Citation: Li Fu, Ziye Su, Shuyang Wu, Yanfen Cheng, Chuan Hu, Jinming Zhang. Redox-responsive hyaluronic acid-celastrol prodrug micelles with glycyrrhetinic acid co-delivery for tumor combination therapy[J]. Chinese Chemical Letters, ;2025, 36(5): 110227. doi: 10.1016/j.cclet.2024.110227 shu

Redox-responsive hyaluronic acid-celastrol prodrug micelles with glycyrrhetinic acid co-delivery for tumor combination therapy

Li Fu ^a ,
Ziye Su ^a ,
Shuyang Wu ^a ,
Yanfen Cheng ^b ,
Chuan Hu ^{a, *,} ,
Jinming Zhang ^{a, *,}

a.
State Key Laboratory of Southwest Characteristic Traditional Chinese Medicine Resources, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
b.
Chengdu University, Institute for Advanced Study, Department of Science and Technology, Chengdu 610106, China

huchuan@cdutcm.edu.cn

cdutcmzjm@126.com

Received Date: 22 March 2024
Revised Date: 4 July 2024
Accepted Date: 8 July 2024
Available Online: 8 July 2024

Figures(4)

Combining cytotoxic drugs with tumor microenvironment (TME) modulator agents is an effective strategy to enhance anti-tumor effects. In this study, two natural anti-tumor active ingredients celastrol (CEL) and glycyrrhetinic acid (GA) were combined for tumor treatment. In order to ensure the precise co-delivery and controllable synchronous release of combined drugs to tumors, it is necessary to construct a suitable nano-drug delivery platform. Based on this, we coupled hyaluronic acid (HA) with CEL by amide reaction to obtain an amphiphilic polymer prodrug HA-SS-CEL, and GA was spontaneously loaded into polymer micelles by self-assembly to obtain G/HSSC-M. G/HSSC-M has ideal size distribution, redox-responsive synchronous drug release, enhanced tumor cell internalization and in vivo tumor targeting. Compared with free drugs, the construction of multifunctional polymer micelles makes G/HSSC-M show better anticancer effect at the same concentration, and can significantly inhibit the proliferation and migration of HepG2 and 4T1 cells. In the in vivo experiments, G/HSSC-M achieved a tumor inhibition rate as high as 75.12% in H22 tumor-bearing mice. The mechanism included regulation of M1/M2 macrophage polarization, inhibition of Janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) signaling pathway, and remodeling of tumor blood vessels. Therefore, the development of prodrug micelles co-loaded with CEL and GA provides a promising drug co-delivery strategy for combined cancer therapy.
- Polymer micelle,
- Celastrol,
- Glycyrrhetinic acid,
- Redox-responsive,
- Tumor microenvironment,
- Antitumor
1. [1]
  L. Zhang, B. Ye, Z. Chen, et al., Acta Pharm. Sin. B 13 (2023) 982–997. doi: 10.1016/j.apsb.2022.10.002
2. [2]
  X. Li, M. Li, M. Huang, et al., Biomed. Pharmacother. 150 (2022) 113064. doi: 10.1016/j.biopha.2022.113064
3. [3]
  A.J. Abadi, S. Mirzaei, M.K. Mahabady, et al., Phytother. Res. 36 (2022) 189–213. doi: 10.1002/ptr.7305
4. [4]
