Vascular oxidative stress is a key component of many lung diseases, but its treatment is inadequate, in part due to sub-optimal delivery of antioxidants to endothelial cells (EC). Previous studies have shown that: 1) antibodies to Platelet Endothelial Adhesion Molecule (PECAM) permit intracellular delivery of drugs to EC via a novel endocytotic pathway distinct from clathrin- and caveoli-mediated endocytosis; and 2) the antioxidant enzyme (AOE) catalase conjugated with anti-PECAM accumulates in the lungs after IV injection and protects against oxidative lung injury in some animal models.
The aim of this translational grant is to enhance the duration and effectiveness of protective effects of this promising strategy to clinically significant levels. We hypothesize that: i) the activity of the conjugates can be prolonged by optimization of their design and by manipulating intracellular trafficking and lysosomal degradation; ii) targeted delivery of additional AOEs to EC will permit enhanced protection from oxidative stress; and iii) pulmonary targeting of optimized AOE conjugates will be protective against hyperoxia. We will test this in the following Specific Aims: 1) define the mechanisms of metabolism of anti-PECAM conjugates in EC. We will test the hypothesis that endocytosis and trafficking involve the cytosolic domain of PECAM, Na+-H+ exchangers (NHE) and rearrangements of cytoskeleton, which can be affected by auxiliary agents to prolong duration of conjugates; 2) design targeting of additional AOE. To enhance protection, tandem SOD/catalase (to detoxify 02- and H202) and 1-CysPrx peroxiredoxin (to detoxify H202 and lipid peroxides) conjugates will be produced. Their composition, activities, EC uptake and protection will be studied in cell culture, while their pharmacokinetics and pulmonary targeting will be determined in naive animals and animals with oxidative lung injury; and 3) evaluate protective effects of the conjugates in animal models. The effectiveness and duration of the effects of new conjugates will be compared and regimens of AOE targeting and mechanisms of protection will be studied in a model of acute EC injury induced by H202 in the pulmonary vasculature in mice. Finally, protection against hyperoxic lung injury by best conjugates will be tested. The overall goal of this proposal is to optimize strategies for vascular AOE targeting, to ultimately initiate translation of this strategy into the clinical domain.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073940-02
Application #
6875601
Study Section
Special Emphasis Panel (ZRG1-LBPA (02))
Program Officer
Harabin, Andrea L
Project Start
2004-04-01
Project End
2008-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
2
Fiscal Year
2005
Total Cost
$396,250
Indirect Cost
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Shuvaev, Vladimir V; Kiseleva, Raisa Yu; Arguiri, Evguenia et al. (2018) Targeting superoxide dismutase to endothelial caveolae profoundly alleviates inflammation caused by endotoxin. J Control Release 272:1-8
Shuvaev, Vladimir V; Muro, Silvia; Arguiri, Evguenia et al. (2016) Size and targeting to PECAM vs ICAM control endothelial delivery, internalization and protective effect of multimolecular SOD conjugates. J Control Release 234:115-23
Shuvaev, Vladimir V; Brenner, Jacob S; Muzykantov, Vladimir R (2015) Targeted endothelial nanomedicine for common acute pathological conditions. J Control Release 219:576-595
Han, Jingyan; Shuvaev, Vladimir V; Davies, Peter F et al. (2015) Flow shear stress differentially regulates endothelial uptake of nanocarriers targeted to distinct epitopes of PECAM-1. J Control Release 210:39-47
Chacko, Ann-Marie; Han, Jingyan; Greineder, Colin F et al. (2015) Collaborative Enhancement of Endothelial Targeting of Nanocarriers by Modulating Platelet-Endothelial Cell Adhesion Molecule-1/CD31 Epitope Engagement. ACS Nano 9:6785-93
Howard, Melissa D; Greineder, Colin F; Hood, Elizabeth D et al. (2014) Endothelial targeting of liposomes encapsulating SOD/catalase mimetic EUK-134 alleviates acute pulmonary inflammation. J Control Release 177:34-41
Howard, Melissa D; Hood, Elizabeth D; Zern, Blaine et al. (2014) Nanocarriers for vascular delivery of anti-inflammatory agents. Annu Rev Pharmacol Toxicol 54:205-26
Hood, Elizabeth D; Chorny, Michael; Greineder, Colin F et al. (2014) Endothelial targeting of nanocarriers loaded with antioxidant enzymes for protection against vascular oxidative stress and inflammation. Biomaterials 35:3708-15
Shuvaev, Vladimir V; Han, Jingyan; Tliba, Samira et al. (2013) Anti-inflammatory effect of targeted delivery of SOD to endothelium: mechanism, synergism with NO donors and protective effects in vitro and in vivo. PLoS One 8:e77002
Hood, Elizabeth D; Greineder, Colin F; Dodia, Chandra et al. (2012) Antioxidant protection by PECAM-targeted delivery of a novel NADPH-oxidase inhibitor to the endothelium in vitro and in vivo. J Control Release 163:161-9

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