Highly effective inhalable voriconazole-loaded nanomicelles for fungal infections in cystic fibrosis patients: A promising therapeutic strategy for allergic bronchopulmonary aspergillosis

In patients with cystic fibrosis (CF), growth of A. fumigatus and other fungal hyphae within the bronchial lumen can trigger an immunoglobulin E-mediated hypersensitivity response known as allergic bronchopulmonary aspergillosis (ABPA) which can potentially advance to fibrosis. The management of ABPA involves the administration of systemic glucocorticoids alongside azole antifungals, such as voriconazole (VRC). This study evaluated the potential of Soluplus® polymeric micelles as an effective nanocarrier for pulmonary delivery of VRC to improve antifungal therapy in CF patients. The micellar nanoformulation prepared in this study could increase up to 51-fold the aqueous solubility of VRC. Their micellar size, evaluated by dynamic light scattering, was 102.2 ± 1.3 nm for loaded freeze-dried nanoformulations with a unimodal size distribution. Nanomicelles showed excellent colloidal stability during the in vitro nebulization process and under dilution in similar interstitial fluids for pulmonary VRC delivery. Nanoformulations demonstrated high in vitro cytocompatibility in A549 and Vero cells. Interestingly, in vitro antifungal activity of VRC-loaded micelles was at least 2-fold higher than the drug aqueous suspension against different fungal species isolated from CF sputum, regardless of the presence of artificial CF mucus layer. Following single intratracheal dose, significantly (p