Directing drugs to the mitochondria is crucial for studying their effects and optimizing efficacy. In small molecules, lipophilic cationic groups like triphenylphosphoniums (TPPs) can target the mitochondria due to their ability to cross the mitochondrial membrane. Polymeric mitochondrial-targeting methods can also offer advantages because of their biocompatibility and ability to release drugs in a controlled manner. Amongst polymers, charged polymers or polymers functionalized by lipophilic cations have garnered interest in mitochondrial drug delivery. This work focuses on mitochondrial delivery of hydrogen sulfide (H₂S), a gasotransmitter that carries out many signaling roles and is closely related to nitric oxide (NO) and carbon monoxide (CO). H₂S has a variety of physiological roles in the body, many of which can be related to its function in maintaining mitochondrial homeostasis. A low concentration and high reactivity of endogenous H₂S limit the scope of understanding its mitochondrial role, hence, mitochondria-targeted H₂S donors have been reported to mimic endogenous H₂S production. The Matson lab reported a library of S-aroylthiooximes (SATOs) in 2014, which release H₂S upon hydrolysis in the presence of cysteine. However, these SATOs lacked mitochondrial specificity. To address this, we synthesized TPP-derived SATOs via oxime formation between S-aroylthiohydroxylamines (SATHAs) and TPP-functionalized aldehydes or ketones. A polymeric mitochondrial-targeted H₂S donor was also synthesized by functionalizing a polymethacrylate backbone with TPP and SATOs via post-polymerization modification. H₂S release rates were analyzed using the methylene blue assay, and mitochondria-specific fluorescent probes confirmed subcellular localization.

John Matson

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