title: Prevention of vascular inflammation by nanoparticle targeting of adherent neutrophils.
abstract: Inflammatory diseases such as acute lung injury and ischaemic tissue injury are caused by the adhesion of a type of white blood cell--polymorphonuclear neutrophils--to the lining of the circulatory system or vascular endothelium and unchecked neutrophil transmigration. Nanoparticle-mediated targeting of activated neutrophils on vascular endothelial cells at the site of injury may be a useful means of directly inactivating neutrophil transmigration and hence mitigating vascular inflammation. Here, we report a method employing drug-loaded albumin nanoparticles, which efficiently deliver drugs into neutrophils adherent to the surface of the inflamed endothelium. Using intravital microscopy of tumour necrosis factor-α-challenged mouse cremaster post-capillary venules, we demonstrate that fluorescently tagged albumin nanoparticles are largely internalized by neutrophils adherent to the activated endothelium via cell surface Fcɣ receptors. Administration of albumin nanoparticles loaded with the spleen tyrosine kinase inhibitor, piceatannol, which blocks 'outside-in' β2 integrin signalling in leukocytes, detached the adherent neutrophils and elicited their release into the circulation. Thus, internalization of drug-loaded albumin nanoparticles into neutrophils inactivates the pro-inflammatory function of activated neutrophils, thereby offering a promising approach for treating inflammatory diseases resulting from inappropriate neutrophil sequestration and activation.
authors.affiliation: 1] Department of Pharmacology, University of Illinois Chicago College of Medicine, Chicago, Illinois 60612, USA [2] Center for Lung and Vascular Biology, University of Illinois Chicago College of Medicine, Chicago, Illinois 60612, USA [3].
authors.forename: Zhenjia
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, University of Illinois Chicago College of Medicine, Chicago, Illinois 60612, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: 1] Department of Pharmacology, University of Illinois Chicago College of Medicine, Chicago, Illinois 60612, USA [2] Center for Lung and Vascular Biology, University of Illinois Chicago College of Medicine, Chicago, Illinois 60612, USA [3] Department of Anesthesiology, University of Illinois Chicago College of Medicine, Chicago, Illinois 60612, USA.
authors.forename: Jaehyung
authors.initials: J
authors.lastname: Cho
authors.affiliation: 1] Department of Pharmacology, University of Illinois Chicago College of Medicine, Chicago, Illinois 60612, USA [2] Center for Lung and Vascular Biology, University of Illinois Chicago College of Medicine, Chicago, Illinois 60612, USA.
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
mesh_terms: D000818:Animals; D002417:Cattle; D002448:Cell Adhesion; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D017452:Receptors, IgG / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000378:metabolism*; D013267:Stilbenes / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D004337:Drug Carriers; C485700:Fcgr3 protein, mouse; D017452:Receptors, IgG; D013267:Stilbenes; D012710:Serum Albumin, Bovine; C041525:3,3',4,5'-tetrahydroxystilbene; D011505:Protein-Tyrosine Kinases