Applying a molecular pharmaceutics framework to the study of ultrasound contrast agents

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  • March 19, 2019
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  • Fix, Samantha
    • Affiliation: Eshelman School of Pharmacy, Pharmaceutical Sciences Program
Abstract
  • Several decades ago, stabilized microbubbles (MBs) were developed as vascular contrast agents for ultrasound imaging, and since then, the physics of MB oscillation and the unique acoustic signatures that MBs create have been relatively well characterized. Less well understood are considerations regarding how MBs interact with biological systems and how they can be exploited for therapeutic purposes. As the diagnostic and therapeutic applications of contrast agents continue to become more sophisticated, these considerations are ever more important. Thus, the purpose of this thesis is to study contrast agents from a new perspective, applying concepts from molecular pharmaceutics to enhance our understanding of contrast agent behavior and therapeutic potential. First, we characterize changes in MB clearance that occur over the course of longitudinal studies that involve repeated MB administrations over several weeks. We show that MB clearance becomes dramatically faster over time, which is associated with an immune response against polyethylene glycol (PEG), a common component of clinical and pre-clinical MB formulations. The effect we demonstrate has important implications for quantitative contrast-enhanced ultrasound imaging studies as well as therapeutic ultrasound applications that require consistent intravascular concentrations of MBs over the course of repeated administrations. Next, we explore the potential of MBs being repurposed for the controlled delivery of therapeutic gases. We thoroughly review the literature surrounding this topic and subsequently show that administering oxygen-filled MBs to rat fibrosarcoma tumors temporarily relieves tumor hypoxia and increases the efficacy of subsequent radiotherapy. Finally, we explore how ultrasound-stimulated contrast agents can be used to enhance drug delivery. Various biological barriers hamper efficient drug accumulation in tissues or cells of interest, presenting a major challenge in pharmaceutics research. Through the final portion of this thesis, we use a new class of contrast agents – phase change contrast agents (PCCAs) – in conjunction with ultrasound to physically manipulate these biological barriers. In vitro, we show that ultrasound stimulated PCCAs can transiently disrupt cell membranes and epithelial monolayers for improved intracellular and transepithelial drug delivery, respectively. We envision in vivo applications of this work focused on enhancing drug delivery to solid tumors and improving gastrointestinal delivery of biologics.
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Advisor
  • Lai, Samuel
  • Jay, Michael
  • McRee, Autumn
  • Pylayeva-Gupta, Yuliya
  • Dayton, Paul
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2019
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