| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Pulmonary Critical Care Division, Department of Medicine, 2 Department of Pathology, 4 Institute of Environmental Medicine, and 5 Department of Pharmacology, University of Pennsylvania Medical Center, Philadelphia 19104; and 3 Department of Pathology, Jefferson University, Philadelphia, Pennsylvania 19107
Vascular immunotargeting is a novel approach for
site-selective drug delivery to endothelium. To validate the strategy,
we conjugated glucose oxidase (GOX) via streptavidin with antibodies to
the endothelial cell surface antigen platelet endothelial cell adhesion
molecule (PECAM). Previous work documented that 1)
anti-PECAM-streptavidin carrier accumulates in the lungs after
intravenous injection in animals and 2) anti-PECAM-GOX binds
to, enters, and kills endothelium via intracellular
H2O2 generation in cell culture. In the present work, we studied the targeting and effect of anti-PECAM-GOX in animals.
Anti-PECAM-GOX, but not IgG-GOX, accumulated in the isolated rat lungs,
produced H2O2, and caused endothelial injury
manifested by a fourfold elevation of angiotensin-converting enzyme
activity in the perfusate. In intact mice, anti-PECAM-GOX accumulated
in the lungs (27 ± 9 vs. 2.4 ± 0.3% injected dose/g for IgG-GOX) and caused severe lung injury and 95% lethality within hours after intravenous injection. Endothelial disruption and blebbing, elevated lung wet-to-dry ratio, and interstitial and alveolar edema indicated that anti-PECAM-GOX damaged pulmonary endothelium. The vascular injury
in the lungs was associated with positive immunostaining for
iPF2
-III isoprostane, a marker for
oxidative stress. In contrast, IgG-GOX caused a minor lung injury and
little (5%) lethality. Anti-PECAM conjugated with inert proteins
induced no death or lung injury. None of the conjugates caused major
injury to other internal organs. These results indicate that an
immunotargeting strategy can deliver an active enzyme to selected
target cells in intact animals. Anti-PECAM-GOX provides a novel model
of oxidative injury to the pulmonary endothelium in vivo.
drug delivery; oxidative stress; CD31; platelet endothelial cell adhesion molecule-1; acute lung injury; hydrogen peroxide; isoprostane
This article has been cited by other articles:
|
|
 |
|
  S. Perkowski, A. Scherpereel, J.-C. Murciano, E. Arguiri, C. C. Solomides, S. M. Albelda, V. Muzykantov, and M. Christofidou-Solomidou Dissociation between alveolar transmigration of neutrophils and lung injury in hyperoxia Am J Physiol Lung Cell Mol Physiol, November 1, 2006; 291(5): L1050 - L1058. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Muro, X. Cui, C. Gajewski, J.-C. Murciano, V. R. Muzykantov, and M. Koval Slow intracellular trafficking of catalase nanoparticles targeted to ICAM-1 protects endothelial cells from oxidative stress Am J Physiol Cell Physiol, November 1, 2003; 285(5): C1339 - C1347. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Christofidou-Solomidou, A. Scherpereel, R. Wiewrodt, K. Ng, T. Sweitzer, E. Arguiri, V. Shuvaev, C. C. Solomides, S. M. Albelda, and V. R. Muzykantov PECAM-directed delivery of catalase to endothelium protects against pulmonary vascular oxidative stress Am J Physiol Lung Cell Mol Physiol, August 1, 2003; 285(2): L283 - L292. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Kanthou and G. M. Tozer The tumor vascular targeting agent combretastatin A-4-phosphate induces reorganization of the actin cytoskeleton and early membrane blebbing in human endothelial cells Blood, March 15, 2002; 99(6): 2060 - 2069. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Scherpereel, J. J. Rome, R. Wiewrodt, S. C. Watkins, D. W. Harshaw, S. Alder, M. Christofidou-Solomidou, E. Haut, J.-C. Murciano, M. Nakada, et al. Platelet-Endothelial Cell Adhesion Molecule-1-Directed Immunotargeting to Cardiopulmonary Vasculature J. Pharmacol. Exp. Ther., March 1, 2002; 300(3): 777 - 786. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. P. McIntosh, X.-Y. Tan, P. Oh, and J. E. Schnitzer Targeting endothelium and its dynamic caveolae for tissue-specific transcytosis in vivo: A pathway to overcome cell barriers to drug and gene delivery PNAS, February 19, 2002; 99(4): 1996 - 2001. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Wiewrodt, A. P. Thomas, L. Cipelletti, M. Christofidou-Solomidou, D. A. Weitz, S. I. Feinstein, D. Schaffer, S. M. Albelda, M. Koval, and V. R. Muzykantov Size-dependent intracellular immunotargeting of therapeutic cargoes into endothelial cells Blood, February 1, 2002; 99(3): 912 - 922. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Stevens, R. Rosenberg, W. Aird, T. Quertermous, F. L. Johnson, J. G. N. Garcia, R. P. Hebbel, R. M. Tuder, and S. Garfinkel NHLBI workshop report: endothelial cell phenotypes in heart, lung, and blood diseases Am J Physiol Cell Physiol, November 1, 2001; 281(5): C1422 - C1433. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Danilov, V. D. Gavrilyuk, F. E. Franke, K. Pauls, D. W. Harshaw, T. D. McDonald, D. J. Miletich, and V. R. Muzykantov Lung uptake of antibodies to endothelial antigens: key determinants of vascular immunotargeting Am J Physiol Lung Cell Mol Physiol, June 1, 2001; 280(6): L1335 - L1347. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
