A “One‐to‐Multi” Activatable Near‐infrared Fluorescent Probe for the Sensitive Imaging of γ‑Glutamyl Transpeptidase Activity in Living Mice

An activatable near-infrared fluorogenic probe that elicits multiple effects—including covalent immobilization, fluorescence turn-on, and change in hydrophilicity and cell-permeability—upon a single interaction with γ-glutamyl transpeptidase, enabling high-contrast in vivo imaging with sustained signal retention at target sites in living animals.

Abstract

γ-Glutamyl transpeptidase (GGT) is a membrane-bounded enzyme closely involved in a wide range of physiological and pathological processes. While numerous fluorescent probes have been developed to image GGT activity noninvasively, in vivo applications remain challenging. A key limitation lies in GGT's localization: activated fluorophores diffuse rapidly from sites of activation, significantly reducing contrast of image in living systems. To overcome this, we adopted the “one-to-multi” design to develop a novel NIR fluorescent probe for GGT. This probe, upon a single GGT activation, triggers a cascade of effects, including markedly reduced aqueous solubility, enhanced cellular permeability, covalent self-immobilization at the target site, and enhancement in near-infrared (NIR) fluorescence intensity. This design allows real-time and sensitive imaging of GGT activity in live cells and achieves high contrast in vivo imaging with long-lasting signal retention at tumor sites in living mice.

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