Development of small-molecule probes for photoacoustic imaging of hypoxia

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.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2020

Author dc:creator

• Knox, Hailey J

Contributors dc:contributor

• Chan, Jefferson
• Moore, Jeffrey S
• Sweedler, Jonathan V
• Zimmerman, Steven C

• photoacoustic imaging
• photoacoustic probes
• fluorescence imaging
• fluorescent probes
• molecular imaging
• hypoxia
• hypoxia imaging
• in vivo imaging

Statement dc:rights

• Copyright 2020 Hailey J. Knox

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/108574

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/108574