  B. Xu, X. Luo, J. Xiong, et al., Adv. Ther. 6 (2023) 2200160. doi: 10.1002/adtp.202200160
5. [5]
  T.W. Corson, C.M. Crews, Cell 130 (2007) 769–774. doi: 10.1016/j.cell.2007.08.021
6. [6]
  G. Chen, X. Zhu, J. Li, et al., Pharmacol. Res. 185 (2022) 106487. doi: 10.1016/j.phrs.2022.106487
7. [7]
  P. Luo, Q. Zhang, S. Shen, et al., Asia. J. Pharm. Sci. 18 (2023) 159–176. doi: 10.1504/ijwmc.2023.130405
8. [8]
  Y. Xiao, J. Liu, M. Guo, et al., Nanoscale 10 (2018) 12639–12649. doi: 10.1039/c8nr02700e
9. [9]
  N. Medatwal, M.N. Ansari, S. Kumar, et al., Nanoscale 12 (2020) 18463–18475. doi: 10.1039/d0nr01066a
10. [10]
  A. Lin, C.J. Giuliano, A. Palladino, et al., Sci. Transl. Med. 11 (2019) eaaw8412. doi: 10.1126/scitranslmed.aaw8412
11. [11]
  W. Yi-Na, W. Yuan-Yuan, W. Jin, et al., J. Immunother. Cancer 11 (2023) e007253. doi: 10.1136/jitc-2023-007253
12. [12]
  Y. Deng, Z. Jiang, Y. Jin, et al., J. Control. Release 340 (2021) 87–101. doi: 10.1016/j.jconrel.2021.10.016
13. [13]
  J. Wang, Q. Zhang, Y. Li, et al., Chin. Chem. Lett. 35 (2024) 108746. doi: 10.1016/j.cclet.2023.108746
14. [14]
  Y. Cheng, X. Zhong, X. Nie, et al., Phytomedicine 114 (2023) 154757. doi: 10.1016/j.phymed.2023.154757
15. [15]
  J. Shi, J. Li, J. Li, et al., Phytomedicine 81 (2021) 153408. doi: 10.1016/j.phymed.2020.153408
16. [16]
  R. Zhang, X. Zhao, A. Jia, et al., Int. J. Biol. Macromol. 249 (2023) 125993. doi: 10.1016/j.ijbiomac.2023.125993
17. [17]
  C. Wu, Q. Liu, Y. Wang, et al., Chin. Chem. Lett. 32 (2021) 2400–2404. doi: 10.1016/j.cclet.2021.02.060
18. [18]
  J. Xing, Q. Gong, R. Zou, et al., Chin. Chem. Lett. 34 (2023) 107786. doi: 10.1016/j.cclet.2022.107786
19. [19]
  Q. Zhu, M. Saeed, R. Song, et al., Chin. Chem. Lett. 31 (2020) 1051–1059. doi: 10.1016/j.cclet.2019.12.002
20. [20]
  M. Liu, H. Du, G. Zhai, et al., Colloid. Surf. B 146 (2016) 235–244. doi: 10.1016/j.colsurfb.2016.06.019
21. [21]
  H. Li, Y. Xue, B. Jia, et al., Carbohydr. Polym. 188 (2018) 92–100. doi: 10.1117/12.2302921
22. [22]
  Y. Zhao, Y. Wang, R. Wang, et al., Chin. Chem. Lett. 35 (2024) 108929. doi: 10.1016/j.cclet.2023.108929
23. [23]
  Y. Wei, S. Song, N. Duan, et al., Adv. Sci. 7 (2020) 1902746. doi: 10.1002/advs.201902746
24. [24]
  C. Hu, X. He, Y. Chen, et al., Adv. Funct. Mater. 31 (2021) 2007149. doi: 10.1002/adfm.202007149
25. [25]
  F. Li, Z. Pei, S. Chen, et al., Chin. Chem. Lett. 35 (2024) 108752. doi: 10.1016/j.cclet.2023.108752
1. [1]
  Huijie An , Chen Yang , Zhihui Jiang , Junjie Yuan , Zhongming Qiu , Longhao Chen , Xin Chen , Mutu Huang , Linlang Huang , Hongju Lin , Biao Cheng , Hongjiang Liu , Zhiqiang Yu . Luminescence-activated Pt(Ⅳ) prodrug for in situ triggerable cancer therapy. Chinese Chemical Letters, 2024, 35(7): 109134-. doi: 10.1016/j.cclet.2023.109134
2. [2]
