Author ORCID Identifier

0000-0002-8445-3343

Date of Graduation

8-2021

Document Type

Dissertation (PhD)

Program Affiliation

Medical Physics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Richard Bouchard, Ph.D.

Committee Member

Jingfei Ma, Ph.D.

Committee Member

Marina Konopleva, M.D., Ph.D.

Committee Member

Seth Gammon, Ph.D.

Committee Member

Marites Melancon, Ph.D.

Committee Member

Christine Peterson, Ph.D.

Abstract

Traditional diagnostic imaging provides clinicians with anatomical information that guides both diagnosis and treatment planning; however, once a tumor has progressed enough to be visible, it has often reached an advanced stage. Molecular imaging techniques allow for real-time visualization of chemical and biological processes via imaging of specific biomarkers, which can facilitate detection of malignancies before they become visible. One biomarker of interest is blood oxygen saturation (SO2) due to its correlation with hypoxia, which is associated with increased tumor malignancy; some studies have also established SO2 as an independent biomarker of disease progression. Additionally, because cancerous cells commonly overexpress specific antigens (e.g., folate receptor alpha [FRa] in ovarian cancer), cell receptor expression is an emerging biomarker that can be leveraged to localize malignant cells and guide patient-specific treatment strategies. Molecular imaging strategies are being explored to assess these biomarkers; however, each suffers from inherent limitations, such as poor spatiotemporal resolution, poor depth penetration, or high regulation from the use of ionizing radiation. To overcome these challenges, photoacoustic (PA) imaging is being investigated due to its sensitivity to nano-sized optical contrast at clinically relevant depths with high spatiotemporal resolution. In this work, multi-wavelength PA imaging techniques were developed for noninvasive, quantitative visualization of two biomarkers: SO2, via imaging of oxy- and deoxyhemoglobin; and cell receptor expression, via imaging of a novel contrast agent, liposome-encapsulated J-aggregated indocyanine green (Lipo-JICG), which is conjugated with anti-FRa antibodies for specific targeting to the FRa receptor on ovarian cancer cells. SO2 was shown to have potential as a biomarker in disease progression of acute lymphoblastic leukemia, with significantly more change in SO2 (relative to individual baseline) in diseased than in control mice. Lipo-JICG was first characterized in phantom environments, demonstrating its ability for simultaneous imaging and unmixing with endogenous hemoglobin (allowing for more straightforward in vivo imaging) and its fluence and photothermal stability during PA imaging. Specificity of Lipo-JICG targeting was also shown in vitro, with more signal from SKOV3 cells (i.e., high FRa expression), as well as in vivo, with increased Lipo-JICG contrast enhancement observed from targeted FRa-Lipo-JICG than non-targeted RG-16-Lipo-JICG in mice with SKOV3 ovarian tumors.

Keywords

Photoacoustic imaging, blood oxygen saturation, cell receptor expression, acute lymphoblastic leukemia, ovarian cancer, breast cancer

Available for download on Thursday, January 06, 2022

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