Research Progress in Near-Infrared Small-Molecule Fluorescent Probes Responsive to γ-Glutamyl Transferase

Abstract

γ-Glutamyl transferase (GGT) is a kind of cell membrane-bound enzyme, which plays a key role in various physiological and pathological processes. The overexpression of GGT is highly connected to diseases including liver disorders, cancers, and cardiovascular conditions. Near-infrared (NIR) fluorescent probes have emerged as powerful tools for detecting and imaging GGT activity due to their deep tissue penetration, minimal autofluorescence interference, and high signal-to-noise ratio. This review summarizes recent progress made in GGT-activated NIR small-molecular fluorescent probes based on fluorophores including hemicyanine, dicyanomethylene derivatives, AIEgens, cyanine derivatives, and others. The design strategies, structural features, and their applications at cellular levels and in tissues are highlighted. Despite significant improvements in sensitivity, selectivity, and biocompatibility, most probes operate in the first NIR window and still face challenges related to water solubility, targeting their specificity and stability under complex physiological conditions, and clinical translation. Future efforts should be directed toward the development of NIR-II (1000–1700 nm) probes, optimization of their physicochemical properties, and the advancement of their applications in deep-tissue imaging, as well as in clinical diagnostics and therapeutics.

Keywords

Fluorescence probe - Near-Infrared - Bioimaging - Tumor - γ-Glutamyl transferase - Hepatocellular carcinoma

