Development of smart optical imaging agents for disease diagnosis

Abstract

Optical imaging has become an indispensable tool in disease diagnosis and treatment. As compared to other imaging modalities, it exhibits high-throughput capacity, high sensitivity with detection at molecular and cellular levels, avoidance of radiative toxicity, and relatively low instrumentation costs. In the clinical settings, optical instrumentations such as endoscopy, microscopy and photoacoustic tomography, has facilitated both pre-clinical and clinical optical imaging applications. Encouraged by preclinical results and the translational potential of optical imaging, a variety of optical imaging agents have been developed, which could be classified into inorganic nanoparticles and organic fluorophores, based on the material of construction. Organic fluorophores show high structural versatility with clear structure-property relationships. These optical agents feature modifiable groups, which enables the combination of different functional moieties to achieve desired biochemical properties in biomarker detection, targeting and even therapy. Particularly, biomarker-activatable optical imaging agents that specifically turn on the optical signals in the presence of disease biomarkers at the molecular and cellular level have the potential for disease detection at an incipient stage. This thesis aims to discuss the application of biomarker-activatable molecular fluorophore for disease diagnosis via both real-time in vivo imaging and in vitro urinalysis. In the real-time imaging approach, both attempts to improve probe design for clinical translation and explore different diseases will be reported. The probe design could be improved from two different aspects: i) tuning optical properties to improve penetration depth and signal-to-noise ratio; ii) tuning pharmacokinetic properties to accelerate body excretion and minimize organ toxicity. Such activatable fluorophores are utilized to detect malignant skin diseases, drug-induced liver injury, drug-induced kidney injury in living mice models. Last but not least, the application of activatable optical probes for in vitro urinalysis is introduced. The in vitro application liberates the stringent requirement of biocompatibility and pharmacokinetic properties on molecular fluorophores. Therefore, the emphasize is on finding appropriate disease biomarkers that are both urinary-secreted and disease-specific. Multiplex urinalysis reporters that specifically emit optical signals in the presence of three different biomarkers are developed and they are applied for disease detection in drug-induced kidney injury model.