Dual-Stimulus Responsive Near-Infrared Reversible Ratiometric Fluorescent and Photoacoustic Probe for In Vivo Tumor Imaging

Abstract

Tumor-specific imaging is a major challenge in clinical tumor resection. To overcome this problem, several activatable probes have been developed for use in tumor imaging. However, most of these probes are activated based on a single-factor stimulation and are irreversible. Therefore, false signals that make tumor-specific imaging difficult are easily generated. We have developed a new dual-stimulus responsive near-infrared (NIR) reversible adenosine 5′-triphosphate (ATP)-pH probe for fluorescence and photoacoustic ratiometric imaging of tumors. Since the H+ and ATP content is significantly higher in the tumor microenvironment than that in normal tissues, the Förster resonance energy transfer-based probe ATP-pH was constructed with silicon rhodamine as the donor, CS dye as the acceptor, and ATP/H+ recognition units that could only be activated when both H+ and ATP were connected to the acceptor. The ATP-pH probe is reversibly activated by both the H+ and ATP, which effectively reduces the cumulative response of the probe in circulation after intravenous injection. Further, the NIR ratiometric property of the probe makes it suitable for in vivo imaging. Finally, our probe was successfully utilized in ratiometric photoacoustic and fluorescence tumor imaging and ratiometric fluorescence imaging-guided tumor resection.

Dual-Mode Tumor Imaging Using Probes That Are Responsive to Hypoxia-Induced Pathological Conditions

“…Because dissociation of MnO 2 produces O 2 , photoacoustic imaging was used to differentiate the optical absorption properties between oxygenated hemoglobin and deoxygenated hemoglobin to estimate oxygen saturation in tumor hypoxic environments [373]. Lu, Fan, and co-workers examined polymer-MnO 2 nanoparticles for dual-activatable photoacoustic and magnetic resonance bimodal imaging in tumor-bearing mice [369]. MnO 2 nanoparticles in their native form do not appreciably enhance the contrast of T 1weighted images.…”

“…With this system, MRI contrast enhancement and photoacoustic signals were used to monitor photothermal therapy of tumors (Figure 59) [375]. Lu, Fan, and co-workers examined polymer-MnO2 nanoparticles for dual-activatable photoacoustic and magnetic resonance bimodal imaging in tumor-bearing mice [369]. MnO2 nanoparticles in their native form do not appreciably enhance the contrast of T1weighted images.…”

“…Therefore, it is important to develop probes that are responsive to more than one stimulus to enhance the accuracy of studies [ 40 ]. Yang, Yuan, and co-workers reported a dual-stimulus responsive near-IR reversible adenosine 5′-triphosphate (ATP) and pH probe, 29a , for fluorescence and photoacoustic ratiometric imaging of tumors [ 369 ]. In hypoxic tumor microenvironments, H + and ATP content are greater than in normal tissues because of the high tumor metabolic rate.…”

Multimodal Contrast Agents for Optoacoustic Brain Imaging in Small Animals

“…Another strategy is to use activable hybrid OA/fluorescence probes for detection with higher specificity. The activable probes that have been reported mainly target at tumor-related hypoxia, glutathione, pH changes, and reactive oxygen species ( Liu et al, 2021c ). Hypoxia plays an important role in tumor metastasis and resistance to chemoradiotherapy and has been an important target for tumor imaging ( Rankin and Giaccia, 2016 ).…”

Low Polarity-Triggered Basic Hydrolysis of Coumarin as an AND Logic Gate for Broad-Spectrum Cancer Diagnosis

“…In addition, recent studies have shown that mitochondrial polarity levels in cancer cells (Δ f ∼ 0.287) are lower than in normal cells (Δ f ∼ 0.295) . While any of these parameters may not separately necessarily indicate cancer, − combining these inputs (MMP, pH, and polarity) via an AND logic gate could improve the accuracy of detection. Herein, we introduce a novel fluorescent probe that simultaneously utilizes MMP, pH, and polarity in mitochondria as inputs to achieve cancer detection (Scheme A).…”