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 journalArticleAcademicpeer-review

5 Citations (Scopus)

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 - 1 May 2017

Fingerprint

Nanocapsules
Thrombosis
Platelet Aggregation Inhibitors
Bleeding Time
Phosphatidylcholines
Tail
Hemorrhage
Microfluidics
eptifibatide
Drug Liberation
Pathologic Constriction
Perfusion
Stroke
Myocardial Infarction
Morbidity
Mortality
Therapeutics

Keywords

  • antiplatelet drugs
  • drug delivery systems
  • microfluidics
  • nanocapsules
  • platelets

Cite this

Molloy, C. P., Yao, Y., Kammoun, H., Bonnard, T., Hoefer, T., Alt, K., ... Westein, E. (2017). Shear-sensitive nanocapsule drug release for site-specific inhibition of occlusive thrombus formation. Journal of thrombosis and haemostasis, 15(5), 972-982. https://doi.org/10.1111/jth.13666
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. / Shear-sensitive nanocapsule drug release for site-specific inhibition of occlusive thrombus formation. In: Journal of thrombosis and haemostasis. 2017 ; Vol. 15, No. 5. pp. 972-982.
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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.",
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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",
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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 2017, 'Shear-sensitive nanocapsule drug release for site-specific inhibition of occlusive thrombus formation' Journal of thrombosis and haemostasis, vol. 15, no. 5, pp. 972-982. https://doi.org/10.1111/jth.13666

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, 01.05.2017, p. 972-982.

Research output: Contribution to journalArticleAcademicpeer-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 - 2017/5/1

Y1 - 2017/5/1

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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