approach may help to better understand the H₂S bioactivities of the H₂S donor ADT–OH