Dual-Locked Fluorescent Probes Activated by Aminopeptidase N and the Tumor Redox Environment for High-Precision Imaging of Tumor Boundaries
Yang Shen
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082 P. R. China
These authors contributed equally to this work.
Search for more papers by this authorDr. Wei Li
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082 P. R. China
School of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing, 211816 P. R. China
These authors contributed equally to this work.
Search for more papers by this authorProf. Zhixuan Zhou
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082 P. R. China
Search for more papers by this authorDr. Junchao Xu
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082 P. R. China
Search for more papers by this authorYuhang Li
Department of Hepatobiliary Surgery/ Central Laboratory, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410005 P. R. China
Search for more papers by this authorHaiyan Li
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082 P. R. China
Search for more papers by this authorXudong Zheng
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082 P. R. China
Search for more papers by this authorCorresponding Author
Dr. Sulai Liu
Department of Hepatobiliary Surgery/ Central Laboratory, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410005 P. R. China
Search for more papers by this authorProf. Xiao-Bing Zhang
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082 P. R. China
Search for more papers by this authorCorresponding Author
Prof. Lin Yuan
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082 P. R. China
Search for more papers by this authorYang Shen
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082 P. R. China
These authors contributed equally to this work.
Search for more papers by this authorDr. Wei Li
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082 P. R. China
School of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing, 211816 P. R. China
These authors contributed equally to this work.
Search for more papers by this authorProf. Zhixuan Zhou
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082 P. R. China
Search for more papers by this authorDr. Junchao Xu
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082 P. R. China
Search for more papers by this authorYuhang Li
Department of Hepatobiliary Surgery/ Central Laboratory, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410005 P. R. China
Search for more papers by this authorHaiyan Li
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082 P. R. China
Search for more papers by this authorXudong Zheng
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082 P. R. China
Search for more papers by this authorCorresponding Author
Dr. Sulai Liu
Department of Hepatobiliary Surgery/ Central Laboratory, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410005 P. R. China
Search for more papers by this authorProf. Xiao-Bing Zhang
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082 P. R. China
Search for more papers by this authorCorresponding Author
Prof. Lin Yuan
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082 P. R. China
Search for more papers by this authorGraphical Abstract
A series of offensive and defensive integration (ODI) strategy-based fluorescent probes depending on the “attack and defense systems” required for the persistence of tumors is reported. FANQ was screened for tumor imaging, distinguishing between cancerous tissue and adjacent tissue with an obvious tumor boundary.
Abstract
Clear delineation of tumor margins is essential for accurate resection and decreased recurrence rate in the clinic. Fluorescence imaging is emerging as a promising alternative to traditional visual inspection by surgeons for intraoperative imaging. However, traditional probes lack accuracy in tumor diagnosis, making it difficult to depict tumor boundaries accurately. Herein, we proposed an offensive and defensive integration (ODI) strategy based on the “attack systems (invasive peptidase) and defense systems (reductive microenvironment)” of multi-dimensional tumor characteristics to design activatable fluorescent probes for imaging tumor boundaries precisely. Screened out from a series of ODI strategy-based probes, ANQ performed better than traditional probes based on tumor unilateral correlation by distinguishing between tumor cells and normal cells and minimizing false-positive signals from living metabolic organs. To further improve the signal-to-background ratio in vivo, derivatized FANQ, was prepared and successfully applied to distinguish orthotopic hepatocellular carcinoma tissues from adjacent tissues in mice models and clinical samples. This work highlights an innovative strategy to develop activatable probes for rapid diagnosis of tumors and high-precision imaging of tumor boundaries, providing more efficient tools for future clinical applications in intraoperative assisted resection.
Conflict of interests
L.Y., Y.S., W.L.,and X.Z. are inventors of the patent (Patent Application number 202311539546.X, pending), which was filed by Hunan University. The other authors declare no competing interests..
Open Research
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
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References
- 1F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, A. Jemal, Ca-Cancer J. Clin. 2018, 68, 394–424.
