Toward Repositioning Niclosamide for Antivirulence Therapy of Pseudomonas aeruginosa Lung Infections: Development of Inhalable Formulations through Nanosuspension Technology

摘要: Inhaled antivirulence drugs are currently considered a promising therapeutic option to treat Pseudomonas aeruginosa lung infections in cystic fibrosis (CF). We have recently shown that the anthelmintic drug niclosamide (NCL) has strong quorum sensing (QS) inhibiting activity against P. and could be repurposed as an drug. In this work, we developed dry powders containing NCL nanoparticles can reconstituted saline solution produce inhalable nanosuspensions. were produced by high-pressure homogenization (HPH) using polysorbate 20 or 80 stabilizers. After cycles of HPH, all formulations showed similar properties form needle-shape nanocrystals with hydrodynamic diameter approximately 450 nm zeta potential -20 mV. Nanosuspensions stabilized at 10% w/w (T80_10) optimal solubility profile simulated interstitial fluid. T80_10 was successfully dried into mannitol-based powder spray drying. Dry (T80_10 DP) vitro aerosol performance. Both DP able inhibit QS concentrations 2.5-10 μM. NCL, these did not significantly affect viability CF bronchial epithelial cells microbiologically active (i.e., ≤10 μM). vivo acute toxicity studies rats confirmed no observable formulation upon intratracheal administration concentration 100-fold higher than anti-QS concentration. These preliminary results suggest nanosuspensions great for local treatment case patients.