title: Vascular Accessibility of Endothelial Targeted Ferritin Nanoparticles.
abstract: Targeting nanocarriers to the endothelium, using affinity ligands to cell adhesion molecules such as ICAM-1 and PECAM-1, holds promise to improve the pharmacotherapy of many disease conditions. This approach capitalizes on the observation that antibody-targeted carriers of 100 nm and above accumulate in the pulmonary vasculature more effectively than free antibodies. Targeting of prospective nanocarriers in the 10-50 nm range, however, has not been studied. To address this intriguing issue, we conjugated monoclonal antibodies (Ab) to ICAM-1 and PECAM-1 or their single chain antigen-binding fragments (scFv) to ferritin nanoparticles (FNPs, size 12 nm), thereby producing Ab/FNPs and scFv/FNPs. Targeted FNPs retained their typical symmetric core-shell structure with sizes of 20-25 nm and ∼4-5 Ab (or ∼7-9 scFv) per particle. Ab/FNPs and scFv/FNPs, but not control IgG/FNPs, bound specifically to cells expressing target molecules and accumulated in the lungs after intravenous injection, with pulmonary targeting an order of magnitude higher than free Ab. Most intriguing, the targeting of Ab/FNPs to ICAM-1, but not PECAM-1, surpassed that of larger Ab/carriers targeted by the same ligand. These results indicate that (i) FNPs may provide a platform for targeting endothelial adhesion molecules with carriers in the 20 nm size range, which has not been previously reported; and (ii) ICAM-1 and PECAM-1 (known to localize in different domains of endothelial plasmalemma) differ in their accessibility to circulating objects of this size, common for blood components and nanocarriers.
authors.forename: Makan
authors.initials: M
authors.lastname: Khoshnejad
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Shuvaev
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Pulsipher
authors.forename: Chuanyun
authors.initials: C
authors.lastname: Dai
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Hood
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pennsylvania, Hospital of the University of Pennsylvania , 835W Gates Building, 3600 Spruce Street, Philadelphia, Pennsylvania 19104, United States.
authors.forename: Evguenia
authors.initials: E
authors.lastname: Arguiri
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pennsylvania, Hospital of the University of Pennsylvania , 835W Gates Building, 3600 Spruce Street, Philadelphia, Pennsylvania 19104, United States.
authors.forename: Melpo
authors.initials: M
authors.lastname: Christofidou-Solomidou
authors.forename: Ivan J
authors.initials: IJ
authors.lastname: Dmochowski
authors.forename: Colin F
authors.initials: CF
authors.lastname: Greineder
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Muzykantov
mesh_terms: D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism*; D005293:Ferritins / Q000737:chemistry*; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles
chemical_list: D005293:Ferritins