No abstract

Despite the fact that heart transplantation (HTx) is a relatively mature procedure, heart ischemic and reperfusion (I/R) injury during HTx remains a challenge. Even after a successful operation, the heart will be at risk of primary graft failure and mortality during the first year. In this study, temperature-sensitive polymer poly(N-n-propylacrylamide-co-Ntert-butyl acrylamide) (PNNTBA) was coated on diallyl trisulfide (DATS)loaded mesoporous silica nanoparticles (DATS-MSN) to synthesize hypothermia-triggered hydrogen sulfide (H 2 S) releasing particles (HT-MSN). Because the PNNTBA shell dissolves in phosphate-buffered saline at 4 °C, the loaded DATS could continuously release H 2 S within 6 h when activated by glutathione (GSH). Furthermore, after co-culturing biocompatible HT-MSN with cardiomyocytes, H 2 S released from HT-MSN at 4 °C was found to protect cardiomyocytes from ischemic and reperfusion (I/R) injury. In detail, the rate of cell apoptosis and lactate dehydrogenase activity was decreased, as manifested by increased BCL-2 expression and decreased BAX expression. More importantly, in an isolated heart preservation experiment, HT-MSN demonstrated potent protection against cardiac I/R injury and reduced expression of inflammatory factors TNF-α and IL-1β. This study provided a new method for the controlled release of H 2 S by the donor and myocardial protection from I/R injury.

Introduction: Hydrogen sulfide is a cardio-protective gas molecule, which prevents cardiocytes from ischemia-reperfusion injury, and then further improves the transplanted heart performance. However, the instability of hydrogen sulfide restricts its application in cryogenic heart reserving solution. The present study aimed to construct a novel hypothermia-triggered mesoporous silica nanoparticles (HT-MSN) for controlled hydrogen sulfide release. Methods: A polymer as hypothermia trigger was synthesized through free radical copolymerization of N-n-propylacrylamide and N-tert-butylacrylamide with azodiisobutyronitrile as the initiator. The selected diallyl trisulfide, as the hydrogen sulfide donor, was encased in mesoporous silica nanoparticles (MSN) to obtain controlled-release and drug-loaded particles. In order to controllably release hydrogen sulfide from drug-loaded particles in hypothermia, the polymers were coated on the surface of drug-loaded MSN. Characteristics of obtained HT-MSN were evaluated. Cytotoxicity and effects on myocardial protection were further assessed. Results: Combination of nuclear magnetic resonance spectroscopy and gel permeation chromatography determined the synthesized success of the hypothermia-triggered polymer. Further, through adjusting composition of those co-monomers, the polymer showed a lower critical solution temperature of around 7 o C estimated by ultraviolet, indicting the potential for application at lower temperatures. Transmission electron microscope identified characteristics of obtained HT-MSN with uniform size and regular mesoporous. Furthermore, the novel HT-MSN system exhibited low cytotoxicity and acceptable myocardial protection, including anti-apoptosis and antioxidant activities. Conclusion: This study provided a novel hypothermia-triggered platform for controlled hydrogen sulfide release to protect cardiocytes against ischemia-reperfusion injury.