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Direct Imaging of Cerebral Thromboemboli Using Computed Tomography and Fibrin-targeted Gold Nanoparticles.

Kim JY, Ryu JH, Schellingerhout D, Sun IC, Lee SK, Jeon S, Kim J, Kwon IC, Nahrendorf M, Ahn CH, Kim K, Kim DE - Theranostics (2015)

Bottom Line: Glycol-chitosan-coated gold nanoparticles (GC-AuNPs) were synthesized and conjugated to fibrin-targeting peptides, forming fib-GC-AuNP.This targeted imaging agent and non-targeted control agent were characterized in vitro and in vivo in C57Bl/6 mice (n = 107) with FeCl3-induced carotid thrombosis and/or embolic ischemic stroke.Fibrin-binding capacity was superior with fib-GC-AuNPs compared to GC-AuNPs, with thrombi visualized as high density on microCT (mCT). mCT imaging using fib-GC-AuNP allowed the prompt detection and quantification of cerebral thrombi, and monitoring of tPA-mediated thrombolytic effect, which reflected histological stroke outcome.

View Article: PubMed Central - PubMed

Affiliation: 1. Molecular Imaging and Neurovascular Research Laboratory, Dongguk University College of Medicine, Goyang, South Korea;

ABSTRACT
Computed tomography (CT) is the current standard for time-critical decision-making in stroke patients, informing decisions on thrombolytic therapy with tissue plasminogen activator (tPA), which has a narrow therapeutic index. We aimed to develop a CT-based method to directly visualize cerebrovascular thrombi and guide thrombolytic therapy. Glycol-chitosan-coated gold nanoparticles (GC-AuNPs) were synthesized and conjugated to fibrin-targeting peptides, forming fib-GC-AuNP. This targeted imaging agent and non-targeted control agent were characterized in vitro and in vivo in C57Bl/6 mice (n = 107) with FeCl3-induced carotid thrombosis and/or embolic ischemic stroke. Fibrin-binding capacity was superior with fib-GC-AuNPs compared to GC-AuNPs, with thrombi visualized as high density on microCT (mCT). mCT imaging using fib-GC-AuNP allowed the prompt detection and quantification of cerebral thrombi, and monitoring of tPA-mediated thrombolytic effect, which reflected histological stroke outcome. Furthermore, recurrent thrombosis could be diagnosed by mCT without further nanoparticle administration for up to 3 weeks. fib-GC-AuNP-based direct cerebral thrombus imaging greatly enhance the value and information obtainable by regular CT, has multiple uses in basic / translational vascular research, and will likely allow personalized thrombolytic therapy in clinic by a) optimizing tPA-dosing to match thrombus burden, b) enabling the rational triage of patients to more radical therapies such as endovascular clot-retrieval, and c) potentially serving as a theranostic platform for targeted delivery of concurrent thrombolysis.

No MeSH data available.


