Controllable in-situ Synthesis of NIR-II Hemicyanine in Living Organisms for Efficient Tumor Imaging

Abstract

Second near-infrared region (NIR-II) small-molecule fluorophores hold great promise for biomedical imaging because of their well-defined chemical structures, superior metabolic properties, deep tissue penetration, and unprecedented clarity. However, it is impossible to apply conventional synthesis methods for the in-situ generation of NIR-II fluorophores in living organisms because of the need for high temperatures, strong acids or bases, and anhydrous conditions. Herein, we report an innovative strategy to create NIR-II hemicyanine (NIR-II-Hcy) with high conversion efficiency (up to 86%) under mild conditions, using β-chloroacroleins derivatives (Pre-Hcy) and meta-aminothiophenol as precursors without harsh conditions. Interestingly, this method can be extended to live mice, and the acidic microenvironment is conducive to the rapid production of NIR-II-Hcy (k_{pH = 6.0}/k_{pH = 8.0} = 10). Furthermore, by leveraging the formation/cleavage of disulfide bonds and the acidic microenvironment, the in-situ generation of NIR-II-Hcy enables the activation to be controlled by glutathione (GSH) and H⁺, thereby enabling high-contrast and discriminative in vivo tumor imaging, and this work establishes the first paradigm for tumor microenvironment-driven NIR-II fluorogenesis. This is a novel finding that will facilitate simpler and faster synthesis of NIR-II dyes with broad applications in biomedical research and clinical diagnostics.

Keywords

NIR-II / Hemicyanine / In-situ synthesis / Dyes / Biosensors / Fluorescence imaging

RIGHTS & PERMISSIONS

2025 SIOC, CAS, Shanghai, & WILEY-VCH GmbH