Nano versus Molecular: Optical Imaging Approaches to Detect and Monitor Tumor Hypoxia

Abstract

Hypoxia is a ubiquitous feature of solid tumors, which plays a key role in tumor angiogenesis and resistance development. Conventional hypoxia detection methods lack continuous functional detection and are generally less suitable for dynamic hypoxia measurement. Optical sensors hereby provide a unique opportunity to noninvasively image hypoxia with high spatiotemporal resolution and enable real‐time detection. Therefore, these approaches can provide a valuable tool for personalized treatment planning against this hallmark of aggressive cancers. Many small optical molecular probes can enable analyte triggered response and their photophysical properties can also be fine‐tuned through structural modification. On the other hand, optical nanoprobes can acquire unique intrinsic optical properties through nanoconfinement as well as enable simultaneous multimodal imaging and drug delivery. Furthermore, nanoprobes provide biological advantages such as improving bioavailability and systemic delivery of the sensor to enhance bioavailability. This review provides a comprehensive overview of the physical, chemical, and biological analytes for cancer hypoxia detection and focuses on discussing the latest nano‐ and molecular developments in various optical imaging approaches (fluorescence, phosphorescence, and photoacoustic) in vivo. Finally, this review concludes with a perspective toward the potentials of these optical imaging approaches in hypoxia detection and the challenges with molecular and nanotechnology design strategies.

Ratiometric hypoxia detection by bright organic room temperature phosphorescence of uniformed silica nanoparticles in water

“…Hypoxia detection is an important biomedical application for phosphorescence, which can provide parameters for the early diagnosis of various diseases, such as chronic kidney diseases, [38] cancer, [39,40] and inflammatory diseases. [41] Nevertheless, utilizing organic long-lived phosphorescence for hypoxia sensing is rarely reported owing to the contradictory requirement of producing phosphorescence by tight packing of organic molecules but allowing oxygen diffusion for sensitivity.…”

Ratiometric hypoxia detection by bright organic room temperature phosphorescence of uniformed silica nanoparticles in water

“…Hypoxia detection is an important biomedical application for phosphorescence, which can provide parameters for the early diagnosis of various diseases, such as chronic kidney diseases, [38] cancer, [39,40] and inflammatory diseases. [41] Nevertheless, utilizing organic long-lived phosphorescence for hypoxia sensing is rarely reported owing to the contradictory requirement of producing phosphorescence by tight packing of organic molecules but allowing oxygen diffusion for sensitivity.…”

Imaging hypoxia for head and neck cancer: current status, challenges, and prospects

“…Optical imaging enables the visualization and quantification of biological processes at the molecular level, offers high practicality and cost-friendliness, and is emerging as a fundamental tool for imaging tumor hypoxia in the field of basic science 8 . Diverse optical techniques, including fluorescence, phosphorescence, photoacoustic, and Cherenkov imaging, employ hypoxia-specific probes and advanced imaging systems to visualize and quantify hypoxic regions within tumors ( Figure 2 ).…”

“…These drawbacks should be addressed for clinicians to develop MRI as a clinically applicable imaging technique for tumor hypoxia 114 . Despite their high sensitivity and specificity, optical imaging modalities are absent from clinical trials owing to their inherent depth limitations (1‒2 cm) 8 . Moreover, the clinical translation of new imaging agents requires a long-term and strict regulatory process, which can explain the gap between basic research and clinical application.…”

Bioengineered nanomaterials for dynamic diagnostics in vivo

“…22 Tumor hypoxia is a defining characteristic of solid tumors, caused by insufficient oxygen delivery due to vascular damage and the rapid metabolic oxygen consumption by cancer cells. 242 Thus, dynamic tumor diagnosis can be achieved through the interaction of nanomaterials with physical analytes (such as partial oxygen pressure or blood oxygen saturation) or biomarkers (including hypoxia-inducible factor-1, carbonic anhydrase IX, lactate, hydrogen peroxide, and hydrogen sulfide) generated by tumor hypoxia. [242][243][244] Leveraging the interaction of biomarkers and altered physicochemical properties in the pathological microenvironment with nanomaterials presents a promising avenue for developing dynamic in vivo diagnostic strategies.…”

Ratiometric hypoxia detection by bright organic room temperature phosphorescence of uniformed silica nanoparticles in water

