Abstract 18315: A Thrombus-specific Drug Delivery System Using Biological Polymer Micelle Complex for the Treatment of Actively Forming Vascular Thromboembolism
Treatments for vascular thrombosis such as systemic anticoagulants are often limited by continuous infusion and bleeding complications. We sought to develop a novel drug-delivery system that is targeted and more effective in inhibiting thrombus formation. Biological micelle was selected for its small size, a modifiable surface structure to attach target-specific molecule, and a drug-loading capacity. Micelle was consisted of hydrophilic-hydrophobic interactions of mPEG-PCL (methoxy poly(ethylene glycol)-poly(caprolactone)) and pluronic F-127. A pentapeptide CREKA (H-Cys-Arg-Glu-Lys-Ala-OH), which has been shown to have a high affinity to fibrinogen-fibrin complex, was covalently bounded to micelle for target specific attachment to actively forming thrombus. Tirofiban, a glycoprotein IIb-IIIa inhibitor, was selected for this study because of its high potency but high risk of bleeding. First, the half-life of micelle complex was about 15 hours. Then, we evaluated these micelles for in vivo bleeding time using tail vein puncture. We found that micelle complex loaded with tirofiban with CREKA showed 40% increase in the bleeding time compared to the micelle without CREKA suggesting effective site-specific attachment and inhibition of thrombus formation. For therapeutic efficacy of drug-loaded micelle complex, inferior vena cava (IVC) was banded to make an 80-90% stenosis, which resulted in subacute thrombus formation within 48 hours. Animals with IVC stenosis were treated with micelle containing 10% of weight-adjusted therapeutic dose of tirofiban. The micelle treated group showed superior thrombus-suppressing effect with 65% reduction in thrombus weight to those treated with 10% of tirofiban without micelle complex in i.p. administration every 8 hours, and 49% reduction compared to continuous administration of tirofiban using osmotic pump. Thus, our micelle complex showed thrombus-specific binding capacity, and demonstrated significantly lower need for therapeutic dose of tirofiban to achieve similar thrombus-suppressing effects as full tirofiban dosage. Thus, this novel drug-delivery system using micelle complex could be used to treat thromboembolism diseases with greater potency and with less bleeding risk.
Author Disclosures: J. Yoon: None. C. Kang: None. O. Hwang: None. B. Cho: None. D. Lee: None. P.M. Kang: None.
- © 2014 by American Heart Association, Inc.