乳腺癌干细胞是乳腺癌发生发展及复发和转移的根源。基于临床联用分化疗法和化疗清除乳腺癌干细胞，采用纳米载体共递送分化诱导剂和化疗药可增强药物协同效应，在乳腺癌治疗中发挥了重要作用。但是分化诱导剂和化疗药的不同作用机制决定了两药在作用时间上存在先后，目前共递送系统未能适时释放两药，限制了药物发挥最大协同作用。为此本项目提出“循时自控释”理念，拟构建共载分化诱导剂和化疗药的脂质-聚合物杂化纳米粒，可自我调节响应不同外界环境控制两药的释放，在乳腺癌干细胞低氧环境中，先释放分化诱导剂，诱导乳腺癌干细胞向子代细胞分化。在分化过程中，胞内线粒体生物合成加快，导致活性氧水平升高，纳米粒响应活性氧变化，自动打开化疗药释放开关，快速释药，杀死子代细胞，实现药物协同作用最大化。本项目将深入研究纳米载体的循时控释机制及其抗乳腺癌干细胞作用和联合治疗效果，为药物共递送系统的发展和乳腺癌的联合治疗提供新方法和新技术。

Breast cancer stem cells (BCSCs) have been considered as the source of breast cancer initiation, progression, relapse, and metastasis. In view of the combined differentiation therapy and chemotherapy as an effective therapeutic strategy to eliminate BCSCs in clinical trials, the application of nanocarrier for co-delivery differentiation-inducing agents (DIAs) and chemotherapeutic drugs can enhance the synergistic effect, which plays a significant role in breast cancer treatment. However, since distinctive mechanism of action of DIAs and chemotherapeutic drugs decides the temporal order of their taking effects, lack of timely drug release property in current co-delivery systems limits the production of maximal synergistic effects. Herein, lipid-polymer hybrid nanoparticles (LPNs) endued with temporally self-controlled release capability have been developed for co-delivery of DIAs and chemotherapeutic drugs, which can self-regulate to respond to different environmental signals for controlled release of two drugs. At hypoxic BCSC niche, DIAs can be firstly and rapidly released from LPNs, and induce the differentiation from BCSCs to their non-tumorigenic offsprings. During the differentiation process, the intracellular ROS level increased as a result of increased mitochondrial biogenesis. The LPNs can respond to such variation of ROS level and automatically switch on the release of chemotherapeutic drugs, which eradicate the differentiated cells to achieve the maximal synergistic effects with DIAs. The in-depth investigation will be performed on the mechanism of the temporally self-controlled release of LPNs, and their anti-BCSC activities and combination therapeutic effects. It provides new approach and technique for the development of nanosystems for co-delivery of multiple drugs and combination treatment of breast cancer.