title: Lung inflammation does not affect the clearance kinetics of lipid nanocapsules following pulmonary administration.
abstract: Lipid nanocapsules (LNCs) are semi-rigid spherical capsules with a triglyceride core that present a promising formulation option for the pulmonary delivery of drugs with poor aqueous solubility. Whilst the biodistribution of LNCs of different size has been studied following intravenous administration, the fate of LNCs following pulmonary delivery has not been reported. We investigated quantitatively whether lung inflammation affects the clearance of 50nm lipid nanocapsules, or is exacerbated by their pulmonary administration. Studies were conducted in mice with lipopolysaccharide-induced lung inflammation compared to healthy controls. Particle deposition and nanocapsule clearance kinetics were measured by single photon emission computed tomography/computed tomography (SPECT/CT) imaging over 48 h. A significantly lower lung dose of (111)In-LNC50 was achieved in the lipopolysaccharide (LPS)-treated animals compared with healthy controls (p<0.001). When normalised to the delivered lung dose, the clearance kinetics of (111)In-LNC50 from the lungs fit a first order model with an elimination half-life of 10.5±0.9h (R(2)=0.995) and 10.6±0.3h (R(2)=1.000) for healthy and inflamed lungs respectively (n=3). In contrast, (111)In-diethylene triamine pentaacetic acid (DTPA), a small hydrophilic molecule, was cleared rapidly from the lungs with the majority of the dose absorbed within 20min of administration. Biodistribution to lungs, stomach-intestine, liver, trachea-throat and blood at the end of the imaging period was unaltered by lung inflammation. This study demonstrated that lung clearance and whole body distribution of lipid nanocapsules were unaffected by the presence of acute lung inflammation.
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, UK; Drug Delivery Research Group, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Aateka
authors.initials: A
authors.lastname: Patel
authors.affiliation: Drug Delivery Research Group, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: A
authors.initials: A
authors.lastname: Woods
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Yanira
authors.initials: Y
authors.lastname: Riffo-Vasquez
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, UK; Drug Delivery Research Group, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Babin-Morgan
authors.affiliation: University of Birmingham, Department of Pharmacy, Birmingham B15 2TT, UK.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Jones
authors.affiliation: Drug Delivery Research Group, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Jones
authors.affiliation: Imaging Chemistry & Biomedical Engineering, King's College London, 4th Floor Lambeth Wing, St. Thomas' Hospital, SE1 7EH London, UK.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Sunassee
authors.affiliation: Imaging Chemistry & Biomedical Engineering, King's College London, 4th Floor Lambeth Wing, St. Thomas' Hospital, SE1 7EH London, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Clark
authors.affiliation: Imaging Chemistry & Biomedical Engineering, King's College London, 4th Floor Lambeth Wing, St. Thomas' Hospital, SE1 7EH London, UK.
authors.forename: Rafael
authors.initials: R
authors.lastname: T M de Rosales
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, UK; Drug Delivery Research Group, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Clive
authors.initials: C
authors.lastname: Page
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, UK. Electronic address: domenico.spina@kcl.ac.uk.
authors.forename: Domenico
authors.initials: D
authors.lastname: Spina
authors.affiliation: Drug Delivery Research Group, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: Forbes
authors.affiliation: Drug Delivery Research Group, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Lea Ann
authors.initials: LA
authors.lastname: Dailey
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D006207:Half-Life; D007700:Kinetics; D008055:Lipids / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D053769:Nanocapsules / Q000008:administration & dosage*; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D014018:Tissue Distribution
chemical_list: D008055:Lipids; D008070:Lipopolysaccharides; D053769:Nanocapsules
keywords: Biodistribution; Inflammation; Lipid nanocapsules; Lung clearance kinetics; Pulmonary drug delivery; SPECT/CT