Traditional means to identify and treat arterial disease are hampered by their inability to localize atheroma components. Novel targeted acoustic, highlighting, and delivery agents, such as liposomes, may overcome these problems. Liposomes are phospholipid vesicles enclosing an aqueous space. We have developed a unique methodology that, by process and composition, makes these liposomes echogenic. This formulation allows modification for antibody conjugation and therapeutic drug/gene incorporation. Preliminary work by this group has demonstrated that these formulations can incorporate therapeutics and deliver drugs and genes to cells while retaining their acoustic properties. The addition of therapeutic ultrasound has an added unique effect on these echogenic liposomes by increasing cellular delivery of the agents. This proposal describes a series of protocols aimed at optimizing therapeutic loading while retaining echogenic properties, quantitating echogenic properties, determining in vitro and in vivo therapeutic delivery and effect, and determining the effect of ultrasound forces on improving therapeutic delivery/effect. We will utilize one prototype drug (tissue plasminogen activator-rt-PA) in a clot/thrombus model and one prototype gene (Beta-galactosidase) in cell culture and an atheroma model. We will translate our therapeutic ultrasound experiments to a modified clinical ultrasound unit. This would allow the development of targeted, echogenic agents with therapeutic loading that could be directed locally with enhanced effect with added ultrasound forces to maximize atheroma effect while minimizing systemic actions. By focusing our experiment, our long term goal would be to bring our techniques into the clinical setting to allow investigators to stage atherosclerosis and apply more directed therapy to improve physiologic flow.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074002-02
Application #
6879519
Study Section
Diagnostic Radiology Study Section (RNM)
Program Officer
Ye, Jane
Project Start
2004-04-01
Project End
2008-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
2
Fiscal Year
2005
Total Cost
$643,600
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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
Miao, Yi-Feng; Peng, Tao; Moody, Melanie R et al. (2018) Delivery of xenon-containing echogenic liposomes inhibits early brain injury following subarachnoid hemorrhage. Sci Rep 8:450
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
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
Raymond, Jason L; Luan, Ying; Peng, Tao et al. (2016) Loss of gas from echogenic liposomes exposed to pulsed ultrasound. Phys Med Biol 61:8321-8339
Sutton, J T; Haworth, K J; Shanmukhappa, S K et al. (2016) Delivery of bevacizumab to atheromatous porcine carotid tissue using echogenic liposomes. Drug Deliv 23:3594-3605
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
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
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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