Fluticasone Particles Bind to Motile Respiratory Cilia: A Mechanism for Enhanced Lung and Systemic Exposure?

Dani Do Hyang Lee, Daniela Cardinale, Wachirun Terakosolphan, Acom Sornsute, Priya Radhakrishnan, Jonathan Coppel, Claire M. Smith, Somavarapu Satyanarayana, Ben Forbes, Christopher O'Callaghan

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Background: Inhaled corticosteroids (ICSs) are the main prophylactic treatment for asthma and are used in other diseases, including chronic pulmonary obstructive disease, yet the interaction of ICS particles with the ciliated epithelium remains unclear. The aim of this study was to investigate the earliest interaction of aerosolized fluticasone propionate (FP) particles with human ciliated respiratory epithelium. Methods: A bespoke system was developed to allow aerosolized FP particles to be delivered to ciliated epithelial cultures by nebulization and from a pressurized metered-dose inhaler (pMDI) through a spacer with interactions observed in real time using high-speed video microscopy. Interaction with nonrespiratory cilia was investigated using steroids on brain ependymal ciliary cultures. The dissolution rate of steroid particles was determined. Results: FP particles delivered by aerosol attached to the tips of rapidly beating cilia. Within 2 hours, 8.7% ± 1.8% (nebulization) and 12.1% ± 2.1% (pMDI through spacer) of ciliated cells had one or more particles attached to motile cilia. These levels decreased to 5.8% ± 1.6% (p = 0.59; nebulization) and 5.3% ± 2.2% (p = 0.14; pMDI through spacer) at 24 hours. Particle attachment did not affect ciliary beat frequency (p > 0.05) but significantly (p < 0.001) reduced ciliary beat amplitude. Steroid particles also attached to the tips of motile ependymal brain cilia and also reduced beat amplitude (24 hours: >2 particles bound p < 0.001). Dissolution of FP particles was slow with only 22.8% ± 1.3% of nebulized and 12.8% ± 0.5% of pMDI-delivered drug dissolving by 24 hours. Conclusions: FP particles adhere to the tips of rapidly moving cilia with significant numbers remaining bound at 24 hours, resisting the shear stress generated by ciliary beating. In vivo, this mechanism may predispose to high local drug concentrations and enhance respiratory and systemic corticosteroid exposure.

Original languageEnglish
Pages (from-to)181-188
Number of pages8
JournalJournal of Aerosol Medicine and Pulmonary Drug Delivery
Volume34
Issue number3
DOIs
Publication statusPublished - 1 Jun 2021

Keywords

  • inhaled corticosteroid
  • nebulization
  • particle binding
  • pMDI
  • respiratory cilia

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