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 risk of hemorrhagic events. 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 demonstrated encapsulation and ultrasound-triggered release of nitric oxide and other bioactive gases to promote vasodilation, and neuroprotection. 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 220-kHz pulsed ultrasound exposure and passive cavitation detection in vitro and in vivo. The ability to monitor stable cavitation throughout treatment will aid in the automated control and optimization of thrombolytic enhancement.
In Aim #2, we will demonstrate the efficacy of 220-kHz ultrasound- enhanced thrombolysis using t-ELIP or rt-PA and a contrast agent through in vivo studies in a porcine hemorrhagic stroke model. As a novel approach in Aim #2, we will also evaluate the degree of neuroprotection achieved by treating the intracerebral hemorrhage with ELIP loaded with a mixture of hydrogen sulfide, a neuroprotectant, and octofluoropropane to nucleate bubble activity, and compare to ELIP loaded with a mixture of xenon, a neuroprotectant, and with a smaller amount of the bubble nucleation agent.
In Aim #3, we will investigate the potential of echogenic liposomes to deliver rt-PA and nitric oxide, a bioactive gas, in a porcine arterial thrombus model. Successful completion of the proposed studies will elucidate the utility and potential risks of ultrasound-enhanced thrombolysis and ultrasound-mediated delivery of vasodilatory or cytoprotective gases and will provide important new information to assist the design of targeted agents to improve thrombolysis and neuroprotection in acute stroke treatment.
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.
| Bader, Kenneth B; Haworth, Kevin J; Maxwell, Adam D et al. (2018) Post Hoc Analysis of Passive Cavitation Imaging for Classification of Histotripsy-Induced Liquefaction in Vitro. IEEE Trans Med Imaging 37:106-115 |
| Lattwein, Kirby R; Shekhar, Himanshu; van Wamel, Willem J B et al. (2018) An in vitro proof-of-principle study of sonobactericide. Sci Rep 8:3411 |
| Mercado-Shekhar, Karla P; Kleven, Robert T; Aponte Rivera, Hermes et al. (2018) Effect of Clot Stiffness on Recombinant Tissue Plasminogen Activator Lytic Susceptibility in Vitro. Ultrasound Med Biol 44:2710-2727 |
| Shekhar, Himanshu; Smith, Nathaniel J; Raymond, Jason L et al. (2018) Effect of Temperature on the Size Distribution, Shell Properties, and Stability of Definity®. Ultrasound Med Biol 44:434-446 |
| Shekhar, Himanshu; Bader, Kenneth B; Huang, Shenwen et al. (2017) In vitro thrombolytic efficacy of echogenic liposomes loaded with tissue plasminogen activator and octafluoropropane gas. Phys Med Biol 62:517-538 |
| Klegerman, Melvin E; Moody, Melanie R; Hurling, Jermaine R et al. (2017) Gas chromatography/mass spectrometry measurement of xenon in gas-loaded liposomes for neuroprotective applications. Rapid Commun Mass Spectrom 31:1-8 |
| Haworth, Kevin J; Bader, Kenneth B; Rich, Kyle T et al. (2017) Quantitative Frequency-Domain Passive Cavitation Imaging. IEEE Trans Ultrason Ferroelectr Freq Control 64:177-191 |
| Bader, Kenneth B; Bouchoux, Guillaume; Holland, Christy K (2016) Sonothrombolysis. Adv Exp Med Biol 880:339-62 |
| Bader, Kenneth B; Holland, Christy K (2016) Predicting the growth of nanoscale nuclei by histotripsy pulses. Phys Med Biol 61:2947-66 |
| Klegerman, Melvin E; Naji, Ali K; Haworth, Kevin J et al. (2016) Ultrasound-enhanced bevacizumab release from echogenic liposomes for inhibition of atheroma progression. J Liposome Res 26:47-56 |
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