The development and application of activity-based sensing probes to monitor inflammation and cancer aggression

Molecular imaging is the real-time visualization of biochemical events in intact systems. This discipline holds several advantages over more traditional biological and analytical methods, such as the ability to collect dynamic spatiotemporal data and complete longitudinal studies. These advantages allow molecular imaging to have applications in several areas, including the discovery of disease mechanisms, diagnostics, and therapeutic monitoring. Molecular imaging is therefore growing in popularity, and imaging agents are under rapid development to include a multitude of output modalities and more advanced analyte detection strategies. Molecular imaging has expanded to include several modalities (e.g., magnetic resonance, ultrasound, optical, and photoacoustic imaging), which can be selected based on the tissue penetration depth and spatial resolution required for the desired application. Activity-based sensing strategies have also been applied to molecular imaging agents to report on the chemical reactivity of biological analytes. Herein, we discuss our efforts to develop activity-based sensing molecular imaging agents, specifically those with optical and photoacoustic outputs. We additionally highlight our efforts to apply these agents for pre-clinical research in several critical disease states. Chapter 1 introduces molecular imaging, activity-based sensing, and our selected imaging modalities. It also introduces our disease states of interest, and it emphasizes the role of molecular imaging in deciphering the mechanisms of these diseases, developing therapeutics, and advancing diagnostics. Chapter 2 discusses the modification of an existing imaging platform to possess optimal photoacoustic properties. This chapter also demonstrates the generalizability of this optimized scaffold to be used in activity-based sensing to detect biological analytes in ex vivo and in vivo mouse models. Chapter 3 describes our work further modifying this new photoacoustic platform to visualize a broader scope of biological analytes, including those involved in obesity-induced inflammation. Chapter 4 details our efforts to develop and apply an isoform-selective aldehyde dehydrogenase 1A1 probe, AlDeSense, to stratify cancer cells with high aldehyde dehydrogenase 1A1 activity, identify small molecule inhibitors, and monitor cancer stemness in vivo. Finally, Chapter 5 reviews our progress to apply activity-based sensing tools and various biological assays to assess the role of nitric oxide in the regulation of aldehyde dehydrogenase activity and cancer stem cells. We envision this work will have applications to further our understanding of these diseases and potentially develop more advanced diagnostics and therapeutics.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biochemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2023

Author dc:creator

• Gardner, Sarah

Contributors dc:contributor

• Chan, Jefferson
• Kalsotra, Auinash
• Zhang, Kai
• Dobrucki, Wawrzyniec

• Activity-based Sensing
• Molecular Imaging
• Cancer
• Cancer Stem Cells
• Inflammation
• Photoacoustic Imaging
• Fluorescence Imaging

Statement dc:rights

• Copyright 2023 Sarah Gardner

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/120499

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F120499