Abstract
Modulation of microRNAs (miRNAs), endogenous regulators of gene expression, is a promising strategy for tackling inflammatory lung diseases. In this proof-of-concept study, we tested delivery of miR-17 to bronchial epithelial cells (BECs) using nebulised lipid–polymer hybrid nanoparticles (LPNs). The primary aim was to reduce the induced secretion of miR-17's target, i.e. the pro-inflammatory chemokine interleukin (IL)-8.
Synthetic miR-17 mimics were loaded into LPNs composed of poly(dl-lactic-co-glycolic acid) (PLGA) and the cationic lipid 1,2-dioleoyloxy-3-(trimethylammonium)propane (DOTAP) using a double emulsion solvent evaporation method and nebulised using the Aerogen Solo nebuliser. The physicochemical, aerosol, inflammatory and cytotoxic properties of LPNs were characterised. The effect of LPNs on lipopolysaccharide (LPS)-induced IL-8 production from human NuLi-1 BECs was tested by ELISA.
The z-average, polydispersity index and ζ-potential of the LPNs and the aerodynamic properties of nebulised suspensions were in a range optimal for deposition in the bronchi and bronchioles post-inhalation. Cytotoxic and pro-inflammatory effects were minimal for LPNs loaded with a model cargo. Nebulisation did not affect the physicochemical or functional properties of the LPNs. Nebulised miR-17-loaded LPNs downregulated LPS-induced IL-8 secretion by >40% in BECs.
This study suggests that DOTAP-modified PLGA LPNs are efficient and well-tolerated carriers for delivery of miRNA mimics to BECs.
Abstract
Nebulised miR-17-loaded DOTAP–PLGA nanoparticles are suitable, nontoxic carriers for knockdown of IL-8 in bronchial epithelial cells and form a platform upon which future miRNA-based therapeutics could be developed for inflammatory lung disease http://ow.ly/5iT330nSNZI
Footnotes
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Conflict of interest: S. Vencken reports grants from Science Foundation Ireland, during the conduct of the study.
Conflict of interest: C. Foged has nothing to disclose.
Conflict of interest: J.M. Ramsey has nothing to disclose.
Conflict of interest: L. Sweeney has nothing to disclose.
Conflict of interest: S-A. Cryan has nothing to disclose.
Conflict of interest: R.J. MacLoughlin has nothing to disclose.
Conflict of interest: C.M. Greene reports grants from the National Children's Research Centre and Cystic Fibrosis Foundation Therapeutics during the conduct of the study.
Support statement: Funding for this work is gratefully acknowledged from the National Children's Research Centre (C/13/1 to C.M. Greene), Cystic Fibrosis Foundation Therapeutics (GREENE15XXO), a Science Foundation Ireland Industrial Fellowship (13/IA/1840 to S. Vencken) and a Science Foundation Ireland Investigators Program (13/IA/1840 to S-A. Cryan and J.M. Ramsey). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received September 14, 2018.
- Accepted February 19, 2019.
- Copyright ©ERS 2019
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