title: Neutrophil-Mediated Delivery of Therapeutic Nanoparticles across Blood Vessel Barrier for Treatment of Inflammation and Infection.
abstract: Endothelial cells form a monolayer in lumen of blood vessels presenting a great barrier for delivery of therapeutic nanoparticles (NPs) into extravascular tissues where most diseases occur, such as inflammation disorders and infection. Here, we report a strategy for delivering therapeutic NPs across this blood vessel barrier by nanoparticle in situ hitchhiking activated neutrophils. Using intravital microscopy of TNF-α-induced inflammation of mouse cremaster venules and a mouse model of acute lung inflammation, we demonstrated that intravenously (iv) infused NPs made from denatured bovine serum albumin (BSA) were specifically internalized by activated neutrophils, and subsequently, the neutrophils containing NPs migrated across blood vessels into inflammatory tissues. When neutrophils were depleted using anti-Gr-1 in a mouse, the transport of albumin NPs across blood vessel walls was robustly abolished. Furthermore, it was found that albumin nanoparticle internalization did not affect neutrophil mobility and functions. Administration of drug-loaded albumin NPs markedly mitigated the lung inflammation induced by LPS (lipopolysaccharide) or infection by Pseudomonas aeruginosa. These results demonstrate the use of an albumin nanoparticle platform for in situ targeting of activated neutrophils for delivery of therapeutics across the blood vessel barriers into diseased sites. This study demonstrates our ability to hijack neutrophils to deliver nanoparticles to targeted diseased sites.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University , Spokane, Washington 99210, United States.
authors.forename: Dafeng
authors.initials: D
authors.lastname: Chu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University , Spokane, Washington 99210, United States.
authors.forename: Jin
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University , Spokane, Washington 99210, United States.
authors.forename: Zhenjia
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D001808:Blood Vessels / Q000378:metabolism*; D002478:Cells, Cultured; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007239:Infections / Q000188:drug therapy; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D009504:Neutrophils / Q000737:chemistry / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D000900:Anti-Bacterial Agents; D004337:Drug Carriers; D012710:Serum Albumin, Bovine
keywords: blood vessel; infection; inflammation; nanoparticles; neutrophils