Development of PEG-treprostinil conjugates for sustained local delivery in pulmonary arterial hypertension
(2025)
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- Abstract
- Pulmonary arterial hypertension is a chronic and fatal cardiovascular disease that affects the small arteries of the lungs. Current treatments, including treprostinil, require repeated administration due to their very short duration of action in the body. The objective of this doctoral thesis was to design new prodrugs capable of prolonging the presence of treprostinil in the lungs after inhalation, in order to improve its therapeutic index while reducing the treatment burden for the patient. In the first part, treprostinil was chemically linked to a polyethylene glycol polymer chain via a cleavable ester bond. By modifying the chemical structure around this bond, we showed that it is possible to control the release of the drug in vitro, allowing us to identify the structural features that determine the kinetics of hydrolysis. In the second part, due to a lack of in vivo stability of the polyethylene glycol–treprostinil conjugates, we developed a double prodrug. Treprostinil was esterified both to a polyethylene glycol chain and to a short-chain fatty acid, requiring a two-step enzymatic activation. This strategy allowed a slow and sustained release of treprostinil, increased lung retention after inhalation, and reduced diffusion into the bloodstream. Overall, this work demonstrates that the rational chemical design of polymer–drug conjugates can enable prolonged and targeted pulmonary delivery of treprostinil for the treatment of pulmonary arterial hypertension.
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Citations
Leone, G. (2025). Development of PEG-treprostinil conjugates for sustained local delivery in pulmonary arterial hypertension.