The Benefits of Macromolecular/Supramolecular Approaches in Hydrogen Sulfide Delivery: A Review of Polymeric and Self-Assembled Hydrogen Sulfide Donors

Significance: Cell homeostasis and redox balance are regulated in part by hydrogen sulfide (H2S), a gaseous signaling molecule known as a gasotransmitter. Given its biological roles, H2S has promising therapeutic potential, but controlled delivery of this reactive and hazardous gas is challenging due to its promiscuity, rapid diffusivity, and toxicity at high doses. Macromolecular and supramolecular drug delivery systems are vital for the effective delivery of many active pharmaceutical ingredients, and H2S stands to benefit greatly from the tunable physical, chemical, and pharmacokinetic properties of polymeric and/or self-assembled drug delivery systems. Recent Advances: Several types of H2S-releasing macro- and supramolecular materials have been developed in the past 5 years, and the field is expanding quickly. Slow-releasing polymers, polymer assemblies, polymer nano- and microparticles, and self-assembled hydrogels have enabled triggered, sustained, and/or localized H2S delivery, and many of these materials are more potent in biological assays than analogous small-molecule H2S donors. Critical Issues: H2S plays a role in a number of (patho)physiological processes, including redox balance, ion channel regulation, modulation of inducible nitric oxide synthase, angiogenesis, blood pressure regulation, and more. Chemical tools designed to (i) deliver H2S to study these processes, and (ii) exploit H2S signaling pathways for treatment of diseases require control over the timing, rate, duration, and location of release. Future Directions: Development of new material approaches for H2S delivery that enable long-term, triggered, localized, and/or targeted delivery of the gas will enable greater understanding of this vital signaling molecule and eventually expedite its clinical application.