THERAPEUTIC APPLICATIONS OF MICROBUBBLES-PHASE II

该项目的长期目标是利用含全氟化碳的白蛋白涂层微泡的多种治疗特性，以非侵入性靶向合成基因治疗并再通血栓形成的通路移植物和冠状动脉。将对静脉内含全氟化碳的白蛋白微泡在冠状动脉内支架展开后结合c-myc原癌基因并将反义寡核苷酸递送到内皮中的能力进行定量，然后在人体中进行测试以确定其是否显著降低再狭窄。其次，将前瞻性评价这些静脉内微泡在低频超声存在下微破碎动脉血栓的能力，以确定其是否可以取代目前的药物和手术技术，用于再通血栓形成的肾透析移植物。将结合含全氟化碳的微泡使急性冠状动脉血栓再通和将氧气从肺部扩散到缺血组织的能力，以确定这些特性如何改善急性冠状动脉综合征患者的临床结局。最后，将在接受电生理测试的患者中评估含全氟化碳的微泡在低频超声存在下诱导心房和心室起搏节律的能力。这些多方面的研究将为使用微泡作为当前心血管治疗的替代或补充提供框架。拟定商业应用：除了诊断应用之外，含全氟化碳的白蛋白微泡可能具有若干治疗应用。首先，它们可能是一种非侵入性的方法，将特异性静脉内反义寡核苷酸靶向递送到受损的内皮。它们还可以靶向缺血组织输送氧气。在经皮低频超声波的存在下，他们空化和打破动脉内血栓。因此，它们可能是治疗血液透析通路移植物血栓形成或急性冠状动脉综合征的纤溶治疗的替代或补充。

The long term objective of this project is to utilize the multiple therapeutic properties of perfluorocarbon containing albumin coated microbubbles to non-invasively target synthetic gene therapy and recanalize thrombosed access grafts and coronary arteries. The ability of intravenous perfluorocarbon containing albumin microbubbles to bind and deliver antisense oligonucleotides to the c-myc protoncogene into the endothelium following intracoronary stent deployment will be quantified, and then tested in humans to determine whether it significantly reduces restenosis. Secondly, the ability of these intravenous microbubbles to microfragment arterial thrombi in the presence of low frequency ultrasound will be prospectively evaluated to determine whether it can replace current pharmacologic and surgical techniques in recanalizing thrombosed renal dialysis grafts. The ability of perfluorocarbon containing microbubbles to both recanalize acute coronary thromboses and diffuse oxygen from the lungs to ischemic tissue will be combined to determine how these properties can improve the clinical outcome of patients with acute coronary syndromes. Finally, the ability of perfluorocarbon containing microbubbles to induce atrial and ventricular paced rhythms in the presence of low frequency ultrasound will be assessed in patients undergoing electrophysiologic testing. These multi-faceted investigations will provide the framework for the use of microbubbles as an alternative or supplement to current cardiovascular therapies. PROPOSED COMMERCIAL APPLICATION: In addition to diagnostic applications, perfluorocarbon containing albumin microbubbles may have several therapeutic applications. First, they could be a noninvasive method of targeting the delivery of specific intravenous antisense oligonucleotides to damaged endothelium. They can also target the delivery of oxygen to ischemic tissue. In the presence of transcutaneous low frequency ultrasound, they cavitate and break up intra arterial thrombi. Therefore, they may be an alternative or supplement to fibrinolytic therapy in treating hemodialysis access graft thrombosis or acute coronary syndromes.