抗肺癌药物目前临床主要通过系统给药。我们的前期研究发现吸入给药M3受体拮抗剂能抑制原位肺癌EMT相关指标的变化以及肿瘤的转移，但对肿瘤的生长影响不明显；预实验发现低浓度的M3受体拮抗剂（格隆溴铵）联合给药低浓度的小分子抗肺癌药物（多柔比星）协同抑制香烟诱导的上皮向间质转化（EMT）和肿瘤细胞的增殖、迁移和侵袭并促进肿瘤细胞的凋亡。至今尚无胆碱能M3受体拮抗剂和抗肺癌药合并靶器官给药治疗肺癌的报道，本项目建立NOD/SCID小鼠肺原位肺癌模型，通过M3受体拮抗剂单独或与小分子抗肺癌药合并靶器官给药来观测肿瘤的生长和转移并测定肺组织mAChRM3、EGFR、ACh和TGF-β1的表达情况。采用M3R基因沉默/M3R特异性拮抗剂联合分子靶向剂协同干预的分子药理学方法，探索M3受体拮抗剂单独处理肺癌细胞以及M3受体拮抗剂与小分子抗肺癌药合并用药的作用与机制，为肺癌治疗提供新的理论和给药途径。

Currently, anti-lung cancer drugs by systemic drug delivery are mainly used in clinical treatments. Our previous studies have found that inhalation of M3 receptor antagonist can inhibit changes in EMT-related markers and the metastasis status of orthotopic mouse lung tumor models, but not with the tumor size. Application of M3 receptor antagonist (Glycopyrronium Bromide, GB) and anti-lung cancer drug (Doxorubicin, DOX) at a low dose have synergistic effects on reversing the changes of the key indicators of EMT and inhibiting tumor cell proliferation, migration, invasion and promoting the apoptosis of tumor cells as well. But muscarinic M3 receptor antagonist and anti-lung cancer drug in the treatment of lung cancer by targeted drug delivery have not been reported. In the project, we will establish a simple and highly efficient orthotopic animal model of lung cancer by NOD/SCID mice. We will detect the growth, invasion and metastasis of tumor and analysis the differences of the biomarkers, mAChRM3, EGFR, ACh and TGF-β1 after targeted drug delivery of muscarinic M3 receptor antagonist or in combination with small molecule anti-lung cancer drug. We will use the molecular pharmacology method of M3R gene knockout/M3R specific antagonist combined with certain molecular targeted agents to study the roles and the signaling pathways of lung cancer. We will show the potential of low-dose M3 receptor antagonist for synergistic use in clinics to enhance the antitumor efficacy of small molecule anti-lung cancer drugs and to reduce the adverse reactions. In addition, we may provide new pathogenesis and drug delivery route for the treatment of lung cancer.