Gao Fangyan, Wu Yueyao, Wang Runtian, Yao Yuhui, Liu Yiqiu, Fan Lingling, Xu Jingtong, Zhang Jian, Han Xin, Guan Xiaoxiang
Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Acta Pharm Sin B. 2024 Jun;14(6):2685-2697. doi: 10.1016/j.apsb.2024.03.012. Epub 2024 Mar 14.
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.
靶向雄激素受体（AR）在三阴性乳腺癌（TNBC）中已显示出巨大的治疗潜力，但其疗效仍不尽人意。在此，我们旨在确定在TNBC中与第二代AR抑制剂恩杂鲁胺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）的药物组合筛选策略，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。发现恩杂鲁胺和MK-8776的组合在TNBC中比分别单独应用恩杂鲁胺或MK-8776具有更显著的抗肿瘤作用。此外，建立了一种基于透明质酸（HA）修饰的中空二氧化锰（HMnO）的纳米颗粒，命名为HMnE&M@H，用于包裹和递送恩杂鲁胺和MK-8776。这种HA修饰的纳米系统实现了靶向激活pH/谷胱甘肽响应性。HMnE&M@H比简单添加无载体的恩杂鲁胺和MK-8776更明显地抑制肿瘤生长。总体而言，我们的研究阐明了恩杂鲁胺和MK-8776在TNBC中的协同作用，并开发了一种新型的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。
