Glutathione-Disrupting Nanotherapeutics Potentiate Ferroptosis for Treating Luminal Androgen Receptor-Positive Triple-Negative Breast Cancer

被引：4
作者：
Li, Jie [1 ,2 ]
Wu, Yao [3 ,4 ]
Li, Yongping [5 ]
Zhu, Hongbo [5 ]
Zhang, Zhiwen [3 ,4 ]
Li, Yaping [1 ,2 ]
机构：
[1] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
[2] Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Pharmaceut, Shanghai 201203, Peoples R China
[3] Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
[4] Fudan Univ, Minist Educ, Key Lab Smart Drug Delivery, Shanghai 201203, Peoples R China
[5] Fudan Univ, Shanghai Pudong Hosp, Pudong Med Ctr, Dept Breast Surg, Shanghai, Peoples R China
来源：
ACS NANO | 2024年 / 18卷 / 39期
基金：
国家重点研发计划; 中国国家自然科学基金;
关键词：
glutathione; glutathioneperoxidase; 4; ferroptosis; nanotherapeutics; triple-negative breast cancer; CELL-DEATH; PH;
D O I：
10.1021/acsnano.4c04322
中图分类号：
O6 [化学];
学科分类号：
0703 ;
摘要：
The refractory luminal androgen receptor (LAR) subtype of triple-negative breast cancer (TNBC) patients is challenged by significant resistance to neoadjuvant chemotherapy and increased immunosuppression. Regarding the distinct upregulation of glutathione (GSH) and glutathione peroxidase 4 (GPX4) in LAR TNBC tumors, we herein designed a GSH-depleting phospholipid derivative (BPP) and propose a BPP-based nanotherapeutics of RSL-3 (GDNS), aiming to deplete intracellular GSH and repress GPX4 activity, thereby potentiating ferroptosis for treating LAR-subtype TNBC. GDNS treatment drastically downregulated the expression of GSH and GPX4, resulting in a 33.88-fold enhancement of lipid peroxidation and significant relief of immunosuppression in the 4T1 TNBC model. Moreover, GDNS and its combination with antibody against programed cell death protein 1 (antiPD-1) retarded tumor growth and produced 2.83-fold prolongation of survival in the LAR-positive TNBC model. Therefore, the GSH-disrupting GDNS represents an encouraging strategy to potentiate ferroptosis for treating refractory LAR-subtype TNBC.
引用
收藏
页码：26585 / 26599
页数：15
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