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

C. P. Molloy, Y. Yao, H. Kammoun, T. Bonnard, T. Hoefer, K. Alt, F. Tovar-Lopez, G. Rosengarten, P. A. Ramsland, A. D. van der Meer, A. van den Berg, A. J. Murphy, C. E. Hagemeyer, K. Peter, E. Westein

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 × 1012) 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-1 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 site-specific antiplatelet potential, and may form a basis for developing more potent and safer antiplatelet drugs.

Original languageEnglish
Pages (from-to)972-982
Number of pages11
JournalJournal of Thrombosis and Haemostasis
Volume15
Issue number5
DOIs
Publication statusPublished - May 2017

Keywords

  • Antiplatelet drugs
  • Drug delivery systems
  • Microfluidics
  • Nanocapsules
  • Platelets

Cite this

@article{06790a95b4dd4b1b8be38e74ba231764,
title = "Shear-sensitive nanocapsule drug release for site-specific inhibition of occlusive thrombus formation",
abstract = "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 × 1012) 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-1 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 site-specific antiplatelet potential, and may form a basis for developing more potent and safer antiplatelet drugs.",
keywords = "Antiplatelet drugs, Drug delivery systems, Microfluidics, Nanocapsules, Platelets",
author = "Molloy, {C. P.} and Y. Yao and H. Kammoun and T. Bonnard and T. Hoefer and K. Alt and F. Tovar-Lopez and G. Rosengarten and Ramsland, {P. A.} and {van der Meer}, {A. D.} and {van den Berg}, A. and Murphy, {A. J.} and Hagemeyer, {C. E.} and K. Peter and E. Westein",
year = "2017",
month = "5",
doi = "10.1111/jth.13666",
language = "English",
volume = "15",
pages = "972--982",
journal = "Journal of Thrombosis and Haemostasis",
issn = "1538-7933",
publisher = "Wiley-Blackwell",
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}

Shear-sensitive nanocapsule drug release for site-specific inhibition of occlusive thrombus formation. / Molloy, C. P.; Yao, Y.; Kammoun, H.; Bonnard, T.; Hoefer, T.; Alt, K.; Tovar-Lopez, F.; Rosengarten, G.; Ramsland, P. A.; van der Meer, A. D.; van den Berg, A.; Murphy, A. J.; Hagemeyer, C. E.; Peter, K.; Westein, E.

In: Journal of Thrombosis and Haemostasis, Vol. 15, No. 5, 05.2017, p. 972-982.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Shear-sensitive nanocapsule drug release for site-specific inhibition of occlusive thrombus formation

AU - Molloy, C. P.

AU - Yao, Y.

AU - Kammoun, H.

AU - Bonnard, T.

AU - Hoefer, T.

AU - Alt, K.

AU - Tovar-Lopez, F.

AU - Rosengarten, G.

AU - Ramsland, P. A.

AU - van der Meer, A. D.

AU - van den Berg, A.

AU - Murphy, A. J.

AU - Hagemeyer, C. E.

AU - Peter, K.

AU - Westein, E.

PY - 2017/5

Y1 - 2017/5

N2 - 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 × 1012) 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-1 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 site-specific antiplatelet potential, and may form a basis for developing more potent and safer antiplatelet drugs.

AB - 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 × 1012) 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-1 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 site-specific antiplatelet potential, and may form a basis for developing more potent and safer antiplatelet drugs.

KW - Antiplatelet drugs

KW - Drug delivery systems

KW - Microfluidics

KW - Nanocapsules

KW - Platelets

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U2 - 10.1111/jth.13666

DO - 10.1111/jth.13666

M3 - Article

VL - 15

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JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

SN - 1538-7933

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