Time-resolved optical tomography platform for mesoscopic lifetime imaging

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Gao, Shan
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Electronic thesis
Biomedical engineering
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Continuous progress in understanding oncogenesis has driven the development of targeted therapies, which leverage the targeted drugs binding to their specific receptors. However, the clinical success of these therapies has faced challenges such as drug resistance, which has been found to be associated with spatial variation in tumor regions, as well as insufficient drug exposure to the affected cells. During drug development, preclinical in vivo molecular imaging is a crucial tool for facilitating the drug discovery pipeline by assessing the drug's biological biodistribution and pharmacodynamics in live intact subjects. Molecular imaging modalities such as positron emission tomography (PET) and optical imaging provide the means to monitor biological processes at the molecular level during targeted treatment. Mesoscopic imaging is a technique used to examine the intricate details of biological systems within an organ or body part. This approach is particularly useful in preclinical cancer research as it allows for the investigation of the interaction between tumors and their surrounding tissue environment, which is much more complex than just a simple collection of cells. However, it is still challenging to noninvasively monitor the intra-tumoral heterogeneity (spatial variation in tumor regions) and assess the drug target engagement (the degree of drugs binding to their specific receptors) during drug delivery at the mesoscopic scale (a few hundred micrometers of resolution and few millimeters imaging depth). Indeed, optical imaging is unique in allowing the monitoring of multiple biomarkers simultaneously while providing structural, functional, and molecular contrasts through various light-tissue interactions. Forster Resonance Energy Transfer (FRET) imaging technique can sense protein-protein interaction processes, such as the binding of targeted antibodies to their respective receptors, through approaches such as the Fluorescence Lifetime Imaging (FLI) modality. On the other hand, fluorescence molecular tomography (FMT) has demonstrated its utility in visualizing the three-dimensional (3D) distribution of fluorescent molecular probes. Considering the binding activity of antibodies and the targeted receptors, intra-tumoral heterogeneity can be reported by retrieving the distribution of the fluorescent-labeled antibodies. This project aims to develop a noninvasive optical imaging platform capable of monitoring target engagement and intratumoral heterogeneity in the mesoscopic regime. With the integration of two imaging modalities -- fluorescence lifetime imaging via Forster Resonance Energy Transfer (FLI-FRET) and fluorescence molecular tomography (FMT) at the mesoscopic scale, we developed a custom-built optical imaging system, Time-domain Mesoscopic Fluorescence Molecular Tomography (TD-MFMT), which enables assessing target engagement via FLI-FRET as well as quantifying 3D distribution of multiplexed fluorescent-labeled antibodies through FMT modality. Hence, the outcomes of this project represent a significant advancement in optical molecular imaging for preclinical research and development.
School of Engineering
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Rensselaer Polytechnic Institute, Troy, NY
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