Issue 36, 2025

Cascade-activatable NIR-II fluorescent carbonic anhydrase inhibitors for imaging-guided cuproptosis/chemodynamic combination therapy of colorectal cancer

Abstract

Colorectal cancer (CRC) is among the malignancies with the highest morbidity, and accurate diagnosis and therapy are essential for improving patient survival. However, CRC is usually diagnosed at an advanced stage, and complete resection of the tumor lesion during treatment is difficult. Herein, we develop a cascade-activatable NIR-II fluorescent inhibitor (Cu@IR783-CAI) for imaging-guided cuproptosis/chemodynamic combination therapy of CRC. Cu@IR783-CAI is synthesized by sequentially modifying a copper complex and a benzenesulfonamide moiety onto NIR-II fluorescent dye IR783. The NIR-II fluorescence signal is quenched by the copper complex via a donor-excited photoinduced electron transfer (d-PeT) process under physiological conditions. In the CRC microenvironment, the overexpressed hydrogen sulfide (H2S) can react with the copper complex to generate copper sulfide, which hinders the d-PeT process and recovers the NIR-II fluorescence signal. Furthermore, Cu@IR783-CAI targets carbonic anhydrase IX (CA IX), which is overexpressed on the surface of tumor cells, thereby restricting intramolecular rotation and further enhancing the NIR-II fluorescence signal, thus achieving cascade activation. In addition, the copper complex of Cu@IR783-CAI can simultaneously trigger cuproptosis and chemodynamic therapy within tumor cells, demonstrating satisfactory anticancer efficacy both in vitro and in vivo. Thus, our study provides a smart NIR-II fluorescent CA inhibitor with cascade-activatable features for CRC theranostics.

Graphical abstract: Cascade-activatable NIR-II fluorescent carbonic anhydrase inhibitors for imaging-guided cuproptosis/chemodynamic combination therapy of colorectal cancer

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Article information

Article type
Edge Article
Submitted
25 Jun 2025
Accepted
13 Aug 2025
First published
13 Aug 2025
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2025,16, 16947-16954

Cascade-activatable NIR-II fluorescent carbonic anhydrase inhibitors for imaging-guided cuproptosis/chemodynamic combination therapy of colorectal cancer

P. Xu, Y. Huang, G. Liu, X. Gu, X. Sun, Y. Bi, W. Zhou, C. Xie and Q. Fan, Chem. Sci., 2025, 16, 16947 DOI: 10.1039/D5SC04668H

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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