Related in: MedlinePlus

A single-dose targeted fib-GC-AuNP injection and repeated mCT imaging capture both the initial episode of acute cerebral thrombosis and subsequent recurrent episodes of carotid artery thromboses. A and B, Repeat mCT imaging to visualize recurrent thrombosis over 24 hours. mCT imaging at baseline (leftmost axial images) permitted the visualization of cerebral thrombi (red reticles) at 1 hour after embolic stroke and 5 minutes after intravenous injection of targeted fib-GC-AuNPs (A, a representative of n = 5 experiments). However, non-targeted GC-AuNPs failed to visualize this thrombus (B, a representative of n = 5 experiments). Then, to model recurrent thromboses, FeCl3 pledgets (1 × 1 mm2) were applied on two different locations of the left common carotid artery (CCA) at different times, ranging from 1 to 24 hours after the initial insult in the same animals (digital photographs). Regardless of the type of imaging agent, recurrent carotid thrombi (yellow arrow-heads) could be detected by circulating nanoparticles without additional injection of AuNPs (6 hours and 24 hours sagittal view images). C, Repeat mCT imaging to visualize recurrent thrombosis over 3 weeks (w). After a single-dose injection of fib-GC-AuNPs, baseline (0 w) and recurrent (yellow arrow-heads) CCA thromboses are visualized over 3 weeks (a representative of n = 3 experiments). Yellow reticles are placed on the CCA areas with FeCl3-induced thrombosis. Scale Bars = 1 mm. Lt. and Rt. denote left and right, respectively.
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Figure 6: A single-dose targeted fib-GC-AuNP injection and repeated mCT imaging capture both the initial episode of acute cerebral thrombosis and subsequent recurrent episodes of carotid artery thromboses. A and B, Repeat mCT imaging to visualize recurrent thrombosis over 24 hours. mCT imaging at baseline (leftmost axial images) permitted the visualization of cerebral thrombi (red reticles) at 1 hour after embolic stroke and 5 minutes after intravenous injection of targeted fib-GC-AuNPs (A, a representative of n = 5 experiments). However, non-targeted GC-AuNPs failed to visualize this thrombus (B, a representative of n = 5 experiments). Then, to model recurrent thromboses, FeCl3 pledgets (1 × 1 mm2) were applied on two different locations of the left common carotid artery (CCA) at different times, ranging from 1 to 24 hours after the initial insult in the same animals (digital photographs). Regardless of the type of imaging agent, recurrent carotid thrombi (yellow arrow-heads) could be detected by circulating nanoparticles without additional injection of AuNPs (6 hours and 24 hours sagittal view images). C, Repeat mCT imaging to visualize recurrent thrombosis over 3 weeks (w). After a single-dose injection of fib-GC-AuNPs, baseline (0 w) and recurrent (yellow arrow-heads) CCA thromboses are visualized over 3 weeks (a representative of n = 3 experiments). Yellow reticles are placed on the CCA areas with FeCl3-induced thrombosis. Scale Bars = 1 mm. Lt. and Rt. denote left and right, respectively.

Mentions: After either cerebral thrombus (n = 5) or carotid thrombus (n = 3) was visualized with fib-AuNP-mCT imaging, two or three (respectively) additional thrombi were formed in the carotid arteries during the following 24 hour or 3 week period, respectively, using FeCl3 pledgets, similar to the technique used to induce in situ thrombosis. These new thrombi, modeling recurrent or ongoing thrombosis, could be clearly detected in all animals without additional injection of fib-GC-AuNPs (Figure 6). This worked, even in animals receiving non-targeted agent. Although cerebral thrombus could not be imaged well with GC-AuNPs (n = 5), recurred carotid thrombi were visualized without additional injection.


Direct Imaging of Cerebral Thromboemboli Using Computed Tomography and Fibrin-targeted Gold Nanoparticles.

Kim JY, Ryu JH, Schellingerhout D, Sun IC, Lee SK, Jeon S, Kim J, Kwon IC, Nahrendorf M, Ahn CH, Kim K, Kim DE - Theranostics (2015)

A single-dose targeted fib-GC-AuNP injection and repeated mCT imaging capture both the initial episode of acute cerebral thrombosis and subsequent recurrent episodes of carotid artery thromboses. A and B, Repeat mCT imaging to visualize recurrent thrombosis over 24 hours. mCT imaging at baseline (leftmost axial images) permitted the visualization of cerebral thrombi (red reticles) at 1 hour after embolic stroke and 5 minutes after intravenous injection of targeted fib-GC-AuNPs (A, a representative of n = 5 experiments). However, non-targeted GC-AuNPs failed to visualize this thrombus (B, a representative of n = 5 experiments). Then, to model recurrent thromboses, FeCl3 pledgets (1 × 1 mm2) were applied on two different locations of the left common carotid artery (CCA) at different times, ranging from 1 to 24 hours after the initial insult in the same animals (digital photographs). Regardless of the type of imaging agent, recurrent carotid thrombi (yellow arrow-heads) could be detected by circulating nanoparticles without additional injection of AuNPs (6 hours and 24 hours sagittal view images). C, Repeat mCT imaging to visualize recurrent thrombosis over 3 weeks (w). After a single-dose injection of fib-GC-AuNPs, baseline (0 w) and recurrent (yellow arrow-heads) CCA thromboses are visualized over 3 weeks (a representative of n = 3 experiments). Yellow reticles are placed on the CCA areas with FeCl3-induced thrombosis. Scale Bars = 1 mm. Lt. and Rt. denote left and right, respectively.
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Related In: Results  -  Collection