- 2
- 2aJ. K. Heimbach, L. M. Kulik, R. S. Finn, C. B. Sirlin, M. M. Abecassis, L. R. Roberts, A. X. Zhu, M. H. Murad, J. A. Marrero, Hepatology 2018, 67, 358–380;
- 2bA. G. Waks, E. P. Winer, Jama 2019, 321, 288–300;
- 2cX. Chen, J. Song, X. Chen, H. Yang, Chem. Soc. Rev. 2019, 48, 3073–3101.
- 3R. W. Gao, N. T. Teraphongphom, N. S. van den Berg, B. A. Martin, N. J. Oberhelman, V. Divi, M. J. Kaplan, S. S. Hong, G. Lu, R. Ertsey, W. Tummers, A. J. Gomez, F. C. Holsinger, C. S. Kong, A. D. Colevas, J. M. Warram, E. L. Rosenthal, Cancer Res. 2018, 78, 5144–5154.
- 4S. Blair, M. Garcia, T. Davis, Z. Zhu, Z. Liang, C. Konopka, K. Kauffman, R. Colanceski, I. Ferati, B. Kondov, S. Stojanoski, M. B. Todorovska, N. T. Dimitrovska, N. Jakupi, D. Miladinova, G. Petrusevska, G. Kondov, W. L. Dobrucki, S. Nie, V. Gruev, Sci. Transl. Med. 2021, 13, eaaw7067.
- 5
- 5aS. Hernot, L. van Manen, P. Debie, J. S. D. Mieog, A. L. Vahrmeijer, Lancet Oncol. 2019, 20, e354–e367;
- 5bL. J. Lauwerends, P. B. A. A. van Driel, R. J. Baatenburg de Jong, J. A. U. Hardillo, S. Koljenovic, G. Puppels, L. Mezzanotte, C. W. G. M. Löwik, E. L. Rosenthal, A. L. Vahrmeijer, S. Keereweer, The Lancet Oncology 2021, 22, e186–e195.
- 6T. Ishizawa, N. Fukushima, J. Shibahara, K. Masuda, S. Tamura, T. Aoki, K. Hasegawa, Y. Beck, M. Fukayama, N. Kokudo, Cancer 2009, 115, 2491–2504.
- 7
- 7aY. Wang, Y. Hu, D. Ye, Angew. Chem. Int. Ed. 2022, 61, e202209512;
- 7bY. Zhang, G. Zhang, Z. Zeng, K. Pu, Chem. Soc. Rev. 2022, 51, 566–593;
- 7cM. Bertolini, M. S. Wong, L. Mendive-Tapia, M. Vendrell, Chem. Soc. Rev. 2023, 52, 5352–5372.
- 8
- 8aQ. J. Duan, Z. Y. Zhao, Y. J. Zhang, L. Fu, Y. Y. Yuan, J. Z. Du, J. Wang, Adv. Drug. Deliv. Rev. 2023, 196, 114793;
- 8bH. Li, D. Kim, Q. Yao, H. Ge, J. Chung, J. Fan, J. Wang, X. Peng, J. Yoon, Angew. Chem. Int. Ed. 2021, 60, 17268–17289;
- 8cJ. Liu, M. Liu, H. Zhang, W. Guo, Angew. Chem. Int. Ed. 2021, 60, 12992–12998;
- 8dZ. Zhao, C. B. Swartchick, J. Chan, Chem. Soc. Rev. 2022, 51, 829–868;
- 8eM. Zhao, J. Wang, Z. Lei, L. Lu, S. Wang, H. Zhang, B. Li, F. Zhang, Angew. Chem. Int. Ed. 2021, 60, 5091–5095;
- 8fG. Jiang, H. Liu, H. Liu, G. Ke, T.-B. Ren, B. Xiong, X.-B. Zhang, L. Yuan, Angew. Chem. Int. Ed. 2024, 63, e202315217.
- 9J. C. Widen, M. Tholen, J. J. Yim, A. Antaris, K. M. Casey, S. Rogalla, A. Klaassen, J. Sorger, M. Bogyo, Nat. Biomed. Eng. 2020, 5, 264–277.
