Contents lists available at ScienceDirect European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb Research paper In vitro/in vivo investigation on the potential of Pluronic® mixed micelles for pulmonary drug delivery Diogo Silva Pellosi a,1 , Ivana d'Angelo b,1 , Sara Maiolino c , Emma Mitidieri d , Roberta d'Emmanuele di Villa Bianca d , Raffaella Sorrentino d , Fabiana Quaglia c, ⁎ , Francesca Ungaro c a Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo (Unifesp), Rua São Nicolau, 210, 09913-030 Diadema, SP, Brazil b Di.S.T.A.Bi.F., University of Campania “Luigi Vanvitelli”, Via Vivaldi 43, 81100 Caserta, Italy c Laboratory of Drug Delivery, Department of Pharmacy, School of Medicine and Surgery, University of Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy d Laboratory of Pharmacology, Department of Pharmacy, School of Medicine and Surgery, University of Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy ABSTRACT In this paper, we shed light on the potential of Pluronic® mixed micelles in lung delivery of poorly water-soluble drugs. To this purpose, Pluronic® P123/F127 mixed micelles (PMM), exhibiting superior stability in biological fluids, were loaded with budesonide (BUD), a model hydrophobic corticosteroid, and fully investigated focusing on their stability in pulmonary-relevant media, transport through the mucus barrier and aerodynamic behaviour in vitro. Then, lung bio-distribution and efficacy were evaluated in vivo, after intra-tracheal administration in rats. PMM showed excellent stability in saline, mucin, artificial airway mucus and simulated interstitial lung fluid. Likely due to their small size coupled with the hydrophilic biofouling shell, PMM did not interact with mucin and consequently diffused through artificial mucus. BUD was loaded with high efficiency in PMM and released at sustained rate in artificial mucus. BUD-PMM dispersion in saline was efficiently delivered through a common jet nebulizer without aggregation. After intratracheal administration in rats, PMM labelled with Rhodamine B persisted in the lung up to 24 h, while serum levels rapidly dropped. Finally, the effects of BUD- PMM in a rat model of lung inflammation induced by intra-tracheal aerosolization of lipopolysaccharide (LPS) from E. coli were investigated. Of note, a single intra-tracheal aerosolization of BUD-PMM significantly reduced bronchoalveolar neutrophil infiltration and the expression of protein/enzymes derived from the arachidonic acid cascade induced by LPS, whereas a control BUD aqueous suspension showed a weaker effect. Overall, this study demonstrates that inhalable formulations of PMM can be considered as a platform for local delivery of hydro- phobic drugs at lungs worth of further consideration. 1. Introduction Pulmonary delivery systems are in the limelight for local release of active agents in severe lung diseases including cancer, asthma, cystic fibrosis and chronic pulmonary infections [1,2]. In fact, inhalation al- lows direct delivery of the drug to the site of action improving its therapeutic potential, while reducing systemic effects. However, the therapeutic effect will strongly depend upon the fraction of the drug that deposits in the airways, diffuses in lung-lining fluids and interacts with the target cell [1]. Assuming the inhaled drug successfully lands at lungs, mucus layer covering respiratory epithelia represents a physical barrier that can entrap the drug, thus preventing its diffusion towards the target cell and encouraging mucociliary clearance [3–5]. When clearance occurs faster than absorption, as in the case of poorly soluble actives, drug avail- ability at lungs may be further limited [5,6]. Delivery of drugs to the lungs by means of nanoparticulate systems is under investigation to solve these issues. [1,7,8]. A huge number of studies have been recently focused on the de- velopment of polymer nanoparticles for lung delivery [7,9–11], while few works have considered polymeric micelles as drug delivery systems for local lung therapies. One representative of such nanocarriers are https://doi.org/10.1016/j.ejpb.2018.06.006 Received 4 August 2017; Received in revised form 5 June 2018; Accepted 8 June 2018 ⁎ Corresponding author. 1 The authors contributed equally to this work. E-mail address: quaglia@unina.it (F. Quaglia). European Journal of Pharmaceutics and Biopharmaceutics 130 (2018) 30–38 0939-6411/ © 2018 Published by Elsevier B.V. T