Photophysical Tuning of N-Oxide-Based Probes Enables Ratiometric Photoacoustic Imaging of Tumor Hypoxia

Abstract

Hypoxia results when the oxygen supply to rapidly growing tumors becomes inadequate to support various physiological processes. This plays a role in tumor metastasis and treatment resistance. Therefore, identifying tumor hypoxia can guide treatment planning and predict patient responses. However, hypoxic volumes are heterogeneously dispersed throughout a tumor, making it a challenge to pinpoint them with any degree of accuracy. Herein, we report the development of ratiometric hypoxia probe 1 (rHyP-1), which is a hypoxia-responsive small-molecule probe designed for reliable hypoxia detection using photoacoustic imaging. Photoacoustic imaging utilizes near-infrared (NIR) light to induce the production of ultrasound signals, enabling high-resolution image acquisition at centimeter depths. Together with the ratiometric capability of rHyP-1, reliable hypoxia detection with unprecedented spatial resolution is possible while minimizing error associated with concentration dependence and tissue heterogeneity.

A Photoacoustic Probe for the Imaging of Tumor Apoptosis by Caspase‐Mediated Macrocyclization and Self‐Assembly

“…[8] PA imaging can produce 3D images with improved spatial resolution (up to tens of micrometers) and penetration depth (up to afew centimeters) in vivo,showing promise for detecting essential physiological and pathological processes. [10][11][12] Activatable PA probes that can selectively switch PA signal "on" from an "off" state upon interaction with essential biomolecules and environments (e.g., ions, [13] reactive oxygen species, [14] nitric oxide, [15] hypoxia, [16] and enzymes [17] )h ave also been reported. [10][11][12] Activatable PA probes that can selectively switch PA signal "on" from an "off" state upon interaction with essential biomolecules and environments (e.g., ions, [13] reactive oxygen species, [14] nitric oxide, [15] hypoxia, [16] and enzymes [17] )h ave also been reported.…”

“…[9] Several PA imaging probes capable of accumulating in disease sites through passive delivery or active targeting have been developed, providing increased PA contrast to assess disease states in living animals. [10][11][12] Activatable PA probes that can selectively switch PA signal "on" from an "off" state upon interaction with essential biomolecules and environments (e.g., ions, [13] reactive oxygen species, [14] nitric oxide, [15] hypoxia, [16] and enzymes [17] )h ave also been reported. These probes have advantages of low background and high sensitivity in vivo, facilitating the real-time detection of molecular targets with high imaging depth and spatial resolution.…”

Nitric oxide imaging in cancer enabled by steric relaxation of a photoacoustic probe platform

“…15 To date, only a handful of approaches have been successfully employed for increasing the sensitivity and ratiometric properties of small-molecule PA probes. Specically, increasing the electron density within the aza-BODIPY 22 and conformational restriction of the pendant phenyl rings 23 have led to improved designs for ratiometric, activatable PA probes compared to nonratiometric 24 or poorly ratiometric probes. 25 While successful in the selected example, increasing electron density may not be trivial, depending on the application.…”

A Gold Nanocage/Cluster Hybrid Structure for Whole‐Body Multispectral Optoacoustic Tomography Imaging, EGFR Inhibitor Delivery, and Photothermal Therapy

“…Compared with pure optical imaging (e.g., fluorescent imaging), the optoacoustic (OA) imaging technique is an attractive imaging modality that functions by detecting the ultrasound waves generated by the thermoelastic expansion of tissue resulting from the laser pulse absorption . This technology is not affected by photon scattering and thus can provide high‐resolution optical images deep inside biological tissues . Particularly, the multispectral optoacoustic tomography (MSOT), which is a spectral optoacoustic technique achieved by irradiating an object with multiple wavelengths and allowing the system to detect ultrasound waves from different photoabsorbing substances in the tissue, has shown its great potential in a wide range of biological imaging.…”