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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047603-12
Application #
9318604
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Koenig, James I
Project Start
2004-07-01
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
12
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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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; Crowe, Michael J; Raymond, Jason L et al. (2016) Effect of Frequency-Dependent Attenuation on Predicted Histotripsy Waveforms in Tissue-Mimicking Phantoms. Ultrasound Med Biol 42:1701-5
Kandadai, Madhuvanthi A; Mukherjee, Prithviraj; Shekhar, Himanshu et al. (2016) Microfluidic manufacture of rt-PA -loaded echogenic liposomes. Biomed Microdevices 18:48
Bader, Kenneth B; Haworth, Kevin J; Shekhar, Himanshu et al. (2016) Efficacy of histotripsy combined with rt-PA in vitro. Phys Med Biol 61:5253-74

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