EGFR酪氨酸激酶活性抑制物（EGFR-TKI）是临床上治疗非小细胞肺癌等恶性肿瘤常用的一种有效的抗肿瘤药物，但几乎所有的病人经过一段时间的治疗后，发生获得性耐药，大大限制了EGFR-TKI的临床应用。如何克服肿瘤病人对EGFR-TKI 的耐药性，临床上缺乏有效方法。我们的研究发现耐药细胞株的耐药蛋白MDR1和自噬水平明显升高，这些结果提示MDR1蛋白和细胞自噬可能在EGFR获得性耐药中发挥重要的作用。用特异性抗体封闭MDR1蛋白和降低自噬水平可以明显增强耐药性肿瘤细胞对EGFR-TKI的敏感性。本课题拟将生物学的技术方法和纳米技术结合，通过构建MDR1单克隆抗体修饰，内部包裹吉非替尼和自噬抑制物壳聚糖纳米粒，在细胞水平检测肿瘤细胞对抗体修饰纳米粒的敏感性，探讨MDR1和自噬双重靶向的纳米粒逆转EGFR-TKI耐药的可能性及相应的分子机制。

EGFR tyrosine kinase inhibitor (TKI) is widely used in the chemical therapy of many human cancers. However, acquired chemoresistance has occurred in almost all the patients and limited the clinical usage of EGFR-TKI. So far, there are no effective methods to resolve this problem. Multiple targeted therapy has been regarded as a possible strategy to overcome acquired resistance to EGFR-TKI. Our previous studies have demonstrated that combination of blocking cell surface MDR1 and inhibiting autophagy sensitizes tumor cells to EGFR-TKI. Based on these findings, we established a novel MDR1 antibody modified gifitinib and autophagy inhibitor chloroquine loaded chitosan nanoparticles, and examined whether it could revert EGFR-TKI resistance. We further explore the reversible effects and underlying mechanisms of MDR1and autophagy directed dual targeted nanoparticles on EGFR-TKI resistance. Our results will provide the theoretical and experimental basis for overcoming EGFR-TKI resistance.

EGFR酪氨酸激酶活性抑制物（EGFR-TKI）是临床上治疗非小细胞肺癌等恶性肿瘤常用的一种有效的抗肿瘤药物，但几乎所有的病人经过一段时间的治疗后，发生获得性耐药，大大限制了EGFR-TKI的临床应用。我们的研究发现耐药细胞株的耐药蛋白MDR1和自噬水平明显升高，这些结果提示MDR1蛋白和细胞自噬可能在EGFR获得性耐药中发挥重要的作用。用特异性抗体封闭MDR1蛋白和降低自噬水平可以明显增强耐药性肿瘤细胞对EGFR-TKI的敏感性。基于此，本研究采用离子交联法和静电吸附法制备了搭载EGFR-TKI经典药物吉非替尼和自噬抑制剂氯奎的MDR1单克隆抗体修饰的壳聚糖纳米颗粒。采用MTT法、流式细胞术和蛋白分子印迹检测技术（western blot法）证实了不同处方的载药纳米粒对耐吉非替尼的SMMC-7721细胞增殖均具有一定的影响。该制剂通过阻断细胞表面MDR1和抑制自噬作用，证明了其实现肿瘤多靶点靶向选择性的理想的抗肿瘤效果。结果表明，MDR1 单克隆抗体修饰的壳聚糖纳米粒搭载经典EGFR-TKI吉非替尼和自噬抑制剂氯奎在抗癌药物的传递方面能够明显增强其靶向和治疗潜力，并通过自噬的调节显著诱导细胞凋亡和阻断MDR1受体的活性的双重靶向调节下抑制EGFR-TKI的耐药。