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A chimeric platelet-targeted urokinase prodrug selectively blocks new thrombus formation
- Source :
- Journal of Clinical Investigation. 126:483-494
- Publication Year :
- 2015
- Publisher :
- American Society for Clinical Investigation, 2015.
-
Abstract
- The use of fibrinolytic agents to prevent new thrombus formation is limited by an increased risk of bleeding due to lysis of hemostatic clots that prevent hemorrhage in damaged blood vessels. We sought to develop an agent that provides thromboprophylaxis without carrying a significant risk of causing systemic fibrinolysis or disrupting hemostatic clots. We previously showed that platelet (PLT) α granule-delivered urokinase plasminogen activator (uPA) is highly effective in preventing thrombosis, while being associated with little systemic fibrinolysis or bleeding. Here, we generated a chimeric prodrug composed of a single-chain version of the variable region of an anti-αIIbβ3 mAb fused to a thrombin-activatable, low-molecular-weight pro-uPA (PLT/uPA-T). PLT/uPA-T recognizes human αIIbβ3 on both quiescent and activated platelets and is enzymatically activated specifically by thrombin. We found that this prodrug binds tightly to human platelets even after gel filtration, has a prolonged half-life in mice transgenic for human αIIb compared with that of uPA-T, and prevents clot formation in a microfluidic system. Importantly, in two murine injury models, PLT/uPA-T did not lyse preexisting clots, even when administration was delayed by as little as 10 minutes, while it concurrently prevented the development of nascent thrombi. Thus, PLT/uPA-T represents the prototype of a platelet-targeted thromboprophylactic agent that selectively targets nascent over preexisting thrombi.
- Subjects :
- Blood Platelets
Recombinant Fusion Proteins
medicine.medical_treatment
Mice, SCID
030204 cardiovascular system & hematology
Mice
03 medical and health sciences
Drug Delivery Systems
0302 clinical medicine
Thrombin
Mice, Inbred NOD
Fibrinolysis
medicine
Animals
Humans
Prodrugs
Platelet
Platelet activation
Thrombus
030304 developmental biology
Mice, Knockout
Urokinase
0303 health sciences
Chemistry
Thrombosis
General Medicine
Prodrug
medicine.disease
Urokinase-Type Plasminogen Activator
3. Good health
Immunology
Cancer research
Fibrinolytic agent
Research Article
medicine.drug
Subjects
Details
- ISSN :
- 15588238 and 00219738
- Volume :
- 126
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....72f74dd42e1533f3fca4314ce3de6964