  Fengyun Li , Zerong Pei , Shuting Chen , Gen li , Mengyang Liu , Liqin Ding , Jingbo Liu , Feng Qiu . Multifunctional nano-herb based on tumor microenvironment for enhanced tumor therapy of gambogic acid. Chinese Chemical Letters, 2024, 35(5): 108752-. doi: 10.1016/j.cclet.2023.108752
3. [3]
  Zhendong Liu , Sainan Liu , Bin Liu , Qi Meng , Meng Yuan , Chunzheng Yang , Yulong Bian , Ping'an Ma , Jun Lin . Fe(Ⅲ)-juglone nanoscale coordination polymers for cascade chemodynamic therapy through synergistic ferroptosis and apoptosis strategy. Chinese Chemical Letters, 2024, 35(11): 109626-. doi: 10.1016/j.cclet.2024.109626
4. [4]
  Yunkang Tong , Haiqiao Huang , Haolan Li , Mingle Li , Wen Sun , Jianjun Du , Jiangli Fan , Lei Wang , Bin Liu , Xiaoqiang Chen , Xiaojun Peng . Cooperative bond scission by HRP/H₂O₂ for targeted prodrug activation. Chinese Chemical Letters, 2024, 35(12): 109663-. doi: 10.1016/j.cclet.2024.109663
5. [5]
  Di ZHANG , Tianxiang XIE , Xu HE , Wanyu WEI , Qi FAN , Jie QIAO , Gang JIN , Ningbo LI . Construction and antitumor activity of pH/GSH dual-responsive magnetic nanodrug. Chinese Journal of Inorganic Chemistry, 2025, 41(4): 786-796. doi: 10.11862/CJIC.20240329
6. [6]
  Jin Wang , Xiaoyan Pan , Junyu Zhang , Qingqing Zhang , Yanchen Li , Weiwei Guo , Jie Zhang . Active molecule-based theranostic agents for tumor vasculature normalization and antitumor efficacy. Chinese Chemical Letters, 2024, 35(8): 109187-. doi: 10.1016/j.cclet.2023.109187
7. [7]
  Yi Cao , Xiaojiao Ge , Yuanyuan Wei , Lulu He , Aiguo Wu , Juan Li . Tumor microenvironment-activatable neuropeptide-drug conjugates enhanced tumor penetration and inhibition via multiple delivery pathways and calcium deposition. Chinese Chemical Letters, 2024, 35(4): 108672-. doi: 10.1016/j.cclet.2023.108672
8. [8]
  Honghao Sun , Huimin Zhao , Ronghui Yin , Chenxi Zhou , Ming Wu , Yueyang Deng , Zhanwei Zhou , Minjie Sun . Injectable hydrogel-based tumor vaccine with fibrotic tumor immune microenvironment remodeling to prevent breast cancer postoperative recurrence and metastases. Chinese Chemical Letters, 2025, 36(5): 110067-. doi: 10.1016/j.cclet.2024.110067
9. [9]
  Tingting Hu , Chao Shen , Xueyan Wang , Fengbo Wu , Zhiyao He . Tumor microenvironment-sensitive polymeric nanoparticles for synergetic chemo-photo therapy. Chinese Chemical Letters, 2024, 35(11): 109562-. doi: 10.1016/j.cclet.2024.109562
10. [10]
  Wenbin Zhou , Yafei Gao , Xinyu Feng , Yanqing Zhang , Cong Yang , Lanxi He , Fenghe Zhang , Xiaoguang Li , Qing Li . Biomimetic nanoplatform integrates FRET-enhanced photodynamic therapy and chemotherapy for cascaded revitalization of the tumor immune microenvironment in OSCC. Chinese Chemical Letters, 2025, 36(1): 109763-. doi: 10.1016/j.cclet.2024.109763
11. [11]
  Yanfei Liu , Yaqin Hu , Yifu Tan , Qiwen Chen , Zhenbao Liu . Tumor acidic microenvironment activatable DNA nanostructure for precise cancer cell targeting and inhibition. Chinese Chemical Letters, 2025, 36(1): 110289-. doi: 10.1016/j.cclet.2024.110289
12. [12]
