Abstract by You Xu

Chronic obstructive pulmonary disease (COPD) is a complex and multifactorial obstructive airway disease that is one of the leading cause of morbidity and mortality worldwide. Thermostable dry powder inhaler (DPI) formulations are attractive inhalable dosage forms for local treatment of COPD. Interactions between inhaled particles and pulmonary surfactant (PS) determine the fate of particles, but the mechanisms of these interactions are unknown. We recently demonstrated that lipidoid-polymer hybrid nanoparticles (LPNs) loaded with small interfering RNA (siRNA) directed against tumor necrosis factor alpha (TNF-α) mediate efficient intracellular siRNA delivery and reduce inflammation in vivo. The hypothesis of this project is that DPI formulations containing TNF-α siRNA-loaded LPNs will be safe and efficacious inhalable therapeutic modalities against airway inflammation in COPD.

In this study, the excipients (amino acid and saccharide) used for stabilization of siRNA loaded LPNs during spray drying process were optimized. Subsequent systematic aerosol performance optimization studies of DPI formulations based on TNF-α loaded siRNA LPNs were performed by varying leucine and saccharides ratios. The correlation of aerosol performance with a number of solid-state properties, i.e., the particle morphology, the MMAD, and the residual moisture content, was identified. Further characterization revealed that the chemical integrity of the TNF-α siRNA was stable and the gene silence ability was maintained after spray drying. In vivo pulmonary distribution studies in mice validated that DPI formulation can achieve homogenous deep lung deposition and is suitable for pulmonary delivery. Long-term stability assay confirmed that the DPI formulation was highly stable even in harsh storage conditions. We further evaluated in vitro biophysical interactions between LPNs and PS. Date generated from the interaction of LPNs with different physicochemical properties, i.e., hydrophobicity, membrane fluidity, and surface charge, with pulmonary surfactant guided the design of an optimized nanocarrier for pulmonary delivery. Further characterization revealed that the optimized LPNs do not affact the biophysical function of PS and maintained excellent permeability in PS films. In conslusion, DPI formulations based on TNF-α loaded siRNA LPNs exhibit excellent properties for pulmonary delivery. The LPNs represent a promising drug delivery system to overcome pulmonary bio-barrier and have therapeutic potential for TNF-α siRNA-mediated gene silencing in COPD.