Over the past decade, molecular imaging has gained traction as a powerful new imaging method to enhance the capabilities of ultrasound by providing assessment of physiology associated with disease on the cellular level. Our team has set out with the goal of developing contrast agents and ultrasound technology to substantially improve the utility of diagnostic molecular imaging for clinical translation. Thus far, our team ha achieved several highly significant advances: (1) we formulated a new type of targeted contrast agent, the buried-ligand microbubble, which is ultrasound-targeted, non-immunogenic and reduces the potential for nonspecific interactions; (2) we illustrated the utility of tailoring thesize distribution of contrast agents to improve imaging contrast; (3) we demonstrated the advantage of acoustic radiation force to enhance sensitivity in molecular imaging studies; (4) we performed acoustic radiation force-enhanced molecular imaging with an unmodified clinical ultrasound system; (5) we illustrated the need for 3-D in ultrasound molecular imaging; (6) we affirmed the utility of ultrasound molecular imaging in assessing tumor response to anti-angiogenic therapy in rodents; and (7) we demonstrated increased targeting specificity with the combination of acoustic radiation force and buried-ligand microbubbles. Several other groups working parallel to ours have corroborated our results, illustrating in rodents that ultrasound molecular imaging can provide an indication of tumor response to therapy significantly sooner than traditional methods, such as tumor size measurements. The significance of this result is that ultrasound molecular imaging can provide robust, low-cost, safe, bedside support for monitoring personalized medicine approaches in oncology. With these technological advances and promising results in rodent models, it is now time to evaluate the translatability of this technology for clinical application. To date, all reported molecular imaging studies in the US have been in small animals. In this project, we will validate the technology of ultrasound molecular imaging in a population of client-owned (pet) dogs with spontaneous soft tissue sarcomas. This large animal model is an ideal platform for validation of the clinical utility of ultrasound molecular imaging. Dogs receive similar radiation and chemotherapeutic treatments as humans, are of a size where clinical ultrasound systems can be utilized, and can be imaged with prototype molecularly targeted contrast agents without FDA and other regulatory hurdles. Thus, the goal of this project is to test the ability of ultrasound molecular imaging to detect eary response of tumors to therapy in canine patients. Patients undergoing chemotherapy will be monitored, and data will be correlated with the gold standards of DCE-CT and immunohistochemistry. This large animal, multi-center, pre-clinical study will be supported with studies to insure optimal performance of molecular imaging in the canine model, such as implementation of a 3-D interface for imaging, optimization of contrast agent and ultrasound parameters, and preliminary studies of toxicity in purpose-bred dogs. Accomplishment of our aims and validation of ultrasound molecular imaging as a treatment monitoring technique of clinical value for veterinary oncology will propel this promising technology toward human applications.

Public Health Relevance

Our goal is to develop a safe and effective ultrasound molecular imaging technology to diagnose, monitor and guide cancer treatment. We hypothesize that the use of non-immunogenic, ultrasound-stimulated targeted microbubble contrast agents and advanced 3D ultrasound imaging methods will prove competitive with dynamic contrast-enhanced x-ray computed tomography when tested in a relevant, spontaneous large animal model. We will develop this novel technology while exploring its use in canine soft tissue sarcomas in a multi- center trial to measure the response to anti-angiogenic pharmacologic therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA195051-04
Application #
9440982
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Redmond, George O
Project Start
2015-04-13
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Colorado at Boulder
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80303
Lum, Jordan S; Dove, Jacob D; Murray, Todd W et al. (2016) Single Microbubble Measurements of Lipid Monolayer Viscoelastic Properties for Small-Amplitude Oscillations. Langmuir 32:9410-7