Grant: Travel Awards - Institute Community Support

Patients with cystic fibrosis are in a state of vitaminD deficiency correlated with a decreased lung function. VitaminD dampens inflammatory mediators release from neutrophils and macrophages after bacterial stimulation and increases antimicrobial host defense of these cells. This project aims to test the efficiency of aerosolization of vitaminD3 metabolite (25-hydroxyvitaminD3), 25(OH)D, on bronchial endothelial cells for prophylaxis and treatment of cystic fibrosis. However, the poor aqueous solubility of 25(OH)D represents a pharmaceutical challenge. Thus, liposomes were chosen as the ideal carrier. Nanodispersions were thoroughly characterized for colloidal (dynamic light scattering and zeta-potential measurement), physicochemical (differential scanning calorimetry, content of lipid ingredients and encapsulation efficiency) and aerodynamic properties as well as stability. Next Generation Impactor was used to simulate the airway deposition. Therapeutic efficacy is being tested in vitro using Calu-3 cells as well as in vivo on mice. Seven reproducible liposomes were developed using different molar ratios of DPPC, cholesterol and 25(OH)D. Liposomes were negatively charged, 200nm and stable for 25 days. Colloidal and 25(OH)D stability were not compromised on nebulisation. Most of nebulized liposomes were deposited in the target bronchiolar region. Liposomes were found non-toxic to calu-3 cells. Experiments demonstrating the therapeutic action of 25(OH)D on Calu-3 cells, including cell stimulation with Pseudomonas aeruginosa are ongoing. Infecting mice with Pseudomonas aeruginosa 24 h following administration of selected liposomal formulations resulted in reduction in cytokines release. However no effect on bacterial colonization from broncho-alveolar lavage analysis was observed. The preliminary in vivo results obtained so far represent a proof of concept of the effect of 25(OH)D on damping the release of inflammation mediators as a response to infection.