Evoking Simultaneous Ferroptosis and Apoptosis by a Dual-Locked Platinum (IV) Prodrug for Synergistic Chemo-immunotherapy
He Meng
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Both authors contributed equally to this work.
Search for more papers by this authorJinhui Wang
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Both authors contributed equally to this work.
Search for more papers by this authorHongyu Wen
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Search for more papers by this authorZilong Xu
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Search for more papers by this authorLiuruiqi Luo
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Search for more papers by this authorWenkai Lin
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Search for more papers by this authorKai Lu
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Search for more papers by this authorYuxiang Lu
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Search for more papers by this authorJing Wang
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Search for more papers by this authorYufang Xiong
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Search for more papers by this authorJianqiao Xu
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Search for more papers by this authorCorresponding Author
Zong-Wan Mao
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
E-mail: [email protected], [email protected]
Search for more papers by this authorCorresponding Author
Wei Xia
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
E-mail: [email protected], [email protected]
Search for more papers by this authorHe Meng
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Both authors contributed equally to this work.
Search for more papers by this authorJinhui Wang
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Both authors contributed equally to this work.
Search for more papers by this authorHongyu Wen
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Search for more papers by this authorZilong Xu
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Search for more papers by this authorLiuruiqi Luo
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Search for more papers by this authorWenkai Lin
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Search for more papers by this authorKai Lu
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Search for more papers by this authorYuxiang Lu
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Search for more papers by this authorJing Wang
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Search for more papers by this authorYufang Xiong
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Search for more papers by this authorJianqiao Xu
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
Search for more papers by this authorCorresponding Author
Zong-Wan Mao
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
E-mail: [email protected], [email protected]
Search for more papers by this authorCorresponding Author
Wei Xia
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006 China
E-mail: [email protected], [email protected]
Search for more papers by this authorGraphical Abstract
A dual-locked Pt(IV) prodrug combines a TLR7/8 agonist (IMDQ) with a GGT-responsive moiety. Reduction to Pt(II) triggers GGT-mediated cleavage of axial ligands, releasing IMDQ to activate immunity. TLR7/8 signaling boosts T-cell infiltration into tumors and stimulates tumor-associated macrophages (TAMs) and dendritic cells (DCs). Synergy between platinum chemotherapy and immune activation achieves potent antitumor efficacy.
Abstract
While platinum-based chemotherapeutics have revolutionized cancer treatment, their clinical potential is limited by off-target toxicity and restricted antitumor mechanisms. Herein, we introduce a dual-locked Pt(IV) prodrug designed for tumor-specific activation, combining platinum-based chemotherapy with TLR7/8-mediated immunotherapy. The prodrug features a γ-glutamyl-caged TLR7/8 agonist as an axial ligand, enabling sequential activation by elevated glutathione (GSH) and γ-glutamyltranspeptidase (GGT) in the tumor microenvironment. Reduction of the Pt(IV) core releases cisplatin and depletes intracellular reductants, amplifying reactive oxygen species to trigger synergistic ferroptosis and apoptosis. Concurrently, GGT-cleaved axial ligand activates tumor-associated macrophages and dendritic cells, repolarizing immunosuppressive M2-like macrophages to pro-inflammatory M1-like phenotypes while recruiting effector and memory T cells. In murine models, the Pt(IV) prodrug demonstrated potent antitumor efficacy by confining immune activation to malignant tissues, eradicating primary tumors, and establishing durable protective immunity against recurrence. This spatiotemporally controlled dual-release strategy minimizes systemic toxicity while synergizing chemotherapy and immunotherapy, offering a transformative approach for targeted cancer therapy.
Conflict of Interests
The authors declare no conflict of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available in the supplementary material of this article.
Supporting Information
| Filename | Description |
|---|---|
| anie202505930-sup-0001-SuppMat.pdf4.4 MB | Supplementary Information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1L. H. Hurley, Nat. Rev. Cancer 2002, 2, 188–200.
- 2K. D. Mjos, C. Orvig, Chem. Rev. 2014, 114, 4540–4563.
- 3M. A. Fuertes, C. Alonso, J. M. Pérez, Chem. Rev. 2003, 103, 645–662.
