“Thrombin sponge”: A potent nanoparticle approach to inhibiting coagulation in acute thrombosis

Abstract

An anticoagulant perfluorocarbon (PFC) nanoparticle (NP) was designed as a new antithrombotic with intrinsic magnetic resonance contrast, concentrated therapeutic impact conferred by a thrombin‐absorbing particle surface, and well‐defined pharmacokinetics controlled by the particle itself.The irreversible thrombin inhibitor, PPACK (Phe(D)‐Pro‐Arg‐Chloromethylketone), was covalently attached to PFC NPs. Optical assay verified that PPACK activity against thrombin and selectivity for thrombin over plasmin was not diminished on the NPs. In vivo activity was assessed for PPACK NPs, PPACK, 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. 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. 19F MR captured PFC NP retention in occluded arteries.PPACK NPs utilize the long circulating half‐life of the PFC NPs to present thrombin absorbing surfaces that prevent thrombus formation. As potent new antithrombotics that can be traced with 19F MR, PPACK NPs are promising therapeutics.