CONICET | Buscador de Institutos y Recursos Humanos

In this work, a NE-U22 vibrating mesh Omron nebulizer was used to deliver Rh-PE and HPTS/ DPX double labelled macrophage-targeted pH-sensitive archaeosomes (ApH, 174±48 nm, - 30 ± 13 mV unilamellar nanovesicles made of dioleoyl-sn-glycero-3-phosphoethanolamine: [total polar archaeolipids from the hyperhalophile archaebacteria Halorubrum tebenquichense]: cholesterylhemisuccinate 4.2:2.8:3 w:w:w) - on J774A1 cells covered by Prosurf pulmonary surfactant (PS) monolayer at or below the equilibrium surface pressure . The uptake and cytoplasmic drug release from ApH were assessed by flow cytometry of Rh-PE and HPTS fluorescence respectively. Despite of being soft matter submitted to dismantling interactions of shear stress of nebulization and contact with surfactant barrier, at least a fraction of nebulized ApH was found to be stable enough to execute higher cytoplasmic delivery than archaeolipids lacking vesicles. Nebulized ApH increased the PS tensioactivity below e only, out of the physiological range. This would mean that in vivo, changes in lung surfactant function induced by nebulized nanovesicles, is poorly likely to occur. The cytoplasmic delivery from ApH slightly decreased across monolayers at , suggesting that nanovesicles crossed the PS in a fashion inversely related to monolayer compression. Laurdan Generalized Polarization and Fluorescence Anisotropy were used to reveal that nanovesicles neither depleted B and C proteins of the PS, not increased its fluidity. Together with the feasibility of cytoplasmic drug delivery upon nebulization, our results suggest that ApH are structurally unique nanovesicles that would not induce biophysical changes leading to PS inactivation, and open the door to future deeper translationalstudies.

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