SBIR-STTR Award

Vascular occlusions involving thrombi are the major predisposing factor in the origin of myocardial infarction, strokes, and phlebitis. Diseases characterized by vascular clots account for up to fifty percent of adult mortality and enormous expense in hospitalization and lost productivity. Clearly, new and improved methods of diagnosing and treating vascular clots are needed. To this end, ImaRx is developing a microbubble-based ultrasound contrast agent with abilities to target and eliminate thrombi. Specifically, ligands that bind determinants on clot surfaces will be incorporated into the walls of acoustically active microbubbles. Following IV administration of these targeted vesicles, ultrasound will locate the thrombus. Then, through ultrasound-induced rupture of the vesicles, targeted delivery of agents will be greatly enhanced. Disruption of the clot will result from the physical effects of ultrasound and from the release of agents such as t-PA, streptokinase, and urokinase. Thus, a single noninvasive procedure will accomplish specific diagnostic localization and instantaneous remediation -both critical to the successful use of thrombolytic agents. Ultimately, ImaRx needs to purify and characterize this contrast agent and conduct efficacy studies, safety studies, and clinical trials. A large market for thrombus-specific diagnostic and drug delivery agents awaits the scale-up and commercialization of this technology.

Thesaurus Terms:
biotechnology, cardiovascular disorder diagnosis, contrast media, diagnosis design /evaluation, microcapsule, thrombosis, ultrasound scanning, ultrasound therapy cardiovascular disorder chemotherapy, drug delivery system, drug design /synthesis /production, streptokinase, urokinase

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