- 4K. Peng, Y. Zheng, W. Xia, Z. W. Mao, Chem. Soc. Rev. 2023, 52, 2790–2832.
- 5K. M. Deo, D. L. Ang, B. McGhie, A. Rajamanickam, A. Dhiman, A. Khoury, J. Holland, A. Bjelosevic, B. Pages, C. Gordon, J. R. Aldrich-Wright, Chem. Soc. Rev. 2018, 375, 148–163.
- 6M. D. Hall, T. W. Hambley, Coord. Chem. Rev. 2002, 232, 49–67.
- 7S. Zhang, X. Wang, Z. Guo, in Advances in Inorganic Chemistry, Vol. 75 (Eds: P. J. Sadler, R. Eldik), Academic Press, San Diego, 2020, pp. 149–182.
- 8L. Ma, N. Wang, R. Ma, C. Li, Z. Xu, M. K. Tse, G. Zhu, Angew. Chem. Int. Ed. 2018, 57, 9098–9102.
- 9Z. Deng, H. Li, S. Chen, N. Wang, G. Liu, D. Liu, W. Ou, F. Xu, X. Wang, D. Lei, P.-C. Lo, Y. Y. Li, J. Lu, M. Yang, M.-L. He, G. Zhu, Nat. Chem. 2023, 15, 930–939.
- 10Z. Deng, N. Wang, Y. Liu, Z. Xu, Z. Wang, T.-C. Lau, G. Zhu, J. Am. Chem. Soc. 2020, 142, 7803–7812.
- 11Q. Fu, S. Zhang, S. Shen, Z. Gu, J. Chen, D. Song, P. Sun, C. Wang, Z. Guo, Y. Xiao, Y. Q. Gao, Z. Guo, Z. Liu, Nat. Biomed. Eng. 2024, 8, 1425–1435.
- 12G. Liu, Y. Zhang, H. Yao, Z. Deng, S. Chen, Y. Wang, W. Peng, G. Sun, M.-K. Tse, X. Chen, J. Yue, Y.-K. Peng, L. Wang, G. Zhu, Sci. Adv. 2023, 9, eadg5964.
- 13H. Z. Yao, Z. G. Wang, N. Wang, Z. Q. Deng, G. Y. Liu, J. H. Zhou, S. Chen, J. H. Shi, G. Zhu, Angew. Chem. Int. Ed. 2022, 61, e202203838.
- 14Y. R. Zheng, K. Suntharalingam, T. C. Johnstone, H. Yoo, W. Lin, J. G. Brooks, S. J. Lippard, J. Am. Chem. Soc. 2014, 136, 8790–8798.
- 15A. Gandioso, E. Shaili, A. Massaguer, G. Artigas, A. González-Cantó, J. A. Woods, P. J. Sadler, V. Marchán, Chem. Commun. 2015, 51, 9169–9172.
- 16D. Y. Q. Wong, C. H. F. Yeo, W. H. Ang, Angew. Chem. Int. Ed. 2014, 53, 6752–6756.
- 17E. Petruzzella, J. P. Braude, J. R. Aldrich-Wright, V. Gandin, D. Gibson, Angew. Chem. Int. Ed. 2017, 56, 11539–11544.
- 18H. Yao, Z. Wang, N. Wang, Z. Deng, G. Liu, J. Zhou, S. Chen, J. Shi, G. Zhu, Angew. Chem. Int. Ed. 2022, 61, e202203838.
- 19Y. Wang, L. Cai, H. Li, H. Chen, T. Yang, Y. Tan, Z. Guo, X. Wang, Angew. Chem. Int. Ed. 2023, 62, e202309043.
- 20L. X. Cai, Y. Wang, H. H. Chen, Y. H. Tan, T. Yang, S. R. Zhang, Z. Guo, X. Y. Wang, J. Med. Chem. 2023, 66, 11351–11364.
- 21Q. Cao, D. J. Zhou, Z. Y. Pan, G. G. Yang, H. Zhang, L. N. Ji, Z. W. Mao, Angew. Chem. Int. Ed. 2020, 59, 18556–18562.
