NIR Fluorescent/Photoacoustic Bimodal Imaging of Ferroptosis in Pancreatic Cancer Using Biothiols-Activable Probes

Abstract

Ferroptosis modulation is a powerful therapeutic option for pancreatic ductal adenocarcinoma (PDAC) with a low 5year survival rate and lack of effective treatment methods. However, due to the dual role of ferroptosis in promoting and inhibiting pancreatic tumorigenesis, regulating the degree of ferroptosis is very important to obtain the best therapeutic effect of PDAC. Biothiols are suitable as biomarkers of imaging ferroptosis due to the dramatic decreases of biothiol levels in ferroptosis caused by the inhibited synthesis pathway of glutathione (GSH) and the depletion of biothiol by reactive oxygen species. Moreover, a very recent study reported that cysteine (Cys) depletion can lead to pancreatic tumor ferroptosis in mice and may be employed as an effective therapeutic strategy for PDAC. Therefore, visualization of biothiols in ferroptosis of PDAC will be helpful for regulating the degree of ferroptosis, understanding the mechanism of Cys depletion-induced pancreatic tumor ferroptosis, and further promoting the study and treatment of PDAC. Herein, two biothiol-activable near-infrared (NIR) fluorescent/photoacoustic bimodal imaging probes (HYD-BX and HYD-DX) for imaging of pancreatic tumor ferroptosis were reported. These two probes show excellent bimodal response performances for biothiols in solution, cells, and tumors. Subsequently, they have been employed successfully for real-time visualization of changes in concentration levels of biothiols during the ferroptosis process in PDAC cells and HepG2 cells. Most importantly, they have been further applied for bimodal imaging of ferroptosis in pancreatic cancer in mice, with satisfactory results. The development of these two probes provides new tools for monitoring changes in concentration levels of biothiols in ferroptosis and will have a positive impact on understanding the mechanism of Cys depletion-induced pancreatic tumor ferroptosis and further promoting the study and treatment of PDAC.

Ratiometric Fluorescent Probe for Super-Resolution Imaging of Lysosome HClO in Ferroptosis Cells

“…We then investigated the efficiency of SRF-HClO in HClO detection during ferroptosis in living cells. At present, RSL3 or erastin is known to induce ferroptosis by inhibiting the activity of glutathione peroxidase 4 (GPX4). , HeLa cells treated with RSL3 (1 μM) or erastin (10 μM), followed by the treatment with SRF-HClO (10 μM) for 0.5 h, showed strong red fluorescent signals from inside the lysosomes with feeble green fluorescent signals (Figure ), indicating that the HClO level increased significantly during the ferroptosis process. However, upon incubating the cells with ferrostatin-1 (Fer-1, a classical ferroptosis inhibitor), the fluorescence intensity of the probe remained basically the same as that of the probe only. , In addition, further validated by flow cytometry, the conclusion was consistent with the above (Figure S8).…”

Point-of-Care Testing of Whole Blood for Liver Injury Auxiliary Diagnosis with Biothiols Activable Chemiluminescent Probe

“…In addition, as shown in Figure S5, there was little difference in the pathological images of H&E staining before and after CL-Bio-CD injection, affirming the favorable biocompatibility of CL-Bio-CD. Leveraging the overexpression of biothiols in mouse pancreatic cancer cells (panc02) and human liver cancer cells (HepG2), we cultured panc02 and HepG2 with CL-Bio-CD to evaluate their ability to detect endogenous biothiols. Remarkably, no signal was observed in panc02 or HepG2 alone.…”

Molecular Engineering of a Doubly Quenched Fluorescent Probe Enables Ultrasensitive Detection of Biothiols in Highly Diluted Plasma and High-Fidelity Imaging of Dihydroartemisinin-Induced Ferroptosis

“…These strategies are certainly effective and have made great progress, but they require complicated design procedures and are not universal. Generally, intramolecular charge transfer (ICT) and photoinduced electron transfer (PET) mechanisms are widely used for constructing analyte-activable fluorescent probes. − However, most ICT-based probes exhibit a high background possibly due to their partially quenched self-fluorescence, leading to a low S/N ratio and high detection limits . PET-based fluorescent probes always display low intrinsic fluorescence when the energy gap between the fluorophores and the recognition/activating group is well matched, while PET is particularly distance-dependent (generally <1 nm) and can be interfered by local environmental properties, e.g., ICT structures .…”