化疗抵抗是胰腺癌治疗中亟待解决的也是长期研究的热点问题。申请人前期证实超声靶向破坏微泡技术(UTMD)在胰腺癌化疗增敏中极具潜力，其优势是安全性好、无药物/载体选择性及具有辐照部位靶向性；在此技术平台上，仍需解决由肿瘤细胞自身改变及间质诱导而来的抵抗作用，且选择合适的药物载体分级靶向到肿瘤组织。前期研究表明，骨膜蛋白（Periostin）是间质中特异的化疗抵抗靶点；树状大分子(PAMAM) -介孔硅(MS)纳米的多重修饰及高效负载特性允许多分子靶标显像的同时高效递送多重药物。据此，本研究拟利用PAMAM-MS枝接Periostin抗体、胰岛素样生长因子1受体抗体及钆螯合物，靶向识别肿瘤细胞及间质；荷载Erlotinib、BMS-754807来协同增效吉西他滨；UTMD促进纳米诊疗体分级靶向到细胞，持续抑制肿瘤，减少药物副作用，MRI分子成像评估疗效，为胰腺癌化疗抵抗的精准治疗提供新的策略。

The problem of chemo-resistance of pancreatic cancer is urgently to be solved, and for a long time it is the hot direction. The applicant found that ultrasound targeted microbubble (UTMD) technology has great potential in sensitization of pancreatic cancer chemotherapy. Its advantages were of good safety, no selectivity of drugs and drug-carriers, and the specific targeting of irradiation site. On UTMD technology platform, the next problem need to addressed is reducing the chemo-resistance not only induced by pancreatic tumor cells themselves but also induced by tumor stroma abduction. The applicant has proved that the gene of Periostin was closely related to chemo-resistance inducing by tumor stroma. Our coalition partner has done a lot of research on PAMAM- mesoporous silica (MS) nanoparticles. Based on above mentioned foundations, this study intends to use multiple modified PAMAM, grafting with the antibody of Periostin, the antibody of insulin-like growth factor 1 receptor (IGF-1R), and with Gd chelate, which is in order to identify the pancreatic tumor cells and tumor stroma. The MS agent will be efficiently loaded with EGFR inhibitors, IGF-1R inhibitors and gemcitabine, and the chemical stability of the chemo-drugs and the performance of slow-release could be maintained by this nano-MS agent. UTMD could promote this "nano-theranostic agent" richly into the tumor, kill the cancer cells persistently, and reduce the drug side effects. Meanwhile this nano-agent could be used for MRI molecular imaging. Hence, this new therapeutic regime could increase the chemotherapy sensitization, and is expected to provide a new strategy for individualized precise treatment of pancreatic cancer.