Sodium Thiosulphate-Loaded Liposomes Control Hydrogen Sulphide Release and Retain Its Biological Properties in Hypoxia-like Environment

Abstract

Hypoxia, or insufficient oxygen availability is a common feature in the development of a myriad of cardiovascular-related conditions including ischemic disease. Hydrogen sulphide (H2S) donors, such as sodium thiosulphate (STS), are known for their cardioprotective properties. However, H2S due to its gaseous nature, is released and cleared rapidly, limiting its potential translation to clinical settings. For the first time, we developed and characterised liposome formulations encapsulating STS and explored their potential for modulating STS uptake, H2S release and the ability to retain pro-angiogenic and biological signals in a hypoxia-like environment mirroring oxygen insufficiency in vitro. Liposomes were prepared by varying lipid ratios and characterised for size, polydispersity and charge. STS liposomal encapsulation was confirmed by HPLC-UV detection and STS uptake and H2S release was assessed in vitro. To mimic hypoxia, cobalt chloride (CoCl2) was administered in conjunction with formulated and non-formulated STS, to explore pro-angiogenic and metabolic signals. Optimised liposomal formulation observed a liposome diameter of 146.42 ± 7.34 nm, a polydispersity of 0.22 ± 0.19, and charge of 3.02 ± 1.44 mV, resulting in 25% STS encapsulation. Maximum STS uptake (76.96 ± 3.08%) from liposome encapsulated STS was determined at 24 h. Co-exposure with CoCl2 and liposome encapsulated STS resulted in increased vascular endothelial growth factor mRNA as well as protein expression, enhanced wound closure and increased capillary-like formation. Finally, liposomal STS reversed metabolic switch induced by hypoxia by enhancing mitochondrial bioenergetics. These novel findings provide evidence of a feasible controlled-delivery system for STS, thus H2S, using liposome-based nanoparticles. Likewise, data suggests that in scenarios of hypoxia, liposomal STS is a good therapeutic candidate to sustain pro-angiogenic signals and retain metabolic functions that might be impaired by limited oxygen and nutrient availability.

Hydrogen Sulphide-Based Therapeutics for Neurological Conditions: Perspectives and Challenges

“…In other scenarios of human disease, preclinical studies of nanoparticle delivery of drugs have reported that nanoparticles could not only increase the compounds half-life time but also decrease the amount of drug being eliminated by the reticuloendothelial system, thus, improving stability and increasing drug exposure [ 106 , 107 ]. Recently, in our laboratory, we have explored nanoparticle approaches to encapsulate H 2 S donors, protecting from rapid degradation and release of H 2 S whilst exploring different routes of administration aiming to reduce administration regimes [ 108 – 110 ]. Whilst observations must be confirmed in an in vivo setting, it was noted that liposomes employed to carry ADT-OH across murine skin observed a delayed flux across the skin compared to formulations without liposomes suggesting liposomes may be beneficial in giving a controlled release of drug [ 108 ].…”

“…Whilst observations must be confirmed in an in vivo setting, it was noted that liposomes employed to carry ADT-OH across murine skin observed a delayed flux across the skin compared to formulations without liposomes suggesting liposomes may be beneficial in giving a controlled release of drug [ 108 ]. Furthermore, cationic liposomes used in the controlled release of H 2 S from sodium thiosulphate were able to retain its biological properties in hypoxia-like environment [ 110 ]. Finally, PLGA nanoparticles carrying sodium thiosulphate observed a sustained cellular drug uptake whilst maintaining the pro-angiogenic potential of H 2 S [ 109 ].…”