Endothelial-targeted delivery of
antioxidant enzymes,
catalase and
superoxide dismutase (SOD), is a promising strategy for protecting organs and tissues from
inflammation and oxidative stress. Here we describe Protective
Antioxidant Carriers for Endothelial Targeting (PACkET), the first carriers capable of targeted endothelial delivery of both
catalase and SOD. PACkET formed through controlled precipitation loaded ~30%
enzyme and protected it from proteolytic degradation, whereas attachment of PECAM
monoclonal antibodies to surface of the
enzyme-loaded carriers, achieved without adversely affecting their stability and functionality, provided targeting.
Isotope tracing and microscopy showed that PACkET exhibited specific endothelial binding and internalization in vitro. Endothelial targeting of PACkET was validated in vivo by specific (vs
IgG-control) accumulation in the pulmonary vasculature after
intravenous injection achieving 33% of injected dose at 30 min.
Catalase loaded PACkET protects endothelial cells from killing by H2O2 and alleviated the
pulmonary edema and leukocyte infiltration in mouse model of
endotoxin-induced
lung injury, whereas SOD-loaded PACkET mitigated
cytokine-induced endothelial pro-inflammatory activation and
endotoxin-induced
lung inflammation. These studies indicate that PACkET offers a modular approach for vascular targeting of therapeutic
enzymes.