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.
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.
