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

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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.