  Jielin Wang , Han Ye , Bozhuang Zhou , Zhen Pan , Yucai Li , Zhenyuan Wei , Bin Chai , Yizhou Gao , Xiaojian Ye , Jiangming Yu . Biomimetic nanofibrillar/hyaluronic acid hydrogels remodel the neuromodulatory microenvironment for enhanced bone regeneration. Chinese Chemical Letters, 2025, 36(5): 110133-. doi: 10.1016/j.cclet.2024.110133
13. [13]
  Jing Zhang , Charles Wang , Yaoyao Zhang , Haining Xia , Yujuan Wang , Kun Ma , Junfeng Wang . Application of magnetotactic bacteria as engineering microrobots: Higher delivery efficiency of antitumor medicine. Chinese Chemical Letters, 2024, 35(10): 109420-. doi: 10.1016/j.cclet.2023.109420
14. [14]
  Huipeng Zhao , Xiaoqiang Du . Polyoxometalates as the redox anolyte for efficient conversion of biomass to formic acid. Chinese Journal of Structural Chemistry, 2024, 43(2): 100246-100246. doi: 10.1016/j.cjsc.2024.100246
15. [15]
  Jingting Wang , Yuanyuan Chen , Linlin Han , Shasha Xia , Xingyao Zhang , Peng Xue , Yuejun Kang , Jian Ming , Zhigang Xu . Microenvironment responsive pod-structured astaxanthin nanocarrier for ameliorating inflammatory bowel disease. Chinese Chemical Letters, 2024, 35(7): 109029-. doi: 10.1016/j.cclet.2023.109029
16. [16]
  Yuanzhe Lu , Yuanqin Zhu , Linfeng Zhong , Dingshan Yu . Long-lifespan aqueous alkaline and acidic batteries enabled by redox conjugated covalent organic polymer anodes. Chinese Journal of Structural Chemistry, 2024, 43(3): 100249-100249. doi: 10.1016/j.cjsc.2024.100249
17. [17]
  Renyuan Wang , Lei Ke , Houxiang Wang , Yueheng Tao , Yujie Cui , Peipei Zhang , Minjie Shi , Xingbin Yan . Facile synthesis of phenazine-conjugated polymer material with extraordinary proton-storage redox capability. Chinese Chemical Letters, 2025, 36(5): 109920-. doi: 10.1016/j.cclet.2024.109920
18. [18]
  Zhaomin Tang , Qian He , Jianren Zhou , Shuang Yan , Li Jiang , Yudong Wang , Chenxing Yao , Huangzhao Wei , Keda Yang , Jiajia Wang . Active-transporting of charge-reversal Cu(Ⅱ)-doped mesoporous silica nanoagents for antitumor chemo/chemodynamic therapy. Chinese Chemical Letters, 2024, 35(7): 109742-. doi: 10.1016/j.cclet.2024.109742
19. [19]
  Jingqi Xin , Shupeng Han , Meichen Zheng , Chenfeng Xu , Zhongxi Huang , Bin Wang , Changmin Yu , Feifei An , Yu Ren . A nitroreductase-responsive nanoprobe with homogeneous composition and high loading for preoperative non-invasive tumor imaging and intraoperative guidance. Chinese Chemical Letters, 2024, 35(7): 109165-. doi: 10.1016/j.cclet.2023.109165
20. [20]
  Shuang Liang , Jianjun Yao , Dan Liu , Mengli Zhou , Yong Cui , Zhaohui Wang . Tumor-responsive covalent organic polymeric nanoparticles enhancing STING activation for cancer immunotherapy. Chinese Chemical Letters, 2025, 36(3): 109856-. doi: 10.1016/j.cclet.2024.109856

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(19)
HTML views(3)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142