Targeted treprostinil delivery inhibits pulmonary arterial remodeling

Introduction: Pulmonary arterial hypertension (PAH) is a fatal disease caused by the progressive remodeling of pulmonary arteries (PAs). Treprostinil (TPS) is a tricyclic benzidine prostacyclin clinically used for PAH treatment. However, due to low bioavailability, short half-times, and severe systemic side effects, TPS efficacy remains limited. Methods: In this study, glucuronic acid (GlcA)-modified liposomes were developed to improve the site-specific delivery of TPS to pulmonary arterial smooth muscle cells (PASMCs) by targeting the glucose transporter-1 (GLUT-1) in vitro and in vivo. Results: Non-GlcA-modified and GlcA-modified liposomes encapsulating TPS were 106 +/- 1.12 nm in diameter. The drug encapsulation efficiency (EE) was 92%. Data from rat PASMCs showed that GlcA-liposomes enhanced the inhibitory effects of TPS on PASMC proliferation and migration by suppressing growth factor expression, including transforming growth factor -beta 1 (TGF-beta 1), connective tissue growth factor (CTGF), and cAMP, which was possibly mediated by the cAMP-C/EBP-alpha p42-p21 signaling pathway. In PAH model rats, GlcA-modified liposomes significantly improved TPS bioavailability and sustained its release over time. Most importantly, the selective inhibition of pulmonary arterial pressure, rather than systemic arterial pressure, indicated the increased pulmonary-specific accumulation of TPS. Of the three TPS formulations, TPS-loaded GlcA-modified liposomes exhibited the most potent activity by inhibiting PA remodeling and muscularization, decreasing PA medial thickening, suppressing collagen deposition in PAs, and attenuating right ventricle hypertrophy (RVH) in sugen-5416-induced PAH rats. Conclusions: The GLUT-1-targeted delivery of TPS increased pulmonary specificity and enhanced TPS anti-PAH activities in vivo and in vitro.

Automated summary

This study developed GlcA-modified liposomes to enhance the delivery of TPS to pulmonary arterial smooth muscle cells (PASMCs) and improve its effectiveness against PAH. The GlcA-liposomes significantly increased TPS bioavailability and sustained release, while also inhibiting PA remodeling and muscularization, decreasing PA medial thickening, suppressing collagen deposition, and attenuating right ventricle hypertrophy. In vitro experiments showed that GlcA-liposomes enhanced the inhibitory effects of TPS on PASMC proliferation and migration.