Abstract
Therapeutic molecules conjugated with antibodies to the platelet-endothelial cell adhesion molecule-1 (PECAM-1) accumulate in the pulmonary endothelium after i.v. injection in mice. In this study, we characterized PECAM-directed targeting to the lung and heart after local versus systemic intravascular administration in a large animal model, pigs. Radiolabel tracing showed that 1 h post-i.v. injection, 35% of anti-PECAM versus 2.5% of control IgG had accumulated in the lungs. Infusion of anti-PECAM via a catheter placed in the right pulmonary artery (RPA) resulted in a 3-fold elevation of the uptake in the right lower lobe and 2-fold reduction of uptake in the left lobes in the lung. Cardiac uptake of anti-PECAM was negligible after i.v. and RPA infusion. In contrast, delivery with a catheter placed in the right coronary artery (RCA) resulted in a 4-fold elevation of cardiac uptake of anti-PECAM, but not IgG, compared with i.v. injection. To estimate the targeting of an active reporter enzyme, streptavidin-conjugated β-galactosidase (β-Gal) was coupled to anti-PECAM or IgG (anti-PECAM/β-Gal and IgG/β-Gal) and injected into the RCA. β-Gal activity was markedly elevated in the heart and lungs (5- and 25-fold increased, respectively) after injection of anti-PECAM/β-Gal, but not IgG/β-Gal. Image analysis confirmed endothelial targeting of anti-PECAM/β-Gal in the heart and lung. In summary, anti-PECAM antibody conjugates deliver agents to the pulmonary endothelium regardless of injection route, whereas local arterial infusion permits targeting to the cardiac vasculature. This paradigm may be useful for drug targeting to endothelium in lungs, heart, and possibly other organs.
Footnotes
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This work was supported by the National American Heart Association (Established Investigator Grant 9640204 to V.R.M. and Initial Investigator Grant SDG 00301920 to M.C.S.), Specialized Center of Research National Institutes of Health (Specialized Center for Research in Atherosclerosis in Acute Lung Injury from National Heart, Lung, and Blood Institute HL 60290, Project 4 to V.R.M. and S.M.A.). A.S. was supported by a grant from French Academy of Medicine (Mitjavile Prize 2000). R.W. is a postdoctoral fellow of the Mildred Scheel Stiftung für Krebsforschung der Deutschen Krebshilfe e. V. (D/98/02288). J.-.C.M. is a fellow from the Spanish Government Research Fellowship. This study was presented as a poster at the American Heart Association Scientific Conference in November 2000.
- Abbreviations:
- PECAM
- platelet-endothelial cell adhesion molecule-1
- mAb
- monoclonal antibody
- SA-β-Gal
- streptavidin-β-galactosidase
- PBS
- phosphate-buffered saline
- ID
- injected dose
- ID/g
- injected dose per gram
- LR
- localization ratio
- ISI
- immunospecificity index
- RPA
- right pulmonary artery
- RCA
- right coronary artery
- FITC
- fluorescein isothiocyanate
- Received October 3, 2001.
- Accepted December 5, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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