title: Direct Imaging of Cerebral Thromboemboli Using Computed Tomography and Fibrin-targeted Gold Nanoparticles.
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.
authors.affiliation: 1. Molecular Imaging and Neurovascular Research Laboratory, Dongguk University College of Medicine, Goyang, South Korea;
authors.forename: Jeong-Yeon
authors.initials: JY
authors.lastname: Kim
authors.affiliation: 2. Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea;
authors.forename: Ju Hee
authors.initials: JH
authors.lastname: Ryu
authors.affiliation: 3. Departments of Radiology and Experimental Diagnostic Imaging, University of Texas M. D. Anderson Cancer Center, Houston, TX;
authors.forename: Dawid
authors.initials: D
authors.lastname: Schellingerhout
authors.affiliation: 2. Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea;
authors.forename: In-Cheol
authors.initials: IC
authors.lastname: Sun
authors.affiliation: 1. Molecular Imaging and Neurovascular Research Laboratory, Dongguk University College of Medicine, Goyang, South Korea;
authors.forename: Su-Kyoung
authors.initials: SK
authors.lastname: Lee
authors.affiliation: 2. Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea;
authors.forename: Sangmin
authors.initials: S
authors.lastname: Jeon
authors.affiliation: 1. Molecular Imaging and Neurovascular Research Laboratory, Dongguk University College of Medicine, Goyang, South Korea;
authors.forename: Jiwon
authors.initials: J
authors.lastname: Kim
authors.affiliation: 2. Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea;
authors.forename: Ick Chan
authors.initials: IC
authors.lastname: Kwon
authors.affiliation: 4. Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA;
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
authors.affiliation: 5. Research Institute of Advanced Materials, Department of Materials Science and Engineering, Seoul National University, Seoul, Republic of Korea.
authors.forename: Cheol-Hee
authors.initials: CH
authors.lastname: Ahn
authors.affiliation: 2. Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea;
authors.forename: Kwangmeyung
authors.initials: K
authors.lastname: Kim
authors.affiliation: 1. Molecular Imaging and Neurovascular Research Laboratory, Dongguk University College of Medicine, Goyang, South Korea;
authors.forename: Dong-Eog
authors.initials: DE
authors.lastname: Kim
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D002341:Carotid Artery Thrombosis / Q000175:diagnosis / Q000000981:diagnostic imaging* / Q000188:drug therapy; D005337:Fibrin / Q000008:administration & dosage* / Q000737:chemistry; D006046:Gold / Q000737:chemistry; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry; D020521:Stroke / Q000175:diagnosis / Q000000981:diagnostic imaging*; D014057:Tomography, X-Ray Computed / Q000295:instrumentation / Q000379:methods*
chemical_list: D006046:Gold; D005337:Fibrin
keywords: cerebral infarction; computed tomography; direct thrombus imaging; gold nanoparticles; molecular imaging