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Purpose: S-propargyl-cysteine (SPRC; alternatively known as ZYZ-802) is a novel modulator of endogenous tissue H 2 S concentrations with known cardioprotective and anti-inflammatory effects. However, its rapid metabolism and excretion have limited its clinical application. To overcome these issues, we have developed some novel liposomal carriers to deliver ZYZ-802 to cells and tissues and have characterized their physicochemical, morphological and pharmacological properties. Methods: Two liposomal formulations of ZYZ-802 were prepared by thin-layer hydration and the morphological characteristics of each liposome system were assessed using a laser particle size analyzer and transmission electron microscopy. The entrapment efficiency and ZYZ-802 release profiles were determined following ultrafiltration centrifugation, dialysis tube and HPLC measurements. LC-MS/MS was used to evaluate the pharmacokinetic parameters and tissue distribution profiles of each formulation via the measurements of plasma and tissues ZYZ-802 and H 2 S concentrations. Using an in vivo model of heart failure (HF), the cardio-protective effects of liposomal carrier were determined by echocardiography, histopathology, Western blot and the assessment of antioxidant and myocardial fibrosis markers. Results: Both liposomal formulations improved ZYZ-802 pharmacokinetics and optimized H 2 S concentrations in plasma and tissues. Liposomal ZYZ-802 showed enhanced cardioprotective effects in vivo. Importantly, liposomal ZYZ-802 could inhibit myocardial fibrosis via the inhibition of the TGF-β1/Smad signaling pathway. Conclusion: The liposomal formulations of ZYZ-802 have enhanced pharmacokinetic and pharmacological properties in vivo. This work is the first report to describe the development of liposomal formulations to improve the sustained release of H 2 S within tissues. Keywords: liposome, S-Propargyl-cysteine, SPRC, ZYZ-802, hydrogen sulfide, heart failure, myocardial fibrosis, TGF-β1/Smad pathway
Tran et al. (Sun,) studied this question.
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