肿瘤细胞在抵抗化疗药物时通过上皮间质转化获得肿瘤干细胞特性是获得性多药耐药的重要原因。我们前期研究发现：胃癌细胞处于甲硫氨酸饥饿时对化疗药物的敏感性增加；同时，与上皮间质转化密切相关的NF-κB、miR-21表达及活性异常。研究表明miRNA可以被核转录因子调控，因此我们设想：甲硫氨酸饥饿可能通过NF-κB/miR-21途径阻止普通胃癌细胞逆分化成肿瘤干细胞，克服肿瘤耐药。基于此新设想，本项目利用外泌体这种新型的天然药物纳米载体，构建具有肿瘤靶向性的iRGD-Exos-rMETase生物纳米囊泡，诱导甲硫氨酸饥饿后综合运用胃癌移植瘤模型、活体成像、流式细胞术、免疫荧光等技术，从整体与细胞、分子等水平系统探讨iRGD-Exos-rMETase逆转胃癌多药耐药性的效应，明确NF-κB/miR-21在胃癌细胞获得性耐药中的作用。本研究将为甲硫氨酸饥饿疗法联合化疗药物清除胃癌干细胞提供理论依据。

It is an important reason that tumor cells acquired multidrug resistance by obtaining the characteristics of the cancer stem cells through epithelial mesenchymal transition in the resistance to chemotherapeutic drugs. Our previous studies have found that gastric cancer cells are sensitive to chemotherapy when methionine is starved. Meanwhile, the expression and activity of NF- kappa B and miR-21 are abnormal. They are closely related to epithelial mesenchymal transition. Studies have shown that miRNA can be regulated by nuclear transcription factors. Therefore, we assume that methionine starvation may prevent gastric cancer cells from being differentiated into cancer stem cells by NF- kappa B/miR-21 pathway, and overcome the drug resistance. Based on this new idea, First ,the project construct targeting iRGD-Exos-rMETase bio nano vesicles to induced methionine starvation by using exosomes. Secondly, we investigate the effect of iRGD-Exos-rMETase reversing the multidrug resistance of gastric cancer by gastric cancer xenograft model, in vivo imaging, flow cytometry and immunofluorescence technique from the whole and the cellular and molecular level of the system . We clarify that the role of NF- kappa B/miR-21 in the acquired resistance of gastric cancer cells. This study will provide a theoretical basis for the treatment of gastric cancer stem cells by methionine starvation therapy combined with chemotherapeutic drugs.