Title: Endothelial targeting of liposomes encapsulating SOD/catalase mimetic EUK-134 alleviates acute pulmonary inflammation.
Authors: Howard, Melissa D; Greineder, Colin F; Hood, Elizabeth D; Muzykantov, Vladimir R
Published In J Control Release, (2014 Mar 10)
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.
PubMed ID: 24412573
MeSH Terms: Animals; Antioxidants/administration & dosage*; Antioxidants/chemistry; Catalase; Cells, Cultured; Human Umbilical Vein Endothelial Cells; Humans; Immunoglobulin G/administration & dosage*; Immunoglobulin G/chemistry; Lipopolysaccharides; Liposomes; Male; Mice; Mice, Inbred C57BL; Organometallic Compounds/administration & dosage*; Organometallic Compounds/chemistry; Platelet Endothelial Cell Adhesion Molecule-1/immunology*; Pneumonia/chemically induced; Pneumonia/drug therapy*; Pneumonia/immunology; Salicylates/administration & dosage*; Salicylates/chemistry; Serum Albumin, Bovine/administration & dosage; Serum Albumin, Bovine/chemistry; Superoxide Dismutase; Vascular Cell Adhesion Molecule-1/immunology