抑制肿瘤干细胞是肿瘤靶向治疗的重要课题之一。双硫仑(DSF)是乙醛脱氢酶(ALDH)抑制剂，能抑制ALDH(+)肿瘤干细胞功能；DSF不稳定性限制其临床应用，故提高稳定性并增加肿瘤蓄积，是提高肿瘤治疗关键。前期研究显示pH敏感可离去PEG脂质纳米载体可提高DSF稳定性和肿瘤靶向性。基于此，本课题利用精氨酸聚合体的强细胞膜穿透性制备内化型载DSF脂质纳米囊，实现稳定载药和肿瘤高效内化；再将该纳米囊与pH敏感聚谷氨酸PEG聚合物静电结合构建环境响应型聚谷氨酸/脂质复合纳米囊，实现DSF长循环、肿瘤蓄积、肿瘤干细胞抑制。研究精氨酸密度对细胞摄取影响，评价其内化特性；研究聚谷氨酸分子量和聚合物接枝率对纳米囊pH敏感性和稳定性影响，评价其肿瘤微环境响应和长循环特性；考察DSF纳米囊对ALDH(+)乳腺癌干细胞生物学影响，评价其干细胞抑制性并探讨机制。该体系将为肿瘤干细胞靶向治疗提供新方法和新策略。

Inhibition of cancer stem cells is essentially important for cancer targeted therapy. Disulfiram (DSF), aldehyde dehydrogenase (ALDH) inhibitor, can inhibit biology functions of ALDH positive cancer stem cells, however its instability in vivo limits its clinical applications. Thus the key to improve cancer treatment is to improve its stability, extend its circulating time and increase its accumulation in tumor site. Our previous results suggested that in vivo stability and tumor targeting efficiency could be significantly improved by encapsulating DSF in pH-sensitive PEG-shedding lipid nanocarriers. Accordingly, in the present study a polyargine modified lipid nanocapsule with strong penetrating to cell membrane is designed to encapsulate DSF to realize the stabilization of DSF-loading and efficient internalization of tumor. pH sensitive polyglutamic acid PEG polymer is then anchored on the surface of the nanocapsule via electrostatic interaction to establish poly glutamic acid/lipid nanocapsule with environmental response for DSF delivery, which may prolong DSF circulating time in vivo, enhance tumor targeting efficiency and inhibitory of cancer stem cells. The tumor cell uptake behaviors affected by arginines can be studied to evaluate the internality of nanocapsule. The tumor microenvironment response and long-circulating properties can be totally assessed and further modified by investigating the effects of polyglutamic acid molecular weight and polymer grafting rate on pH sensitivity and stability. The effects of DSF nanocapsules on ALDH positive breast cancer stem cells in vitro and in vivo are investigated to evaluate the inhibition and mechanism on cancer stem cells. The polyglutamic acid/lipid nanocapsule with environmental response for DSF delivery may provide a new method and stratergy for cancer stem cells targeting therapy.