Journal
JOURNAL OF CONTROLLED RELEASE
Volume 329, Issue -, Pages 286-298Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2020.11.060
Keywords
Pulmonary arterial hypertension; Hydrogen sulfide; Microspheres; Endothelial-to-mesenchymal transition
Funding
- National Natural Science Foundation of China [81570037, 81971734]
- Guiding Medical Project of Shanghai Science and Technology Committee [19411963300]
- Program for Innovative Research Team in Science and Technology in Fujian Province University
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The designed microfluidics-assisted ACS14-containing LPMs have shown great potential to be used as an inhalable and efficacious H2S donor in the treatment of PAH.
Hydrogen sulfide (H2S) has recently emerged as a novel gaseous mediator with protective actions in the treatment of pulmonary arterial hypertension (PAH). However, the therapeutic potential of H2S in PAH has been substantially hampered due to the lack of appropriate donors that could mimic the slow and continuous generation of H2S in vivo. Large porous microspheres (LPMs) have low density and large surface area leading to excellent absorption capabilities and aerodynamic properties. They are extensively studied as pulmonary delivery carriers for controlled and sustained release of drug molecules in the treatment of pulmonary disorders. Therefore, we hypothesized that LPMs containing H2S-releasing aspirin derivative (ACS14), a novel synthetic H2S donor may be a feasible option to facilitate the use of H2S in PAH treatment. LPMs were prepared with a biodegradable polymer, poly(lactic-co-glycolic acid) (PLGA) by a microfluidic technique. Surface morphology, lung deposition characteristics, safety and H2S release profiles of the formulation were evaluated. The resulting ACS14-containing LPMs (ACS14 MSs) displayed excellent aerodynamic properties (mass median aerodynamic diameter of 4.4 +/- 0.4 mu m), desirable drug loading and entrapment efficiency (25.8 +/- 2.7% and 77.4 +/- 6.9%, respectively) with slow and sustained H2S release for 24 h and negligible cytotoxicity (similar to 95% cell viability). Daily intratracheally administered with ACS14 MSs elicited improvement in the severity of PAH in a rat model of monocrotaline-induced PAH, with comparable efficacy to oral administration with sildenafil, a conventional PAH treatment. It also inhibited the process of endothelial-to-mesenchymal transition (EndMT), an important process in vascular remodeling of PAH by suppressing the induction of NF-kappa B-Snail pathway. Moreover, ACS14 MSs dose-dependently inhibited TGF-beta 1-induced EndMT and the activation of NF-kappa B-Snail pathway in human pulmonary artery endothelial cells. In conclusion, our findings demonstrated that the designed microfluidics-assisted ACS14-containing LPMs have shown great potential to be used as an inhalable and efficacious H2S donor in the treatment of PAH.
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