Optimization and aerodynamic performance of nebulizable pirfenidone-loaded human serum albumin nanoparticles for targeted pulmonary delivery

Idiopathic pulmonary fibrosis (IPF) is a severe fibrotic lung disease associated with poor survival and limited therapeutic efficacy. Oral pirfenidone (PFD), though clinically used, exhibits poor lung accumulation and systemic adverse effects. Human serum albumin (HSA) is a promising drug carrier due to its biocompatibility and ability to enhance solubility and lung targeting. This study developed nebulizable PFD-loaded HSA nanoparticles (PFD-HNPs) to improve pulmonary delivery and antifibrotic efficacy while minimizing systemic toxicity. Formulation parameters, including HSA concentration, pH, and drug loading, were optimized. The resulting PFD-HNPs (∼100 nm, PDI < 0.25, -50 mV) exhibited high entrapment efficiency (63-68%) and maintained physicochemical stability after nebulization. Next-Generation Impactor (NGI) analysis confirmed efficient aerosolization with preferential deposition in stages 5 and 6, indicating favorable lung retention. Cellular studies showed efficient PFD-HNP uptake by NR8383 macrophages and cytoplasmic retention, supporting localized drug reservoir formation. In MRC-5 cells, PFD-HNPs significantly inhibited TGF-β1-induced profibrotic marker expression, demonstrating anti-fibrotic efficacy comparable to that of free PFD. In vivo studies via nebulized inhalation showed no detectable toxicity in major organs. With their stability, efficient aerosol performance, potent antifibrotic effects, and favorable safety profile, PFD-HNPs represent a promising platform for inhaled PFD therapy and offer a potentially safer, more effective strategy for IPF treatment than conventional oral administration.