循时自控释药物共递送系统用于乳腺癌的联合治疗研究

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.

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。

根据乳腺癌干样细胞的生物学特征和分化诱导剂与化疗药物联用的要求，将循时自控释药物的理念引入药物共递送系统的设计和构建中，设计含低氧敏感偶氮苯基团的脂质和活性氧敏感苯硼酸频哪醇酯修饰的右旋糖酐，以全反式维甲酸和阿霉素为模型药物，构建脂质-聚合物杂化纳米粒。该载体具有壳核结构，由荷载全反式维甲酸的脂质外膜包裹荷载阿霉素的纳米粒内核构成。在乳腺癌干样细胞的低氧环境中，脂质降解，纳米粒快速释放全反式维甲酸，诱导干样细胞向子代非干样细胞分化，降低其耐药性，增加其对化疗药物敏感性。在分化过程中，胞内线粒体生物合成加快，活性氧升高，活性氧敏感右旋糖酐降解，适时释放阿霉素，高效诱导分化的干样细胞凋亡，提高两药协同作用。进一步拓展课题研究思路，设计低氧敏感硝基咪唑修饰透明质酸-草酸酯-喜树碱偶联前药，物理包埋全反式维甲酸，构建自组装聚合物胶束作为循时自控释全反式维甲酸和喜树碱共递送系统。聚合物胶束在维持两药在血液和肿瘤组织中药物比例的同时，更精准调控全反式维甲酸和喜树碱的释放，全面清除乳腺癌干样细胞和乳腺癌细胞，显著增强两药的协同抗肿瘤作用。这种针对乳腺癌干样细胞在未分化和分化状态下以及普通乳腺癌细胞中生理信号变化循时调控两药释放的策略，解决了分化诱导剂和化疗药物共同递送和不同作用机制的矛盾，解决了现有两药共递送系统无差异释药导致协同抗干性相关肿瘤耐药效果有限的问题，为基于靶向干样细胞的乳腺癌治疗提供新策略，为纳米药物共递送系统的发展提供新方法，具有重要的学术意义和参考价值。