Development of Novel Molecular Imaging Contrast Agents for Detection of Oxidative Stress
An early and precise diagnosis of disease is a crucial requirement for fast and targeted therapy in the era of precision medicine. Most diseases possess molecular alterations in their early stages, which precede noticeable morphological changes. One important molecular change that contributes to dysfunction in a wide range of pathologies, including cancer and neurological disorders, is an increase in levels of reactive oxygen species (ROS) and associated oxidative damage. Our understanding of how ROS influence disease biology is currently limited by our inability to perform sensitive and specific assessment of ROS levels with high spatial and temporal resolution in living systems. The goal of the research described in this thesis was to overcome the challenge of assessing ROS during disease development in cancer and neurodegenerative disease through the design, synthesis and validation of two classes of novel bifunctional, ROS-sensitive contrast agents. To shed light on the complex redox biology in cancer, the new method of photoacoustic imaging was exploited. A novel activatable, targeted near infrared cyanine dye is reported that enables specific detection of pathological levels of hydrogen peroxide, a major and abundant ROS in living organisms. This approach uses photoacoustic and fluorescence imaging in cancerous tissue to evaluate the performance of the new probe under in vitro and in vivo conditions. In neurodegeneration, there exists a bidirectional interaction between oxidative stress and protein aggregates. To scrutinise this relationship, both bulk and single-molecule fluorescence imaging methods were used to assess the capability of novel bifunctional fluorescence dyes to localise the presence of the two putative disease-causing species, ROS and protein aggregates, simultaneously under in vitro conditions. The data shown here provides a promising foundation for the systematic design of contrast agents based on small molecule dyes, that possess ideal optical and biological characteristics to study oxidative stress in a broad range of pathological applications with high temporal and spatial resolution.
contrast agent, oxidative stress, photoacoustic imaging, fluorescence imaging/microscopy, amyloid aggregates
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