Citation: Lin Li, Bingjun Sun, Jin Sun, Lin Chen, Zhonggui He. Binary prodrug nanoassemblies combining chemotherapy and ferroptosis activation for efficient triple-negative breast cancer therapy[J]. Chinese Chemical Letters, ;2024, 35(10): 109538. doi: 10.1016/j.cclet.2024.109538 shu

Binary prodrug nanoassemblies combining chemotherapy and ferroptosis activation for efficient triple-negative breast cancer therapy

Lin Li ^a ,
Bingjun Sun ^b ,
Jin Sun ^b ,
Lin Chen ^{a, *,} ,
Zhonggui He ^{b, *,}

a.
Department of Pharmacy, Women and Children’s Hospital of Chongqing Medical University/Chongqing Health Center for Women and Children, Chongqing 401147, China
b.
Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China

clfxmm@163.com

hezhgui_student@aliyun.com

Received Date: 6 November 2023
Revised Date: 7 January 2024
Accepted Date: 12 January 2024
Available Online: 20 January 2024

Figures(5)

Chemotherapy has been recommended as the standard protocol for triple-negative breast cancer (TNBC) at the advanced stage. However, the current treatment is unsatisfactory due to inefficient drug accumulation and rapid chemo-resistance. Thus, rational design of advanced drug delivery systems that can induce multiple cell death pathways is a promising strategy to combat TNBC. Ferroptosis is a powerful non-apoptotic cell death modality, showing potential in tumor inhibition. Herein, we propose a binary prodrug nanoassemblies that combines chemotherapy with ferroptosis for TNBC treatment. In this system, paclitaxel is linked with paracetamol (ferroptosis activator) by a disulfide linkage to construct self-assembly prodrug. Meanwhile, 2-distearoyl-sn-glycerol-3-phosphoethanolamine-N-methyl(polyethylene glycol)-2000-tyrosine (DSPE-PEG_2k-tyrosine) is applied for large neutral amino acid transporter 1 (LAT1) targeting, which is highly expressed in TNBC. The prodrug nanoassemblies exhibit good stability and a glutathione (GSH)-responsive release profile. Furthermore, the LAT1-targeted nanoassemblies show stronger cytotoxicity, higher cellular uptake, and more obvious ferroptosis activation than non-decorated ones. In a TNBC mice model, the prodrug nanoassemblies demonstrate strong anti-tumor efficacy. The application of ferroptosis-assisting chemotherapy may provide a promising strategy for TNBC therapy.
- Prodrug nanoassemblies,
- Paclitaxel,
- Ferroptosis,
- LAT1,
- Triple-negative breast cancer
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