Recent advances in 4-hydroxy-1,8-naphthalimide-based small-molecule fluorescent probes

Ferroptosis is an iron-dependent, non-apoptotic form of programmed cell death driven by excessive lipid peroxidation (LPO). Mounting evidence suggests that the unique modality of cell death is involved in the development and progression of several diseases including cancer, cardiovascular diseases (CVDs), neurodegenerative disorders, etc. However, the pathogenesis and signalling pathways of ferroptosis are not fully understood, possibly due to the lack of robust tools for the highly selective and sensitive imaging of ferroptosis analytes in complex living systems. Up to now, various small-molecule fluorescent probes have been applied as promising chemosensors for studying ferroptosis through tracking the biomolecules or microenvironment-related parameters in vitro and in vivo. In this review, we comprehensively reviewed the recent development of small-molecule fluorescent probes for studying ferroptosis, with a focus on the analytes, design strategies and bioimaging applications. We also provided new insights to overcome the major challenges in this emerging field.

Recent advances in small-molecule fluorescent probes for studying ferroptosis.

Tumor microenvironment (TME) is the survival environment for tumor cells to proliferate and metastasize in deep tissue. TME contains tumor cells, immune cells, stromal cells and a variety of active molecules including reactive oxygen species (ROS). Inside the TME, ROS regulate the oxidation-reduction (redox) homeostasis and promote oxidative stress. Due to the rapid proliferation ability and specific metabolic patterns of the TME, ROS pervade virtually all complex physiological processes and play irreplaceable roles in protein modification, signal transduction, metabolism, and energy production in various tumors. Therefore, measurements of the dynamically, multicomponent simultaneous changes of ROS in the TME are of great significance to reveal the detailed proliferation and metastasis mechanisms of the tumor. Near-infrared (NIR) and two-photon (TP) fluorescence imaging techniques possess real-time, dynamic, highly sensitive, and highly signal-to-noise ratios with deep tissue penetration abilities. With the rationally designed probes, the NIR and TP fluorescence imaging techniques have been widely used to reveal the mechanisms of how ROS regulates and constructs complex signals and metabolic networks in TME. Therefore, we summarize the design principles and performances of NIR and TP fluorescence imaging of ROS in the TME in the last four years, as well as discuss the advantages and potentials of these works. This Review can provide guidance and prospects for future research work on TME and facilitate the development of antitumor drugs.

Deep-Tissue Fluorescence Imaging Study of Reactive Oxygen Species in a Tumor Microenvironment.

Construction of a novel mitochondria-targeted near-infrared (NIR) probe for detection of viscosity changes in cancer cells ferroptosis process

Aberrant production of H2O2 is involved in cancer. The levels of H2O2 are significantly higher in tumor cells than in normal cells. It is important to develop fluorescent probes to image basal H2O2 selectively in tumor cells. So far, a cancer cell-targeting probe to image basal H2O2 has not been reported. Thus, we developed a fluorescent probe, BBHP, which contains benzil as a H2O2-recognition site and biotin as a target binding motif for the selective and sufficient detection of H2O2 in tumor cells. BBHP enables a selective fluorescence turn-on response to H2O2. The binding of the probe with biotin receptors can greatly accelerate the fluorescence response to H2O2. As a result, BBHP can sufficiently image basal H2O2 in biotin receptor-positive cancer cells and tumor tissues. Finally, BBHP was successfully applied to discriminate between cancerous and normal tissues.

Dejun Dong

Papers

A biotin-guided two-photon fluorescent probe for detection of hydrogen peroxide in cancer cells ferroptosis process.