Publications & Reports

Shear sensitive nanocapsule drug release for site specific inhibition of occlusive thrombus formation.

Molloy CP, Yao Y, Kammoun H, Bonnard T, Hoefer T, Alt K, Tovar-Lopez F, Rosengarten G, Ramsland PA, van der Meer AD, van den Berg A, Murphy AJ, Hagemeyer CE, Peter K, Westein E

Abstract

BACKGROUND: Myocardial infarction and stroke remain the leading causes of mortality and morbidity. The major limitation of current antiplatelet therapy is that their effective concentrations are limited due to bleeding complications. Targeted delivery of antiplatelet drug to sites of thrombosis would overcome these limitations.

OBJECTIVES: Here, we have exploited a key biomechanical feature specific to thrombosis; significantly increased blood shear stress due to a reduction in the lumen of the vessel, to achieve site directed delivery of the clinically used antiplatelet agent eptifibatide using shear-sensitive phosphatidylcholine based nanocapsules.

METHODS: 2.8x1012 PC based nanocapsules with high dose encapsulated eptifibatide were introduced in microfluidic blood perfusion assays and in in vivo models of thrombosis and tail bleeding.

RESULTS: Shear-triggered nanocapsule delivery of eptifibatide inhibited in vitro thrombus formation selectively under stenotic and high shear flow conditions above 1,000 s-1 shear rate while leaving thrombus formation under physiological shear rates unaffected. Thrombosis was effectively prevented in in vivo models of vessel wall damage. Importantly, mice infused with shear sensitive antiplatelet nanocapsules did not display prolonged bleeding times.

CONCLUSIONS: Targeted delivery of eptifibatide by shear-sensitive nanocapsules offers site specific antiplatelet potential and may form a basis for developing more potent and safer antiplatelet drugs. This article is protected by copyright. All rights reserved.

Link to publisher’s web site

This work was supported by grants from the National Health and Medical Research Council Australia (NHMRC; 1083138 and 1050018) and Perpetual grants Australia (FR2014/0941). CEH and EW were supported by the National Heart Foundation (CR 11M 6066, 100123). AJM is supported by a career development fellowship from the NHMRC (APP1085752) and a future leader fellowship from the National Heart Foundation (100440). KP is supported by an NHMRC fellowship (1079492). We thank Irene Ung for technical assistance with the in vitro blood perfusion experiments. The authors gratefully acknowledge the contribution toward this study from the Victorian Operational Infrastructure Support Program.

Publication

  • Journal: Journal of Thrombosis and Haemostasis
  • Published: 01/05/2017
  • Volume: 15
  • Issue: 5
  • Pagination: 972-982

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