H₂S Click Delivery: Responsive Release for Multidimensional Therapy of Thoracic Aortic Dissection

Area of Science:

• Biomaterials Science
• Cardiovascular Research
• Drug Delivery Systems

Background:

• Thoracic aortic dissection (TAD) is a life-threatening cardiovascular emergency with limited pharmacological treatments.
• Endothelial dysfunction and reduced hydrogen sulfide (H2S) levels are key factors in TAD progression.
• Current H2S therapies face challenges due to uncontrolled release and toxicity.

Purpose of the Study:

• To develop a novel, controlled hydrogen sulfide (H2S)-releasing polymer for treating thoracic aortic dissection (TAD).
• To evaluate the efficacy of the developed polymer (PSG12) in cellular and animal models of TAD.

Main Methods:

• A glutathione (GSH)-responsive H2S-releasing polymer (PSG12) was synthesized using a gas-click polymerization strategy.
• PSG12's H2S release kinetics and pharmacokinetic profile were characterized.
• The therapeutic effects of PSG12 were assessed in TNF-α-challenged endothelial cells and BAPN-induced TAD mouse models.

Main Results:

• PSG12 demonstrated tunable and sustained H2S release, maintaining therapeutic plasma levels for 12 hours.
• In vitro, PSG12 significantly reduced oxidative stress, senescence, apoptosis, and inflammation in endothelial cells while preserving the extracellular matrix.
• In vivo, PSG12 treatment reduced aortic rupture incidence and improved survival rates in a mouse model of TAD.

Conclusions:

• PSG12 effectively restores endothelial cell homeostasis through multi-pathway synergistic modulation.
• This GSH-responsive polymer represents a promising precision gas therapy platform for managing thoracic aortic dissection.
• The developed polymer offers a controlled and targeted approach to H2S delivery for cardiovascular emergencies.