SBIR-STTR Award

Heart attacks and strokes account for 3.4 million deaths annually in the United States. Moreover, the morbidity from vascular disease accounts for billions of healthcare dollars as well. The basis for these vascular diseases generally involves the formation of occlusive clots in the vasculature, leading to loss of blood supply, anoxia and tissue death. Current treatments involve the use of procedures that 1) promote fibrinolysis (tissue plasminogen activator), 2) prevent blood coagulation (heparin), 3) retard platelet-induced clotting (aspirin, ticlopidine) or 4) require surgical intervention (angioplasty, bypass, transendarterectomy). These therapies are either invasive or involve significant adverse effects. We recently have developed a targeted microbubble that binds to intravascular clots with high avidity. Preliminary work suggests that these microbubbles in conjunction with ultrasound can aid in the dissolution of vascular clots, It is the objective of this proposal to determine the feasibility and practicality of using targeted microbubbles along with ultrasound as a potential therapeutic modality in the treatment of vascular occlusion.

Thesaurus Terms:
blood coagulation, fibrinolysis, ligand, technology /technique development, ultrasound therapy glycoprotein, integrin clinical research, human tissue

The long-term objective of this Phase II SBIR proposal is to develop targeted microbubbles in conjunction with ultrasound for the treatment of vascular thrombosis (Sonothrombolysis). Gas-filled microbubbles are currently used as vascular ultrasound diagnostic agents because of their exquisite ability to reflect sound. In addition, recent pre-clinical studies have demonstrated that ultrasound-mediated cavitation of microbubbles has utility in lysing platelet thrombi (clots). During the Phase I period, we have developed targeted microbubble agents and have demonstrated; 1) binding to thrombi in the mouse cremasteric artery model and 2) lysing thrombi in vitro more efficiently than non-targeted microbubbles. The research in the Phase II period of the grant will involve five parts: 1) synthesize bioconjugate ligands selective for the GP IIb/llla receptor on activated platelet thrombi, 2) develop microbubble formulations with shell membranes that possess efficient cavitational force for clot lysis, 3) undertake ultrasound physics studies to optimize cavitation of microbubbles for efficient ultrasound-mediated thrombolysis, 4) conduct preclinical studies in the occluded rabbit femoral artery model to determine safety and efficacy of targeted microbubbles and ultrasound using parameters based upon objectives 2) and 3), 5) perform pre-clinical studies in the left anterior descending (LAD) or left circumflex branch occlusion model in pigs examining safety and efficacy of ultrasound-mediated targeted microbubble thrombolysis therapy, and 6) perform CMC and stability studies. We hypothesize that ultrasound-mediated targeted microbubble therapies will offer efficient, less invasive, and safer alternatives to thrombolytic agents or emergency thrombectomies. Furthermore, ultrasoundmediated therapies will provide affodable treatments that can be used in small hospitals and emergency rooms where expensive treatment is prohibitive.

Thesaurus Terms:
blood coagulation, fibrinolysis, ligand, technology /technique development, ultrasound therapy biological model, glycoprotein, lipid clinical research, human tissue, laboratory rabbit, swine