GSH/HAase/pH Triple-responsive Nanotheranostic Agent for Synergistic Therapy Guided by Tumor-targeting Fluorescence/Photoacoustic Dual-mode Imaging
Received date: 2024-04-05
Online published: 2024-08-12
Supported by
Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), the Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), and the open research fund of State Key Laboratory of Organic Electronics and Information Displays
In this work, a multifunctional nanotheranostic agent FePDA/DOX@HA-CYS-TTDPP was constructed for photo/chemodynamic/chemo synergistic therapy guided by tumor-targeting fluorescence/photoacoustic dual-mode imaging. The diketopyrrolopyrrole (DPP) derivative (TTDPP) with near-infrared (NIR) absorption was coupled with tumor-targeting biomolecule hyaluronic acid (HA) via cystamine (CYS) to obtain the amphiphilic polymer HA-CYS-TTDPP. It was then self-assembled with Fe3+-coordinated polydopamine nanoparticles (FePDA) and anti-tumor drug doxorubicin (DOX) to form this nanomaterial. Its photothermal conversion efficiency reached 65.6% and it showed good photoacoustic performance, which can be attributed to the excellent photothermal conversion performance of TTDPP and PDA. TTDPP was a D-π-A-π-D type DPP derivative formed by the electron acceptor (A) DPP, the electron donor (D) triphenylamine, and the conjugated bridge thiophene, which exhibited excellent photothermal and photoacoustic performance, and a certain degree of photodynamic effect. PDA was formed by dopamine oxidation self-polymerization, which showed the advantages of good biocompatibility, high photothermal conversion efficiency, and easy functionalization; moreover, due to the d-d transition of exogenous Fe3+ in FePDA, the photothermal effect of PDA can be further enhanced. Furthermore, the weak acidity of tumor microenvironment (TME) facilitated the dissolution and release of DOX, and the overexpressed hyaluronidase (HAase) and glutathione (GSH) in tumor cells can also trigger the degradation of HA and the cleavage of disulfide bonds in CYS, respectively, leading to the release of DOX. Thus, the distance between DOX and PDA and TTDPP was increased, and the fluorescence of DOX was recovered, thereby achieving TME-responsive fluorescence activation and controlled drug release, and the tumor-targeting effect was further enhanced. Therefore, this nanotheranostic agent can realize triple response to the weak acidity, overexpressed GSH and HAase of TME. On the other hand, Fe3+ can react with GSH and H2O2 in tumor cells to induce Fenton reaction, generating cytotoxic •OH and resulting in chemodynamic therapeutic performance. Cell experiments confirmed that FePDA/DOX@HA-CYS-TTDPP can intelligently respond to TME and achieve targeted fluorescence imaging, and effectively inhibit the proliferation of HeLa tumor cells through photo/chemodynamic/chemo synergistic therapy. This system provides new ideas for achieving precise and efficient tumor theranostics.
