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

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  • Additional Information
    • Source:
      Publisher: BioMed Central Country of Publication: England NLM ID: 101152208 Publication Model: Electronic Cited Medium: Internet ISSN: 1477-3155 (Electronic) Linking ISSN: 14773155 NLM ISO Abbreviation: J Nanobiotechnology Subsets: MEDLINE
    • Publication Information:
      Original Publication: London : BioMed Central, 2003-
    • Subject Terms:
      Antifungal Agents/*administration & dosage ; Clathrin/*pharmacology ; Lung/*drug effects ; Nanoparticles/*chemistry ; Pulmonary Aspergillosis/*drug therapy ; Voriconazole/*administration & dosage; A549 Cells ; Administration, Inhalation ; Animals ; Antifungal Agents/chemistry ; Cell Survival ; Chitosan ; Drug Carriers/chemistry ; Drug Delivery Systems ; Humans ; Lipids ; Lung/pathology ; Mice, Inbred BALB C ; Particle Size ; Polymers/pharmacology ; Voriconazole/chemistry ; Mice
    • 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, T max , 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.
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    • Contributed Indexing:
      Keywords: Antifungal; Cell uptake; Chitosan; Hybrid nanoparticles; Inhalation; Lung retention; Phospholipid; Pulmonary aspergillosis; Voriconazole
    • Accession Number:
      0 (Antifungal Agents)
      0 (Clathrin)
      0 (Drug Carriers)
      0 (Lipids)
      0 (Polymers)
      9012-76-4 (Chitosan)
      JFU09I87TR (Voriconazole)
    • Publication Date:
      Date Created: 20210112 Date Completed: 20210914 Latest Revision: 20240226
    • Publication Date:
      20250114
    • Accession Number:
      PMC7798018
    • Accession Number:
      10.1186/s12951-020-00731-1
    • Accession Number:
      33430888