Type of Document Dissertation Author Weller, Gregory Eugene Robert URN etd-04062003-174803 Title DEVELOPMENT AND CHARACTERIZATION OF ULTRASOUND CONTRAST MICROBUBBLES TARGETED TO DYSFUNCTIONAL ENDOTHELIUM Degree Doctor of Philosophy Program Bioengineering School School of Engineering Advisory Committee
Advisor Name Title Flordeliza S. Villanueva Committee Co-Chair William R. Wagner Committee Co-Chair Harvey S. Borovetz Committee Member Michael K. K. Wong Committee Member William J. Federspiel Committee Member Keywords
- molecular imaging
- ultrasound
- adhesion
- cell adhesion molecules
- endothelium
- contrast media
- inflammation
- targeted imaging
- myocardial contrast echocardiography
Date of Defense 2003-03-26 Availability unrestricted Abstract Endothelial dysfunction is characterized by the upregulation of leukocyte adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), and has been identified in numerous disease processes including inflammation, atherosclerosis, transplant rejection, and neoplasia, yet current clinical techniques to assess endothelial dysfunction are limited. An ultrasound-based molecular imaging technique to detect cell surface markers of endothelial dysfunction may offer non-invasive assessment of associated disease processes.Lipid-based ultrasound contrast microbubbles were targeted to ICAM-1 by conjugation with anti-ICAM-1 antibodies. These targeted microbubbles should selectively adhere to dysfunctional endothelium overexpressing ICAM-1, producing stronger and more persistent contrast enhancement during ultrasound imaging. Previous results from our laboratory demonstrated that ICAM-1-targeted microbubbles preferentially adhere to inflammatory versus normal endothelium in vitro under static conditions.
In the current studies, we first verified that ICAM-1 was upregulated in a variety of inflammatory models using immunohistochemistry. Next, various parameters that modulate adhesion of targeted microbubbles to dysfunctional endothelium were investigated. We quantified and demonstrated control over the final antibody density on the microbubble. Using a parallel plate perfusion chamber and a radial flow chamber, ICAM-1-targeted microbubble adhesion to cultured human endothelium was shown to be greater to inflammatory than non-inflammatory cells, and linearly dependent on microbubble antibody density, wall shear rate, and endothelial ICAM-1 density.
In vivo experiments using a rat heart transplant model demonstrated that ultrasound imaging using ICAM-1-targeted microbubbles can non-invasively detect acute cardiac allograft rejection. Using a mouse subcutaneous tumor model, we demonstrated that ultrasound imaging using microbubbles targeted via a tumor endothelium-specific binding peptide can non-invasively identify tumor vasculature.
These data have implications for the development of targeted contrast agents capable of identifying endothelial molecular markers of disease, and offer promise for the optimization and clinical application of a targeted, contrast-enhanced ultrasound imaging technique for the diagnosis and monitoring of disease states associated with endothelial dysfunction.
Files
Filename Size Approximate Download Time (Hours:Minutes:Seconds)
28.8 Modem 56K Modem ISDN (64 Kb) ISDN (128 Kb) Higher-speed Access WellerGER_2003.pdf 20.12 Mb 01:33:07 00:47:53 00:41:54 00:20:57 00:01:47 If you have questions or comments please send mail to ETD-Feedback.