Efficient nebulization and pulmonary biodistribution of polymeric nanocarriers in an acute lung injury preclinical model

Acute respiratory distress syndrome (ARDS) has no a definitive pharmacological treatment, in part, due to the singularity of the lung physiological barrier. Here, we demonstrate the suitability of polymeric nanocapsules (NCs) as a platform for pulmonary delivery of therapeutics by nebulization, evaluating their structural properties and biodistribution in a model of acute lung injury (ALI). Fluorescent poly(lactic-co-glycolic acid) (PLGA) NCs were prepared by a double emulsion-solvent evaporation method. Nebulization was conducted with a commercial vibrating mesh nebulizer. To study the hydrodynamic diameter and morphology of the NCs, a nanoparticle tracking analysis and a scanning electron microscopy evaluation was performed. Besides, the in vivo biodistribution and uptake of NCs was evaluated in healthy and ALI rats. The lungs were analyzed by flow cytometry, confocal microscopy and IVIS. After nebulization the NCs remained spherical and monodispersed, without significant morphological changes. The in vivo studies proved that nebulized NCs were homogeneously distributed in all lung lobes, even in the ALI animals. The cellular uptake of the NCs by epithelial alveolar type II (ATII) cells was significantly higher in healthy animals compared to injured rats (showing 64% and 43% of retention, respectively). Also, nebulization reduced the macrophage-mediated lung clearance of our PLGA NCs promoting NCs tissue retention and absorption. Overall, PLGA NCs are proposed as excellent vehicles for non-invasive pulmonary delivery due to their capacity to withstand nebulization, the ability to accumulate in all the lung lobes, and the capacity to target ATII cells.