Pulmonary surfactant-based pirfenidone-loaded nanovesicles for inhalation therapy of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal chronic disease. One of the Food and Drug Administration (FDA)-approved therapies for IPF, oral pirfenidone (PFD), has limited clinical applications owing to its systemic side effects. In contrast to oral administration, inhaled therapy offers enhanced therapeutic efficacy at the target organ while minimizing systemic side effects. However, its application has challenges, such as limited drug delivery to the distal lung region and rapid clearance. In this study, we developed pulmonary surfactant (PS)-based PFD-loaded nanovesicles (PFD-PSNVs) for targeted delivery to the lung area and prolonged retention and examined their safety, stability, and antifibrotic efficacy. PFD-PSNVs were prepared using the thin-film hydration and extrusion method. The mean size and zeta potential of PFD-PSNVs were 149.7 ± 10.1 nm and - 31.3 ± 2.3 mV, respectively. An in vitro antifibrotic study showed that PFD-PSNVs inhibited the expression of fibrotic factors such as p-ERK, p-SMAD2/3, and α-SMA proteins on fibroblasts activated by transforming growth factor-β1. When inhaled in mice using a nebulizer, the PFD-PSNVs remained in lung tissues for 24 h, whereas Arikayce, an FDA-approved liposomal formulation for inhalation, was eliminated within 6 h. In a bleomycin sulfate-induced IPF mouse model, inhalation treatment with PFD-PSNVs significantly reduced collagen deposition (76.2 ± 4.1 %, p < 0.01) and α-SMA expression (60.8 ± 3.7 %, p < 0.05) compared with inhalation treatment with the PFD-loaded CtrlNV (PFD-CNVs) formulation and oral administration of PFD. These results indicate that PSNVs have great potential as an inhaled drug delivery system for the treatment of IPF.