Development of Quantitative Ultrasound-Mediated Molecular Imaging of the Tumor Microenvironment

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 \u3e95%) 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

Photoacoustic imaging driven by an interstitial irradiation source

AbstractPhotoacoustic (PA) imaging has shown tremendous promise in providing valuable diagnostic and therapy-monitoring information in select clinical procedures. Many of these pursued applications, however, have been relatively superficial due to difficulties with delivering light deep into tissue. To address this limitation, this work investigates generating a PA image using an interstitial irradiation source with a clinical ultrasound (US) system, which was shown to yield improved PA signal quality at distances beyond 13mm and to provide improved spectral fidelity. Additionally, interstitially driven multi-wavelength PA imaging was able to provide accurate spectra of gold nanoshells and deoxyhemoglobin in excised prostate and liver tissue, respectively, and allowed for clear visualization of a wire at 7cm in excised liver. This work demonstrates the potential of using a local irradiation source to extend the depth capabilities of future PA imaging techniques for minimally invasive interventional radiology procedures

Photoacoustic-based sO2 estimation through excised bovine prostate tissue with interstitial light delivery

Photoacoustic (PA) imaging is capable of probing blood oxygen saturation (sO2), which has been shown to correlate with tissue hypoxia, a promising cancer biomarker. However, wavelength-dependent local fluence changes can compromise sO2 estimation accuracy in tissue. This work investigates using PA imaging with interstitial irradiation and local fluence correction to assess precision and accuracy of sO2 estimation of blood samples through ex vivo bovine prostate tissue ranging from 14% to 100% sO2. Study results for bovine blood samples at distances up to 20 mm from the irradiation source show that local fluence correction improved average sO2 estimation error from 16.8% to 3.2% and maintained an average precision of 2.3% when compared to matched CO-oximeter sO2 measurements. This work demonstrates the potential for future clinical translation of using fluence-corrected and interstitially driven PA imaging to accurately and precisely assess sO2 at depth in tissue with high resolution

Optimization of Molecular Ultrasound Imaging using Nanodroplet Contrast Agents for In Vivo Translation

https://openworks.mdanderson.org/sumexp21/1123/thumbnail.jp