PECAM‐targeted delivery of SOD inhibits endothelial inflammatory response

Abstract

Elevated generation of reactive oxygen species (ROS) by endothelial enzymes, including NADPH-oxidase, is implicated in vascular oxidative stress and endothelial proinflammatory activation involving exposure of vascular cell adhesion molecule-1 (VCAM-1). Catalase and superoxide dismutase (SOD) conjugated with antibodies to platelet/endothelial cell adhesion molecule 1 (PECAM-1) bind specifically to endothelium and inhibit effects of corresponding ROS, H(2)O(2), and superoxide anion. In this study, anti-PECAM/SOD, but not anti-PECAM/catalase or nontargeted enzymes, including polyethylene glycol (PEG)-SOD, inhibited 2- to 3-fold VCAM expression caused by tumor necrosis factor (TNF), interleukin-1β, and lipopolysaccharide. Anti- PECAM/SOD, but not nontargeted counterparts, accumulated in vascular endothelium after intravenous injection, localized in endothelial endosomes, and inhibited by 70% lipopolysaccharide-caused VCAM-1 expression in mice. Anti-PECAM/SOD colocalized with EEA-1-positive endothelial vesicles and quenched ROS produced in response to TNF. Inhibitors of NADPH oxidase and anion channel ClC3 blocked TNF-induced VCAM expression, affirming that superoxide produced and transported by these proteins, respectively, mediates inflammatory signaling. Anti-PECAM/SOD abolished VCAM expression caused by poly(I:C)-induced activation of toll-like receptor 3 localized in intracellular vesicles. These results directly implicate endosomal influx of superoxide in endothelial inflammatory response and suggest that site-specific interception of this signal attained by targeted delivery of anti-PECAM/SOD into endothelial endosomes may have anti-inflammatory effects.

Antioxidant-based therapies for angiotensin II-associated cardiovascular diseases

“…In addition to augmenting antioxidant defenses, Muzykantov and colleagues propose that this immunetargeting strategy may have the added benefit of reducing inflammation and leukocyte-mediated vascular damage by blocking ICAM-1 and PECAM-1 uptake (92,129,138). PECAM-targeted SOD nanocarriers were successful in reducing vascular inflammation (128), while both the immunitytargeted SOD and catalase nanocarriers prevented ROS-induced vascular hyperpermeability (45). The advantageous properties substantiate the therapeutic potential of immunetargeting strategies for tissue edema.…”

The pulmonary endothelium in acute respiratory distress syndrome: insights and therapeutic opportunities

“…Coupled with advanced drug delivery systems (such as liposomes, nanocarriers and host carriers) this methodology may facilitate targeting of specific aspects of lung endothelial injury in ARDS. For example, antioxidants conjugated with antibodies to the endothelial determinant Platelet/Endothelial Cell Adhesion Molecule 1 (PECAM-1) inhibited endothelial activation and reduced VCAM-1 expression in murine lung injury 34. Similarly, dexamethasone-loaded nanogels targeted to ICAM-1 accumulated in murine LPS-injured lungs and blocked expression of ICAM-1 and VCAM-1 at 24 h 35.…”

Endothelial targeting of liposomes encapsulating SOD/catalase mimetic EUK-134 alleviates acute pulmonary inflammation

“…However, ROS are also produced in intracellular compartments of the endothelial cells lining blood vessels in response to inflammatory mediators and other damage-associated signals [10, 11]. In particular, ROS produced in the endosomes activate the NF-κB-mediated signaling pathway leading to endothelial activation and dysfunction, as manifested by expression of inducible adhesion molecules (e.g., VCAM-1) [12], enhanced permeability [13], and loss of the anti-thrombotic phenotype [14], aggravating tissue injury and propagating the vicious cycle of vascular oxidative stress and inflammation [15]. …”