- 22M. V. Babak, Y. Zhi, B. Czarny, T. B. Toh, L. Hooi, E. K. H. Chow, W. H. Ang, D. Gibson, G. Pastorin, Angew. Chem. Int. Ed. 2019, 58, 8109–8114.
- 23S. R. Zhang, D. F. Song, W. H. Yu, J. Li, X. Y. Wang, Y. C. Li, Z. H. Zhao, Q. Xue, J. Zhao, J. P. Li, Z. Guo, Natl. Sci. Rev. 2024, 11, nwae020.
- 24S. X. Jin, N. Muhammad, Y. W. Sun, Y. H. Tan, H. Yuan, D. F. Song, Z. Guo, X. Y. Wang, Angew. Chem. Int. Ed. 2020, 59, 23313–23321.
- 25S. X. Jin, E. M. Yin, C. Y. Feng, Y. W. Sun, T. Yang, H. Yuan, Z. Guo, X. Y. Wang, Chem. Sci. 2023, 14, 8327–8337.
- 26T. Yang, S. R. Zhang, H. Yuan, Y. Wang, L. X. Cai, H. H. Chen, X. Y. Wang, D. F. Song, X. H. Wang, Z. Guo, X. Y. Wang, Angew. Chem. Int. Ed. 2023, 62, e202213337.
- 27R. M. Fan, A. H. Deng, B. Qi, S. Zhang, R. X. Sang, L. X. Luo, J. K. Gou, Y. Q. Liu, R. Z. Lin, M. G. Zhao, Y. Liu, L. Yang, M. S. Cheng, G. F. Wei, J. Med. Chem. 2023, 66, 875–889.
- 28Y. H. Tan, H. H. Chen, J. Zhang, L. X. Cai, S. X. Jin, D. F. Song, T. Yang, Z. Guo, X. Y. Wang, Eur. J. Med. Chem. 2022, 229, 114047.
- 29B. Z. Qian, J. W. Pollard, Cell 2010, 141, 39–51.
- 30S. K. Biswas, A. Mantovani, Nat. Immunol. 2010, 11, 889–896.
- 31R. Narayan, H. Nguyen, J. J. Bentow, L. Moy, D. K. Lee, S. Greger, J. Haskell, V. Vanchinathan, P. L. Chang, S. Tsui, T. Konishi, B. Comin-Anduix, C. Dauphine, H. I. Vargas, J. S. Economou, A. Ribas, K. W. Bruhn, N. Craft, J. Invest. Dermatol. 2012, 132, 163–169.
- 32K. A. Michaelis, M. A. Norgard, X. X. Zhu, P. R. Levasseur, S. Sivagnanam, S. M. Liudahl, K. G. Burfeind, B. Olson, K. R. Pelz, D. M. A. Ramos, H. C. Maurer, K. P. Olive, L. M. Coussens, T. K. Morgan, D. L. Marks, Nat. Commun. 2019, 10, 4682.
- 33A. Banete, K. Gee, S. Basta, J. Leukoc. Biol. 2022, 111, 401–413.
- 34S. J. Wang, J. R. Wang, Z. Q. Chen, J. M. Luo, W. Guo, L. L. Sun, L. Z. Lin, NPJ. Precis. Oncol. 2024, 8, 31.
- 35H. Hemmi, T. Kaisho, O. Takeuchi, S. Sato, H. Sanjo, K. Hoshino, T. Horiuchi, H. Tomizawa, K. Takeda, S. Akira, Nat. Immunol. 2002, 3, 196–200.
- 36B. J. Weigel, S. Cooley, T. DeFor, D. J. Weisdorf, A. Panoskaltsis-Mortari, W. Chen, B. R. Blazar, J. S. Miller, Am. J. Hematol. 2012, 87, 953–956.
- 37L. I. Harrison, C. Astry, S. Kumar, C. Yunis, J. Clin. Pharmacol. 2007, 47, 962–969.
