Application of Photoacoustic and Multimodality Imaging in Biomarker Detection

Abstract

Photoacoustic (PA) imaging (PAI) is an imaging technique that fills the gap of penetration and resolution between optical imaging and ultrasound imaging, allowing imaging with optical contrast at deep tissue with high resolution. It serves as a powerful tool in disease research for its capabilities of providing rich information about the tissue physiological parameters. Disease research, on the other hand, needs the investigation of the pathological alterations to guide disease etiology and treatment evaluation. Driven by the need, this thesis discussed several methodologies involving PAI and PAI-based multimodality imaging techniques to investigate the biomarkers related to two disease model: rodent prostate cancer model and rodent Alzheimer’s disease (AD) model. In the first disease model, we used multispectral photoacoustic tomography (MSPT), assisted with a tumor-targeting hypoxia-sensing probe (NOx-JS013) to investigate hypoxia in aggressive and non-aggressive tumors. We showed that NOx-JS013 is capable of targeting aggressive cancer cells, while shifting absorption and fluorescence spectrum upon incubation in a hypoxia environment. We developed a method for MSPT unmixing successfully unmixed signals of NOx-JS013 from the tumor environment. With NOx-JS013 and MSPT, we can visualize the tumor hypoxia with high specificity and sensitivity, and hence provide insight into tumor microenvironment. The second disease models were investigated in three experiments. In chapter 3, we present the application of a multimodality imaging system in retinal biomarker detection for mice with AD. We developed a multimodality ophthalmoscope combining OR-PAM and OCT, targeting the vasculature, retinal layer structure and Aβ deposition in the retina of mice with AD. We successfully demonstrated the Aβ deposition in the retina of AD mice with a customized antibody-conjugated gold nanochain as a contrast agent. Meanwhile, our OCT result suggests that certain layers of the retina may be affected by AD, reflected by the thickness changing correlated with AD. In chapter 4 and 5, we further explore the application of multimodality imaging in cerebral biomarker detection of AD mice. With OR-PAM and confocal fluorescence microscopy (CFM) combined system, we investigated cortical brain vasculature and Aβ plaque deposition in AD mice. The Aβ is labeled with a fluorescent dye, CRANAD-3. With resolution capable of imaging capillaries and single plaque deposition, we observed the decline of small vessel density correlated with AD, and the increase of Aβ density correlated with both AD and aging. Furthermore, we expanded the study and performed a longitudinal imaging for a period of three months. We described a longitudinal brain window that’s transparent to both optics and ultrasound, with which we monitored vasculature, Aβ plaque deposition, blood flow and blood oxygenation. The result suggests that the trend of both small vessel density and Aβ density are affected by AD in the age span from nine to twelve months. Meanwhile, we observed a decline in blood oxygen saturation in the vein of AD. In this study. The multimodal platform proves to be a powerful tool for multi-dimensional biomarker monitoring.