Revascularization of a diseased blood vessel is currently performed by balloon angioplasty and deployment of a metal stent. A major clinical hurdle is the maintenance of vessel patency following stent deployment. That is, following stent deployment, smooth muscle cells that compose the vessel wall, rapidly proliferate and divide and can lead to concomitant vessel re-narrowing;a clinical process known as in-stent restenosis. To address this, several major medical device companies have developed stents that release anti-proliferative agents to prevent restenosis and are currently on the US market. These drugs are released from a thin polymer coating on the stent;drug eluting stent or DES. However, in December 2006, the FDA released a statement reflecting widespread international concern relating to stent thrombosis (i.e. a blood clot in the stent) occurring in patients who have received a DES, resulting in a small, but significant, rise in deaths and myocardial infarctions. As noted by the FDA and experts in the field, this poorly understood phenomenon is believed to result from an inflammatory response to the non-degradable polymer coating once the anti-proliferative agent has been completely released. The very recent and rapid growth of the use of DESs and the fact that these troubling findings are only now being observed, underscores the potential for a major health crisis affecting an estimated two million Americans - with obvious implications on morbidity and mortality for those affected. Current treatment in patients that have a DES requires the maintained use of clopidogrel (Plavix), an anti-clotting agent, to minimize the risk of sub-acute thrombosis which is not without risk and long term efficacy is, as yet, unproven. The work proposed herein addresses the need to develop new instrumentation, methods and biomaterials to deliver anti-proliferative agents to diseased blood vessels that have undergone angioplasty and stent implantation. This proposal will focus on the use of existing modalities and reagents to employ ultrasound to direct the focal release of an anti-proliferative agent from microbubbles to a blood vessel following angioplasty-induced stenosis under ultrasound imaging guidance. The method that we propose to investigate involves an intravenous injection of ultrasound microbubble contrast agent modified so as to include a small amount of an antiproliferative drug. This proposal addresses a very significant public health concern (stent thrombosis) in the US - central to the mission of the NIH. In the past few months, the interventional cardiology community (including the FDA that regulates the field) has come to realize that drug eluting stents, that have been widely implanted as a therapy for coronary artery disease, pose greater risk than initially anticipated. Specifically, the efficacy of these stents as a means for maintaining an open coronary artery diminishes over time.

Public Health Relevance

This grant addresses this profoundly important public health concern by investigating the potential of early stage, high risk, promising new ultrasound image guided, minimally invasive, therapies for resolving this problem using focused delivery of "antiproliferative" drugs to the precise region of a vessel of concern.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090700-05
Application #
8296580
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Danthi, Narasimhan
Project Start
2008-08-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$356,473
Indirect Cost
$108,973
Name
University of Virginia
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Kilroy, Joseph P; Klibanov, Alexander L; Wamhoff, Brian R et al. (2014) Localized in vivo model drug delivery with intravascular ultrasound and microbubbles. Ultrasound Med Biol 40:2458-67
Chen, Johnny L; Dhanaliwala, Ali H; Dixon, Adam J et al. (2014) Synthesis and characterization of transiently stable albumin-coated microbubbles via a flow-focusing microfluidic device. Ultrasound Med Biol 40:400-9
Kilroy, Joseph P; Patil, Abhay V; Rychak, Joshua J et al. (2014) An IVUS transducer for microbubble therapies. IEEE Trans Ultrason Ferroelectr Freq Control 61:441-9
Dhanaliwala, Ali Haider; Chen, Johnny L; Wang, Shiying et al. (2013) Liquid Flooded Flow-Focusing Microfluidic Device for in situ Generation of Monodisperse Microbubbles. Microfluid Nanofluidics 14:457-467
Dixon, Adam J; Dhanaliwala, Ali H; Chen, Johnny L et al. (2013) Enhanced intracellular delivery of a model drug using microbubbles produced by a microfluidic device. Ultrasound Med Biol 39:1267-76
Dixon, Adam J; Hossack, John A (2013) Intravascular near-infrared fluorescence catheter with ultrasound guidance and blood attenuation correction. J Biomed Opt 18:56009
Phillips, Linsey C; Klibanov, Alexander L; Wamhoff, Brian R et al. (2011) Localized ultrasound enhances delivery of rapamycin from microbubbles to prevent smooth muscle proliferation. J Control Release 154:42-9
Phillips, Linsey C; Dhanaliwala, Ali H; Klibanov, Alexander L et al. (2011) Focused ultrasound-mediated drug delivery from microbubbles reduces drug dose necessary for therapeutic effect on neointima formation--brief report. Arterioscler Thromb Vasc Biol 31:2853-5
Patil, Abhay V; Rychak, Joshua J; Klibanov, Alexander L et al. (2011) Real-time technique for improving molecular imaging and guiding drug delivery in large blood vessels: in vitro and ex vivo results. Mol Imaging 10:238-47
Phillips, Linsey C; Klibanov, Alexander L; Wamhoff, Brian R et al. (2010) Targeted gene transfection from microbubbles into vascular smooth muscle cells using focused, ultrasound-mediated delivery. Ultrasound Med Biol 36:1470-80

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