title: PECAM-directed delivery of catalase to endothelium protects against pulmonary vascular oxidative stress.
abstract: Targeted delivery of drugs to vascular endothelium promises more effective and specific therapies in many disease conditions, including acute lung injury (ALI). This study evaluates the therapeutic effect of drug targeting to PECAM (platelet/endothelial cell adhesion molecule-1) in vivo in the context of pulmonary oxidative stress. Endothelial injury by reactive oxygen species (e.g., H2O2) is involved in many disease conditions, including ALI/acute respiratory distress syndrome and ischemia-reperfusion. To optimize delivery of antioxidant therapeutics, we conjugated catalase with PECAM antibodies and tested properties of anti-PECAM/catalase conjugates in cell culture and mice. Anti-PECAM/catalase, but not an IgG/catalase counterpart, bound specifically to PECAM-expressing cells, augmented their H2O2-degrading capacity, and protected them against H2O2 toxicity. Anti-PECAM/catalase, but not IgG/catalase, rapidly accumulated in the lungs after intravenous injection in mice, where it was confined to the pulmonary endothelium. To test its protective effect, we employed a murine model of oxidative lung injury induced by glucose oxidase coupled with thrombomodulin antibody (anti-TM/GOX). After intravenous injection in mice, anti-TM/GOX binds to pulmonary endothelium and produces H2O2, which causes lung injury and 100% lethality within 7 h. Coinjection of anti-PECAM/catalase protected against anti-TM/GOX-induced pulmonary oxidative stress, injury, and lethality, whereas polyethylene glycol catalase or IgG/catalase conjugates afforded only marginal protective effects. This result validates vascular immunotargeting as a prospective strategy for therapeutic interventions aimed at immediate protective effects, e.g., for augmentation of antioxidant defense in the pulmonary endothelium and treatment of ALI.
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6068, USA.
authors.forename: Melpo
authors.initials: M
authors.lastname: Christofidou-Solomidou
authors.forename: Arnaud
authors.initials: A
authors.lastname: Scherpereel
authors.forename: Rainer
authors.initials: R
authors.lastname: Wiewrodt
authors.forename: Kimmie
authors.initials: K
authors.lastname: Ng
authors.forename: Thomas
authors.initials: T
authors.lastname: Sweitzer
authors.forename: Evguenia
authors.initials: E
authors.lastname: Arguiri
authors.forename: Vladimir
authors.initials: V
authors.lastname: Shuvaev
authors.forename: Charalambos C
authors.initials: CC
authors.lastname: Solomides
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Muzykantov
mesh_terms: D000818:Animals; D000906:Antibodies; D002374:Catalase / Q000008:administration & dosage* / Q000494:pharmacology; D004337:Drug Carriers; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008171:Lung Diseases / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D055370:Lung Injury; D008654:Mesothelioma; D051379:Mice; D008833:Microcirculation / Q000187:drug effects / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology / Q000502:physiology*; D011652:Pulmonary Circulation / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017382:Reactive Oxygen Species / Q000633:toxicity; D014407:Tumor Cells, Cultured
chemical_list: D000906:Antibodies; D004337:Drug Carriers; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D002374:Catalase