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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. 

Author information

​Kim JY1, Ryu JH2, Schellingerhout D3, Sun IC2, Lee SK1, Jeon S2, Kim J1, Kwon IC2, Nahrendorf M4, Ahn CH5, Kim K2, Kim DE1.​

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

22. Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea;

33. Departments of Radiology and Experimental Diagnostic Imaging, University of Texas M. D. Anderson Cancer Center, Houston, TX;

44. Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA;

55. Research Institute of Advanced Materials, Department of Materials Science and Engineering, Seoul National University, Seoul, Republic of Korea.