A mitochondrial-targetable dual functional near-infrared fluorescent probe to monitor pH and H₂O₂ in living cells and mice

Abstract

A lower pH level and high hydrogen peroxide (H2O2) concentration in mitochondria is closely associated with a variety of diseases including cancer and inflammation.

Activity-Based Sensing for Chemistry-Enabled Biology: Illuminating Principles, Probes, and Prospects for Boronate Reagents for Studying Hydrogen Peroxide

“…93 More recent examples of pH and H 2 O 2 dualresponsive systems rely on single small-molecule probes and have been translated to in vivo LPS stimulated or H 2 O 2 injected mouse models. 94,95 HOCl is also an important target for sensor systems due to its involvement with H 2 O 2 in immune response. 106 As such, dual-responsive single molecule fluorophore systems have been designed to monitor both analytes simultaneously.…”

“…The development of single probes able to respond to multiple analytes was a significant advance in the activity-based sensing field. , Indeed, multianalyte sensing can generate new insights on the complex interplay between different biological phenomena, as cellular metabolic and signaling pathways rely on the synergy of multiple chemical species. In the context of H 2 O 2 sensing, many probes have been designed that simultaneously respond to hypochlorite, − nitrous oxide, hydrogen sulfide, , thiols, pH, − enzymes, − protein aggregates, , and viscosity. − Indeed, structure design for multianalyte sensing has been applied to prepare dual-locked prodrugs; these systems are beyond the scope of this review and covered extensively elsewhere. , Dual-responsive probes hold some general advantages over the simultaneous use of single-analyte probes. Notably, differences in membrane permeability, localization, and metabolism of two probes can result in confounding results or data misinterpretation.…”

“…Application of this dendrimer system to immune stimulated RAW264.7 macrophage models of phagocytosis elucidated the role of Nox in pH regulation as pharmacological Nox inhibition during oxidative bursts resulted in phagosomal acidification . More recent examples of pH and H 2 O 2 dual-responsive systems rely on single small-molecule probes and have been translated to in vivo LPS stimulated or H 2 O 2 injected mouse models. , …”

Engineering AND-Gate Aptamer-Signal Base Conjugates for Targeted Magnetic Resonance Molecular Imaging of Metastatic Cancer

“…Preliminary mechanistic studies indicate that (i) the probe actively targets tumor-associated membrane markers through aptamer-mediated recognition, (ii) precise response to two tumor hallmarks, acidic pH and H 2 O 2 overproduction, is enabled in an AND-gate manner for activation of the signal bases, and finally (iii) specific and amplified T 1 -weighted MR signals are generated in both primary tumors and micrometastases with a remarkably improved signal-to-background ratio. In addition, compared to traditional small-molecule and nanoparticulate imaging probes, including previously reported pH and H 2 O 2 dual-responsive probes, − the small molecular weight and biodegradability of the engineered aptamer-signal base conjugate (ApSC), along with the targeting capability of aptamers, enable rapid excretion from the body after imaging, thus promising to overcome limitations of traditional imaging strategies, those being the lack of active recognition and safety concerns caused by long-term body retention. Also, automatic synthesis allows excellent batch-to-batch reproducibility for future pharmaceutics.…”

A benzothiazolium-based fluorescent probe with ideal pKa for mitochondrial pH imaging and cancer cell differentiation

“…Song et al 18 synthesized a fluorescein probe with a carboxyl group as a sensing site to respond to the pH changes for pH mito detection; nevertheless, the pK a (5.77 AE 0.03) of this probe is far from satisfactory. To improve sensitivity, Qi et al [19][20][21][22][23] prepared fluorescein or rhodamine-based probes by introducing cycloimide as a pH responsive group, which raised the pK a of the probe close to the neutral range. By employing the phenolic hydroxyl groups as a pH mito -sensing group, several pH mito probes with higher fluorescence yield and wider monitoring range have been reported.…”