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"Activation and Processing Strategies of Phase-Change Nanodroplets for Multiplex Ultrasound Imaging"

Abstract

Personalized medicine can drastically improve cancer diagnosis, treatment planning, and outcomes by utilizing information on a tumor's biological profile. However, due to the complexity of intratumor heterogeneity, biopsy analysis cannot always provide optimal targeted treatment strategies. Tumors, particularly those hidden deep in biological tissue, require better imaging tools to visualize the molecular underpinnings governing cancer's genetic complexity. In the current standard of cancer imaging, there is a need for real-time, high-resolution molecular level information to detect malignant lesions and better identify cellular biomarkers for personalized medicine. Ultrasound is a low-cost, non-invasive, non-ionizing, and deep penetrating imaging modality that could be ideal for molecular imaging with improvements to resolution, specificity, and contrast agents. Molecular imaging capabilities of ultrasound, however, are limited by contrast agent properties and current image acquisition strategies.

This thesis describes the development of molecularly targeted, phase-change nanodroplet contrast agents for ultrasound imaging that have the potential to obtain high resolution images of multiple biomarkers. First, the fabrication, functionalization, and characterization of molecularly targeted phase-change nanodroplets is presented. The developed nanodroplets have a perfluorocarbon core that undergoes a liquid-to-gas phase transition and generates strong ultrasound contrast when provided with an optical or acoustic activation stimulus. We show that by using a high boiling point perfluorocarbon, the nanodroplets naturally recondense and can be reactivated hundreds of times. Second, the development of an integrated imaging system to vaporize and visualize the nanodroplet activation is described. The system is comprised of a high-frequency research ultrasound imaging system synchronized with either a near-infrared pulsed laser or a high intensity focused ultrasound transducer. Using this system, we demonstrate repeatable selective vaporization of nanodroplets deep in tissue. Third, multiplex ultrasound imaging using the differing temporal profiles of low versus high boiling point perfluorocarbon nanodroplets is demonstrated. The multiplex imaging is supplemented by novel image processing techniques to improve nanodroplet visualization. Overall, this work provides a path towards molecular ultrasound imaging of multiple biomarkers simultaneously.

Thesis Committee

• Geoffrey Luke, PhD (Chair)
• Brian Pogue, PhD
• Alexander Hartov, PhD
• Tyrone Porter, PhD

Contact

For more information, contact Theresa Fuller at theresa.d.fuller@dartmouth.edu.