RT Journal Article
SR Electronic
T1 Platelet-Endothelial Cell Adhesion Molecule-1-Directed Immunotargeting to Cardiopulmonary Vasculature
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 777
OP 786
DO 10.1124/jpet.300.3.777
VO 300
IS 3
A1 Arnaud Scherpereel
A1 Jonathan J. Rome
A1 Rainer Wiewrodt
A1 Simon C. Watkins
A1 David Winslow Harshaw
A1 Sean Alder
A1 Melpo Christofidou-Solomidou
A1 Elliott Haut
A1 Juan-Carlos Murciano
A1 Marian Nakada
A1 Steven M. Albelda
A1 Vladimir R. Muzykantov
YR 2002
UL http://jpet.aspetjournals.org/content/300/3/777.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics