Persulfides (RSSH) have been hypothesized as critical components in sulfur-mediated redox cycles and as potential signaling compounds, similar to hydrogen sulfide (H S). Hindering the study of persulfides is a lack of persulfide-donor compounds with selective triggers that release discrete persulfide species. Reported here is the synthesis and characterization of a ROS-responsive (ROS=reactive oxygen species), self-immolative persulfide donor. The donor, termed BDP-NAC, showed selectivity towards H O over other potential oxidative or nucleophilic triggers, resulting in the sustained release of the persulfide of N-acetyl cysteine (NAC) over the course of 2 h, as measured by LCMS. Exposure of H9C2 cardiomyocytes to H O revealed that BDP-NAC mitigated the effects of a highly oxidative environment in a dose-dependent manner over relevant controls and to a greater degree than common H S donors sodium sulfide (Na S) and GYY4137. BDP-NAC also rescued cells more effectively than a non-persulfide-releasing control compound in concert with common H S donors and thiols.

Significance: Cell homeostasis and redox balance are regulated in part by hydrogen sulfide (H 2 S), a gaseous signaling molecule known as a gasotransmitter. Given its biological roles, H 2 S 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 H 2 S 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 H 2 S-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 nanoand microparticles, and self-assembled hydrogels have enabled triggered, sustained, and/or localized H 2 S delivery, and many of these materials are more potent in biological assays than analogous small-molecule H 2 S donors. Critical Issues: H 2 S 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 H 2 S to study these processes, and (ii) exploit H 2 S 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 H 2 S 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. Antioxid. Redox Signal. 32, 79-95.

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Drug delivery from polymer micelles has been widely studied, but methods to precisely tune rates of drug release from micelles are limited. Here, the mobility of hydrophobic micelle cores was varied to tune the rate at which a covalently bound drug was released. This concept was applied to cysteine-triggered release of hydrogen sulfide (H 2 S), a signaling gas with therapeutic potential. In this system, thiol-triggered H 2 S donor molecules were covalently linked to the hydrophobic blocks of self-assembled polymer amphiphiles. Because release of H 2 S is triggered by cysteine, diffusion of cysteine into the hydrophobic micelle core was hypothesized to control the rate of release. We confirmed this hypothesis by carrying out release experiments from H 2 S-releasing micelles in varying compositions of EtOH/H 2 O. Higher EtOH concentrations caused the micelles to swell, facilitating diffusion in and out of their hydrophobic cores and leading to faster H 2 S release from the micelles. To achieve a similar effect without addition of organic solvent, we prepared micelles with varying core mobility via incorporation of a plasticizing co-monomer in the core-forming block. The glass transition temperature (T g ) of the core block could therefore be precisely varied by changing the amount of the plasticizing co-monomer in the polymer. In aqueous solution under identical conditions, the release rate of H 2 S varied over 20-fold (t ½ = 0.18 -4.2 h), with the lowest T g hydrophobic block resulting in the fastest H 2 S release. This method of modulating release kinetics from polymer micelles by tuning core mobility may be applicable to many types of physically encapsulated and covalently linked small molecules in a variety of drug delivery systems.

Self-assembly of amphiphilic peptide-based building blocks gives rise to a plethora of interesting nanostructures such as ribbons, fibers, and tubes. However, it remains a great challenge to employ peptide self-assembly to directly produce nanostructures with lower symmetry than these highly symmetric motifs. We report here our discovery that persistent and regular crescent nanostructures with a diameter of 28 ± 3 nm formed from a series of tetrapeptides with the general structure AdK S K S EX (Ad = adamantyl group, K S = lysine residue functionalized with an S-aroylthiooxime (SATO) group, E = glutamic acid residue, and X = variable amino acid residue). In the presence of cysteine, the biological signaling gas hydrogen sulfide (H 2 S) was released from the SATO units of the crescent nanostructures, termed peptide− H 2 S donor conjugates (PHDCs), reducing levels of reactive oxygen species (ROS) in macrophage cells. Additional in vitro studies showed that the crescent nanostructures alleviated cytotoxicity induced by phorbol 12-myristate-13-acetate more effectively than common H 2 S donors and a PHDC of a similar chemical structure, AdK S K S E, that formed short nanoworms instead of nanocrescents. Cell internalization studies indicated that nanocrescent-forming PHDCs were more effective in reducing ROS levels in macrophages because they entered into and remained in cells better than nanoworms, highlighting how nanostructure morphology can affect bioactivity in drug delivery.