Delivery of anti-platelet-endothelial cell adhesion molecule single-chain variable fragment-urokinase fusion protein to the cerebral vasculature lyses arterial clots and attenuates postischemic brain edema.
Efficacy and safety of current means to prevent cerebrovascular thrombosis in patients at high risk of stroke are suboptimal. In theory, anchoring fibrinolytic plasminogen activators to the luminal surface of the cerebral endothelium might arrest formation of occlusive clots in this setting. We tested this approach using the recombinant construct antiplatelet-endothelial cell adhesion molecule (PECAM) single-chain variable fragment (scFv)-urokinase-type plasminogen activator (uPA), fusing low-molecular-weight single-chain urokinase-type plasminogen activator with a scFv of an antibody directed to the stably expressed endothelial surface determinant PECAM-1, implicated in inflammation and thrombosis. Studies in mice showed that scFv-uPA, but not unconjugated uPA 1) accumulates in the brain after intravascular injection, 2) lyses clots lodged in the cerebral arterial vasculature without hemorrhagic complications, 3) provides rapid and stable cerebral reperfusion, and 4) alleviates post-thrombotic brain edema. Effective and safe thromboprophylaxis in the cerebral arterial circulation by anti-PECAM scFv-uPA represents a prototype of a new paradigm to prevent recurrent cerebrovascular thrombosis.
Danielyan
Kristina
K
Department of Pharmacology and Targeted Therapeutics Program, Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104-6068, USA.
Ding
Bi-Sen
BS
Gottstein
Claudia
C
Cines
Douglas B
DB
Muzykantov
Vladimir R
VR
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects; D001929:Brain Edema / Q000473:pathology / Q000517:prevention & control*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods*; D005342:Fibrinolysis / Q000187:drug effects; D007128:Immunoglobulin Fragments / Q000235:genetics / Q000276:immunology*; D007269:Injections, Intra-Arterial; D020767:Intracranial Thrombosis / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology*; D011355:Prodrugs / Q000008:administration & dosage / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics; D013702:Temporal Lobe / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015912:Thrombolytic Therapy / Q000379:methods; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
D007128:Immunoglobulin Fragments; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011355:Prodrugs; D011993:Recombinant Fusion Proteins; D014568:Urokinase-Type Plasminogen Activator