Abstract
BackgroundIncidence of pulmonary aspergillosis is rising worldwide, owing to an increased population of immunocompromised patients. Notable potential of the pulmonary route has been witnessed in antifungal delivery due to distinct advantages of direct lung targeting and first-pass evasion. The current research reports biomimetic surface-active lipid-polymer hybrid (LPH) nanoparticles (NPs) of voriconazole, employing lung-specific lipid, i.e., dipalmitoylphosphatidylcholine and natural biodegradable polymer, i.e., chitosan, to augment its pulmonary deposition and retention, following nebulization.ResultsThe developed nanosystem exhibited a particle size in the range of 228–255 nm and drug entrapment of 45–54.8%. Nebulized microdroplet characterization of NPs dispersion revealed a mean diameter of ≤ 5 μm, corroborating its deep lung deposition potential as determined by next-generation impactor studies. Biophysical interaction of LPH NPs with lipid-monolayers indicated their surface-active potential and ease of intercalation into the pulmonary surfactant membrane at the air-lung interface. Cellular viability and uptake studies demonstrated their cytocompatibility and time-and concentration-dependent uptake in lung-epithelial A549 and Calu-3 cells with clathrin-mediated internalization. Transepithelial electrical resistance experiments established their ability to penetrate tight airway Calu-3 monolayers. Antifungal studies on laboratory strains and clinical isolates depicted their superior efficacy against Aspergillus species. Pharmacokinetic studies revealed nearly 5-, 4- and threefolds enhancement in lung AUC, Tmax, and MRT values, construing significant drug access and retention in lungs.ConclusionsNebulized LPH NPs were observed as a promising solution to provide effective and safe therapy for the management of pulmonary aspergillosis infection with improved patient compliance and avoidance of systemic side-effects.
Highlights
Pulmonary aspergillosis (PAP) has raised vital concerns in clinical healthcare, as it mainly affects people with weak immune systems
design of experiments (DoE)‐based screening and optimization studies Considered as a vital prioritization exercise as a prelude to optimization studies, factor screening assumes factor additivity and absence of any interaction(s), calling for employment of an apt linear model (Eq 2)
Additional file 1: Figure S3 illustrates the overlay plot, with design space marked in yellow colour and values of the critical quality attributes (CQAs) obtained for the optimized formulation of chitosan nanoparticles (CH NPs), comprising of CH (2.1 mg mL−1), TPP (1.9 mg mL−1) and Tween 80 (T80) (3.6 mg mL−1) [29]
Summary
Pulmonary aspergillosis (PAP) has raised vital concerns in clinical healthcare, as it mainly affects people with weak immune systems. It is one of the major co-morbid infections in diseases like asthma, influenza, chronic obstructive pulmonary disease, tuberculosis, cancer, etc. Voriconazole, administered through conventional routes, has demonstrated equivalent or superior efficacy to AmB with reduced side-effects in various clinical trials [14, 15]. The current research reports biomimetic surface-active lipid-polymer hybrid (LPH) nanoparticles (NPs) of voriconazole, employing lung-specific lipid, i.e., dipalmitoylphosphatidylcholine and natural biodegradable polymer, i.e., chitosan, to augment its pulmonary deposition and retention, following nebulization
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