Micellar nanoformulations for voriconazole pulmonary delivery to optimize allergic bronchopulmonary aspergillosis in cystic fibrosis patients.

MORETTON MA; BRICEÑO FERNANDEZ V; HERMIDA ALAVA KS; FUENTES P; RIEDEL J; BERNABEU, EZEQUIEL; BERTERA F; HOCHT C; CHIAPPETTA DA; CUESTAS ML

Congreso; VI International Congress in Translational Medicine; 2023

Background and Aims: Allergic bronchopulmonary aspergillosis (ABPA) is a severe inflammatory respiratory disorder triggered by repeated exposure to Aspergillus fumigatus in fungal-colonized cystic fibrosis (CF) patients, resulting in pulmonary fibrosis and decline of lung function. ABPA pharmacotherapy involves the oral administration of glucocorticoids alongside azole antifungals, such as voriconazole (VCZ). However, VCZ may induce dose-related side effects (hepatotoxicity, cutaneous malignancies, visual disturbances and neuropsychiatric symptoms). The usefulness of VCZ may be also limited by the inability to reach therapeutic levels in the main focus of infection: the lung using the oral route. Nanotechnology-based pulmonary drug delivery offers an interesting opportunity for an optimized therapy of respiratory diseasesThis study aimed to evaluate the potential of Soluplus® based polymeric micelles as nanosystems for VCZ pulmonary delivery. Methods: Soluplus®, a graft-copolymer based in poly(ethylene glycol) and poly(vinyl caprolactam) poly(vinyl acetate), was employed as biomaterial. VCZ-loaded polymeric micelles (10% w/v) were prepared by a solvent-diffusion technique. Micellar size and size distribution were determined by dynamic light scattering (DLS). Their physicochemical stability was also assessed after sample nebulization in normal saline solution and after sample dilution in simulated interstitial lung fluids by DLS. In vitro cytocompatibility was performed in different cell-lines. The in-vitro susceptibility of the formulation against Aspergillus fumigatus in CF artificial mucus was also tested. Pharmacokinetic profiles and lung exposure were evaluated after intratracheal administration.Results: A highly-concentrated VCZ micellar nanoformulation (5 mg/mL) was developed, within excellent colloidal stability, a micellar size in the nano-scale (~100 nm) and high cytocompatibility. Interestingly, the drug-loaded nanomicelles demonstrated high physicochemical stability during in vitro nebulization and under dilution in simulated interstitial lung fluid. A significant decrement of the in vitro MIC values was observed for VCZ-loaded micelles in all fungal species tested versus the drug suspension. Furthermore, it was observed a significant increment of the VCZ lung exposure (2.1-fold) after the intratracheal administration of the drug-loaded nanomicelles versus VCZ suspension. Conclusions: This highly-concentrated VCZ-micellar system arises as a promising nanoformulation that might be potentially used for the controlled pulmonary VCZ delivery for local therapy of ABPA in FQ patients and other fungal respiratory disorders.