Vascular in vivo MRI for the detection of arterial thrombosis by targeting activated platelets - new imaging agents for MRI approaches

活化血小板是不稳定动脉粥样硬化斑块纤维帽即将破裂的早期指标。因此，活化血小板的非侵入性MRI将具有重要的临床意义。在之前的研究中，我们评估了在活化的糖蛋白IIb/IIIa上包裹单链抗体靶向配体诱导结合位点（LIBS）的氧化铁微粒（MPIO）对小鼠颈动脉血栓形成的成像效果。尽管这些研究成功地实现了成像，但该技术的局限性在于血小板聚集较小的模型和血小板表面的高剪切应力，这不能导致这些微粒的充分结合。此外，所使用颗粒的毒性阻止了对人类的应用。因此，我们的目标是将基于纳米颗粒的显像剂（尺寸为10-100 nm）与libs特异性抗体结合，并将其应用于小血管血小板粘附模型（小鼠股骨丝损伤模型）和壁粘附性动脉血栓形成模型（颈动脉损伤模型）。基于纳米颗粒的显像剂将被研究用于可能的人类应用，包括超顺磁氧化铁纳米颗粒、钆树状大分子和脂质体封装的氟化标记物。利用这种方法，我们的目标是继续开发一种基于血小板的造影剂，这种造影剂可以在未来的项目中直接应用于人类。该项目的最终目的是使临床医生能够在容易破裂的动脉粥样硬化斑块引起心肌梗死或中风之前对其进行成像。

Activated platelets are early indicators of imminent rupture of the fibrous cap in unstable atherosclerotic plaques. Therefore, non-invasive MRI of activated platelets would be of great clinical interest. In previous studies we evaluated microparticles of iron oxide (MPIO) coated with a single-chain antibody targeting ligand-induced binding sites (LIBS) on activated glycoprotein IIb/IIIa to image carotid artery thrombosis in mice. Even though these studies allowed successful imaging, limitations of this technique are models of minor platelet aggregation and high shear stress on the platelet surface, which do not result in sufficient binding of such microparticles. Furthermore, toxicity of the used particles prevents application in humans. We therefore aim to conjugate nanoparticle based imaging agents (size 10-100 nm) to LIBS-specific antibodies and apply these in a model of minor vascular platelet adhesion (femoral wire injury model in mice) and wall adherent arterial thrombosis (carotid artery injury model). The nanoparticle-based imaging agents that will be investigated for possible human applications include superparamagetic iron oxide nanoparticles, gadolinium dendrimers, and liposome encapsulated fluorinated markers. Using this approach, we aim to continue the development of a platelet-based contrast agent that can be directly transferred into human applications in future projects. The ultimate aim of the project is to enable the clinician to image rupture-prone atherosclerotic plaques before they cause myocardial infarction or stroke.