TARGETED MICROBUBBLES FOR DIAGNOSIS OF VASCULAR CLOTS

血栓(血栓)继发的血管闭塞是中风、心肌梗死和血管血栓形成的易感因素。在美国，每年有340万人死于中风和心脏病，而与这些疾病有关的发病率会导致瘫痪和运动和认知功能丧失。显然，需要更可靠的诊断和治疗。最近，我们开发了用于诊断超声的靶向微泡，以检测血管凝块。血栓上GPIIbIIIa受体IIIa亚组分微泡上的靶向配体。第一阶段的工作已经证明了这些靶向微泡在体外和体内选择性地与血栓结合用于超声检测的可行性。实验还表明，这些微泡也可能用于治疗应用，如声溶栓和药物输送。这一第二阶段应用的目标是：1)合成一系列具有更好的结合和稳定性的靶向配体类似物；2)通过各种物理技术表征这些类似物；3)进行详细的声学研究；4)建立一种体外结合试验，以确定微泡结合效率；5)在啮齿动物、灵长类动物和犬模型中进行体内实验；以及6)在啮齿动物模型中进行急性和慢性毒性研究。拟议的商业应用：这些血栓靶向研究中具有商业适用性的产品和技术将直接导致一种或多种血栓特异性血管内造影剂的开发。此外，预计将开发新的导管、支架、外周血管装置和溶栓剂，以补充新的造影剂的引入。

Vascular occlusions secondary to thrombi (blood clots) are predisposing factors to strokes, myocardial infarctions, and vascular thrombosis. Mortality for strokes and heart attacks in the United States number 3.4 million annually while morbidity associated with these diseases results in paralysis and loss of motor and cognitive functions. Clearly, more reliable diagnosis and treatment are needed. Recently, we have developed targeted microbubbles for diagnostic ultrasound to detect vascular clots. The targeting ligand on the microbubbles for the IIIa subcomponent of the GPIIbIIIa receptor on thrombi. Phase I efforts have demonstrated feasibility for these targeted microbubbles to bind selectively to thrombi both in vitro and in vivo for ultrasound detection. Experiments have also indicated that these microbubbles may also be useful for therapeutic applications such as sonothrombolysis and drug delivery. The objectives of this Phase II application are: 1) Synthesize a series of targeting ligand analogs with improved binding and stability properties; 2) Characterize these analogs by a variety of physical techniques; 3) Perform detailed acoustic studies; 4) Develop an vitro binding assay to determine microbubble binding efficiency; 5) Perform in vivo experiments in rodent, primate and canine models; and 6) perform acute and chronic toxicity studies in the rodent model. PROPOSED COMMERCIAL APPLICATIONS: Products and techniques with commercial applicability from these thrombus targeting studies will directly lead to the development of one or more thrombus-specific intravascular contrast agents. In addition, it is envisioned that new catheters, stents, peripheral vascular devices and thrombolytic agents will be developed to complement the introduction of new contrast agents.