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

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

Ba Hieu Tran et al. Int J Nanomedicine.

Abstract

Purpose: 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: S-Propargyl-cysteine; SPRC; TGF-β1/Smad pathway; ZYZ-802; heart failure; hydrogen sulfide; liposome; myocardial fibrosis.

Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Characterization of liposomal ZYZ-802. Morphological analysis of DP-ZYZ-802 and SA-ZYZ-802 was performed by using Transmission electron micrograph.
Figure 2
Figure 2
SA-ZYZ-802 and DP-ZYZ-802 prolong the release of ZYZ-802 as determined in vitro and in vivo. (A) Representative in vitro release profiles of ZYZ-802, DP-ZYZ-802 and SA-ZYZ-802 measured by HPLC (n=3). (B) Plasma concentration–time curves after intravenous injection of ZYZ-802, DP-ZYZ-802 and SA-ZYZ-802 in rats (n=6). (CG) Heart, liver, kidney, spleen and lung tissues ZYZ-802 concentrations at different time points (1, 6, 12 and 24 hrs) after intravenous injection of ZYZ-802, DP-ZYZ-802 and SA-ZYZ-802 in rats (n=6). ZYZ-802 plasma and tissue concentration were measured using LC-MS/MS. The graph is representative of six rats per group and the results are expressed as mean ± SEM. Detailed data are listed in Supplementary Tables S1 and S2.
Figure 3
Figure 3
Liposome formulations increased plasma and tissue H2S concentrations and the protein expression of CSE. (A) Plasma H2S concentrations at different time points after intravenous injection of ZYZ-802, DP-ZYZ-802 and SA-ZYZ-802 in rats, respectively (n=6). The graph is representative of six rats per group and the results are expressed as mean ± SEM. (BF) Heart, liver, kidney, spleen and lung tissues H2S concentrations at different time points after intravenous injection of ZYZ-802, DP-ZYZ-802 and SA-ZYZ-802 in rats, respectively (n=6). After intravenous injection, the concentrations of H2S gas at 1 hr, 6 hrs, 12 hrs and 24 hrs were measured using LC-MS/MS, respectively. The graph is representative of six rats per group and the results are expressed as mean ± SEM. (GH). Finally, the expression of CSE in tissue of animals determined by Western blot (n=6), the blot and bar graph are representative of six independent experiments. Data are presented as fold change of the heart. Results are expressed as mean ± SEM. &P<0.05 vs heart. Detailed data are listed in Supplementary Tables S3 and S4.
Figure 4
Figure 4
DP-ZYZ-802 decreased cardiac fibrosis, infarct size and HW/BW. (A) High-magnification microphotograph of Masson-stained sections from border zones in indicated treatment groups. (B) Photograph of infarct size which was determined following staining with 1% triphenyltetrazolium chloride (TTC). (C) The infarct sizes were calculated by the ratio of the infarct area and left ventricle. The picture and bar graph are representative of eight rats per group (n=8) and the results are expressed as mean ± SEM. (D) Representative statistical analysis of HW/BW with Sham (n=8), HF (n=12), ZYZ-802 (n=10) and DP-ZYZ-802 (n=10). Results are expressed as mean ± SEM, #P<0.05 vs Sham, *P<0.05 vs HF, &P<0.05 vs ZYZ-802.
Figure 5
Figure 5
DP-ZYZ-802 improves cardiac function after myocardial infarction. (AF) Echocardiographic recordings obtained from a short-axis mid-ventrical view of hearts indicating the changes in the ejection fraction (EF), and fractional shortening (FS), left ventricular internal dimension in systole (LVIDs), left ventricular internal dimension in systole (LVAWs), left ventricular posterior wall in systole (LVPWs) and left ventricular volume in systole (LVs) (n=6). The bar graph is representative of six rats per group and the results are expressed as mean ± SEM, #P<0.05 vs Sham, *P<0.05 vs HF, &P<0.05 vs ZYZ-802.
Figure 6
Figure 6
DP-ZYZ-802 alters antioxidant defences and improves cardiac function in myocardial infarction. (AB) Serum levels of BNP and TGF-β1 6 weeks after infarction induction (n=6), and (CE) serum levels of SOD, GSH and MDA in all groups 6 weeks after infarction (n=6). Data are presented as fold change of Sham group. The bar graph is representative of six independent experiments and the results are expressed as mean ± SEM; #P<0.05 vs Sham, *P<0.05 vs HF, &P<0.05 vs ZYZ-802.
Figure 7
Figure 7
DP-ZYZ-802 increases the expression of the H2S biosynthetic enzymes CSE in heart tissues and alleviates cardiac fibrosis after myocardial infarction. (A) The expression of CSE in the heart following Western blot analysis (n=6). (BI) Western blot and statistically analysis indicate that DP-ZYZ-802 decreases the expression of p-Smad2/3, CTGF, Collagen I, α-SMA, MMP-2 and MMP-9 in hearts following myocardial infarction (n=6). The blot and bar graph are representative of six independent experiments. Data are presented as fold change of Sham group. Results are expressed as mean ± SEM, #P<0.05 vs Sham, *P<0.05 vs HF, &P<0.05 vs ZYZ-802.

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