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

页码：26585 / 26599

页数：15

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