Targeting androgen receptor (AR) has shown great therapeutic potential in triple-negative breast cancer (TNBC), yet its efficacy remains unsatisfactory. Here, we aimed to identify promising targeted agents that synergize with enzalutamide, a second-generation AR inhibitor, in TNBC. By using a strategy for screening drug combinations based on the Sensitivity Index (SI), we found that MK-8776, a selective checkpoint kinase1 (CHK1) inhibitor, showed favorable synergism with enzalutamide in AR-positive TNBC. The combination of enzalutamide and MK-8776 was found to exert more significant anti-tumor effects in TNBC than the single application of enzalutamide or MK-8776, respectively. Furthermore, a nanoparticle-based on hyaluronic acid (HA)-modified hollow-manganese dioxide (HMnO), named HMnE&M@H, was established to encapsulate and deliver enzalutamide and MK-8776. This HA-modified nanosystem managed targeted activation pH/glutathione responsiveness. HMnE&M@H repressed tumor growth more obviously than the simple addition of enzalutamide and MK-8776 without a carrier. Collectively, our study elucidated the synergy of enzalutamide and MK-8776 in TNBC and developed a novel tumor-targeted nano drug delivery system HMnE&M@H, providing a potential therapeutic approach for the treatment of TNBC.

中文翻译：

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基于纳米系统的精准药物递送和协同治疗雄激素受体阳性三阴性乳腺癌

靶向雄激素受体（AR）在三阴性乳腺癌（TNBC）中显示出巨大的治疗潜力，但其疗效仍不令人满意。在这里，我们的目的是寻找在 TNBC 中与第二代 AR 抑制剂 enzalutamide 具有协同作用的有前景的靶向药物。通过使用基于敏感性指数（SI）筛选药物组合的策略，我们发现选择性检查点激酶1（CHK1）抑制剂MK-8776在AR阳性TNBC中与恩杂鲁胺显示出良好的协同作用。研究发现，恩杂鲁胺和 MK-8776 的组合在 TNBC 中比单独使用恩杂鲁胺或 MK-8776 发挥更显着的抗肿瘤作用。此外，还建立了一种基于透明质酸（HA）修饰的空心二氧化锰（HMnO）的纳米颗粒（名为HMnE&M@H）来封装和递送恩杂鲁胺和MK-8776。这种 HA 修饰的纳米系统可控制目标激活 pH/谷胱甘肽响应性。 HMnE&M@H 比简单添加恩杂鲁胺和 MK-8776（无载体）更明显地抑制肿瘤生长。总的来说，我们的研究阐明了恩杂鲁胺和MK-8776在TNBC中的协同作用，并开发了一种新型肿瘤靶向纳米药物递送系统HMnE&M@H，为TNBC的治疗提供了一种潜在的治疗方法。