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
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