Combined ultrasound and tissue plasminogen activator (rt-PA) therapy, or sonothrombolysis, has been shown to improve recanalization in patients with acute ischemic stroke. Effective methods of enhancing thrombolysis have been examined in an attempt to reduce the dosage of the thrombolytic agent and reduce the risk of hemorrhagic events. We have investigated the synergistic effect of rt-PA and 120-KHz ultrasound on thrombolysis using in vitro porcine and human whole blood clot models. In our ongoing studies, we have demonstrated that significant enhancement of thrombolysis correlates with the presence of stable cavitation and this type of gentle bubble activity can be sustained using an intermittent infusion of a contrast agent. In addition, we have shown that inertial cavitation, which elicits broadband acoustic emissions, is counter-productive for enhanced thrombolysis. Rather, the most effective form of bubble activity is stable cavitation, which elicits ultrasonic subharmonic generation. Importantly, we have shown encapsulation of rt-PA in a contrast agent specifically targeted to clot. These preliminary data strongly support the central hypothesis of our proposal that ultrasound enhances thrombolysis primarily via mechanical mechanisms. To test this hypothesis we propose to investigate three Specific Aims:
In Aim #1, we will develop a dual-element annular array transducer to facilitate simultaneous 120-kHz pulsed ultrasound exposure and passive cavitation detection in vitro and in vivo.
In Aim #2, we will demonstrate the efficacy of 120-kHz ultrasound-enhanced thrombolysis through in vivo studies in a porcine intracerebral hemorrhagic stroke model using fluorescently labeled rt-PA-loaded liposomes or gas contrast agents and neuropathologic examination. As a novel approach in Aim #3, we will investigate the potential of echogenic liposomes to deliver rt-PA and nitric oxide, a bioactive gas, near an intravascular clot in an ex vivo porcine carotid model. Vascular reactivity and the degree of rt-PA leakage across the vascular endothelium will be assessed to clarify the potential risks for sonothrombolysis in the presence of gas contrast agents. Successful completion of these studies will contribute significantly to our long-term goal to develop a sonothrombolysis system that delivers and enhances thrombolytic therapy in the cerebral vasculature and rapidly restores perfusion after ischemic stroke.
Our long-term objective is to develop a transcranial, ultrasound-enhanced thrombolysis system that minimizes the risk of intracranial hemorrhage, increases the number of stroke survivors, improves long-term prognosis, and reduces health care costs. The development of the agents and techniques listed in this proposal would have far reaching implications in improving directed therapeutic treatment of stroke.
|Kandadai, Madhuvanthi A; Meunier, Jason M; Hart, Kimberley et al. (2015) Plasmin-loaded echogenic liposomes for ultrasound-mediated thrombolysis. Transl Stroke Res 6:78-87|
|Klegerman, Melvin E; Zou, Yuejiao; Golunski, Eva et al. (2014) Use of thermodynamic coupling between antibody-antigen binding and phospholipid acyl chain phase transition energetics to predict immunoliposome targeting affinity. J Liposome Res 24:216-22|
|Raymond, Jason L; Haworth, Kevin J; Bader, Kenneth B et al. (2014) Broadband attenuation measurements of phospholipid-shelled ultrasound contrast agents. Ultrasound Med Biol 40:410-21|
|Kim, Hyunggun; Britton, George L; Peng, Tao et al. (2014) Nitric oxide-loaded echogenic liposomes for treatment of vasospasm following subarachnoid hemorrhage. Int J Nanomedicine 9:155-65|
|Bouchoux, Guillaume; Shivashankar, Ravishankar; Abruzzo, Todd A et al. (2014) In silico study of low-frequency transcranial ultrasound fields in acute ischemic stroke patients. Ultrasound Med Biol 40:1154-66|
|Gruber, Matthew J; Bader, Kenneth B; Holland, Christy K (2014) Cavitation thresholds of contrast agents in an in vitro human clot model exposed to 120-kHz ultrasound. J Acoust Soc Am 135:646-53|
|Bader, Kenneth B; Holland, Christy K (2013) Gauging the likelihood of stable cavitation from ultrasound contrast agents. Phys Med Biol 58:127-44|
|Rim, Yonghoon; McPherson, David D; Kim, Hyunggun (2013) Volumetric three-dimensional intravascular ultrasound visualization using shape-based nonlinear interpolation. Biomed Eng Online 12:39|
|Sutton, Jonathan T; Haworth, Kevin J; Pyne-Geithman, Gail et al. (2013) Ultrasound-mediated drug delivery for cardiovascular disease. Expert Opin Drug Deliv 10:573-92|
|Sutton, Jonathan T; Ivancevich, Nikolas M; Perrin Jr, Stephen R et al. (2013) Clot retraction affects the extent of ultrasound-enhanced thrombolysis in an ex vivo porcine thrombosis model. Ultrasound Med Biol 39:813-24|
Showing the most recent 10 out of 38 publications