Abstract 15949: Bivalirudin Nanoparticles Enable Simultaneous Detection and Potent Inhibition of Acute Clotting
Optimization of antithrombotics for emergency treatment of acute arterial or venous occlusions remains a significant research challenge. In recent work, a thrombin-inhibiting perfluorocarbon nanoparticle (PFC NP), functionalized by the direct thrombin inhibitor, PPACK (Phe(D)-Pro-Arg-Chloromethylketone), was presented as a prototype for novel class of targeted antithrombotic. Here, an NP functionalized with Bivalirudin (BVR), was compared to its component drug and the PPACK NP. PPACK or BVR were covalently attached to PFC NPs. Optical assay verified that PPACK and BVR selectivity and activity against thrombin was not diminished on the NPs. In vivo activity was assessed for PPACK NPs, PPACK, BVR, BVR NPs, heparin, non-functionalized NPs, or saline in C57BL6 mice subjected to laser injury of the carotid artery. Time to thrombotic occlusion of the injured artery was assessed via Doppler flow measurement. Selected arteries were excised to assess NP retention via 19F magnetic resonance (MR). PPACK NPs exceeded PPACK's activity against thrombin. BVR activity on NPs was insignificantly diminished versus free BVR. Previously, PPACK NPs outperformed both heparin (p=.001) and PPACK (p=.0006) in delaying occlusion of the carotid artery. PPACK or non-functionalized NPs failed to delay occlusion of the carotid artery. BVR NPs significantly delayed occlusion (p=.02) whereas an equivalent dose of free BVR (120 mg/kg) did not (figure 1a). 19F MR captured PFC NP retention in occluded arteries (figure 1b). Anticoagulant PFC NPs were designed as new antithrombotics with intrinsic magnetic resonance contrast, concentrated therapeutic impact conferred by a thrombin-specific particle surface, and well-defined pharmacokinetics controlled by the particle itself. As potent agents that can enhance the therapeutic performance of different thrombin inhibitors, these NPs are promising new antithrombotics.
- © 2011 by American Heart Association, Inc.