title: In vivo biocompatibility, clearance, and biodistribution of albumin vehicles for pulmonary drug delivery.
abstract: The development of clinically acceptable albumin-based nanoparticle formulations for use in pulmonary drug delivery has been hindered by concerns about the toxicity of nanomaterials in the lungs combined with a lack of information on albumin nanoparticle clearance kinetics and biodistribution. In this study, the in vivo biocompatibility of albumin nanoparticles was investigated following a single administration of 2, 20, and 390μg/mouse, showing no inflammatory response (TNF-α and IL-6, cellular infiltration and protein concentration) compared to vehicle controls at the two lower doses, but elevated mononucleocytes and a mild inflammatory effect at the highest dose tested. The biodistribution and clearance of (111)In labelled albumin solution and nanoparticles over 48h following a single pulmonary administration to mice was investigated by single photon emission computed tomography and X-ray computed tomography imaging and terminal biodistribution studies. (111)In labelled albumin nanoparticles were cleared more slowly from the mouse lung than (111)In albumin solution (64.1±8.5% vs 40.6±3.3% at t=48h, respectively), with significantly higher (P<0.001) levels of albumin nanoparticle-associated radioactivity located within the lung tissue (23.3±4.7%) compared to the lung fluid (16.1±4.4%). Low amounts of (111)In activity were detected in the liver, kidneys, and intestine at time points >24h indicating that small amounts of activity were cleared from the lungs both by translocation across the lung mucosal barrier, as well as mucociliary clearance. This study provides important information on the fate of albumin vehicles in the lungs, which may be used to direct future formulation design of inhaled nanomedicines.
authors.affiliation: Drug Delivery Research Group, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London, SE1 9NH, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Woods
authors.affiliation: Drug Delivery Research Group, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London, SE1 9NH, United Kingdom; Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Patel
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom.
authors.forename: D
authors.initials: D
authors.lastname: Spina
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom.
authors.forename: Y
authors.initials: Y
authors.lastname: Riffo-Vasquez
authors.affiliation: Drug Delivery Research Group, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London, SE1 9NH, United Kingdom; Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Babin-Morgan
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, King's College London, 4th Floor Lambeth Wing, St Thomas' Hospital, London SE1 7EH, United Kingdom.
authors.forename: R T M
authors.initials: RT
authors.lastname: de Rosales
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, King's College London, 4th Floor Lambeth Wing, St Thomas' Hospital, London SE1 7EH, United Kingdom.
authors.forename: K
authors.initials: K
authors.lastname: Sunassee
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, King's College London, 4th Floor Lambeth Wing, St Thomas' Hospital, London SE1 7EH, United Kingdom.
authors.forename: S
authors.initials: S
authors.lastname: Clark
authors.affiliation: Division of Immunology, Infection & Inflammatory Diseases, Guy's Campus, King's College London, 15-16 Newcomen Street, London SE1 1UL, United Kingdom.
authors.forename: H
authors.initials: H
authors.lastname: Collins
authors.affiliation: Drug Delivery Research Group, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London, SE1 9NH, United Kingdom.
authors.forename: K
authors.initials: K
authors.lastname: Bruce
authors.affiliation: Drug Delivery Research Group, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London, SE1 9NH, United Kingdom. Electronic address: lea_ann.dailey@kcl.ac.uk.
authors.forename: L A
authors.initials: LA
authors.lastname: Dailey
authors.affiliation: Drug Delivery Research Group, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London, SE1 9NH, United Kingdom.
authors.forename: B
authors.initials: B
authors.lastname: Forbes
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D016503:Drug Delivery Systems; D015850:Interleukin-6 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000196:embryology; D008168:Lung / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage; D009569:Nitric Oxide / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D012710:Serum Albumin, Bovine; D009569:Nitric Oxide
keywords: Albumin nanoparticles; Alveolar macrophages; Biodistribution; Nanomedicine; Pulmonary drug delivery; SPECT/CT