- 10
- 10aR. Obara, M. Kamiya, Y. Tanaka, A. Abe, R. Kojima, T. Kawaguchi, M. Sugawara, A. Takahashi, T. Noda, Y. Urano, Angew. Chem. Int. Ed. 2020, 60, 2125–2129;
- 10bQ. Gong, W. Shi, L. Li, H. Ma, Chem. Sci. 2016, 7, 788–792;
- 10cH. Li, Q. Yao, W. Sun, K. Shao, Y. Lu, J. Chung, D. Kim, J. Fan, S. Long, J. Du, Y. Li, J. Wang, J. Yoon, X. Peng, J. Am. Chem. Soc. 2020, 142, 6381–6389.
- 11
- 11aM. Matsui, J. H. Fowler, L. L. Walling, Biol. Chem. 2006, 387, 1535–1544;
- 11bA. Pompella, V. De Tata, A. Paolicchi, F. Zunino, Biochem. Pharmacol. 2006, 71, 231–238;
- 11cI. Ranogajec, J. Jakic-Razumovic, V. Puzovic, J. Gabrilovac, Med. Oncol. 2012, 29, 561–569.
- 12
- 12aL. Wu, J. Huang, K. Pu, T. D. James, Nat. Chem. Rev. 2021, 5, 406–421;
- 12bX. Wei, C. Zhang, S. He, J. Huang, J. Huang, S. S. Liew, Z. Zeng, K. Pu, Angew. Chem. Int. Ed. 2022, 61, e202202966;
- 12cF. F. Faucher, K. J. Liu, E. D. Cosco, J. C. Widen, J. Sorger, M. Guerra, M. Bogyo, ACS Cent. Sci. 2023, 9, 1059–1069;
- 12dJ. Li, L. Wang, X. Luo, Y. Xia, Y. Xie, Y. Liu, W. Tan, Anal. Chem. 2023, 95, 3996–4004;
- 12eX. Wang, S. He, P. Cheng, K. Pu, Adv. Mater. 2023, 35, e2206510;
- 12fX. Zhang, T. Xiu, H. Wang, H. Wang, P. Li, B. Tang, Chem. Commun. 2023, 59, 11017–11027.
- 13L. Wu, J. Liu, X. Tian, R. R. Groleau, B. Feng, Y. Yang, A. C. Sedgwick, H. H. Han, Y. Wang, H. M. Wang, F. Huang, S. D. Bull, H. Zhang, C. Huang, Y. Zang, J. Li, X. P. He, P. Li, B. Tang, T. D. James, J. L. Sessler, J. Am. Chem. Soc. 2022, 144, 174–183.
- 14
- 14aM. Chen, C. Wang, Z. Ding, H. Wang, Y. Wang, Z. Liu, ACS Cent. Sci. 2022, 8, 837–844;
- 14bH. Peng, T. Wang, G. Li, J. Huang, Q. Yuan, Anal. Chem. 2022, 94, 1070–1075.
- 15
- 15aC. Zhang, Q. Z. Zhang, K. Zhang, L. Y. Li, M. D. Pluth, L. Yi, Z. Xi, Chem. Sci. 2019, 10, 1945–1952;
- 15bX.-B. Zhao, J.-Y. Kang, Y.-P. Shi, Anal. Chem. 2022, 94, 6574–6581.
- 16M. G. V. Heiden, L. C. Cantley, C. B. Thompson, Science 2009, 324, 1029–1033.
- 17
- 17aA. L. Harris, Nat. Rev. Cancer 2002, 2, 38–47;
- 17bD. F. Quail, J. A. Joyce, Nat. Med. 2013, 19, 1423–1437;
- 17cL. A. Horn, K. Fousek, C. Palena, Trends Cancer 2020, 6, 432–441.
- 18L. Gai, Y. Liu, Z. Zhou, H. Lu, Z. Guo, Coord. Chem. Rev. 2023, 481, 215041.
- 19
- 19aA. Sharma, J. F. Arambula, S. Koo, R. Kumar, H. Singh, J. L. Sessler, J. S. Kim, Chem. Soc. Rev. 2019, 48, 771–813;
- 19bJ. Ouyang, L. Sun, Z. Zeng, C. Zeng, F. Zeng, S. Wu, Angew. Chem. Int. Ed. 2019, 59, 10111–10121.
