Endothelial targeting of nanocarriers loaded with antioxidant enzymes for protection against vascular oxidative stress and inflammation.
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.
Institute for Translational Medicine and Therapeutics, Department of Pharmacology, University of Pennsylvania School of Medicine, USA; Institute for Translational Medicine and Therapeutics, University of Pennsylvania, USA. Electronic address: ehood@mail.med.upenn.edu.
Elizabeth D
ED
Hood
Department of Pediatrics, The Children's Hospital of Philadelphia, USA; Institute for Translational Medicine and Therapeutics, University of Pennsylvania, USA.
Michael
M
Chorny
Institute for Translational Medicine and Therapeutics, Department of Pharmacology, University of Pennsylvania School of Medicine, USA; Institute for Translational Medicine and Therapeutics, University of Pennsylvania, USA.
Colin F
CF
Greineder
Department of Pediatrics, The Children's Hospital of Philadelphia, USA; Institute for Translational Medicine and Therapeutics, University of Pennsylvania, USA.
Ivan
I
S Alferiev
Department of Pediatrics, The Children's Hospital of Philadelphia, USA; Institute for Translational Medicine and Therapeutics, University of Pennsylvania, USA.
Robert J
RJ
Levy
Institute for Translational Medicine and Therapeutics, Department of Pharmacology, University of Pennsylvania School of Medicine, USA; Institute for Translational Medicine and Therapeutics, University of Pennsylvania, USA. Electronic address: muzykant@mail.med.upenn.edu.
Vladimir R
VR
Muzykantov
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D019921:Biotinylation; D002374:Catalase / Q000378:metabolism*; D002417:Cattle; D004337:Drug Carriers / Q000737:chemistry*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D018384:Oxidative Stress / Q000187:drug effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D020442:Poloxamer / Q000737:chemistry; D051381:Rats; D013482:Superoxide Dismutase / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D004337:Drug Carriers; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D020442:Poloxamer; D002374:Catalase; D013482:Superoxide Dismutase
Antioxidant enzymes; Inflammation; In vivo vascular targeting; Nanoparticles; Platelet endothelial cellular adhesion molecules