Prophylactic fibrinolysis through selective dissolution of nascent clots by tPA-carrying erythrocytes.
A fibrinolytic agent consisting of a tissue-type plasminogen activator (tPA) coupled to the surface of red blood cells (RBCs) can dissolve nascent clots from within the clot, in a Trojan horse-like strategy, while having minimal effects on preexisting hemostatic clots or extravascular tissue. After intravenous injection, the fibrinolytic activity of RBC-tPA persisted in the bloodstream at least tenfold longer than did that of free tPA. In a model of venous thrombosis induced by intravenously injected fibrin microemboli aggregating in pulmonary vasculature, soluble tPA lysed pulmonary clots lodged before but not after tPA injection, whereas the converse was true for RBC-tPA. Free tPA failed to lyse occlusive carotid thrombosis whether injected before or after vascular trauma, whereas RBC-tPA circulating before, but not injected after, thrombus formation restored blood flow. This RBC-based drug delivery strategy alters the fibrinolytic profile of tPA, permitting prophylactic fibrinolysis.
Murciano
Juan-Carlos
JC
Institute for Environmental Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, Pennsylvania 19104, USA.
Medinilla
Sandra
S
Eslin
Donald
D
Atochina
Elena
E
Cines
Douglas B
DB
Muzykantov
Vladimir R
VR
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D002341:Carotid Artery Thrombosis / Q000188:drug therapy*; D016503:Drug Delivery Systems / Q000379:methods*; D017707:Erythrocyte Transfusion / Q000379:methods*; D004912:Erythrocytes / Q000378:metabolism*; D005342:Fibrinolysis; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D007275:Injections, Intravenous; D051379:Mice; D011655:Pulmonary Embolism / Q000188:drug therapy*; D051381:Rats; D015912:Thrombolytic Therapy / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000378:metabolism*; D016896:Treatment Outcome
D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator