Inhalable disulfiram pure-drug nanoparticles stabilized by phospholipid/TPSS for effective pulmonary fibrosis treatment in mice.

Abstract

Idiopathic pulmonary fibrosis (IPF) remains an intractable clinical challenge with limited therapeutic options. Disulfiram (DSF), an FDA-approved drug for alcohol disorder, has recently been found to have potential applications in anti-fibrotic therapy. Repurposing DSF for its anti-fibrotic potential is hampered by its poor metabolic stability and bioavailability after oral administration. To overcome these limitations, an innovative inhalable dry powder aerosol was developed in this study for the targeted pulmonary delivery of DSF. A high-drug-loading (41.27%) DSF nanosuspension (DSF-NS) was first prepared via an anti-solvent precipitation method using a novel combined stabilizer composed of hydrogenated soybean phosphatidylcholine (HSPC) and tocopheryl polysarcosine succinate (TPSS). This nanosuspension was subsequently formulated into a porous, wrinkled dry powder using the ultrasonic spray freeze-drying (USFD) technique. The DSF dry powder exhibited an exceptional aerodynamic profile for deep lung deposition, with a fine particle fraction of 43% and a mass median aerodynamic diameter of 3.90 μm. Crucially, in vivo studies confirmed that DSF dry powder achieved extensive and uniform lung distribution, covering approximately 80% of the total lung area, with nanoparticles effectively penetrating the airway mucus and reaching the respiratory bronchioles and alveoli. In a bleomycin-induced mouse model of IPF, inhalation of DSF dry powder at a very low dose (5 mg/kg) significantly attenuated pulmonary fibrosis, demonstrating efficacy comparable to a 60-fold higher oral dose of pirfenidone (300 mg/kg), one of the two FDA-approved first-line therapies for IPF treatment, with no obvious systemic toxicity. This work presents a robust, efficacious, and safe inhalation-based novel DSF dry powder formulation for targeting IPF therapy, effectively leveraging drug repurposing through advanced dry powder aerosol formulation design to achieve remarkable dose-sparing effects and strong clinical translation potential.