Development of small molecule probes for fluorescence and photoacoustic molecular imaging

Molecular imaging;Fluorescence and photoacoustic;Activatable probes

Li, Hao ; Chan ; Jefferson

关键词: Molecular imaging;    Fluorescence and photoacoustic;    Activatable probes;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/97260/LI-THESIS-2017.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Molecular imaging enables the visualization, characterization and quantification of biochemical processes taking place at the molecular levels within intact living subjects. As such, it has become an indispensable tool for both basic research and biomedical applications. In particular, fluorescence imaging allows us to study molecular processes at the cellular level in real time because of its excellent sensitivity, high resolution and non-invasive nature. The use of reaction-based small-molecule fluorescent probes, a class of probes that exhibit differential fluorescence signals upon reacting with their intended target, has further rendered fluorescence imaging with good selectivity and higher sensitivity. Such reaction-based small-molecule fluorescent probes is often comprised of at least two components: a dye capable of generating a large fluorescence signal upon excitation and a target-specific reactive handle. The selection of both components are important as the dye often determines the spacial resolution as well as biocompatibility, whereas the reactive handle dictates selectivity and sensitivity. As such, finding new dye platforms as well as new reactive handles are essential to expanding the repertoire of reaction-based probes for non-invasive real-time fluorescence imaging. In Chapter 1, I will describe the development of a formaldehyde (FA)-responsive small-molecule fluorescent probe, formaldehyde probe 1 (FP1). Specifically, we utilized a FA-specific biorthogonal chemical transformation to render FP1 FA-specific. Moreover, we also developed a neutral, red-shifted fluorophore platform with exceptional photostability to enable the real-time tracking of FA and in the hope of studying the long-term effect of FA in living systems.While fluorescence imaging excels at studying cellular systems, its usage in vivo is challenging due to the limited imaging depth up to 1 mm as a result of light scatting. In other word, if the imaging target resides deeper than 1 mm, the outcoming fluorescence will scatter and hence erodes the resolution.As the thickness of the human skin varies from 0.5 to 4 mm depending on different parts of the human body, most optical methods including fluorescence imaging can only be applied ex-vivo or to study superficial subjects such as skin. On the other hand, photoacoustic imaging (PAI), an imaging technique based on the detection of ultrasonic waves generated by light absorption, circumvents this problem because it detects ultrasonic waves which scatters 3000 times less than light. As a result, PAI can reach several centimeters of depth penetration while retaining high special resolution. When coupled with small-molecule stimuli-responsive photoacoustic probes that yield a different PA signal upon activation by the molecular target, PAI becomes a versatile molecular imaging technique that holds great promise for both animal models studies and human diagnostics. In Chapter 2, I will describe the development of two copper(II)-responsive small-molecule photoacoustic probes APC-1 and APC-2. Specifically, we equipped both APCs with a 2-picolinic ester sensing module that is readily hydrolysed in the presence of Cu(II) but not by other divalent metal ions. Additionally, APC-1 and APC-2 were explicitly designed for ratiometric photoacoustic imaging by using an aza-BODIPY dye scaffold exhibiting two spectrally resolved near-infrared absorbance bands, one below 700 nm and the other above, that are associated with the 2-picolinic ester capped and uncapped phenoxide forms, respectively. The ratiometric photoacoustic turn-on responses for APC-1 and APC-2 were verified using tissue-mimicking phantoms.