International Journal of Nanomedicine (Dec 2019)
A Novel Liposomal S-Propargyl-Cysteine: A Sustained Release of Hydrogen Sulfide Reducing Myocardial Fibrosis via TGF-β1/Smad Pathway
Abstract
Ba Hieu Tran,1–3 Ying Yu,1,4 Lingling Chang,1 Bo Tan,5 Wanwan Jia,1 Ying Xiong,1 Tao Dai,1 Rui Zhong,1 Weiping Zhang,6 Van Minh Le,7 Peter Rose,8 Zhijun Wang,1,2 Yicheng Mao,1,* Yi Zhun Zhu1,2,* 1School of Pharmacy, Fudan University, Shanghai, People’s Republic of China; 2School of Pharmacy, Macau University of Science and Technology, Taipa, Macau; 3Institute of Biomedicine and Pharmacy, Vietnam Military Medical University, Hanoi, Vietnam; 4Department of Cardiology, Xinhua Hospital, Shanghai, People’s Republic of China; 5Department of Clinical Pharmacology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 6Department of Hematology, Institute of Hematology of PLA, Changhai Hospital, Shanghai, People’s Republic of China; 7NTT Institute of Hi-Technology (NIH), Nguyen Tat Thanh University, Ho Chi Minh City, Viet Nam; 8School of Biosciences, University of Nottingham, Loughborough, LE12 5RD, UK*These authors contributed equally to this workCorrespondence: Yicheng Mao; Yi Zhun ZhuSchool of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, People’s Republic of ChinaTel +86 21 5198 0041; +853 8897 2880Fax +853 2882 3575Email [email protected]; [email protected]: S-propargyl-cysteine (SPRC; alternatively known as ZYZ-802) is a novel modulator of endogenous tissue H2S 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 H2S 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 H2S 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 H2S within tissues.Keywords: liposome, S-Propargyl-cysteine, SPRC, ZYZ-802, hydrogen sulfide, heart failure, myocardial fibrosis, TGF-β1/Smad pathway
