Nebulised surface-active hybrid nanoparticles of voriconazole for pulmonary Aspergillosis demonstrate clathrin-mediated cellular uptake, improved antifungal efficacy and lung retention

Abstract

Background Incidence 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. Results The 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. Conclusions Nebulized 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.

Unraveling the pulmonary drug delivery carriers in inhalable nanostructures

“…In recent decades, inhalation as an intake approach for nano-systems has turned to be a research hotspot. On the one hand, nano-systems for inhalation can augment the accumulation of the drug in the lesion site, which is favorable for the treatment of pulmonary diseases (Kaur et al 2021). On the other hand, the inhaled nano-systems in the environment may cause severe pulmonary diseases like lung fibrosis (Wang et al 2017) and silicosis , particularly for the less degradable ones.…”

Aerosol Delivery of Surfactant Liposomes for Management of Pulmonary Fibrosis: An Approach Supporting Pulmonary Mechanics

“…Langmuir−Blodgett (LB) trough instrument (Biolin Scientific, Manchester, UK) was used. The trough was filled with subphase, 10 mM (pH 7.4) phosphate-buffered saline maintained at 37 ± 0.5 • C [6]. Formulation (3 mL) was added and allowed the formation of a uniform monolayer of surfactant molecules.…”

“…Native pulmonary surfactant consists of a few surfactant proteins and various lipids. Phosphatidylcholine constitutes the major fraction of the lung surfactant [6]. We hypothesized that liposomes engineered using safe, biocompatible endogenous pulmonary surfactant mimetic lipids could support pulmonary mechanics by maintaining airway patency and achieving deep alveolar reach without exhibiting pulmonary toxicity will be a possible approach for efficient yet safe aerosol delivery of the anti-fibrotic drug.…”

Aerosolizable Lipid-Nanovesicles Encapsulating Voriconazole Effectively Permeate Pulmonary Barriers and Target Lung Cells

“…LNVs (i.e., 2 ml) were centrifuged at 20,000 g for 2 h at 10°C. The supernatant was analysed for free voriconazole content using HPLC technique ( Kaur et al, 2021a ; 2021b ) with the mobile phase of acetic acid solution and ACN (50:50) at 1 ml min −1 of flow rate and 20 µL of injection volume. The following equation was used for the calculation of entrapment efficiency.…”