Development Of Quantitative Ultrasound-Mediated Molecular Imaging Of The Tumor Microenvironment

Author

Trevor Mitcham, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical SciencesFollow

Author ORCID Identifier

0000-0001-6985-5486

Date of Graduation

5-2021

Document Type

Dissertation (PhD)

Program Affiliation

Medical Physics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Richard Bouchard, PhD

Committee Member

David Fuentes, PhD

Committee Member

Christine Peterson, PhD

Committee Member

Konstantin Sokolov, PhD

Committee Member

R. Jason Stafford, PhD

Abstract

While conventional diagnostic imaging modalities provide anatomical information to clinicians, these techniques are not sensitive to critical physiological processes. In order to properly classify cancer, it is necessary to investigate noninvasive methods which can provide insight into these processes, allowing clinicians to determine personalized therapeutic options. Therefore, molecular imaging is focused on visualization and characterization of biomarkers within the tumor microenvironment (TME), which can then be combined with the anatomical information provided from diagnostic imaging.

Two such biomarkers of interest are blood oxygen saturation (SO₂) and cell receptor expression. SO₂ is a measure of the fraction of hemoglobin which is bound to oxygen, which has been shown to correlate to tumor progression. Additionally, several cancer subtypes have been shown to overexpress specific cell receptors (e.g., EGFR). Therefore, cell receptor expression has emerged as a biomarker which can help the physician to identify potential beneficial treatment options. While molecular imaging methods are being explored in order to assess these two biomarkers, current methods suffer from limitations such as poor spatio-temporal resolution and poor depth penetration. To overcome these limitations, ultrasound (US)-mediated imaging techniques have been investigated to characterize these molecular imaging biomarkers.

The objective of this work is to develop and validate US-mediated techniques to investigate the TME biomarkers of SO₂ and cell receptor expression. In this work, photoacoustic (PA) imaging methods were developed along with optical fluence modeling techniques in order to improve accuracy and precision of SO₂ estimates. SO₂ estimation accuracy was shown to improve from 16.8% error to 3.2% error with a precision of 2.3% in tissue-mimicking phantoms, while in vivo estimation of SO₂ in a rat artery (i.e., expected value >95%) increased from 92.9±2.9% to 95.5±1.2%.

Additionally, a high-frequency US-mediated imaging platform was developed to image and activate phase-changing perfluorocarbon nanodroplet contrast agents (PNCAs). Using this imaging platform, PNCAs were activated and imaged to determine PNCA enhancement. Optimal PNCA particles generated a median signal enhancement of 6.2 in a phantom environment after US activation, while a pilot in vivo study showed significant US-mediated PNCA activation of two separate intra-muscular injections in the hind limb.

Keywords

Ultrasound-mediated Imaging, Quantitative Imaging, Photoacoustic Imaging, Activatable Perfluorocarbon Nanodroplet Contrast Agents