Abstract 12645: Development of Thrombus-Targeting, Stealth Type Nanoparticles Reactivated by Ultrasound For Coronary Thrombolysis
Backgrounds ; Collagen binds von Willebrand factor (vWF) which is a key molecule to form platelet rich thrombus. Based on this data, we developed the thrombus-targeted drug delivery system (DDS) regulated by ultrasound (US) with nanoparticles containing basic gelatin (heat-denatured collagen), and tested its efficacy in thrombolysis with the swine model of acute coronary syndrome (ACS).
Methods and Results ; We generated nanoparticles (100 to 150nm in diameter) composed of tPA (0.5mg/ml), basic gelatin (10mg/ml), and zinc acetate (5mM). In vitro binding assay revealed that basic gelatin and nanoparticles bind vWF, though tPA alone did not. To confirm whether the nanoparticle is targeted to the thrombi in vivo, we generated the nanoparticle with radio-labeled tPA. In the mouse model of arterial thrombosis, intravenous injection of radio-labeled-nanoparticles resulted in 3-fold higher radioactivity at the thrombus site than the injection of radio-labeled-tPA alone (figure 1). Next, we generated the transthoracic US device (1.0MHz, 1.0W/cm2) (TUS), and swine ACS model by balloon injury of left circumflex coronary artery (LCx) with distal balloon protection in 30 swines. The swines were devided into three groups (n=10 in each group): tPA (55,000 units/kg, iv) alone group, tPA+TUS group, and DDS (nanoparticle containing 55,000 units/kg tPA, iv, +TUS) group. The rate of TIMI grade over 2 at 30 minutes were significantly higher in the DDS group (90%) than in the tPA alone (10%, p<0.01) and tPA+TUS (40%, p<0.05) groups (figure 2). Plasma tPA concentration was reduced by 75% by nanoparticle, and was recovered completely at LCx but not at femoral artery by 5 minutes-application of TUS.
Conclusions ; Our new DDS, characterized with thrombus-targeting, stealth type and activity fully recovered with US, is effective for high success rate of coronary thrombolyis. The DDS would be applicable to quick coronary thrombolysis in the ambulance.
- © 2011 by American Heart Association, Inc.