Direct Imaging of Cerebral Thromboemboli Using Computed Tomography and Fibrin-targeted Gold Nanoparticles.
Direct Imaging of Cerebral Thromboemboli Using Computed Tomography and Fibrin-targeted Gold Nanoparticles.
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作者：
Kim JY;Ryu JH;Schellingerhout D;Sun IC;Lee SK;Jeon S;Kim J;Kwon IC;Nahrendorf M;Ahn CH;Kim K;Kim DE
计算机断层扫描（CT）是卒中患者时间关键决策的当前标准，可为使用组织纤溶酶原激活剂（tPA）进行溶栓治疗的决策提供信息，tPA的治疗指数较窄。我们的目标是开发一种基于CT的方法来直接可视化脑血管血栓并指导溶栓治疗。合成了乙二醇-壳聚糖包覆的金纳米颗粒（GC-AuNPs），并将其与纤维蛋白靶向肽偶联，形成GC-GC-AuNPs。在患有FeCl 3诱导的颈动脉血栓形成和/或栓塞性缺血性卒中的C57 Bl/6小鼠（n = 107）中，对该靶向显像剂和非靶向对照剂进行体外和体内表征。与GC-AuNPs相比，使用GC-GC-AuNPs的纤维蛋白结合能力是上级的，血栓在microCT（mCT）上显示为高密度。mCT成像，使用NH3-GC-AuNP允许及时检测和定量脑血栓，并监测tPA介导的溶栓作用，这反映了组织学中风结果。此外，复发性血栓形成可以通过mCT诊断，而无需进一步的纳米颗粒给药长达3周。基于FD-GC-AuNP的直接脑血栓成像极大地增强了常规CT可获得的价值和信息，在基础/转化血管研究中具有多种用途，并且可能通过以下方式允许临床中的个性化溶栓治疗：a）优化tPA剂量以匹配血栓负荷，B）使得能够将患者合理分诊为更激进的治疗，例如血管内凝块取出，和c）潜在地用作同时溶栓的靶向递送的治疗诊断平台。
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.