Molecular imaging is a very new contrast-enhanced technique that can be used to detect changes within the vasculature occurring at the molecular level by utilizing contrast agents targeted to epitopes associated with specific diseases. This is a paradigm shift from traditional ultrasound imaging, which is primarily utilized to assess anatomical features or blood flow, and it adds the capability of functional biomarker imaging to ultrasound. After injection and systemic circulation, targeted contrast agents will preferentially bind to molecular markers (such as integrins) expressed by pathologic tissue, and enable non-invasive assessment of molecular changes long before gross phenotypic manifestations of the disease occur. Over the past several years, our group has been focused on improving this technology, which still suffers from many challenges.
Figure: A side-by-side comparison of two 3D conically-stratified hinged cutaway images, illustrating enhanced signal from radiation-force targeted imaging. B-mode images (grayscale) are registered to the corresponding CPS images acquired 10 minutes after contrast injection (green). In both of these images, the same dose of targeted microbubbles was administered to the same animal. Radiation force was not applied in image A, and was applied at 13.4 kPa in image B. The imaging field of view was 1.2 cm x 1.1 cm x 0.08 cm.
Limitations in molecular imaging with ultrasound include a low number of targeted contrast agents retained at the target site, a low sensitivity to targeted contrast agents with a high background signal from untargeted agents, a long waiting time prior to imaging, immunogenicity issues, and limitations of interrogation area. We have hypothesized several approaches to overcome these limitations. We have demonstrated that the sensitivity of ultrasound to molecularly targeted contrast agents can be improved approximately an order of magnitude by using size-optimized contrast agents. Furthermore, we have illustrated new signal processing methods to detect targeted contrast with a high background signal of freely circulating contrast, enabling real-time molecular imaging. Our recent studies have illustrated the utility of radiation force to substantially improve microbubble targeting, and thus enhance molecular imaging in-vivo. The Dayton lab primarily utilizes molecular imaging for the assessment of angiogenic biomarkers in tumor growth, and we have illustrated the first application of ultrasound molecular imaging in 3-D to comprehensively assess biomarkers expressed in heterogeneous tumors.
Figure: Ultrasound molecular imaging to evaluate the efficacy of an aurora kinase inhibitor in treating human pancreatic adenocarcinoma xenografts in a mouse model. A) Ultrasound images of a representative tumor before and after treatment. The green color overlay illustrates contrast agent targeted to αvβ3, an angiogenic biomarker. The brightness of the green image overlay is correlated with the degree of molecular marker expression. B) Three dimensional ultrasound rendering of a treated pancreatic adenocarcinoma tumor on day 0. C) Percent increase or decrease in volumetric contrast targeting before and after therapy (Untreated – N=5, Treated – N=5). * p < 0.05 compared to untreated tumors on day 2. D) Percent increase or decrease in volume as measured by regions of interest from brightness mode ultrasound images taken at known distances across the tumor (Untreated – N=5, Treated – N=5). (In collaboration with Jen Jen Yeh lab).