Yanqin Huang , Jiwen Luo , Jiaqi Li , Rui Zhang , Xingfen Liu , Quli Fan , Wei Huang . GSH/HAase/pH Triple-responsive Nanotheranostic Agent for Synergistic Therapy Guided by Tumor-targeting Fluorescence/Photoacoustic Dual-mode Imaging[J]. Acta Chimica Sinica, 2024 , 82(8) : 903 -913 . DOI: 10.6023/A24040115
| [1] | Salgia, R.; Kulkarni, P. Trends Cancer 2018, 4, 110. |
| [2] | Chang, T. H.; Qiu, Q.; Ji, A. Y.; Qu, C. R.; Chen, H.; Cheng, Z. Biomaterials 2022, 287, 9. |
| [3] | Xu, C.; Pu, K. Y. Chem. Soc. Rev. 2021, 50, 1111. |
| [4] | Wang, M.; Yan, D. Y.; Wang, M.; Wu, Q.; Song, R. X.; Huang, Y. M.; Rao, J.; Wang, D.; Zhou, F. F.; Tang, B. Z. Adv. Funct. Mater. 2022, 32, 11. |
| [5] | Huang, Y. Q.; Li, L. J.; Yang, S. P.; Zhang, R.; Liu, X. F.; Fan, Q. L.; Huang, W. Acta Chim. Sinica 2023, 81, 1687 (in Chinese). |
| [5] | (黄艳琴, 栗丽君, 杨书培, 张瑞, 刘兴奋, 范曲立, 黄维, 化学学报, 2023, 81, 1687.) |
| [6] | Cai, Y.; Ni, D. Q.; Cheng, W. Y.; Ji, C. D.; Wang, Y. L.; Mullen, K.; Su, Z. Q.; Liu, Y.; Chen, C. Y.; Yin, M. Z. Angew. Chem.-Int. Ed. 2020, 59, 14014. |
| [7] | Zhang, X.; Machuki, J. O.; Pan, W. Z.; Cai, W. B.; Xi, Z. Q.; Shen, F. Z.; Zhang, L. J.; Yang, Y.; Gao, F. L.; Guan, M. ACS Nano 2020, 14, 4045. |
| [8] | Li, Y. R.; Wang, Z. G.; Tang, Z. H. Acta Chim. Sinica 2022, 80, 6 (in Chinese). |
| [8] | (李嫣然, 王子贵, 汤朝晖, 化学学报, 2022, 80, 6.) |
| [9] | Yan, Y. H.; Liang, P. Z.; Zou, Y.; Yuan, L.; Peng, X. J.; Fan, J. L.; Zhang, X. B. Acta Chim. Sinica 2023, 81, 1642 (in Chinese). |
| [9] | (闫英红, 梁平兆, 邹杨, 袁林, 彭孝军, 樊江莉, 张晓兵, 化学学报, 2023, 81, 1642.) |
| [10] | Sun, Q. Q.; Wang, Z.; Liu, B.; He, F.; Gai, S. L.; Yang, P. P.; Yang, D.; Li, C. X.; Lin, J. Coord. Chem. Rev. 2022, 451, 70. |
| [11] | Lin, L. S.; Huang, T.; Song, J. B.; Ou, X. Y.; Wang, Z. T.; Deng, H. Z.; Tian, R.; Liu, Y. J.; Wang, J. F.; Liu, Y.; Yu, G. C.; Zhou, Z. J.; Wang, S.; Niu, G.; Yang, H. H.; Chen, X. Y. J. Am. Chem. Soc. 2019, 141, 9937. |
| [12] | Qian, X. Q.; Zhang, J.; Gu, Z.; Chen, Y. Biomaterials 2019, 211, 1. |
| [13] | Varon, E.; Blumrosen, G.; Sinvani, M.; Haimov, E.; Polani, S.; Natan, M.; Shoval, I.; Jacob, A.; Atkins, A.; Zitoun, D.; Shefi, O. Int. J. Mol. Sci. 2022, 23, 15. |
| [14] | Huang, Y. Q.; Liu, K. L.; Ni, H. L.; Zhang, R.; Liu, X. F.; Fan, Q. L.; Wang, L. H.; Huang, W. ACS Appl. Polym. Mater. 2022, 4, 7739. |
| [15] | Wang, T.; Zhao, L.; Wang, K. W.; Bai, Y. F.; Feng, F. Acta Chim. Sinica 2021, 79, 600 (in Chinese). |
| [15] | (王涛, 赵璐, 王科伟, 白云峰, 冯锋, 化学学报, 2021, 79, 600.) |
| [16] | Manivasagan, P.; Joe, A.; Han, H. W.; Thambi, T.; Selvaraj, M.; Chidambaram, K.; Kim, J.; Jang, E. S. Mater. Today Bio. 2022, 13, 35. |
| [17] | Zhang, S. C.; Cao, C. Y.; Lv, X. Y.; Dai, H. M.; Zhong, Z. H.; Liang, C.; Wang, W. J.; Huang, W.; Song, X. J.; Dong, X. C. Chem. Sci. 2020, 11, 1926. |
