共载沙利霉素和自噬基因siRNA的靶向性纳米脂质体的抗CD44阳性头颈部鳞癌干细胞作用和机制研究

Salinomycin is a very potent anticancer drug, and has shown significant anticancer effects towards various types of cancer stem cells. Our previous results have demonstrated that salinomycin shown significant anticancer effects towards head and neck squamous cell carcinoma（HNSCC）. However, salinomycin has severe side effects, and can induce autophagy which inactivates drugs. Although the combination of salinomycin and chemical autophagy inhibitors can increase the anticancer effect of salinomycin, the obvious side effects and difficulty of achieving synergic effect of both drugs in vivo are two major problems. On the basis of previous research of nanocarriers of chemotherapeutic drugs and small interfering RNA (siRNA), we would construct CD44+ HNSCC stem cells targetd nanoliposome（Sal-Atg-Lip-CD44）, which co-loaded with salinomycin and autophagy related genes (Atg) siRNA (autophagy inhibitors) according to optimized the proportion, modified with CD44 aptamer on the surface of liposome in this study. The study will investigate the anti-HNSCC effect and mechanism of the nanoliposomes. The nanoliposomes are expected to achieve the synergic effect of salinomycin and autophagy inhibitors in vitro and in vivo, significantly enhance the anti-HNSCC stem cell effect without the side effect. The study will provide new idea and new approach for the targeted therapy of cancer stem cells.

肿瘤干细胞导致头颈鳞癌（HNSCC）治疗耐受，目前尚缺乏有效解决方法。研究发现沙利霉素（SAL）能选择性杀伤HNSCC干细胞，但会诱发细胞产生自噬而限制其抗肿瘤活性。联用化学自噬抑制剂虽可增强SAL的肿瘤杀伤作用，但会在体内产生较强的毒副反应且药物协同效果欠佳。为此，课题组通过RNA文库技术构建了针对自噬基因的ATG siRNA，可高效低毒的增强SAL抗肿瘤作用。我们进一步通过纳米脂质载体将沙利霉素和ATG siRNA按协同比例进行包裹，并利用CD44核酸适体修饰形成靶向性共载纳米脂质体Sal-siRNA-Lip-CD44，以针对CD44阳性HNSCC干细胞开展靶向治疗研究，还将对该纳米脂质载体的理化表征、药物释放、自噬抑制效率、体内安全性、抗肿瘤活性及作用机制进行研究。旨在利用纳米载体实现SAL和自噬抑制剂的靶向协同作用，将为提高头颈鳞癌及其它恶性肿瘤的治疗效果提供一种新的方法与思路。