title: Size and targeting to PECAM vs ICAM control endothelial delivery, internalization and protective effect of multimolecular SOD conjugates.
abstract: Controlled endothelial delivery of SOD may alleviate abnormal local surplus of superoxide involved in ischemia-reperfusion, inflammation and other disease conditions. Targeting SOD to endothelial surface vs. intracellular compartments is desirable to prevent pathological effects of external vs. endogenous superoxide, respectively. Thus, SOD conjugated with antibodies to cell adhesion molecule PECAM (Ab/SOD) inhibits pro-inflammatory signaling mediated by endogenous superoxide produced in the endothelial endosomes in response to cytokines. Here we defined control of surface vs. endosomal delivery and effect of Ab/SOD, focusing on conjugate size and targeting to PECAM vs. ICAM. Ab/SOD enlargement from about 100 to 300nm enhanced amount of cell-bound SOD and protection against extracellular superoxide. In contrast, enlargement inhibited endocytosis of Ab/SOD and diminished mitigation of inflammatory signaling of endothelial superoxide. In addition to size, shape is important: endocytosis of antibody-coated spheres was more effective than that of polymorphous antibody conjugates. Further, targeting to ICAM provides higher endocytic efficacy than targeting to PECAM. ICAM-targeted Ab/SOD more effectively mitigated inflammatory signaling by intracellular superoxide in vitro and in animal models, although total uptake was inferior to that of PECAM-targeted Ab/SOD. Therefore, both geometry and targeting features of Ab/SOD conjugates control delivery to cell surface vs. endosomes for optimal protection against extracellular vs. endosomal oxidative stress, respectively.
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Center for Translational Targeted Therapeutics and Nanomedicine of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Shuvaev
authors.affiliation: Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Muro
authors.affiliation: Department of Medicine, Pulmonary, Allergy and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Evguenia
authors.initials: E
authors.lastname: Arguiri
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Center for Translational Targeted Therapeutics and Nanomedicine of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Makan
authors.initials: M
authors.lastname: Khoshnejad
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Center for Translational Targeted Therapeutics and Nanomedicine of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Samira
authors.initials: S
authors.lastname: Tliba
authors.affiliation: Department of Medicine, Pulmonary, Allergy and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Melpo
authors.initials: M
authors.lastname: Christofidou-Solomidou
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Center for Translational Targeted Therapeutics and Nanomedicine of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: muzykant@mail.med.upenn.edu.
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Muzykantov
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D019446:Endotoxemia / Q000188:drug therapy; D061307:Human Umbilical Vein Endothelial Cells; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology*; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry; D018384:Oxidative Stress / Q000187:drug effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology*; D013482:Superoxide Dismutase / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D013481:Superoxides; D018799:Intercellular Adhesion Molecule-1; D013482:Superoxide Dismutase
keywords: Cell adhesion molecules; Endocytosis; Endothelial cells; Intracellular delivery; Vascular immunotargeting