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2014 ; 25
(39
): 395101
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Thrombin-inhibiting nanoparticles rapidly constitute versatile and detectable
anticlotting surfaces
#MMPMID25200815
Myerson JW
; He L
; Allen JS
; Williams T
; Lanza G
; Tollefsen D
; Caruthers S
; Wickline S
Nanotechnology
2014[Oct]; 25
(39
): 395101
PMID25200815
show ga
Restoring an antithrombotic surface to suppress ongoing thrombosis is an
appealing strategy for treatment of acute cardiovascular disorders such as
erosion of atherosclerotic plaque. An antithrombotic surface would present an
alternative to systemic anticoagulation with attendant risks of bleeding. We have
designed thrombin-targeted nanoparticles (NPs) that bind to sites of active
clotting to extinguish local thrombin activity and inhibit platelet deposition
while exhibiting only transient systemic anticoagulant effects. Perfluorocarbon
nanoparticles (PFC NP) were functionalized with thrombin inhibitors (either
D-phenylalanyl-L-prolyl-L-arginyl-chloromethyl ketone or bivalirudin) by covalent
attachment of more than 15 000 inhibitors to each PFC NP. Fibrinopeptide A (FPA)
ELISA demonstrated that thrombin-inhibiting NPs prevented cleavage of fibrinogen
by both free and clot-bound thrombin. Magnetic resonance imaging (MRI) confirmed
that a layer of thrombin-inhibiting NPs prevented growth of clots in vitro.
Thrombin-inhibiting NPs were administered in vivo to C57BL6 mice subjected to
laser injury of the carotid artery. NPs significantly delayed thrombotic
occlusion of the artery, whereas an equivalent bolus of free inhibitor was
ineffective. For thrombin-inhibiting NPs, only a short-lived (?10 min) systemic
effect on bleeding time was observed, despite prolonged clot inhibition. Imaging
and quantification of in vivo antithrombotic NP layers was demonstrated by MRI of
the PFC NP. (19)F MRI confirmed colocalization of particles with arterial
thrombi, and quantitative (19)F spectroscopy demonstrated specific binding and
retention of thrombin-inhibiting NPs in injured arteries. The ability to rapidly
form and image a new antithrombotic surface in acute vascular syndromes while
minimizing risks of bleeding would permit a safer method of passivating active
lesions than current systemic anticoagulant regimes.
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