A Novel Liposomal S-Propargyl-Cysteine: A Sustained Release of Hydrogen Sulfide Reducing Myocardial Fibrosis via TGF-β1/Smad Pathway

• Published in: International journal of nanomedicine 2019, Vol.14, p.10061-10077
• Main Authors: Tran, Ba Hieu, Yu, Ying, Chang, Lingling, Tan, Bo, Jia, Wanwan, Xiong, Ying, Dai, Tao, Zhong, Rui, Zhang, Weiping, Le, Van Minh, Rose, Peter, Wang, Zhijun, Mao, Yicheng, Zhu, Yi Zhun
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants - therapeutic use; Cardiotonic Agents - pharmacology; Cardiotonic Agents - therapeutic use; Cystathionine gamma-Lyase - metabolism; Cysteine - analogs & derivatives; Cysteine - chemistry; Disease Models, Animal; Fibrosis; heart failure; Heart Failure - drug therapy; hydrogen sulfide; Hydrogen Sulfide - blood; Hydrogen Sulfide - therapeutic use; liposome; Liposomes; Male; Morphology; myocardial fibrosis; Myocardium - pathology; Original Research; Rats, Sprague-Dawley; s-propargyl-cysteine (sprc; Signal Transduction - drug effects; Smad Proteins - metabolism; tgf-β1/smad pathway; Transforming Growth Factor beta1 - metabolism; zyz-802
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S216667

S-propargyl-cysteine (SPRC; alternatively known as ZYZ-802) is a novel modulator of endogenous tissue H 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. 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 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. Both liposomal formulations improved ZYZ-802 pharmacokinetics and optimized H 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. 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 S within tissues.