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

Abstract

AD, van den Berg A, Murphy AJ, Hagemeyer CE, Peter K, Westein E. Shear-sensitive nanocapsule drug release for site-specific inhibition of occlusive thrombus formation. J Thromb Haemost 2017; 15: 972-82. Essentials• Vessel stenosis due to large thrombus formation increases local shear 1-2 orders of magnitude.• High shear at stenotic sites was exploited to trigger eptifibatide release from nanocapsules.• Local delivery of eptifibatide prevented vessel occlusion without increased tail bleeding times.• Local nanocapsule delivery of eptifibatide may be safer than systemic antiplatelet therapies.Summary. Background: Myocardial infarction and stroke remain the leading causes of mortality and morbidity. The major limitation of current antiplatelet therapy is that the effective concentrations are limited because of 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, i.e. significantly increased blood shear stress resulting from a reduction in the lumen of the vessel, to achieve site-directed delivery of the clinically used antiplatelet agent eptifibatide by using shear-sensitive phosphatidylcholine (PC)-based nanocapsules. Methods: PC-based nanocapsules (2.8 9 10 12) with high-dose encapsulated eptifibatide were introduced into microfluidic blood perfusion assays and into 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 a shear rate of 1000 s À1 while leaving thrombus formation under physiologic 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 show prolonged bleeding times. Conclusions: Targeted delivery of eptifibatide by shear-sensitive nanocapsules offers sitespecific antiplatelet potential, and may form a basis for developing more potent and safer antiplatelet drugs.

Targeting Nanotechnologies for the Treatment of Thrombosis and Cardiovascular Disease

“…Lipid nanocarriers are one such promising mode of nanotechnology that demonstrates substantial potential as a novel drug delivery platform. Preclinical investigations into lipid nanocarriers and their suitability as a drug delivery vehicle in the treatment of thrombosis has been conducted with promising findings, as demonstrated in the study of Molloy et al 17 This group aimed to exploit a key biochemical feature characteristic to thrombosis, being the significantly increased shear stress levels present at the site of thrombus formation. 18 These elevated shear stress levels occur primarily due to the thrombi's restriction of the blood vessel's lumen.…”

“…Hence, the authors reasoned that shear-sensitive nanocapsules could function as a viable means by which to locally deliver antithrombotic drugs to the thrombus. 17 In their study, Molloy et al encapsulated the antiplatelet drug eptifibatide within shear-sensitive phosphatidylcholine (PC)-based (liposomal) nanocapsules, collectively denoted as E-NCs. Using these novel shear-sensitive nanocapsules, they performed an array of in vitro microfluidic flow channel blood perfusion experiments whereby they demonstrated site-specific delivery of eptifibatide to areas of vessel stenosis as well as a shear-dependent release of eptifibatide and inhibition of platelet aggregation.…”

Shear-, Sound-, and Light-Sensitive Nanoparticles for Thrombolytic Drug Delivery

“…28 Recently, Molloy et al reported on shear-sensitive phosphatidylcholine-based nanocapsules to achieve site-directed delivery of the antiplatelet drug eptifibatide. 30 When the blood shear stress increased, as resulting from a reduction in the lumen of the vessel, eptifibatide could be released from the system to prevent thrombosis. A polydimethylsiloxane microfluidic stenosis model was also constructed for evaluating platelet function of human blood in stenosis channels.…”

“…This microfluidic blood perfusion assay showed that the shear-induced eptifibatide nanocapsules inhibited thrombus formation efficiently, particularly at the stenotic section with high shear stress. 30 The second strategy is shear-sensitive nanoparticle aggregates (SS-NPAs) composed of multiple smaller nanoparticles, which are designed to break up in response to high shear rates at site of vascular stenosis. 29,43,44 The micron size SS-NPAs are comparable with platelets, which allow them to aggregate toward the obstructed vessels with high shear.…”

Targeting functionalized nanoparticles to activated endothelial cells under high wall shear stress

“…Yet, so far these have been limited to healthy or low WSS conditions and have not addressed VTC adhesion under pathological levels of high WSS where WSS can be 100 dyne/cm 2 and higher . Studies addressing NPs targeting under high WSS region have so far focused on targeting thrombotic arteries and not the endothelium. However, high WSS and endothelial activation are critical aspects known to occur in several disease conditions including vaso‐constricted arteries or at early stages of arteriogenesis following occlusion of a neighboring artery .…”