Department of Mastopathy, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing 210004, China.
School of Public Health Yale University, New Haven, CT 06510-3201, USA; Graduate School of Arts and Science, Columbia University, New York, NY 10027, USA.
Eur J Pharm Biopharm. 2023 Dec;193:16-27. doi: 10.1016/j.ejpb.2023.10.014. Epub 2023 Oct 20.
Triple-negative breast cancer (TNBC) has been regarded as the strongest malignancy in cases of breast cancer with a poor prognosis. The development of effective treatment strategies for TNBC has always been an urgent and unmet need. The intracellular redox balance is essential for maintaining TNBC cell malignancy. Disrupting intracellular redox balance by enlarging reactive oxygen species (ROS) generation and facilitating glutathione (GSH) depletion to amplify intracellular oxidative stress may be an alternative strategy to eliminate TNBC cells. However, inducing ROS generation and GSH depletion concurrently may be challenging. Herein, a diselenium linked-dimeric prodrug nanomedicine FA-SeSe-NPs was developed to break the intracellular redox homeostasis for TNBC targeted therapy. The dimeric prodrug was synthesized by conjugating two cucurbitacin B (CuB) molecules via one diselenium bond, which was subsequently assembled with FA-PEG-DSPE to form the final nanomedicine FA-SeSe-NPs. Using the active targeting potential of folic acid (FA), FA-SeSe-NPs could accumulate in tumor tissue with elevated levels and then be specifically internalized by cancer cells. In the high ROS and GSH conditions of TNBC cells, the diselenium bond can specifically respond to ROS to produce selenium free radicals to increase ROS and react with GSH to generate S-Se bond to deplete GSH. The released CuB further induced ROS production in TNBC cells. The diselenium bond and CuB functioned synergistically to amplify oxidative stress to kill the TNBC cells. Here, we provide a promising strategy to disrupt the intracellular redox balance of cancer cells for effective TNBC therapy.
三阴性乳腺癌（TNBC）被认为是乳腺癌中预后最差的最强恶性肿瘤。开发有效的 TNBC 治疗策略一直是一个紧迫和未满足的需求。细胞内氧化还原平衡对于维持 TNBC 细胞恶性至关重要。通过增加活性氧（ROS）的产生和促进谷胱甘肽（GSH）耗竭来扩大细胞内氧化应激，破坏细胞内氧化还原平衡可能是消除 TNBC 细胞的另一种策略。然而，同时诱导 ROS 产生和 GSH 耗竭可能具有挑战性。在此，开发了一种二硒键连接的二聚前药纳米药物 FA-SeSe-NPs，以打破 TNBC 的细胞内氧化还原平衡，进行靶向治疗。二聚前药是通过一个二硒键将两个葫芦素 B（CuB）分子连接而成，然后与 FA-PEG-DSPE 组装形成最终的纳米药物 FA-SeSe-NPs。利用叶酸（FA）的主动靶向潜力，FA-SeSe-NPs 可以在肿瘤组织中积累并升高水平，然后被癌细胞特异性内化。在 TNBC 细胞的高 ROS 和 GSH 条件下，二硒键可以特异性地响应 ROS 产生硒自由基，增加 ROS，并与 GSH 反应生成 S-Se 键以耗尽 GSH。释放的 CuB 进一步诱导 TNBC 细胞中 ROS 的产生。二硒键和 CuB 协同作用，放大氧化应激，杀死 TNBC 细胞。在这里，我们为破坏癌细胞的细胞内氧化还原平衡提供了一种有前途的策略，以实现有效的 TNBC 治疗。
