Drug targeting to the endothelial cells (EC) along with proper sub-cellular targeting of specific drugs are important and challenging therapeutic goals. One area of special interest is the pulmonary vasculature, a circulation that is a privileged target after IV administration. Pulmonary thrombosis and oxidative stress are important pathological factors in many cardiovascular and pulmonary diseases, such as acute lung injury (ALl). Normal or pathological EC surface determinants could be used for the targeting. Preliminary data indicates that antibodies to InterCellular Adhesion Molecule-i (anti-ICAM) might be especially useful in vascular targeting since: 1) EC poorly internalize monomeric antibodies thus permitting targeting of certain drugs (e.g., anti-thrombotic agents) to the vascular lumen, 2) modification of anti-ICAM antibodies to produce conjugates that are 100-250 nm in diameter allows the intracellular delivery of drugs (e.g antioxidant enzymes, AOE) to EC, 3) expression of ICAM-1, a constitutive EC antigen, is further enhanced upon inflammation, thus potentially facilitating targeting to activated EC, and 4) blockade of ICAM-i by anti-ICAM conjugates may provide secondary anti-inflammatory benefit. The fundamental hypotheses of this proposal are that: 1) anli-ICAM is a unique carrier permitting both surface and intracellular targeting of drugs to endothelium; 2) cellular targeting may be controlled more precisely by regional administration of anti-ICAM conjugates; 3) sub-cellular targeting of cargo may be controlled by the size of the conjugates; and, 4) inflammation facilitates ICAM targeting, while antibody/conjugate binding to ICAM suppresses inflammation. This study will systematically characterize ICAM immunotargeting to endothelium in cell culture and animal models by pursuing the following Specific Aims: 1) Define mechanisms regulating sub-cellular targeting of anti-ICAM conjugates of diverse size; 2) Characterize ICAM-directed targeting in vivo; 3). Evaluate fibrinolysis by anti-thrombotic drugs targeted via ICAM to EC surface; 4) Evaluate protection by antioxidant enzymes (AOE) targeting to ICAM. Our long-term objective is to develop strategies for safe, specific and effective delivery of drugs to EC and to develop methodologies that may be applicable to other cell types. This study will extend and strengthen the ICAM-directed vascular immunotargeting paradigm that may be used for a prophylaxis and therapies of diverse pulmonary and cardiovascular diseases, in particular, ALl.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071175-02
Application #
6637865
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Harabin, Andrea L
Project Start
2002-07-01
Project End
2006-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$342,467
Indirect Cost
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Myerson, Jacob W; Anselmo, Aaron C; Liu, Yaling et al. (2016) Non-affinity factors modulating vascular targeting of nano- and microcarriers. Adv Drug Deliv Rev 99:97-112
Greineder, Colin F; Hood, Elizabeth D; Yao, Anning et al. (2016) Molecular engineering of high affinity single-chain antibody fragment for endothelial targeting of proteins and nanocarriers in rodents and humans. J Control Release 226:229-37
Simone, Eric; Ding, Bi-Sen; Muzykantov, Vladimir (2009) Targeted delivery of therapeutics to endothelium. Cell Tissue Res 335:283-300
Ding, Bi-Sen; Hong, Nankang; Christofidou-Solomidou, Melpo et al. (2009) Anchoring fusion thrombomodulin to the endothelial lumen protects against injury-induced lung thrombosis and inflammation. Am J Respir Crit Care Med 180:247-56
Garnacho, Carmen; Albelda, Steven M; Muzykantov, Vladimir R et al. (2008) Differential intra-endothelial delivery of polymer nanocarriers targeted to distinct PECAM-1 epitopes. J Control Release 130:226-33
Ding, Bi-Sen; Hong, Nankang; Murciano, Juan-Carlos et al. (2008) Prophylactic thrombolysis by thrombin-activated latent prourokinase targeted to PECAM-1 in the pulmonary vasculature. Blood 111:1999-2006
Garnacho, Carmen; Shuvaev, Vladimir; Thomas, Anu et al. (2008) RhoA activation and actin reorganization involved in endothelial CAM-mediated endocytosis of anti-PECAM carriers: critical role for tyrosine 686 in the cytoplasmic tail of PECAM-1. Blood 111:3024-33
Rossin, Raffaella; Muro, Silvia; Welch, Michael J et al. (2008) In vivo imaging of 64Cu-labeled polymer nanoparticles targeted to the lung endothelium. J Nucl Med 49:103-11
Dziubla, Thomas D; Shuvaev, Vladimir V; Hong, Nan Kang et al. (2008) Endothelial targeting of semi-permeable polymer nanocarriers for enzyme therapies. Biomaterials 29:215-27
Shuvaev, Vladimir V; Tliba, Samira; Nakada, Marian et al. (2007) Platelet-endothelial cell adhesion molecule-1-directed endothelial targeting of superoxide dismutase alleviates oxidative stress caused by either extracellular or intracellular superoxide. J Pharmacol Exp Ther 323:450-7

Showing the most recent 10 out of 23 publications