THERAPEUTIC APPLICATIONS OF MICROBUBBLES-PHASE II

该项目的长期目标是利用全氟碳白蛋白包裹的微泡的多种治疗特性来非侵入性地靶向合成基因治疗，并对血栓形成的通路移植物和冠状动脉进行再通。在冠状动脉内支架植入后，含有白蛋白微泡的静脉注射全氟碳结合并将c-myc原癌基因反义寡核苷酸结合并输送到内皮细胞的能力将被量化，然后在人类身上进行测试，以确定它是否显著减少再狭窄。其次，我们将前瞻性地评估这些静脉微泡在低频超声作用下粉碎动脉血栓的能力，以确定它是否可以取代目前的药物和外科技术，用于血栓形成的肾透析移植物的再通。含有全氟化碳的微泡既能再通急性冠脉血栓，又能将氧气从肺部扩散到缺血组织，将结合起来确定这些特性如何改善急性冠脉综合征患者的临床结果。最后，在接受电生理测试的患者中，将评估含有全氟化碳的微泡在低频超声存在下诱发房室起搏节律的能力。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。拟议的商业应用：除了诊断应用外，含有白蛋白微泡的全氟碳可能还有几种治疗应用。首先，它们可能是一种非侵入性的方法，将特定的静脉反义寡核苷酸输送到受损的内皮细胞。它们还可以靶向向缺血组织输送氧气。在经皮低频超声存在的情况下，它们空化并分解动脉内血栓。因此，在治疗血液透析通路移植物血栓形成或急性冠脉综合征时，它们可能是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.