- 38Z. F. Zhong, M. H. Deventer, Y. Chen, S. Vanhee, I. Lammens, K. Deswarte, Y. Huang, T. T. Ye, H. X. Wang, L. Nuhn, M. M. Vandeputte, M. Gontsarik, X. L. Cui, N. N. Sanders, S. Lienenklaus, B. N. Lambrecht, A. P. Baptista, C. P. Stove, B. G. De Geest, Angew. Chem. Int. Ed. 2024, 64, e202419031.
- 39L. Nuhn, S. De Koker, S. Van Lint, Z. F. Zhong, J. P. Catani, F. Combes, K. Deswarte, Y. P. Li, B. N. Lambrecht, S. Lienenklaus, N. N. Sanders, S. A. David, J. Tavernier, B. G. De Geest, Adv. Mater. 2018, 30, e1803397.
- 40A. Huppertsberg, L. Kaps, Z. F. Zhong, S. Schmitt, J. Stickdorn, K. Deswarte, F. Combes, C. Czysch, J. De Vrieze, S. Kasmi, N. Choteschovsky, A. Klefenz, C. Medina-Montano, P. Winterwerber, C. J. Chen, M. Bros, S. Lienenklaus, N. N. Sanders, K. Koynov, D. Schuppan, B. N. Lambrecht, S. A. David, B. G. De Geest, L. Nuhn, J. Am. Chem. Soc. 2021, 143, 9872–9883.
- 41J. Stickdorn, L. Stein, D. Arnold-Schild, J. Hahlbrock, C. Medina-Montano, J. Bartneck, T. Ziss, E. Montermann, C. Kappel, D. Hobernik, M. Haist, H. Yurugi, M. Raabe, A. Best, K. Rajalingam, M. P. Radsak, S. A. David, K. Koynov, M. Bros, S. Grabbe, H. Schild, L. Nuhn, ACS Nano 2022, 16, 4426–4443.
- 42M. H. Hanigan, in Advances in Cancer Research, Vol. 122 (Eds: D. M. Townsend, K. D. Tew), Academic Press, Cambridge, MA USA, 2014, pp. 103–141.
- 43F. Wang, Y. Zhu, L. Zhou, L. Pan, Z. Cui, Q. Fei, S. Luo, D. Pan, Q. Huang, R. Wang, C. Zhao, H. Tian, C. Fan, Angew. Chem. Int. Ed. 2015, 54, 7349–7353.
- 44S. Zhang, H. Yuan, Y. Guo, K. Wang, X. Wang, Z. Guo, Chem. Commun. 2018, 54, 11717–11720.
- 45S. Zhang, D. Song, W. Yu, J. Li, X. Wang, Y. Li, Z. Zhao, Q. Xue, J. Zhao, J. P. Li, Z. Guo, Natl. Sci. Rev. 2024, 11, nwae020.
- 46M. Chiba, Y. Ichikawa, M. Kamiya, T. Komatsu, T. Ueno, K. Hanaoka, T. Nagano, N. Lange, Y. Urano, Angew. Chem. Int. Ed. 2017, 56, 10418–10422.
- 47R. G. Kenny, C. J. Marmion, Chem. Rev. 2019, 119, 1058–1137.
- 48S. Y. Akaydin, E. M. Salihoglu, D. G. Güngör, H. Karanlik, S. Demokan, Eur. J. Breast. Health. 2020, 16, 72–76.
- 49I. S. Fentiman, Br. J. Cancer 2012, 106, 1467–1468.
- 50W. Rzeski, L. Turski, C. Ikonomidou, Proc. Natl. Acad. Sci. USA 2001, 98, 6372–6377.
- 51S. Koda, J. Hu, X. Ju, G. Sun, S. Shao, R. X. Tang, K. Y. Zheng, J. Yan, Front. Immunol. 2023, 14, 1123841.
- 52J. De Vrieze, B. Louage, K. Deswarte, Z. Zhong, R. De Coen, S. Van Herck, L. Nuhn, C. Kaas Frich, A. N. Zelikin, S. Lienenklaus, N. N. Sanders, B. N. Lambrecht, S. A. David, B. G. De Geest, Angew. Chem. Int. Ed. 2019, 58, 15390–15395.
- 53Z. Shen, G. Reznikoff, G. Dranoff, K. L. Rock, J. Immunol. 1997, 158, 2723–2730.
