Lung Disease Management by Iloprost-Loaded Nanoparticles to Address Hyperinflammation Associated with Cystic Fibrosis

Abstract

Here, iloprost-loaded polymeric nanoparticles were embedded into mannitol microparticles by the nano into micro (NiM) strategy and were proposed as an inhalable formulation for the management of hyperinflammation associated with cystic fibrosis (CF). To do this, a polymeric derivate was synthesized by functionalization of alpha,beta-poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA) with 3.2 mol % of poly(lactic-co-glycolic acid) (PLGA) and 4.5 mol % of poly(ethylene glycol) (PEG), which was used as a starting material to produce iloprost-loaded pegylated nanoparticles (NP_PEG+Ilo) by nanoprecipitation. These nanoparticles showed colloidal size (similar to 150 nm) and negative zeta potential; thanks to the high surface pegylation degree (35 molecules/100 nm(2)), they did not interact with mucins and were able to ensure a sustained release of the entrapped drug in a simulated physiological fluid (55 wt % after 24 h incubation). Then, the NP_PEG+Ilo particles were embedded in mannitol-based microparticles by spray-drying. The obtained NiM showed adequate characteristics for pulmonary administration in CF patients, such as spherical shape, micrometric size (similar to 2 mu m), the capability to not interact with the components of CF artificial mucus, and, once dispersed with water, the ability to rapidly dissolve and release the NP_PEG+Ilo. Moreover, the NP_PEG+Ilo, entrapped into NiM particles, exhibited high cytocompatibility and a pronounced anti-inflammatory effect toward CFBE cells overexpressing F508del CFTR (CFBE-F508del) in terms of reduction of IL-1 beta, TNF-alpha, IL-6, and IL-8 gene expression, thus demonstrating that this formulation could represent a potential pulmonary carrier for iloprost.