State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
School of Pharmacy & Key Laboratory of Smart Drug Delivery (Ministry of Education), Fudan University, Shanghai 201203, China.
ACS Nano. 2024 Oct 1;18(39):26585-26599. doi: 10.1021/acsnano.4c04322. Epub 2024 Sep 17.
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.
具有难治性管腔雄激素受体 (LAR) 亚型的三阴性乳腺癌 (TNBC) 患者对新辅助化疗具有显著的耐药性，并伴有免疫抑制增加。鉴于 LAR TNBC 肿瘤中谷胱甘肽 (GSH) 和谷胱甘肽过氧化物酶 4 (GPX4) 的明显上调，我们在此设计了一种消耗 GSH 的磷脂衍生物 (BPP)，并提出了基于 BPP 的 RSL-3 (GDNS) 纳米治疗药物，旨在消耗细胞内 GSH 并抑制 GPX4 活性，从而增强铁死亡以治疗 LAR 亚型 TNBC。GDNS 治疗可显著下调 GSH 和 GPX4 的表达，使 4T1 TNBC 模型中的脂质过氧化增强 33.88 倍，并显著缓解免疫抑制。此外，GDNS 及其与抗程序性细胞死亡蛋白 1（antiPD-1）抗体的联合治疗可抑制肿瘤生长，并使 LAR 阳性 TNBC 模型的生存延长 2.83 倍。因此，破坏 GSH 的 GDNS 代表了一种有希望的策略，可以增强铁死亡以治疗难治性 LAR 亚型 TNBC。
