Abstract 9768: Cr(nMe)eka-Conjugated Micellar Formulation Improves Anticoagulation Efficacy of Bivalirudin
Anticoagulant therapies are the primary treatment modalities for preventing and treating thrombosis. However, high rate of bleeding complications is a serious side effect of anticoagulant therapies, which compromised their applications. Bivalirudin is an oligopeptide anticoagulant that has the advantage of not causing thrombocytopenia and exhibits lower potential for bleeding risk compared to heparin. Nevertheless, hemorrhage is still the most common complication. And there is no effective antidote for bivalirudin. We report here a strategy to deliver bivalirudin specifically to the site of clotting area, and thereby reduce the bleeding risk. The site-specific delivery of bivalirudin was achieved with micellar nanocarriers which has a thrombosis-targeting peptide CR(Nme)EKA. These peptide-conjugated micellar nanocomplexes are highly dispersed and stable in aqueous solution with an average size of 30 nm. The anticoagulant activity of bivalirudin was well remained after it was incorporated into the micelles. These micellar nanocomplexes specifically accumulated in the site of clotting in mice lung thrombosis. Moreover, the micellar formulation significantly prolonged the half-life and increased the bioavailability of bivalirudin. Most importantly, this effective formulation significantly improved the anticoagulant activity of bivalirudin, when tested in both thromboplastin-induced lung thrombosis mouse model and ferric chloride (FeCl3)-induced carotid artery thrombosis mouse model. Taken together, these results demonstrate that the micellar nanocomplexes specifically target thrombi, deliver bivalirudin directly into site of clotting and exhibit improved antithrombotic activity over free bivalirudin. This strategy may improve the safety and efficacy of bivalirudin in clinical use.
Author Disclosures: Z. She: Research Grant; Modest; EnduRx. X. Liu: None. V.R. Kotamraju: None. E. Ruoslahti: None.
- © 2014 by American Heart Association, Inc.