Abstract 15896: Platelet-Targeted Microbubbles Allow Monitoring and Efficacy Testing of Thrombolytic Drugs in Molecular Ultrasound Imaging
Molecular ultrasound imaging offers a non-invasive technology widely available for rapid clinical diagnosis. We tested whether microbubbles (MBs), which are selectively targeted to activated platelets, provide a high-resolution, real-time imaging of thrombosis and monitoring of thrombolysis. We used this approach to evaluate a platelet targeted urokinase plasminogen activator (targ-scuPA) that is hypothesized to offer anti-thrombolytic potency without bleeding complications.
MBs were conjugated to a single-chain antibody specific for an epitope called Ligand Induced Binding Site on activated GPIIb/IIIa (LIBS-MB). LIBS-MBs strongly adhered to immobilized activated platelets and micro-thrombi under flow. Carotid artery thrombi in mice, induced by ferric chloride, were assessed with ultrasound before and after MB injection. Analysis of the thrombus area demonstrated a significant increase in decibel after LIBS-MB but not after MB injection (p<0.01). After thrombolysis with 500U/g BW of commercial urokinase (commUPA), LIBS-MB ultrasound imaging allows monitoring of the reduction in thrombus size (p<0.001). Similar results were obtained when comparing the size to grayscale intensity reduction. In addition, 75U/g BW of targ-scuPA is sufficient for thrombolysis, whereas 75U/g BW of commUPA or non-targ-scuPA are not (p<0.01). 500U/g BW of commUPA, the concentration required to match the effectiveness of 75U/g BW of targ-scuPA, resulted in prolonged tail bleeding time, whereas no increase in bleeding was observed when the equally effective but lower dose of 75U/g BW scuPA (p<0.001). The initial dose of MB administered for imaging of thrombus was sufficient to monitor thrombolysis if this occurred within 30 min. If thrombolytics are applied later than 30 min after the initial MB injection a 2nd dose of MB allowed monitoring of thrombolytic success.
In conclusion, we are able to demonstrate that our targeted MB specifically bind to activated platelets enabling real-time molecular ultrasound imaging of thrombosis and monitoring of success or failure of thrombolysis in vivo. In an exemplary application a highly promising clot-targeted thrombolytic drug was shown to provide effective thrombolytic potential without compromising haemostasis.
- © 2012 by American Heart Association, Inc.