Transdermal hydrogen sulfide delivery enabled by open metal site metal-organic frameworks

Hydrogen sulfide (H2S) is an endogenously produced gasotransmitter involved in many physiological processes that are integral to proper cellular functioning, including chemical signaling, redox balancing, and modification of vital proteins. Due to its profound anti-inflammatory and antioxidant properties, H2S plays important roles in preventing inflammatory skin disorders and improving wound healing. Transdermal H2S delivery is a therapeutically viable option for the man-agement of such disorders. However, current small-molecule H2S donors are not optimally suited for transdermal deliv-ery and typically generate electrophilic byproducts that may lead to undesired toxicity. Here, we demonstrate that H2S release from metal-organic frameworks (MOFs) bearing coordinatively unsaturated metal centers is a promising alterna-tive for controlled transdermal delivery of gaseous H2S without the release of unwanted byproducts. In particular, exten-sive gas sorption measurements and powder X-ray diffraction (PXRD) studies of eleven MOFs support that the Mg-based framework Mg2(dobdc) (dobdc4− = 2,5-dioxidobenzene-1,4-dicarboxylate) is uniquely well-suited for transdermal H2S delivery due to its strong yet completely reversible binding of H2S, high capacity (14.7 mmol/g or 33.3 wt% at 1 bar and 25 °C), and lack of toxicity. In addition, Rietveld refinement of high-quality synchrotron PXRD data from a H2S-dosed mi-crocrystalline sample of Mg2(dobdc) supports that the high H2S capacity of this framework arises due to the presence of three distinct binding sites: at the Mg centers through a Mg⋅⋅⋅S interaction (primary site), through a short S⋅⋅⋅S interaction to the polarized H2S molecules at the primary sites (secondary site), and in the center of the pores (tertiary site). Last, we demonstrate that transdermal delivery of H2S from this framework is sustained over a 24 h period through porcine skin. Not only is this significantly longer than sodium sulfide (Na2S), but this represents the first example of controlled trans-dermal delivery of pure H2S gas. Overall, H2S-loaded Mg2(dobdc) is an easily accessible, solid-state source of H2S, ena-bling safe storage and transdermal delivery of this therapeutically relevant gas.