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: Jeong-Yeon Kim, Ju Hee Ryu, Dawid Schellingerhout, In-Cheol Sun, Su-Kyoung Lee, Sangmin Jeon, Jiwon Kim, Ick Chan Kwon, Matthias Nahrendorf, Cheol-Hee Ahn, Kwangmeyung Kim, Dong-Eog Kim
• Journal: Theranostics (Theranostics) Vol. 5 Issue 10 Pg. 1098-114 ( 2015) ISSN: 1838-7640 [Electronic] Australia
• PMID: 26199648 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Gold
• Fibrin

Topics

• Animals
• Brain (diagnostic imaging)
• Carotid Artery Thrombosis (diagnosis, diagnostic imaging, drug therapy)
• Fibrin (administration & dosage, chemistry)
• Gold (chemistry)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Nanoparticles (chemistry)
• Stroke (diagnosis, diagnostic imaging)
• Tomography, X-Ray Computed (instrumentation, methods)