“…Hypoxia detection is an important biomedical application for phosphorescence, which can provide parameters for the early diagnosis of various diseases, such as chronic kidney diseases, [38] cancer, [39,40] and inflammatory diseases. [41] Nevertheless, utilizing organic long-lived phosphorescence for hypoxia sensing is rarely reported owing to the contradictory requirement of producing phosphorescence by tight packing of organic molecules but allowing oxygen diffusion for sensitivity.…”

Imaging hypoxia for head and neck cancer: current status, challenges, and prospects

“…Optical imaging enables the visualization and quantification of biological processes at the molecular level, offers high practicality and cost-friendliness, and is emerging as a fundamental tool for imaging tumor hypoxia in the field of basic science 8 . Diverse optical techniques, including fluorescence, phosphorescence, photoacoustic, and Cherenkov imaging, employ hypoxia-specific probes and advanced imaging systems to visualize and quantify hypoxic regions within tumors ( Figure 2 ).…”

“…These drawbacks should be addressed for clinicians to develop MRI as a clinically applicable imaging technique for tumor hypoxia 114 . Despite their high sensitivity and specificity, optical imaging modalities are absent from clinical trials owing to their inherent depth limitations (1‒2 cm) 8 . Moreover, the clinical translation of new imaging agents requires a long-term and strict regulatory process, which can explain the gap between basic research and clinical application.…”

Bioengineered nanomaterials for dynamic diagnostics in vivo

“…22 Tumor hypoxia is a defining characteristic of solid tumors, caused by insufficient oxygen delivery due to vascular damage and the rapid metabolic oxygen consumption by cancer cells. 242 Thus, dynamic tumor diagnosis can be achieved through the interaction of nanomaterials with physical analytes (such as partial oxygen pressure or blood oxygen saturation) or biomarkers (including hypoxia-inducible factor-1, carbonic anhydrase IX, lactate, hydrogen peroxide, and hydrogen sulfide) generated by tumor hypoxia. [242][243][244] Leveraging the interaction of biomarkers and altered physicochemical properties in the pathological microenvironment with nanomaterials presents a promising avenue for developing dynamic in vivo diagnostic strategies.…”

Ratiometric hypoxia detection by bright organic room temperature phosphorescence of uniformed silica nanoparticles in water

“…Hypoxia detection is an important biomedical application for phosphorescence, which can provide parameters for the early diagnosis of various diseases, such as chronic kidney diseases, [38] cancer, [39,40] and inflammatory diseases. [41] Nevertheless, utilizing organic long-lived phosphorescence for hypoxia sensing is rarely reported owing to the contradictory requirement of producing phosphorescence by tight packing of organic molecules but allowing oxygen diffusion for sensitivity.…”

Imaging hypoxia for head and neck cancer: current status, challenges, and prospects

“…Optical imaging enables the visualization and quantification of biological processes at the molecular level, offers high practicality and cost-friendliness, and is emerging as a fundamental tool for imaging tumor hypoxia in the field of basic science 8 . Diverse optical techniques, including fluorescence, phosphorescence, photoacoustic, and Cherenkov imaging, employ hypoxia-specific probes and advanced imaging systems to visualize and quantify hypoxic regions within tumors ( Figure 2 ).…”

“…These drawbacks should be addressed for clinicians to develop MRI as a clinically applicable imaging technique for tumor hypoxia 114 . Despite their high sensitivity and specificity, optical imaging modalities are absent from clinical trials owing to their inherent depth limitations (1‒2 cm) 8 . Moreover, the clinical translation of new imaging agents requires a long-term and strict regulatory process, which can explain the gap between basic research and clinical application.…”

Bioengineered nanomaterials for dynamic diagnostics in vivo

“…22 Tumor hypoxia is a defining characteristic of solid tumors, caused by insufficient oxygen delivery due to vascular damage and the rapid metabolic oxygen consumption by cancer cells. 242 Thus, dynamic tumor diagnosis can be achieved through the interaction of nanomaterials with physical analytes (such as partial oxygen pressure or blood oxygen saturation) or biomarkers (including hypoxia-inducible factor-1, carbonic anhydrase IX, lactate, hydrogen peroxide, and hydrogen sulfide) generated by tumor hypoxia. [242][243][244] Leveraging the interaction of biomarkers and altered physicochemical properties in the pathological microenvironment with nanomaterials presents a promising avenue for developing dynamic in vivo diagnostic strategies.…”