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Figure 6: A single-dose targeted fib-GC-AuNP injection and repeated mCT imaging capture both the initial episode of acute cerebral thrombosis and subsequent recurrent episodes of carotid artery thromboses. A and B, Repeat mCT imaging to visualize recurrent thrombosis over 24 hours. mCT imaging at baseline (leftmost axial images) permitted the visualization of cerebral thrombi (red reticles) at 1 hour after embolic stroke and 5 minutes after intravenous injection of targeted fib-GC-AuNPs (A, a representative of n = 5 experiments). However, non-targeted GC-AuNPs failed to visualize this thrombus (B, a representative of n = 5 experiments). Then, to model recurrent thromboses, FeCl3 pledgets (1 × 1 mm2) were applied on two different locations of the left common carotid artery (CCA) at different times, ranging from 1 to 24 hours after the initial insult in the same animals (digital photographs). Regardless of the type of imaging agent, recurrent carotid thrombi (yellow arrow-heads) could be detected by circulating nanoparticles without additional injection of AuNPs (6 hours and 24 hours sagittal view images). C, Repeat mCT imaging to visualize recurrent thrombosis over 3 weeks (w). After a single-dose injection of fib-GC-AuNPs, baseline (0 w) and recurrent (yellow arrow-heads) CCA thromboses are visualized over 3 weeks (a representative of n = 3 experiments). Yellow reticles are placed on the CCA areas with FeCl3-induced thrombosis. Scale Bars = 1 mm. Lt. and Rt. denote left and right, respectively.
Mentions: After either cerebral thrombus (n = 5) or carotid thrombus (n = 3) was visualized with fib-AuNP-mCT imaging, two or three (respectively) additional thrombi were formed in the carotid arteries during the following 24 hour or 3 week period, respectively, using FeCl3 pledgets, similar to the technique used to induce in situ thrombosis. These new thrombi, modeling recurrent or ongoing thrombosis, could be clearly detected in all animals without additional injection of fib-GC-AuNPs (Figure 6). This worked, even in animals receiving non-targeted agent. Although cerebral thrombus could not be imaged well with GC-AuNPs (n = 5), recurred carotid thrombi were visualized without additional injection.

Bottom Line: Glycol-chitosan-coated gold nanoparticles (GC-AuNPs) were synthesized and conjugated to fibrin-targeting peptides, forming fib-GC-AuNP.This targeted imaging agent and non-targeted control agent were characterized in vitro and in vivo in C57Bl/6 mice (n = 107) with FeCl3-induced carotid thrombosis and/or embolic ischemic stroke.Fibrin-binding capacity was superior with fib-GC-AuNPs compared to GC-AuNPs, with thrombi visualized as high density on microCT (mCT). mCT imaging using fib-GC-AuNP allowed the prompt detection and quantification of cerebral thrombi, and monitoring of tPA-mediated thrombolytic effect, which reflected histological stroke outcome.

View Article: PubMed Central - PubMed

Affiliation: 1. Molecular Imaging and Neurovascular Research Laboratory, Dongguk University College of Medicine, Goyang, South Korea;

ABSTRACT
Computed tomography (CT) is the current standard for time-critical decision-making in stroke patients, informing decisions on thrombolytic therapy with tissue plasminogen activator (tPA), which has a narrow therapeutic index. We aimed to develop a CT-based method to directly visualize cerebrovascular thrombi and guide thrombolytic therapy. Glycol-chitosan-coated gold nanoparticles (GC-AuNPs) were synthesized and conjugated to fibrin-targeting peptides, forming fib-GC-AuNP. This targeted imaging agent and non-targeted control agent were characterized in vitro and in vivo in C57Bl/6 mice (n = 107) with FeCl3-induced carotid thrombosis and/or embolic ischemic stroke. Fibrin-binding capacity was superior with fib-GC-AuNPs compared to GC-AuNPs, with thrombi visualized as high density on microCT (mCT). mCT imaging using fib-GC-AuNP allowed the prompt detection and quantification of cerebral thrombi, and monitoring of tPA-mediated thrombolytic effect, which reflected histological stroke outcome. Furthermore, recurrent thrombosis could be diagnosed by mCT without further nanoparticle administration for up to 3 weeks. fib-GC-AuNP-based direct cerebral thrombus imaging greatly enhance the value and information obtainable by regular CT, has multiple uses in basic / translational vascular research, and will likely allow personalized thrombolytic therapy in clinic by a) optimizing tPA-dosing to match thrombus burden, b) enabling the rational triage of patients to more radical therapies such as endovascular clot-retrieval, and c) potentially serving as a theranostic platform for targeted delivery of concurrent thrombolysis.

No MeSH data available.


Related in: MedlinePlus