Theranostics 2015; 5(10):1098-1114. doi:10.7150/thno.11679

Research Paper

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

Jeong-Yeon Kim1*, Ju Hee Ryu2*, Dawid Schellingerhout3, In-Cheol Sun2, Su-Kyoung Lee1, Sangmin Jeon2, Jiwon Kim1, Ick Chan Kwon2, Matthias Nahrendorf4, Cheol-Hee Ahn5, Kwangmeyung Kim2✉, Dong-Eog Kim1✉

1. Molecular Imaging and Neurovascular Research Laboratory, Dongguk University College of Medicine, Goyang, South Korea;
2. Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea;
3. Departments of Radiology and Experimental Diagnostic Imaging, University of Texas M. D. Anderson Cancer Center, Houston, TX;
4. Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA;
5. Research Institute of Advanced Materials, Department of Materials Science and Engineering, Seoul National University, Seoul, Republic of Korea.
*These authors contributed equally to this work.

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Citation:
Kim JY, Ryu JH, Schellingerhout D, Sun IC, Lee SK, Jeon S, Kim J, Kwon IC, Nahrendorf M, Ahn CH, Kim K, Kim DE. Direct Imaging of Cerebral Thromboemboli Using Computed Tomography and Fibrin-targeted Gold Nanoparticles. Theranostics 2015; 5(10):1098-1114. doi:10.7150/thno.11679. Available from http://www.thno.org/v05p1098.htm

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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.

Keywords: direct thrombus imaging, gold nanoparticles, computed tomography, cerebral infarction, molecular imaging