title: Endothelial targeting of liposomes encapsulating SOD/catalase mimetic EUK-134 alleviates acute pulmonary inflammation.
abstract: Production of excessive levels of reactive oxygen species (ROS) in the vascular endothelium is a common pathogenic pathway in many dangerous conditions, including acute lung injury, ischemia-reperfusion, and inflammation. Ineffective delivery of antioxidants to the endothelium limits their utility for management of these conditions. In this study, we devised a novel translational antioxidant intervention targeted to the vascular endothelium using PEG-liposomes loaded with EUK-134 (EUK), a potent superoxide dismutase/catalase mimetic. EUK loaded into antibody-coated liposomes (size 197.8±4.5 nm diameter, PDI 0.179±0.066) exerted partial activity in the intact carrier, while full activity was recovered upon liposome disruption. For targeting we used antibodies (Abs) to platelet-endothelial cell adhesion molecule (PECAM-1). Both streptavidin-biotin and SATA/SMCC conjugation chemistries provided binding of 125-150 Ab molecules per liposome. Ab/EUK/liposomes, but not IgG/EUK/liposomes: i) bound to endothelial cells and inhibited cytokine-induced inflammatory activation in vitro; and, ii) accumulated in lungs after intravascular injection, providing >60% protection against pulmonary edema in endotoxin-challenged mice (vs <6% protection afforded by IgG/liposome/EUK counterpart). Since the design elements of this drug delivery system are already in clinical use (PEG-liposomes, antibodies, SATA/SMCC conjugation), it is an attractive candidate for translational interventions using antioxidant molecules such as EUK and other clinically acceptable drugs.
authors.affiliation: Department of Pharmacology and Center for Targeted Therapeutics and Translational Nanomedicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Howard
authors.affiliation: Department of Pharmacology and Center for Targeted Therapeutics and Translational Nanomedicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Emergency Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Colin F
authors.initials: CF
authors.lastname: Greineder
authors.affiliation: Department of Pharmacology and Center for Targeted Therapeutics and Translational 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 Targeted Therapeutics and Translational 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; D000975:Antioxidants / Q000008:administration & dosage* / Q000737:chemistry; D002374:Catalase; D002478:Cells, Cultured; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage* / Q000737:chemistry; D008070:Lipopolysaccharides; D008081:Liposomes; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009942:Organometallic Compounds / Q000008:administration & dosage* / Q000737:chemistry; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology*; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D012459:Salicylates / Q000008:administration & dosage* / Q000737:chemistry; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000737:chemistry; D013482:Superoxide Dismutase; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology
chemical_list: D000975:Antioxidants; C433928:EUK-134; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D008081:Liposomes; D009942:Organometallic Compounds; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012459:Salicylates; D019010:Vascular Cell Adhesion Molecule-1; D012710:Serum Albumin, Bovine; D002374:Catalase; D013482:Superoxide Dismutase
keywords: Antioxidant enzyme mimetic; Antioxidant therapy; Endothelial targeting; Inflammation; Liposomes; Targeted drug delivery