Citation: Xiaoyi Meng, Xinyue Sun, Zhaogang Sun, Yue Cheng, Yong Wang, Jun Ye, Yin Xiao, Hongqian Chu. Supramolecular-orchestrated carrier-free chemodynamic synergists with augmented oxidative damage for potentiated cancer therapy[J]. Chinese Chemical Letters, ;2025, 36(5): 110765. doi: 10.1016/j.cclet.2024.110765 shu

Supramolecular-orchestrated carrier-free chemodynamic synergists with augmented oxidative damage for potentiated cancer therapy

Xiaoyi Meng ^{a, 1} ,
Xinyue Sun ^{d, 1} ,
Zhaogang Sun ^c ,
Yue Cheng ^{a, *,} ,
Yong Wang ^a ,
Jun Ye ^{e, *,} ,
Yin Xiao ^{b, *,} ,
Hongqian Chu ^{c, *,}

a.
Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, China
b.
Department of Fine Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
c.
Translational Medicine Center, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China
d.
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR 999078, China
e.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

chengyue90@tju.edu.cn

yelinghao@imm.ac.cn

xiaoyin@tju.edu.cn

chuhongqian@bjxkyy.cn

Received Date: 20 October 2024
Revised Date: 12 December 2024
Accepted Date: 13 December 2024
Available Online: 13 December 2024

Figures(5)

Metal ions trigger Fenton/Fenton-like reactions, generating highly toxic hydroxyl radicals (^•OH) for chemodynamic therapy (CDT), which is crucial in inducing lethal oxidative DNA damage and subsequent cell apoptosis. However, tumor cells can counteract this damage through repair pathways, particularly MutT homolog 1 (MTH1) protein attenuation of oxidative DNA damage. Suppression of MTH1 can enhance CDT efficacy, therefore, orderly integrating Fenton/Fenton-like agents with an MTH1 inhibitor is expected to significantly augment CDT effectiveness. Carrier-free CuTH@CD, self-assembled through the supramolecular orchestration of γ-cyclodextrin (γ-CD) with Cu²⁺ and the MTH1 inhibitor TH588, effectively overcoming tumor resistance by greatly amplifying oxidative damage capability. Without additional carriers and mediated by multiple supramolecular regulatory effects, CuTH@CD enables high drug loading content, stability, and uniform size distribution. Upon internalization by tumor cells, CuTH@CD invalidates repair pathways through Cu²⁺-mediated glutathione (GSH) depletion and TH588-mediated MTH1 inhibition. Meanwhile, both generated Cu⁺ ions and existing ones within the nanoassembly initiate a Fenton-like reaction, leading to the accumulation of ^•OH. This strategy enhances CDT efficiency with minimal side effects, improving oxidative damage potency and advancing self-delivery nanoplatforms for developing effective chemodynamic tumor therapies.
- Supramolecular orchestration,
- Carrier-free delivery,
- MTH1 inhibition,
- Chemodynamic therapy,
- Oxidative damage
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