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Assessment of Aptamer-Targeted Contrast Agents for Monitoring of Blood Clots in Computed Tomography and Fluoroscopy Imaging
Bioconjugate Chemistry ( IF 4.7 ) Pub Date : 2020-11-24 , DOI: 10.1021/acs.bioconjchem.0c00525
Anna Koudrina 1 , Jonathan O'Brien 2 , Roberto Garcia 3 , Spencer Boisjoli 1 , Peter T M Kan 3 , Eve C Tsai 4, 5, 6 , Maria C DeRosa 1
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Objective: Random formation of thrombi is classified as a pathological process that may result in partial or complete obstruction of blood flow and limited perfusion. Further complications include pulmonary embolism, thrombosis-induced myocardial infraction, ischemic stroke, and others. Location and full delineation of the blood clot are considered to be two clinically relevant aspects that could streamline proper diagnosis and treatment follow-up. In this work, we prepared two types of X-ray attenuating contrast formulations, using fibrinogen aptamer as the clot-seeking moiety. Methods: Two novel aptamer-targeted formulations were designed. Iodine-modified bases were directly incorporated into a fibrinogen aptamer (iodo-FA). Isothermal titration calorimetry was used to confirm that these modifications did not negatively impact target binding. Iodo-FA was tested for its ability to produce concentration-dependent contrast enhancement in a phantom CT. It was subsequently tested in vitro with clotted human and swine blood. This allowed for translation into ex vivo testing, using fluoroscopy. FA was also used to functionalize gold nanoparticles (FA-AuNPs), and contrast capabilities were confirmed. This formulation was tested in vitro using clotted human blood in a CT scan. Results: Unmodified FA and iodo-FA demonstrated a nearly identical affinity toward fibrin, confirming that base modifications did not impact target binding. Iodo-FA and FA-AuNPs both demonstrated excellent concentration-dependent contrast enhancement capabilities (40.5 HU mM–1 and 563.6 HU μM–1, respectively), which were superior to the clinically available agent, iopamidol. In vitro CT testing revealed that iodo-FA is able to penetrate into the blood clots, producing contrast enhancement throughout, while FA-AuNPs only accumulated on the surface of the clot. Iodo-FA was thereby translated to ex vivo testing, confirming target-binding associated accumulation of the contrast material at the location of the clot within the dilation of the external carotid artery. This resulted in a 34% enhancement of the clot. Conclusions: Both iodo-FA and FA-AuNPs were confirmed to be effective contrast formulations in CT. Targeting of fibrin, a major structural constituent of thrombi, with these novel contrast agents would allow for higher contrast enhancement and better clot delineation in CT and fluoroscopy.

中文翻译:

评估适体靶向造影剂在计算机断层扫描和荧光透视成像中监测血栓的作用

目的:血栓的随机形成被归类为可能导致部分或完全阻塞血流和有限灌注的病理过程。其他并发症包括肺栓塞,血栓形成引起的心肌梗塞,缺血性中风等。血块的位置和完全描绘被认为是两个临床相关方面,可以简化正确的诊断和治疗随访。在这项工作中,我们使用纤维蛋白原适体作为寻求凝块的部分,准备了两种类型的X射线衰减对比剂。方法:设计了两种新型的适体靶向制剂。将碘修饰的碱基直接掺入纤维蛋白原适体(iodo-FA)中。等温滴定热法用于确认这些修饰不会对靶标结合产生负面影响。测试了Iodo-FA在幻影CT中产生浓度依赖性对比度增强的能力。随后在体外用凝结的人血和猪血进行了测试。这允许使用荧光检查法翻译成离体测试。FA还用于功能化金纳米颗粒(FA-AuNPs),并证实了对比能力。在CT扫描中使用凝结的人血对该制剂进行了体外测试。结果:未修饰的FA和碘-FA对纤维蛋白表现出几乎相同的亲和力,从而证实碱基修饰不会影响靶标结合。碘-FA和FA-AuNPs均表现出出色的浓度依赖性对比增强能力(分别为40.5 HU mM –1和563.6 HUμM –1),优于临床上可用的药物iopamidol。体外CT测试显示,碘-FA能够渗入血凝块,从而在整个过程中增强对比度,而FA-AuNP仅在血凝块表面积累。从而碘-FA被翻译成离体测试,确认造影剂在颈外动脉扩张内凝块位置的靶标结合相关积累。这导致凝块增加了34%。结论:碘-FA和FA-AuNPs均被证实是CT中有效的造影剂。使用这些新型造影剂靶向血栓的主要结构成分血纤蛋白将在CT和荧光透视中实现更高的对比度增强和更好的血凝块轮廓。
更新日期:2020-12-16
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