Nature Biotechnology
21, 891 - 896 (2003)
Published online: 6 July 2003; | doi:10.1038/nbt846
Prophylactic fibrinolysis through selective dissolution of nascent
clots by tPA-carrying erythrocytesJuan-Carlos Murciano1, Sandra Medinilla1, Donald Eslin2, Elena Atochina3, Douglas B Cines4
& Vladimir R Muzykantov1, 51
Institute for Environmental Medicine, University
of Pennsylvania, 3620 Hamilton Walk,
Philadelphia, Pennsylvania 19104,
USA. 2
Division of Pediatric Hematology, Children's
Hospital of Philadelphia, 1 Civic Center,
Philadelphia, Pennsylvania 19104,
USA. 3
Department of Medicine, University of
Pennsylvania, 421 Curie Blvd., Philadelphia,
Pennsylvania 19104, USA. 4
Department of Pathology and Laboratory Medicine,
University of Pennsylvania, 422 Curie Blvd.,
Philadelphia, PA 19104, USA. 5
Department of Pharmacology, University of
Pennsylvania, 3620 Hamilton Walk,
Philadelphia, Pennsylvania 19104,
USA.
Correspondence should be addressed to Vladimir R Muzykantov muzykant@mail.med.upenn.eduA 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.
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