- 20
- 20aG. Xu, Q. Yan, X. Lv, Y. Zhu, K. Xin, B. Shi, R. Wang, J. Chen, W. Gao, P. Shi, C. Fan, C. Zhao, H. Tian, Angew. Chem. Int. Ed. 2018, 57, 3626–3630;
- 20bR. Wang, K. Dong, G. Xu, B. Shi, T. Zhu, P. Shi, Z. Guo, W.-H. Zhu, C. Zhao, Chem. Sci. 2019, 10, 2785–2790.
- 21
- 21aS. Son, M. Won, O. Green, N. Hananya, A. Sharma, Y. Jeon, J. H. Kwak, J. L. Sessler, D. Shabat, J. S. Kim, Angew. Chem. Int. Ed. 2019, 58, 1739–1743;
- 21bE. T. Oh, J. W. Kim, J. M. Kim, S. J. Kim, J. S. Lee, S. S. Hong, J. Goodwin, R. J. Ruthenborg, M. G. Jung, H. J. Lee, C. H. Lee, E. S. Park, C. Kim, H. J. Park, Nat. Commun. 2016, 7, 13593;
- 21cG. Jiang, X. F. Lou, S. Zuo, X. Liu, T. B. Ren, L. Wang, X. B. Zhang, L. Yuan, Angew. Chem. Int. Ed. 2023, 62, e202218613.
- 22S. Y. Park, S. A. Yoon, Y. Cha, M. H. Lee, Coord. Chem. Rev. 2021, 428, 213613.
- 23S. He, P. Cheng, K. Pu, Nat. Biomed. Eng. 2023, 7, 281–297.
- 24
- 24aL. K. J. Dixon, H. Turley, I. D. Hickson, R. D. Leek, A. L. Harris, K. C. Gatter, J. Clin. Pathol. 1994, 47, 43–47;
- 24bG. Pathuri, V. Madka, A. F. Hedrick, S. A. Lightfoot, V. Awasthi, B. D. Cowley Jr., C. V. Rao, H. Gali, Mol. Pharmacol. 2014, 11, 2948–2953.
- 25J. Huang, L. He, J. L. Wang, J. C. Xu, L. Yuan, Synlett 2024, 35, 21–28.
- 26H. Zheng, Z. Li, J. Jing, X. S. Xue, J. P. Cheng, Angew. Chem. Int. Ed. 2021, 60, 9401–9406.
- 27S. Ling, X. Yang, C. Li, Y. Zhang, H. Yang, G. Chen, Q. Wang, Angew. Chem. Int. Ed. 2020, 59, 7219–7223.
- 28
- 28aA. Vogel, T. Meyer, G. Sapisochin, R. Salem, A. Saborowski, The Lancet 2022, 400, 1345–1362;
- 28bY. Wen, N. Jing, M. Zhang, F. Huo, Z. Li, C. Yin, Adv. Sci. 2023, 10, 2206681.
- 29A. L. Vahrmeijer, M. Hutteman, J. R. van der Vorst, C. J. H. van de Velde, J. V. Frangioni, Nat. Rev. Clin. Oncol. 2013, 10, 507–518.
- 30
- 30aR. Toshiyama, M. Konno, H. Eguchi, H. Takemoto, T. Noda, A. Asai, J. Koseki, N. Haraguchi, Y. Ueda, K. Matsushita, K. Asukai, T. Ohashi, Y. Iwagami, D. Yamada, D. Sakai, T. Asaoka, T. Kudo, K. Kawamoto, K. Gotoh, S. Kobayashi, T. Satoh, Y. Doki, N. Nishiyama, M. Mori, H. Ishii, Oncogene 2018, 38, 244–260;
- 30bH.-Z. Zhou, H.-Q. Zeng, D. Yuan, J.-H. Ren, S.-T. Cheng, H.-B. Yu, F. Ren, Q. Wang, Y.-P. Qin, A.-L. Huang, J. Chen, Cell Commun. Signaling 2019, 17, 168.
- 31X. Wen, R. Zhang, Y. Hu, L. Wu, H. Bai, D. Song, Y. Wang, R. An, J. Weng, S. Zhang, R. Wang, L. Qiu, J. Lin, G. Gao, H. Liu, Z. Guo, D. Ye, Nat. Commun. 2023, 14, 800.
- 32
- 32aD. R. Coman, Science 1947, 105, 347–348;
- 32bA. Patel, JAMA Oncol. 2020, 6, 1488.
