A ROS-responsive, self-immolative and self-reporting hydrogen sulfide donor with multiple biological activities for the treatment of myocardial infarction

Abstract

Myocardial infarction (MI), as one of the leading causes of global death, urgently needs effective therapies. Recently, hydrogen sulfide (H 2 S) has been regarded as a promising therapeutic agent for MI, while its spatiotemporally controlled delivery remains a major issue limiting clinical translation. To address this limitation, we designed and synthesized a novel H 2 S donor (HSD-R) that can produce H 2 S and emit fluorescence in response to reactive oxygen species (ROS) highly expressed at diseased sites. HSD-R can specifically target mitochondria and provide red fluorescence to visualize and quantify H 2 S release in vitro and in vivo . Therapeutically, HSD-R significantly promoted the reconstruction of cardiac structure and function in a rat MI model. Mechanistically, myocardial protection is achieved by reducing cardiomyocyte apoptosis, attenuating local inflammation, and promoting angiogenesis. Furthermore, inhibition of typical pro-apoptotic genes (Bid, Apaf-1, and p53) played an important role in the anti-apoptotic effect of HSD-R to achieve cardioprotection, which were identified as new therapeutic targets of H 2 S against myocardial ischemia injury. This ROS-responsive, self-immolative, and fluorescent H 2 S donor can serve as a new theranostic agent for MI and other ischemic diseases.

A novel fluorescent probe for real-time imaging of thionitrous acid under inflammatory and oxidative conditions

“…S24 ). This result is in accordance with the previous report that this kind of phthalic anhydride derivatives are biocompatible at relatively low concentrations (<60 μM) [ 58 , 59 ]. Then, we evaluated the possible side effects of SNP-1 in mice after intravenous injection of SNP-1 at 50 mg/kg (five folds higher than the dose used for imaging studies in mice).…”

Mitigation of doxorubicin-induced cardiotoxicity with an H2O2-Activated, H2S-Donating hybrid prodrug

“…Pluth and co-workers were the first to report on a small series of H 2 S donors (via the ensuing enzyme-mediated hydrolysis of COS) using this chemistry [ 42 ]. Since this initial report, numerous examples have emerged in the literature [ [45] , [46] , [47] , [48] , [49] ], confirming this as a well-established approach for delivering H 2 S under conditions of cellular oxidative stress. Therefore, with our strategic design of c1 , it was predicted to undergo rapid boronate ester oxidation in the presence of H 2 O 2 , yielding a phenol which would then self-immolate to release both H 2 S (via COS hydrolysis) and free DOX ( Fig.…”

Intelligent polymeric hydrogen sulfide delivery systems for therapeutic applications

“…When photoactivated groups such as o -nitrobenzyl [ 106 ] or boron dipyrromethene chromophores with different substituents [ 107 , 108 ] were linked, UV to NIR light activated H 2 S release could be achieved. In addition, through the linkage of appropriate fluorophores, self-reporting release of COS could also be achieved for real-time monitoring [ [109] , [110] , [111] , [112] ]. Furthermore, an oligo(thiourethane) containing S -alkyl thiocarbamate linkers was synthesized through the polyaddition of 4-isothiocyanatobenzyl alcohol and end-capped with aryl azide, which could undergo self-amplified depolymerization to release multiple equivalents COS in response to per equivalent of H 2 S [ 113 ].…”