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Title:Development of small-molecule probes for photoacoustic imaging of hypoxia
Author(s):Knox, Hailey J
Director of Research:Chan, Jefferson
Doctoral Committee Chair(s):Chan, Jefferson
Doctoral Committee Member(s):Moore, Jeffrey S; Sweedler, Jonathan V; Zimmerman, Steven C
Department / Program:Chemistry
Discipline:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):photoacoustic imaging
photoacoustic probes
fluorescence imaging
fluorescent probes
molecular imaging
hypoxia
hypoxia imaging
in vivo imaging
Abstract:Hypoxia occurs when tissue oxygen supply is restricted, inhibiting normal physiological processes. Because of the irregular vasculature of rapidly growing tumors, hypoxia is a hallmark of cancer and exists in 50-60% of solid tumors. Hypoxia-induced changes in gene expression lead to treatment resistance, aggressive phenotypes, and increased metastatic potential; thus, imaging tumor hypoxia has important implications in treatment planning and predicting patient prognosis. Herein we discuss our approach for hypoxia detection using photoacoustic (PA) imaging. This method combines the resolution of optical imaging with the tissue penetration of ultrasound to enable high-resolution image acquisition at clinically relevant depths. While PA imaging can detect endogenous absorbers, a powerful application of this modality lies in its combination with small-molecule probes that can provide a specific molecular readout. To this end, we have outlined key strategies for developing activatable PA probes and applied these methods to the development of small-molecule probes that can be used for PA imaging of hypoxia in deep tissue. Our design for small-molecule, hypoxia-responsive probes relies on a prodrug-inspired N- oxide-based trigger that is reduced selectively in hypoxic conditions to produce a change in the PA signal of the probe. Our first-generation probe is capable of reporting on both acute and chronic hypoxia in vivo using PA and fluorescence imaging. To further develop this design, we employ several strategies for photophysical tuning that improve the PA wavelength and signal intensity. We also demonstrate the application of our design for simultaneous PA imaging of tissue and blood oxygenation. Finally, we show progress toward the application of this design for targeted agents that can report on prostate tumor hypoxia. We envision that these probes will be useful preclinical tools for hypoxia imaging and may lead to new agents that can be used in a clinical setting.
Issue Date:2020-07-02
Type:Thesis
URI:http://hdl.handle.net/2142/108574
Rights Information:Copyright 2020 Hailey J. Knox
Date Available in IDEALS:2020-10-07
Date Deposited:2020-08


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