Improved Techniques in Ultrasonic Molecular Imaging for Evaluating Response to Cancer Therapy

Streeter, Jason Eric

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March 21, 2019

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Streeter, Jason Eric
- Affiliation: School of Medicine, UNC/NCSU Joint Department of Biomedical Engineering

Abstract

Molecular imaging is a broad term for describing a technique designed to evaluate molecular activity in biological systems. Recently, ultrasound has gained interest in molecular imaging due to the practical advantages over traditional imaging modalities: it is inexpensive, safe and portable. The principle behind ultrasonic molecular imaging (USMI) is the selective targeting of acoustically active intravascular microbubbles to biomarkers expressed on the endothelium. Once accumulated at the target site, the microbubbles enhance the acoustic backscatter from pathologic tissue that might otherwise be difficult to distinguish from normal tissues. Since USMI has the potential to provide information prior to the appearance of phenotypic changes, it is proposed that this method can facilitate early assessment of disease progression. Pre-clinical imaging studies have demonstrated the efficacy of USMI for applications including, but not limited to, assessment of tumor angiogenesis, evaluation of cardiovascular disease, and imaging dysfunctional endothelium, thrombus and inflammation. Although significant advances in USMI have been made, there remain challenges that need to be addressed as this technique advances toward clinical relevance. The ultimate goal of USMI is to determine the degree to which biomarkers are expressed by the target tissue. Therefore, it is essential that targeted microbubbles adhere in quantities that produce backscattered intensities in greater magnitude than the signal from non-specific targeting. Given this requirement, research has primarily focused on improving the sensitivity to bound microbubbles, improving the ability to quantify biomarker expression, increasing the quantity of targeted microbubbles retained at the site of pathology, and improving microbubble architecture to minimize the non-specific retention of microbubbles and immunogenic response. This dissertation supports the following hypotheses for in vivo USMI experiments: 1. Producing size-selected microbubbles increases detection sensitivity. 2. Implementing a 3-D ultrasound platform improves our ability to quantify biomarker expression. 3. Using acoustic radiation force enhances microbubble targeting. 4. Creating buried-ligand microbubbles reduces immunogenic response and non-specific targeting. These improvements will ultimately provide a basis of methods, which we will draw from to assess a tumor's response to therapy and compare it to more traditional methods.

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