- Title
- Local inflammation alters the lung disposition of a drug loaded pegylated liposome after pulmonary dosing to rats
- Creator
- Haque, Shadabul; Feeney, Orlagh; Meeusen, Els; Boyd, Ben; McIntosh, Michelle; Pouton, Colin; Whittaker, Michael; Kaminskas, Lisa
- Date
- 2019
- Type
- Text; Journal article
- Identifier
- http://researchonline.federation.edu.au/vital/access/HandleResolver/1959.17/187688
- Identifier
- vital:17109
- Identifier
-
https://doi.org/10.1016/j.jconrel.2019.05.043
- Identifier
- ISSN:0168-3659
- Abstract
- The development of inhalable ‘nanomedicines’ based on biocompatible lipids and polymers is attracting increasing interest worldwide. Our understanding of how pulmonary inflammation impacts on lung distribution and clearance kinetics however, is limited. Similarly, there is limited information on how the inhaled delivery of biocompatible nanomaterials affects existing respiratory disease. We have addressed these knowledge gaps by describing and comparing the pulmonary pharmacokinetic behaviour of a 3H-labelled PEGylated liposome loaded with a model drug (ciprofloxacin) after intratracheal administration to healthy rats and rats with bleomycin-induced lung inflammation by following both 3H label and drug. Cell- and cytokine-based markers of lung inflammation were used to evaluate the response of healthy and inflamed lungs to the liposome. Liposomes were initially cleared more rapidly from inflamed lungs than from healthy lungs, but exhibited similar rates of lung clearance after 3 days. This was interesting given that mucociliary clearance was more efficient from healthy lungs, despite evidence of higher mucus retention in inflamed lungs and reduced association of the liposome with lung tissue. Although the plasma pharmacokinetics of ciprofloxacin did not differ between rats with healthy or inflamed lungs after pulmonary administration, the plasma pharmacokinetics of 3H-phosphatidylcholine suggested higher liposome bioavailability and more prolonged absorption from inflamed lungs. Concentrations of the pro-inflammatory cytokine IL-1β were increased in bronchoalveolar lavage fluid after a single pulmonary dose of liposomes to rats with inflamed lungs, but no other significant changes in lung inflammatory markers were identified in healthy or bleomycin-challenged rats. Pulmonary inflammation has a significant impact on the short term disposition, and longer term clearance kinetics and response of the lungs to inhaled drug-loaded PEGylated liposomes after a single pulmonary dose. [Display omitted] •Pulmonary inflammation had a significant impact on the lung disposition of liposome.•Systemic absorption of lipids, but not of drug, was increased in the inflamed lungs.•Lung inflammation reduced the mucociliary clearance of the liposome dose.•A single liposome dose was not found to exacerbate pre-existing lung inflammation.
- Publisher
- Netherlands: Elsevier B.V
- Relation
- Journal of Controlled Release Vol. 307, no. (2019), p. 32-43
- Rights
- All metadata describing materials held in, or linked to, the repository is freely available under a CC0 licence
- Rights
- Copyright Elsevier
- Subject
- Clearance; Drug delivery; Drug delivery systems; Drugs; Inflammation; Inhalation; Lipids; Liposome; Lung inflammation; Mitogens; Pulmonary; Vehicles; 3214 Pharmacology and pharmaceutical sciences; 4003 Biomedical engineering
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