Doctor of Philosophy, Case Western Reserve University, 2018, Biomedical Engineering
Bulk nanobubbles, also known as ultrafine bubbles (ISO/ TC281), have recently gained the interest of the research community for their potential application as ultrasound contrast agents for molecular imaging and cancer therapy. However, even with this growing interest, the very existence of nanobubbles and their use as contrast agents have been a subject of controversy for over a decade. This is due to the theoretical effect of reducing the bubble diameter to the nanoscale on both its Laplace pressure and resonance frequency leading to instability and reduced imaging quality, respectively. Despite these theoretical limitations, we have developed a stable and echogenic nanobubble formulation through incorporation of Pluronic, a nonionic triblock co-polymer surfactant, into the lipid shell of perfluorocarbon gas bubbles. To further understand the biophysical properties of these novel nanobubbles, we explored factors contributing to their echogenicity, stability, and fate after gas dissipation. Bubbles were confirmed to be in the sub-micron range and produced strong contrast at clinical ultrasound frequencies. Additionally, it was demonstrated that the incorporation of Pluronic into the lipid membrane increases the stability of nanobubbles under ultrasound by decreasing its monolayer surface tension. Due to the strong interest in the use of nanobubbles as drug delivery agents, their ultimate fate when destroyed by high-power ultrasound was investigated using cryo-EM. Lastly, as a proof of study, CA-125 and PSMA-targeted nanobubbles were developed for the detection of ovarian and prostate cancer, respectively. Results demonstrated that nanobubbles can be used to target and reach antigens expressed on cancer cells beyond the tumor vasculature. Characterization and optimization of nanobubble properties achieved the creation of novel, stabilized nanobubbles for numerous potential clinical applications.
Committee: Agata Exner Ph.D. (Advisor); Horst von Recum Ph.D. (Committee Chair); James Basilion Ph.D. (Committee Member); Dean Nakamoto M.D. (Committee Member)
Subjects: Biomedical Engineering