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)
Type
Research Project (R01)
Project #
2R01NS047603-09
Application #
8761905
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Koenig, James I
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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Haworth, Kevin J; Raymond, Jason L; Radhakrishnan, Kirthi et al. (2016) Trans-Stent B-Mode Ultrasound and Passive Cavitation Imaging. Ultrasound Med Biol 42:518-27
Haworth, Kevin J; Raymond, Jason L; Radhakrishnan, Kirthi et al. (2016) Erratum to: "Trans-stent B-mode Ultrasound and Passive Cavitation Imaging" in Ultrasound Med Biol 2016;42(2):518-527. Ultrasound Med Biol 42:1244
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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
Bader, Kenneth B; Bouchoux, Guillaume; Holland, Christy K (2016) Sonothrombolysis. Adv Exp Med Biol 880:339-62
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
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
Haworth, Kevin J; Weidner, Christopher R; Abruzzo, Todd A et al. (2015) Mechanical properties and fibrin characteristics of endovascular coil-clot complexes: relevance to endovascular cerebral aneurysm repair paradigms. J Neurointerv Surg 7:291-6
Raymond, Jason L; Luan, Ying; van Rooij, Tom et al. (2015) Impulse response method for characterization of echogenic liposomes. J Acoust Soc Am 137:1693-703

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