Enzyme-activatable dual-locked fluorescent probe for precision imaging of cutaneous squamous cell carcinoma

Abstract

Cutaneous squamous cell carcinoma (cSCC), the second most common skin cancer, requires early and accurate detection to optimize clinical management. Fluorescence imaging has emerged as a non-invasive and cost-effective tool with high sensitivity for tumor diagnosis; however, existing probes for cSCC are limited in achieving rapid and specific imaging. In this study, we introduce FC-1, a dual-tandem activatable fluorescent probe designed for precise cSCC diagnosis by simultaneously targeting fibroblast activation protein α and cathepsin C (CTSC). This dual-locked activation strategy effectively reduces nonspecific signals in normal tissues while enhancing diagnostic specificity. In vivo studies in SCC-7 xenografted mice demonstrated FC-1's ability to visualize subcutaneous tumors with high sensitivity and specificity. Moreover, FC-1 enabled clear differentiation between cSCC and keloids. The probe's dual-activation mechanism and robust performance underscore its potential as a clinically translatable tool for early cSCC detection and differential diagnosis.

Keywords

cutaneous squamous cell carcinoma / disease diagnosis / dual-locked probes / enzyme / fluorescent probes

References

[1] C. Y. Chong, M. S. Goh, S. V. Porceddu, D. Rischin, A. M. Lim, Am. J. Clin. Dermatol. 2023, 24, 25.

[2] A. Wysong, N. Engl. J. Med. 2023, 388, 2262.

[3] P. S. Karia, J. Han, C. D. Schmults, J. Am. Acad. Dermatol. 2013, 68, 957.

[4] J. Caudill, J. E. Thomas, C. G. Burkhart, Int. J. Dermatol. 2023, 62, 483.

[5] M. C. G. Winge, L. N. Kellman, K. Guo, J. Y. Tang, S. M. Swetter, S. Z. Aasi, K. Y. Sarin, A. L. S. Chang, P. A. Khavari, Nat. Rev. Cancer 2023, 23, 430.

[6] S. K. T. Que, F. O. Zwald, C. D. Schmults, J. Am. Acad. Dermatol. 2018, 78, 237.

[7] C. Dessinioti, M. Pitoulias, A. J. Stratigos, J. Eur. Acad. Dermatol. Venereol. 2022, 36, 39.

[8] P. Gjersvik, R. S. Falk, I. Roscher, S. M. H. Rizvi, G. Mjøen, E. Gude, I. Leuckfeld, K. M. Boberg, M. B. Veierød, T. E. Robsahm, JAMA Dermatol. 2023, 159, 923.

[9] R. Comune, A. Ruggiero, A. Portarapillo, A. Villani, M. Megna, S. Tamburrini, S. Masala, G. Sica, F. Sandomenico, C. Bortolotto, L. Preda, M. Scaglione, Cancers 2024, 16, 2960.

[10] A. Combalia, C. Carrera, Dermatol. Pract. Concept. 2020, 10, e2020066.

[11] K. Fujita, Y. Urano, Chem. Rev. 2024, 124, 4021.

[12] H. Li, D. Kim, Q. Yao, H. Ge, J. Chung, J. Fan, J. Wang, X. Peng, J. Yoon, Angew. Chem. Int. Ed. 2021, 60, 17268.

[13] Y. Zhang, X. Lv, Y. Wang, X. Chen, J. Zhang, D. Su, Smart Mol. 2024, 2, e20240031.

[14] L. Chen, Y. Lyu, X. Zhang, L. Zheng, Q. Li, D. Ding, F. Chen, Y. Liu, W. Li, Y. Zhang, Q. Huang, Z. Wang, T. Xie, Q. Zhang, Y. Sima, K. Li, S. Xu, T. Ren, M. Xiong, Y. Wu, J. Song, L. Yuan, H. Yang, X.-B. Zhang, W. Tan, Sci. China Chem. 2023, 66, 1336.

[15] H.-W. Liu, L. Chen, C. Xu, Z. Li, H. Zhang, X.-B. Zhang, W. Tan, Chem. Soc. Rev. 2018, 47, 7140.

