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.

Theranostic Nanoparticles for Tracking and Monitoring Disease State

“…40 tPA is the only FDA-approved therapy for acute ischemic stroke and is used to lyse thrombi. However, the dosing could be personalized such that thrombolysis is effective and hemorrhagic complications are minimized.…”

Gold Nanoparticles as X-Ray, CT, and Multimodal Imaging Contrast Agents: Formulation, Targeting, and Methodology

“…Cerebral embolisms were induced by injecting fluorescently labeled thrombi into the cerebral artery of mice. Fluorescence imaging was used to colocalize visualization of the particles and found a significant signal at the site of clots [70]. Ghann et al coated AuNP with Lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, and targeted ACE in vivo to track the progression of heart disease.…”

In vivo stepwise immunomodulation using chitosan nanoparticles as a platform nanotechnology for cancer immunotherapy

“…Since DCs have a high capacity for antigen uptake, various nanomaterials have been developed for their specific physicochemical properties and are currently studied for their potential as drug delivery systems for immunotherapy14 as tools for molecular imaging1516, and as antitumor therapeutics1718. Chitosan (CH) is a particularly attractive option for clinical and biological applications because of its low immunogenicity, low toxicity, biocompatibility, and biodegradability19202122.…”