Publication History

Received: 08 September 2025

Accepted after revision: 04 November 2025

Accepted Manuscript online:
04 November 2025

Article published online:
27 January 2026

• References

• 1a Verma VV, Gupta R, Goel M. Biol Direct 2015; 10: 49
• 1b West MB, Chen Y, Wickham S. et al. J Biol Chem 2013; 288: 31902
• 1c Okada T, Suzuki H, Wada K, Kumagai H, Fukuyama K. Proc Natl Acad Sci USA 2006; 103: 6471
• 2a Hanigan MH, Ricketts WA. Biochemist 1993; 32: 6302
• 2b Mehdi K, Penninckx MJ. Microbiology 1885; 1997: 143
• 3a Ritz D, Beckwith J. Ann Rev Microbiol 2001; 55: 21
• 3b Hinchman CA, Ballatori N. J Toxicol Environ Health 1994; 41: 387
• 3c Suthanthiran M, Anderson ME, Sharma VK, Meister A. Proc Natl Acad Sci USA 1990; 87: 3343
• 4a Schulman JD, Goodman SI, Mace JW, Patrick AD, Tietze F, Butler EJ. Biochem Biophys Res Commun 1975; 65: 68
• 4b Castellano I, Merlino A. Cell Mol Life Sci 2012; 69: 3381
• 4c Wright EC, Stern J, Ersser R, Patrick AD. J Inherit Metab Dis 1980; 2: 3
• 5a Pompella A, De Tata V, Paolicchi A, Zunino F. Biochem Pharmacol 2006; 71: 231
• 5b Luo M, Sun W, Wu C. et al. Oncotarget 2017; 8: 67651
• 5c Choi YJ, Lee DH, Han KD. et al. PLoS One 2017; 12: e0177053
• 6 Kiuchi K, Kiuchi K, Nagatsu T, Togari A, Kumagai H. J Chromatogr 1986; 357: 191
• 7 Orlowski M, Meister A. Biochim Biophys Acta – Specializ Sect Enzymol Subj 1963; 73: 679
• 8 Kulhanek V, Dimov DM. Clin Chim Acta 1966; 14: 619
• 9 Luo Z, An R, Ye D. Chembiochem 2019; 20: 474
• 10 Bruemmer KJ, Crossley SWM, Chang CJ. Angew Chem Int Ed 2020; 59: 13734
• 11a Zhang Y, Zhang Z, Wu M, Zhang R. ACS Meas Sci Au 2024; 4: 54
• 11b Hu Z-Y, Chen X-Y, Yang Y-S, Wang S-J, Hu Z-G, Wang K. Coord Chem Rev 2024; 501: 215562
• 12a Fei G, Ma S, Wang C. et al. Coord Chem Rev 2021; 447: 214134
• 12b Sun W, Guo S, Hu C, Fan J, Peng X. Chem Rev 2016; 116: 7768
• 13 Lavis LD. Annu Rev Biochem 2017; 86: 825
• 14 Raunio H, Pentikäinen O, Juvonen RO. Int J Mol Sci 2020; 21: 4708
• 15a Duke RM, Veale EB, Pfeffer FM, Kruger PE, Gunnlaugsson T. Chem Soc Rev 2010; 39: 3936
• 15b Dong H-Q, Wei T-B, Ma X-Q. et al. J Mater Chem C 2020; 8: 13501
• 16a Nguyen V-N, Ha J, Cho M, Li H, Swamy KMK, Yoon J. Coord Chem Rev 2021; 439: 213936
• 16b Wang J, Yu C, Hao E, Jiao L. Coord Chem Rev 2022; 470: 214709
• 17a Kwok RTK, Leung CWT, Lam JWY, Tang BZ. Chem Soc Rev 2015; 44: 4228
• 17b Mei J, Leung NLC, Kwok RTK, Lam JWY, Tang BZ. Chem Rev 2015; 115: 11718
• 18 Yang M, Huang J, Fan J, Du J, Pu K, Peng X. Chem Soc Rev 2020; 49: 6800
• 19a Wolf M, Ferrari M, Quaresima V. J Biomed Opt 2007; 12: 062104
• 19b Salehpour F, Cassano P, Rouhi N. et al. Photobiomodul Photomed Laser Surg 2019; 37: 581
• 20a Li H, Kim H, Xu F. et al. Chem Soc Rev 2022; 51: 1795
• 20b Luo P, Wang M, Liu W, Liu L, Xu P. Molecules. 2022; 27
• 20c Muhammad S, Ahmad H, Yan Y. et al. Coord Chem Rev 2025; 534
• 20d Sun Y, Zhang Y, Zhou C, Yan L. Analyst 2025; 150: 4233
• 21 Li L, Shi W, Wu X, Gong Q, Li X, Ma H. Biosens Bioelectron 2016; 81: 395
• 22 Luo Z, Feng L, An R. et al. Chem Eur J 2017; 23: 14778
• 23 Liu H, Liu F, Wang F, Yu RQ, Jiang JH. Analyst 2018; 143: 5530
• 24 Luo Z, Huang Z, Li K. et al. Anal Chem 2018; 90: 2875
• 25 Li L, Shi W, Wu X, Li X, Ma H. Anal Bioanal Chem 2018; 410: 6771
• 26 Li Y, Xue C, Fang Z, Xu W, Xie H. Anal Chem 2020; 92: 15017
• 27 Liu F, Zhu D, Li Y. et al. Sens Actuators B Chem 2022; 363: 131838
• 28 Wang K, Chen XY, Zhang B. et al. Biosens Bioelectron 2023; 241: 115721
• 29 Gui L, Li W, Pan Y. et al. Sens Actuators B Chem 2024; 398: 134718
• 30 Liu Q, Yuan J, Jiang R. et al. Anal Chem 2023; 95: 2062
• 31 Wang K, Yue Y, Chen XY. et al. ACS Sens 2024; 9: 962
• 32 Wang K, Chen XY, Zhang RW. et al. Biomaterials 2024; 310: 122635
• 33 Feng Q, Li Z, Shen J. Dyes Pigments 2024; 225: 112086
• 34a Guo Z, Zhu W, Tian H. Chem Commun 2012; 48
• 34b Sun Y, Zhang Y, Zhou C, Yan L. Analyst 2025; 150: 4233
• 35 Zhang P, Jiang XF, Nie X. et al. Biomaterials 2016; 80: 46
• 36 Li H, Yao Q, Xu F. et al. Biomaterials 2018; 179: 1
• 37 Liu F, Wang Z, Wang W, Luo JG, Kong L. Anal Chem 2018; 90: 7467
• 38 Liu F, Wang Z, Zhu T. et al. Talanta 2019; 191: 126
• 39 Xie H, Gao J, Sun X. et al. Talanta 2023; 253: 123943
• 40 Jin C, Cao Z, Zhu HL, Li Z. Biosens Bioelectron 2024; 261: 116484
• 41 Lai C-K, Magesh K, Velmathi S, Wu S-P. J Mater Chem B 2025; 13: 201
• 42 Liu Y, Feng B, Cao X. et al. Analyst 2019; 144: 5136
• 43 Shen H, Du L, Xu C. et al. ACS Nano 2024; 18: 20268
• 44 Ou-Yang J, Li Y, Jiang WL, He SY, Liu HW, Li CY. Anal Chem 2019; 91: 1056
• 45 He N, Wang Y, Huang Y, Wang X, Chen L, Lv C. Sens Actuators B Chem 2020; 322: 128565
• 46 Li L, Shi W, Wang Z, Gong Q, Ma H. Anal Chem 2015; 87: 8353
• 47 Shi B, Zhang Z, Jin Q. et al. J Mater Chem B 2018; 6: 7439
• 48 Reo YJ, Jun YW, Sarkar S, Dai M, Ahn KH. Anal Chem 2019; 91: 14101
• 49 Reo YJ, Dai M, Yang YJ, Ahn KH. Anal Chem 2020; 92: 12678
• 50 Huang Z, An R, Wei S, Wang J, Ye D. Analyst 2021; 146: 1865
• 51 Liu F, Li Y, Zhu J. et al. Bioorg Chem 2023; 141: 106899
• 52 Chu F, Feng B, Zhou Y. et al. Chem Sci 2025; 16: 4490