Thrombosis (blood clot) is characterized by the recruitment and aggregation of platelets and fibrin deposition. Hydrogen peroxide (H2O2) is a key mediator of platelet activation and aggregation and H2O2-mediated platelet activation is one of mechanisms leading to prothrombotic phenotypes. H2O2 activates platelet-endothelium interactions, facilitating inflammation and development of atherosclerotic vascular diseases. As a clotted plasma protein, Fibrin exists in the form of cross-linked mesh deposited both inside and on the surface of atherosclerotic plaques and plays an important role in the stabilization of thrombus. By taking advantages of elevated level of H2O2 and abundance of fibrin during thrombus formation, we developed a novel thrombus-targeted imaging and antithrombotic nanoplatform, which is able to specifically target thrombus, scavenge H2O2 and inhibit thrombus formation in injured vasculature. The nanoplatform was formulated with antioxidant and anti-inflammatory boronate polymer (BAP-IR) and fibrin targeted lipopeptides (DSPE-CREKA). BAP-IR was designed to covalently incorporate H2O2-scavenging boronate and near infrared fluorescent IR-820 and release bioactive hydroxybenzyl alcohol (HBA) after H2O2-mediated boronate oxidation. BAP-IR rapidly scavenged H2O2 and underwent H2O2-triggered hydrolysis to release HBA. BAP-IR and lipopeptides were self-assembled to form thermodynamically stable micelles with a mean diameter of ~120 nm. The micelles could target blot clots and reduce the generation of H2O2 in platelets activated by calcium chloride and thrombin in vitro. In the study of a mouse model of ferric chloride-induced carotid artery thrombosis, the micelles could image ferric chloride-induced thrombus, reduce inflammatory responses and significantly inhibited blot clotting. When anti-thrombotic drug, tirofiban was loaded in the micelles, they exerted remarkable anti-thrombotic effects. Given their excellent biocompatibility, antioxidant and anti-inflammatory activity, BAP-IR has great potential as an imaging and therapeutic agent for obstructive thrombosis.

H2O2-activatable and clot-targeting antithrombotic polymeric nanoparticles

251st National Meeting (2016)

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