Targeted delivery of glucocorticoids in the treatment of acute lung injury

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Glucocorticoids (GC) are used to treat a variety of inflammatory diseases including acute lung injury (ALI). Due to a number of complications, efforts are being made to improve this therapeutic regimen. Besides chemical modification, this can be achieved by using novel nanoformulations that allow targeted GC delivery. One example are inorganic-organic hybrid nanoparticles containing betamethasone (BMP-NP), which have a strong anti-inflammatory potential and preferentially act on cells with high endocytic activity. Since we have found that macrophages are important for GC treatment of ALI in mice, we want to investigate the suitability of BMP-NP to replace the free drug and thereby improve efficacy. We will apply BMP-NP in a mouse model of ALI and analyze leukocyte infiltration, production of pro-inflammatory mediators, alveolar-capillary permeability, and structural changes in the lung. Furthermore, we want to determine the cell types being relevant for BMP-NP treatment by using genetically modified mice selectively lacking the GC receptor in macrophages or airway epithelial cells. Based on these results we will test approaches for an active delivery of BMP-NP to these cell types by coupling them to monoclonal antibodies. Since a thorough characterization of BMP-NP is mandatory for further application, mechanistic studies will be conducted as well. We will investigate the endocytic pathway of BMP-NP uptake and their tissue distribution after intraperitoneal injection in mice by imaging flow cytometry, confocal microscopy, magnetic resonance imaging (MRI) and inductively coupled plasma mass spectrometry (ICP-MS). In combination, these experiments will provide a first impression if BMP-NP have the potential for improving ALI therapy in the future.