Citation: Chuyu Huang, Zhishan Liu, Linping Zhao, Zuxiao Chen, Rongrong Zheng, Xiaona Rao, Yuxuan Wei, Xin Chen, Shiying Li. Metal-coordinated oxidative stress amplifier to suppress tumor growth combined with M2 macrophage elimination[J]. Chinese Chemical Letters, ;2024, 35(12): 109696. doi: 10.1016/j.cclet.2024.109696 shu

Metal-coordinated oxidative stress amplifier to suppress tumor growth combined with M2 macrophage elimination

Chuyu Huang ^{a, 1} ,
Zhishan Liu ^{a, 1} ,
Linping Zhao ^a ,
Zuxiao Chen ^a ,
Rongrong Zheng ^a ,
Xiaona Rao ^a ,
Yuxuan Wei ^a ,
Xin Chen ^{b, *,} ,
Shiying Li ^{a, b, *,}

a.
The Fifth Affiliated Hospital, Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, the School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China
b.
Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China

chen_xin1020@163.com

lisy-sci@gzhmu.edu.cn

Received Date: 18 December 2023
Revised Date: 20 February 2024
Accepted Date: 23 February 2024
Available Online: 1 March 2024

Figures(5)

The anti-oxidative characteristic and immunosuppressive microenvironment contribute to a high resistance of tumor to many treatments. In this work, a glutathione (GSH)-responsive metal-coordinated oxidative stress amplifier (designated as CuPA) is fabricated to suppress tumor growth through elevating the cellular level of reactive oxygen species (ROS) and eliminating M2 macrophages. Among which, cooper ion (Cu²⁺) is capable of coordinating with thioredoxin (Trx) inhibitor of PX-12 and signal transducer and activator of transcription 6 (STAT6) inhibitor of AS1517499 with the assistance of distearoyl phosphoethanolamine-PEG₂₀₀₀ (DSPE-PEG₂₀₀₀), which can extensively increase the stability to enhance drug delivery in vitro and in vivo. Furthermore, CuPA can upregulate intracellular ROS to cause tumor cell death through restraining Trx and degrading GSH. Also, CuPA-mediated STAT6 inhibition results in the elimination of M2 macrophage to reverse the immunosuppressive tumor microenvironment. Finally, the elevated oxidative stress and increased immune activation amplify the synergistic antitumor effect without causing obvious side effect. This work provides a new sight for synergistic tumor suppression through chemo-immunotherapy in consideration of the complex resistant tumor microenvironment.
- Oxidative stress,
- M2 macrophage,
- Metal coordination,
- Chemotherapy,
- GSH degradation
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沈阳化工大学材料科学与工程学院沈阳 110142