Design and Development of a Bioorthogonal, Visualizable and Mitochondria‐Targeted Hydrogen Sulfide (H₂S) Delivery System

Abstract

Hydrogen sulfide (H2S) is an important endogenous gasotransmitter, but the targeted delivery and real‐time feedback of exogenous H2S are still challenging. With the aid of density functional theory (DFT) calculations, we designed a new 1,3‐dithiolium‐4‐olate (DTO) compound, which can react with a strained alkyne via the 1,3‐dipolar cycloaddition and the retro‐Diels–Alder reaction to generate carbonyl sulfide (COS) as the precursor of H2S, and a thiophene derivative with turn‐on fluorescence. Moreover, the diphenylamino substituent in DTO greatly increases the mitochondrial targeting of this H2S delivery system. Such a bioorthogonal click‐and‐release reaction has integrated three functions in one system for the first time: (1) in situ controllable H2S release, (2) concomitant fluorescence response, and (3) mitochondria‐targeted delivery. In addition, we investigated the mitochondrial membrane potential loss alleviation by using this system in H9c2 cells under oxidative stress.

Fluorescent small molecule donors

“…67(C) ). 201 Moreover, the introduction of diphenylamino enables mitochondrial targeting and fluorescence tracking of living cells. In addition, the donor alleviates the loss of mitochondrial membrane potential of H9C2 cells under oxidative stress, providing a novel strategy for GT.…”

Smart Lipid Nanoparticle that Remodels Tumor Microenvironment for Activatable H2S Gas and Photodynamic Immunotherapy

“…Gas therapy using the gasotransmitters [e.g., carbon monoxide (CO), nitric oxide (NO)] has shown promise to improve the antitumor effect by regulating the TME, such as ameliorating tumor blood flow, − inducing vascular normalization, − and overcoming hypoxia . Besides NO and CO, H 2 S, the third gaseous signaling molecule, also contributes to maintain homeostasis in biology. − It is recognized that endogenous H 2 S exerts its physiological effects on vasodilation, , angiogenesis, cytoprotection, − and anti-inflammation, , and excessive H 2 S can suppress tumor growth. − Plenty of H 2 S donors have been reported to liberate H 2 S for H 2 S gas therapy; ,− however, it is challenging to precisely control the release of sufficient amount of H 2 S from the donors in tumors to exert the antitumor (not cytoprotection and anti-inflammation) effect. Furthermore, it is still controversial why the excess H 2 S could have an antitumor effect.…”

“…18 Besides NO and CO, H 2 S, the third gaseous signaling molecule, also contributes to maintain homeostasis in biology. 19−22 It is recognized that endogenous H 2 S exerts its physiological effects on vasodilation, 23,24 angiogenesis, 25 cytoprotection, 26−28 and antiinflammation, 28,29 and excessive H 2 S can suppress tumor growth. 30−37 Plenty of H 2 S donors have been reported to liberate H 2 S for H 2 S gas therapy; 31,38−44 however, it is challenging to precisely control the release of sufficient amount of H 2 S from the donors in tumors to exert the antitumor (not cytoprotection and anti-inflammation) effect.…”