| [18] | Dong, S. M.; Dong, Y. S.; Jia, T.; Zhang, F. M.; Wang, Z.; Feng, L. L.; Sun, Q. Q.; Gai, S. L.; Yang, P. P. Chem. Mater. 2020, 32, 9868. |
| [19] | Hu, P.; Wu, T.; Fan, W. P.; Chen, L.; Liu, Y. Y.; Ni, D. L.; Bu, W. B.; Shi, J. L. Biomaterials 2017, 141, 86. |
| [20] | Yao, H. C.; Qiao, P.; Zhu, Z. H.; Sun, F. F.; Zhou, H. J.; Geng, M. L.; Du, B. ACS Biomater. Sci. Eng. 2022, 8, 4413. |
| [21] | Wang, L. H. V.; Yao, J. J. Nat. Methods 2016, 13, 627. |
| [22] | Choi, W.; Park, B.; Choi, S.; Oh, D.; Kim, J.; Kim, C. Chem. Rev. 2023, 123, 7379. |
| [23] | Choi, W.; Oh, D.; Kim, C. J. Appl. Phys. 2020, 127, 15. |
| [24] | Wang, P.; Wu, W. B.; Gao, R. F.; Zhu, H.; Wang, J.; Du, R. L.; Li, X. Y.; Zhang, C. L.; Cao, S. K.; Xiang, R. ACS Appl. Mater. Interfaces 2019, 11, 13935. |
| [25] | Li, J.; Wang, R. N.; Sun, Y.; Xiao, P. P.; Yang, S.; Wang, X.; Fan, Q. L.; Wu, W.; Jiang, X. Q. ACS Appl. Mater. Interfaces 2021, 13, 54830. |
| [26] | Cai, Y.; Liang, P. P.; Tang, Q. Y.; Yang, X. Y.; Si, W. L.; Huang, W.; Zhang, Q.; Dong, X. C. ACS Nano 2017, 11, 1054. |
| [27] | Li, W. T.; Wang, L. Y.; Tang, H.; Cao, D. R. Dyes Pigment. 2019, 162, 934. |
| [28] | Jung, H. S.; Verwilst, P.; Sharma, A.; Shin, J.; Sessler, J. L.; Kim, J. S. Chem. Soc. Rev. 2018, 47, 2280. |
| [29] | Kim, K.; Choi, H.; Choi, E. S.; Park, M. H.; Ryu, J. H. Pharmaceutics 2019, 11, 22. |
| [30] | Xie, H. F.; Zeng, F.; Wu, S. Z. Biomacromolecules 2014, 15, 3383. |
| [31] | Liu, Y. L.; Ai, K. L.; Lu, L. H. Chem. Rev. 2014, 114, 5057. |
| [32] | Yuan, Z.; Lin, C. C.; He, Y.; Tao, B. L.; Chen, M. W.; Zhang, J. X.; Liu, P.; Cai, K. Y. ACS Nano 2020, 14, 3546. |
| [33] | Chen, Q.; Shan, X. R.; Shi, S. Q.; Jiang, C. Z.; Li, T. H.; Wei, S. S.; Zhang, X. Y.; Sun, G. Y.; Liu, J. H. J. Mater. Chem. B 2020, 8, 4056. |
| [34] | Chen, G.; Yang, Y. Y.; Xu, Q.; Ling, M. J.; Lin, H. M.; Ma, W.; Sun, R.; Xu, Y. C.; Liu, X. Q.; Li, N.; Yu, Z. Q.; Yu, M. Nano Lett. 2020, 20, 8141. |
| [35] | Huang, Y. Q.; Song, C. X.; Li, H. C.; Zhang, R.; Jiang, R. C.; Liu, X. F.; Zhang, G. W.; Fan, Q. L.; Wang, L. H.; Huang, W. ACS Appl. Mater. Interfaces 2015, 7, 21529. |
| [36] | Ma, J. B.; Shen, J. M.; Yue, T.; Wu, Z. Y.; Zhang, X. L. Eur. J. Pharm. Sci. 2021, 159, 15. |
| [37] | Huang, Y. Q.; Sun, L. J.; Zhang, R.; Hu, J.; Liu, X. F.; Jiang, R. C.; Fan, Q. L.; Wang, L. H.; Huang, W. ACS Appl. Bio Mater. 2019, 2, 2421. |
| [38] | Wu, K.; Zhao, H. H.; Sun, Z. Q.; Wang, B.; Tang, X. Y.; Dai, Y. N.; Li, M. X.; Shen, Q. M.; Zhang, H.; Fan, Q. L.; Huang, W. Theranostics 2019, 9, 7697. |
| [39] | Pan, L. X.; Huang, Y. Q.; Sheng, K.; Zhang, R.; Fan, Q. L.; Huang, W. Acta Chim. Sinica 2021, 79, 1097 (in Chinese). |
| [39] | (潘立祥, 黄艳琴, 盛况, 张瑞, 范曲立, 黄维, 化学学报, 2021, 79, 1097.) |
| [40] | Stalker, R. A.; Munsch, T. E.; Tran, J. D.; Nie, X. P.; Warmuth, R.; Beatty, A.; Aaker?y, C. B. Tetrahedron 2002, 58, 4837. |
/
| 〈 |
|
〉 |
