title: Platelet-endothelial cell adhesion molecule-1-directed immunotargeting to cardiopulmonary vasculature.
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 beta-galactosidase (beta-Gal) was coupled to anti-PECAM or IgG (anti-PECAM/beta-Gal and IgG/beta-Gal) and injected into the RCA. Beta-Gal activity was markedly elevated in the heart and lungs (5- and 25-fold increased, respectively) after injection of anti-PECAM/beta-Gal, but not IgG/beta-Gal. Image analysis confirmed endothelial targeting of anti-PECAM/beta-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.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6068, USA.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Scherpereel
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Rome
authors.forename: Rainer
authors.initials: R
authors.lastname: Wiewrodt
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: David Winslow
authors.initials: DW
authors.lastname: Harshaw
authors.forename: Sean
authors.initials: S
authors.lastname: Alder
authors.forename: Melpo
authors.initials: M
authors.lastname: Christofidou-Solomidou
authors.forename: Elliott
authors.initials: E
authors.lastname: Haut
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Murciano
authors.forename: Marian
authors.initials: M
authors.lastname: Nakada
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Muzykantov
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology*; D001710:Biotin / Q000737:chemistry; D003326:Coronary Circulation / Q000187:drug effects*; D003429:Cross Reactions; D016503:Drug Delivery Systems; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D007074:Immunoglobulin G / Q000737:chemistry / Q000276:immunology; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D008168:Lung / Q000166:cytology / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009928:Organ Specificity; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology* / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects*; D013552:Swine; D014018:Tissue Distribution; D001616:beta-Galactosidase / Q000493:pharmacokinetics
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D001710:Biotin; D001616:beta-Galactosidase