HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by SCHERPEREEL, A. Articles by MUZYKANTOV, V. R. Search for Related Content PubMed PubMed Citation Articles by SCHERPEREEL, A. Articles by MUZYKANTOV, V. R.

Cell-selective intracellular delivery of a foreign enzyme to endothelium in vivo using vascular immunotargeting

ARNAUD SCHERPEREEL^*,1, RAINER WIEWRODT^*,1, MELPO CHRISTOFIDOU-SOLOMIDOU^*, RADJ GERVAIS^*, JUAN-CARLOS MURCIANO, STEVEN M. ALBELDA^* and VLADIMIR R. MUZYKANTOV^,2

^* Pulmonary, Allergy and Critical Care Division, Department of Medicine,
Institute of Environmental Medicine and
Department of Pharmacology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104-6068, USA

²Correspondence: Institute of Environmental Medicine, University of Pennsylvania Medical Center, 1 John Morgan Building, 36th Street and Hamilton Walk, Philadelphia, PA 19104-6068, USA. E-mail: muzykant{at}mail.med.upenn.edu

Vascular immunotargeting, the administration of drugs conjugated with antibodies to endothelial surface antigens, has the potential for drug delivery to the endothelium. Our previous cell culture studies showed that biotinylated antibodies to PECAM-1 (a highly expressed endothelial surface antigen) coupled with streptavidin (SA, a cross-linking protein that facilitates anti-PECAM internalization and targeting) may provide a carrier for the intracellular delivery of therapeutic enzymes. This paper describes the PECAM-directed vascular immunotargeting of a reporter enzyme (ß-galactosidase, ß-Gal) in intact animals. Intravenous injection of [¹²⁵I]SA-ß-Gal conjugated with either anti-PECAM or IgG led to a high ¹²⁵I uptake in liver and spleen, yet ß-Gal activity in these organs rapidly declined to the background levels, suggesting rapid degradation of the conjugates. In contrast, anti-PECAM/[¹²⁵I]SA-ß-Gal, but not IgG/[¹²⁵I]SA-ß-Gal, accumulated in the lungs (36.0±1.3 vs. 3.9±0.6% injected dose/g) and induced a marked elevation of ß-Gal activity in the lung tissue persisting for up to 8 h after injection (10-fold elevation 4 h postinjection). Using histochemical detection, the ß-Gal activity in the lungs was detected in the endothelial cells of capillaries and large vessels. The anti-PECAM carrier also provided ¹²⁵I uptake and ß-Gal activity in the renal glomeruli. Predominant intracellular localization of anti-PECAM/SA-ß-Gal was documented in the PECAM-expressing cells in culture by confocal microscopy and in the pulmonary endothelium by electron microscopy. Therefore, vascular immunotargeting is a feasible strategy for cell-selective, intracellular delivery of an active foreign enzyme to endothelial cells in vivo, and thus may be potentially useful for the treatment of acute pulmonary or vascular diseases.—Scherpereel, A., Wiewrodt, R., Christofidou-Solomidou, M., Gervais, R., Murciano, J.-C., Albelda, S. M., Muzykantov, V. R. Cell-selective intracellular delivery of a foreign enzyme to endothelium in vivo using vascular immunotargeting.

Key Words: drug targeting • lung • PECAM-1 • ß-galactosidase • streptavidin

This article has been cited by other articles:

				V. V. Shuvaev, S. Tliba, M. Nakada, S. M. Albelda, and V. R. Muzykantov 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., November 1, 2007; 323(2): 450 - 457. [Abstract] [Full Text] [PDF]

				B.-S. Ding, T. Dziubla, V. V. Shuvaev, S. Muro, and V. R. Muzykantov Advanced drug delivery systems that target the vascular endothelium. Mol. Interv., April 1, 2006; 6(2): 98 - 112. [Abstract] [Full Text] [PDF]

				B.-S. Ding, C. Gottstein, A. Grunow, A. Kuo, K. Ganguly, S. M. Albelda, D. B. Cines, and V. R. Muzykantov Endothelial targeting of a recombinant construct fusing a PECAM-1 single-chain variable antibody fragment (scFv) with prourokinase facilitates prophylactic thrombolysis in the pulmonary vasculature Blood, December 15, 2005; 106(13): 4191 - 4198. [Abstract] [Full Text] [PDF]

				Y. Zhang and W. M. Pardridge Delivery of {beta}-Galactosidase to Mouse Brain via the Blood-Brain Barrier Transferrin Receptor J. Pharmacol. Exp. Ther., June 1, 2005; 313(3): 1075 - 1081. [Abstract] [Full Text] [PDF]

				S. M. Moghimi, A. C. Hunter, and J. C. Murray Nanomedicine: current status and future prospects FASEB J, March 1, 2005; 19(3): 311 - 330. [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]

				J.-C. Murciano, S. Muro, L. Koniaris, M. Christofidou-Solomidou, D. W. Harshaw, S. M. Albelda, D. N. Granger, D. B. Cines, and V. R. Muzykantov ICAM-directed vascular immunotargeting of antithrombotic agents to the endothelial luminal surface Blood, May 15, 2003; 101(10): 3977 - 3984. [Abstract] [Full Text] [PDF]

				S. Muro, R. Wiewrodt, A. Thomas, L. Koniaris, S. M. Albelda, V. R. Muzykantov, and M. Koval A novel endocytic pathway induced by clustering endothelial ICAM-1 or PECAM-1 J. Cell Sci., April 15, 2003; 116(8): 1599 - 1609. [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]

				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]

				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]