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.
photoacoustic imaging, photoacoustic probes, fluorescence imaging, fluorescent probes, molecular imaging, hypoxia, hypoxia imaging, in vivo imaging
University of Illinois - Urbana-Champaign
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University of Illinois at Urbana-Champaign