[16] S. Zuo, G. Jiang, Y. Zheng, X. Zhang, Z. Qin, L. Chen, T. Ren, X.-B. Zhang, L. Yuan, Anal. Chem. 2023, 95, 898.

[17] W. Shu, Y. Xiao, L. Wang, M. Liang, Z. Li, X. Wu, Q. Cao, Molecules 2022, 27, 7609.

[18] R. Pola, E. Grosmanová, M. Pechar, D. Horák, T. Krunclová, J. Pankrác, M. Henry, M. Kaňa, J. Bouček, L. Šefc, J.-L. Coll, T. Etrych, Adv. Healthc. Mater. 2023, 12, 2301183.

[19] L.-Y. Li, F.-F. Xiang, H. Zhang, D.-J. Wang, L.-X. Fan, Z. Jiang, F. Chen, J. Liu, K. Li, Sens. Actuator B-chem. 2024, 421, 136485.

[20] E. J. Hamson, F. M. Keane, S. Tholen, O. Schilling, M. D. Gorrell, Proteom. Clin. Appl. 2014, 8, 454.

[21] A. A. Fitzgerald, L. M. Weiner, Cancer Metastasis Rev. 2020, 39, 783.

[22] B. Lv, F. E. I. Xie, P. Zhao, X. Ma, W. G. Jiang, J. Yu, X. Zhang, J. U. N. Jia, Cancer Genomics Proteomics 2016, 13, 201.

[23] Q. Miao, D. C. Yeo, C. Wiraja, J. Zhang, X. Ning, C. Xu, K. Pu, Angew. Chem. Int. Ed. 2018, 57, 1256.

[24] J. Jagdeo, E. Kerby, D. A. Glass, JAMA Dermatol. 2021, 157, 744.

[25] O. C. Olson, J. A. Joyce, Nat. Rev. Cancer 2015, 15, 712.

[26] F. Gong, X. Peng, C. Luo, G. Shen, C. Zhao, L. Zou, L. Li, Y. Sang, Y. Zhao, X. Zhao, Mol. Cancer 2013, 12125.

[27] B. Ruffell, N. I. Affara, L. Cottone, S. Junankar, M. Johansson, D. G. DeNardo, L. Korets, T. Reinheckel, B. F. Sloane, M. J. G. Bogyo, L. M. Coussens, Genes Dev. 2013, 27, 2086.

[28] P. Cheng, K. Pu, Chem. Soc. Rev. 2024, 53, 10171.

[29] Y. Li, G. Jiang, J. Zhou, L. Shi, L. Yuan, Chem.-Asian J. 2025, 20, e202401647.

[30] L. Wu, J. Huang, K. Pu, T. D. James, Nat. Rev. Chem 2021, 5, 406.

[31] Y. Shen, W. Li, Z. Zhou, J. Xu, Y. Li, H. Li, X. Zheng, S. Liu, X.-B. Zhang, L. Yuan, Angew. Chem.-Int. Edit. 2024, 63, e202406332.

[32] G. Deng, G. Jiang, L. Yuan, Chin. Sci. Bull.-Chin. 2025, 70, 1782.

[33] L. Yuan, W. Lin, S. Zhao, W. Gao, B. Chen, L. He, S. Zhu, J. Am. Chem. Soc. 2012, 134, 13510.

[34] S. Zuo, Y. Li, Y. Chen, G. Jiang, Z. Zhou, T.-B. Ren, L. Chen, S. Liu, S. Huang, X.-B. Zhang, L. Yuan, Sci. Adv. 2025, 11, eadr5541.

[35] K. Jansen, L. Heirbaut, R. Verkerk, J. D. Cheng, J. Joossens, P. Cos, L. Maes, A.-M. Lambeir, I. De Meester, K. Augustyns, P. Van der Veken, J. Med. Chem. 2014, 57, 3053.

[36] K. Matsumoto, K. Mizoue, K. Kitamura, W.-C. Tse, C. P. Huber, T. Ishida, Biopolymers 1999, 51, 99.

[37] P. O'Brien, B. F. O'Connor, BBA-Proteins Proteomics 2008, 1784, 1130.

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2025 The Author(s). Smart Molecules published by John Wiley & Sons Australia, Ltd on behalf of Dalian University of Technology.