title: Mechanisms that determine nanocarrier targeting to healthy versus inflamed lung regions.
abstract: Inflamed organs display marked spatial heterogeneity of inflammation, with patches of inflamed tissue adjacent to healthy tissue. To investigate how nanocarriers (NCs) distribute between such patches, we created a mouse model that recapitulates the spatial heterogeneity of the inflammatory lung disease ARDS. NCs targeting the epitope PECAM strongly accumulated in the lungs, but were shunted away from inflamed lung regions due to hypoxic vasoconstriction (HVC). In contrast, ICAM-targeted NCs, which had lower whole-lung uptake than PECAM/NCs in inflamed lungs, displayed markedly higher NC levels in inflamed regions than PECAM/NCs, due to increased regional ICAM. Regional HVC, epitope expression, and capillary leak were sufficient to predict intra-organ of distribution of NCs, antibodies, and drugs. Importantly, these effects were not observable with traditional spatially-uniform models of ARDS, nor when examining only whole-organ uptake. This study underscores how examining NCs' intra-organ distribution in spatially heterogeneous animal models can guide rational NC design.
authors.affiliation: Pulmonary and Critical Care Division, University of Pennsylvania, Philadelphia, PA, USA; Department of Pharmacology and Center for Translational Targeted Therapeutics and Nanomedicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jacob S
authors.initials: JS
authors.lastname: Brenner
authors.affiliation: Department of Pharmacology and Center for Translational Targeted Therapeutics and Nanomedicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Kartik
authors.initials: K
authors.lastname: Bhamidipati
authors.affiliation: Department of Pharmacology and Center for Translational Targeted Therapeutics and Nanomedicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Glassman
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Ramakrishnan
authors.affiliation: Department of Respiratory Medicine, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Depeng
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Pulmonary and Critical Care Division, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Paris
authors.affiliation: Department of Pharmacology and Center for Translational Targeted Therapeutics and Nanomedicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jacob W
authors.initials: JW
authors.lastname: Myerson
authors.affiliation: Department of Pharmacology and Center for Translational Targeted Therapeutics and Nanomedicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Pan
authors.affiliation: Department of Pharmacology and Center for Translational Targeted Therapeutics and Nanomedicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Shuvaev
authors.affiliation: Department of Pharmacology and Center for Translational Targeted Therapeutics and Nanomedicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Carlos H
authors.initials: CH
authors.lastname: Villa
authors.affiliation: Department of Pharmacology and Center for Translational Targeted Therapeutics and Nanomedicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Hood
authors.affiliation: Department of Pharmacology and Center for Translational Targeted Therapeutics and Nanomedicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Raisa
authors.initials: R
authors.lastname: Kiseleva
authors.affiliation: Department of Pharmacology and Center for Translational Targeted Therapeutics and Nanomedicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Colin F
authors.initials: CF
authors.lastname: Greineder
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Radhakrishnan
authors.affiliation: Department of Pharmacology and Center for Translational Targeted Therapeutics and Nanomedicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: muzykant@mail.med.upenn.edu.
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Muzykantov
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics*; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D000860:Hypoxia / Q000503:physiopathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology; D012128:Respiratory Distress Syndrome / Q000378:metabolism / Q000473:pathology; D014661:Vasoconstriction
chemical_list: D000906:Antibodies; D004337:Drug Carriers; D000939:Epitopes; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1
keywords: ARDS; Inflammation; Nano-bio interface; Nanocarriers; Nanoparticle biological interactions; Nanoparticles; Patchy; Spatial heterogeneity; Whole organ distribution