title: Targeting of antibody conjugated, phosphatidylserine-containing liposomes to vascular cell adhesion molecule 1 for controlled thrombogenesis.
abstract: Phosphatidylserine (PS) membrane exposure plays an important role in blood coagulation, and the development of a liposome formulation containing PS may be of potential therapeutic utility if they can be designed to achieve tumor selective thrombosis. The objective of this study was to develop proof-of-principle data for a thrombogenic PS liposome targeted to vascular cell adhesion molecule 1 (VCAM-1) via the attachment of an anti-VCAM-1 monoclonal antibody (Ab). We have evaluated binding of the anti-VCAM-1 Ab-conjugated PS liposomes to VCAM-1 using two in vitro models, as well as assessing the ability of these liposomes to catalyze blood coagulation reactions. Binding of the Ab-conjugated PS liposomes containing 2 or 14 mol% 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[poly(ethylene glycol) 2000] (DSPE-PEG(2000)) to interleukin 1alpha stimulated human umbilical vein endothelial cells was 8- and 16-fold higher than those without conjugated Ab, respectively, based on the percentage relative increase in cell associated lipid for these liposomes. Binding to VCAM-1-coated ELISA plates produced similar results. The VCAM-1-bound Ab-conjugated PS liposomes were capable of catalyzing blood coagulation reactions upon the exposure of the thrombogenic PS membrane surface. This control of PS surface exposure was achieved using exchangeable PEG-derivatized phosphatidylethanolamines (PE-PEG), with 97% of clotting activity recovered after PE-PEG exchanged out. Our results demonstrate the potential for considering further development of procoagulant liposomes that selectively target thrombogenesis in tumor vasculature.
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, Canada.
authors.forename: Gigi N C
authors.initials: GN
authors.lastname: Chiu
authors.forename: Marcel B
authors.initials: MB
authors.lastname: Bally
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Mayer
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology; D061067:Antibodies, Monoclonal, Humanized; D001665:Binding Sites; D001777:Blood Coagulation / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006801:Humans; D008081:Liposomes; D009369:Neoplasms / Q000098:blood supply; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010718:Phosphatidylserines / Q000494:pharmacology*; D000068878:Trastuzumab; D014471:Umbilical Veins; D019010:Vascular Cell Adhesion Molecule-1 / Q000737:chemistry* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005343:Fibrinolytic Agents; D008081:Liposomes; D010718:Phosphatidylserines; D019010:Vascular Cell Adhesion Molecule-1; D000068878:Trastuzumab