Citation: Huiyang Chen, Zibo Li, Xiaoying Li, Chenhong Tang, Xiaoyu Liu, Minyi Nie, Ying Huang, Xiaoyu Chen, Kuncai Liu, Yilan Dai, Qiaoling Zhang, Ling Lin, Siming Zhang, Bingchen Zhang, Zhiqiang Yu. A novel mitochondria-targeted nanoprodrug amplifies oxidative stress to enhance cisplatin chemotherapy for the treatment of hepatocellular carcinoma[J]. Chinese Chemical Letters, ;2025, 36(10): 111313. doi: 10.1016/j.cclet.2025.111313 shu

A novel mitochondria-targeted nanoprodrug amplifies oxidative stress to enhance cisplatin chemotherapy for the treatment of hepatocellular carcinoma

Huiyang Chen ^{a, b, 1} ,
Zibo Li ^{a, b, 1} ,
Xiaoying Li ^{a, b} ,
Chenhong Tang ^c ,
Xiaoyu Liu ^a ,
Minyi Nie ^{a, b} ,
Ying Huang ^d ,
Xiaoyu Chen ^a ,
Kuncai Liu ^a ,
Yilan Dai ^a ,
Qiaoling Zhang ^{a, b} ,
Ling Lin ^{a, b} ,
Siming Zhang ^e ,
Bingchen Zhang ^{a, b, *,} ,
Zhiqiang Yu ^{a, b, *,}

a.
Department of Laboratory Medicine, Guangdong Provincial Clinical Research Center for Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People’s Hospital), Southern Medical University, Dongguan 523058, China
b.
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
c.
Animal Research Center, The Tenth Affiliated Hospital, Southern Medical University (Dongguan People’s Hospital), Dongguan 523000, China
d.
Health Management Center, The Tenth Affiliated Hospital of Southern Medical University, Dongguan 523059, China
e.
Department of Breast Surgery, Meizhou People’s Hospital, Meizhou 541000, China

zbc19921314@163.com

yuzq@smu.edu.cn

Received Date: 4 March 2025
Revised Date: 12 May 2025
Accepted Date: 13 May 2025
Available Online: 13 May 2025

Figures(4)

Liposomal drugs have significantly improved cancer treatment in recent years. However, the clinical application of conventional liposomes is limited by factors such as the complexity of the preparation process and the multitude of auxiliary components. By replacing phospholipids and cholesterol with vitamin E succinate (VES), this study addresses these shortcomings by developing a novel modified nanoprodrug, and the new formulation is used to deliver cisplatin. Concurrently, liposomes encapsulating cisplatin were prepared by conventional formulations for comparative experiments. Moreover, VES can inhibit the expression of mitochondrial uncoupling protein 2 (UCP2), further enhancing mitochondrial damage in tumor cells within the tumor microenvironment (TME) and suppressing the tricarboxylic acid cycle, thereby reducing ATP production. Additionally, cisplatin damages DNA structure, affecting the binding of Nrf2 to the antioxidant response element (ARE), thereby inhibiting the signaling expression of heme oxygenase 1 (HO-1). The combined action of cisplatin and VES disrupts the redox balanceleading to a significant accumulation of reactive oxygen species (ROS). The nanoprodrug effectively alters the redox state of the TME and inhibits antioxidant defenses, thereby amplifying oxidative stress damage and enhancing the efficacy of cisplatin. Notably, compared to free cisplatin, the nanoprodrug demonstrates greater efficacy in both cell line-derived xenograft (CDX) and patient-derived tumor xenograft (PDX) liver cancer models. Overall, this study successfully develops a novel mitochondrial-targeted nanoprodrug by modifying the conventional liposome formulation. This provides a new strategy for amplifying oxidative stress in order to disrupt redox balance, and enhance cisplatin efficacy.
- Cisplatin,
- Vitamin E succinate,
- Conventional liposome,
- Oxidative stress,
- Mitochondria
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沈阳化工大学材料科学与工程学院沈阳 110142