胰腺癌间质致密，构成天然屏障致化疗药物难以渗入，是导致耐药的重要原因之一。胰腺星状细胞（PSCs）对肿瘤间质形成和纤维化起重要作用。我们前期发现三氧化二砷（ATO）可减轻胰腺癌间质纤维化，预实验ATO可下调PSCs中galectin-1、α-SMA和纤维化相关蛋白表达；并证明由AP4介导且依赖PI3K/AKT通路，提出ATO可通过PI3K/AKT/AP4下调galectin-1抑制基质蛋白合成、减轻PSCs活化，减轻间质纤维化的假设。本课题拟：①在细胞水平和动物体内实验进一步验证该通路的调控机制；②构建靶向PSCs载ATO纳米微粒，在模拟胰腺癌间质纤维化模型中，联合载吉西他滨氧化铁纳米微粒，通过减轻胰腺癌间质纤维化、打破药物屏障、增加吉西他滨瘤内浓度，达到协同抗瘤作用；并利用氧化铁纳米微粒实现动态示踪肿瘤转移。本课题完成将为胰腺癌治疗提供新方法和实验依据。

Pancreatic cancer tumors are densely matrixed, forming a natural barrier to the infiltration of chemotherapeutic drugs, which is one of the important reasons of drug resistance. Pancreatic stellate cells (PSCs) activation plays a significant role in promoting stroma formation and fibrosis. Our previous study found that arsenic trioxide (ATO) could reduce interstitial fibrosis in pancreatic cancer. In the pre-experiments, ATO down-regulated galectin-1 expression, and alleviated fibrosis indexes such as α-SMA，collagen type I and fibronectin in PSCs. Further experiments have shown that this process was mediated by AP4，depending on the PI3K/AKT pathway. Those results suggested that ATO may down-regulate galectin-1, inhibit PSCs activation, and reduce matrix collagen synthesis by PI3K/AKT/AP4 pathway. On this basis，①We will conduct a series of experiments to further verify the regulatory mechanism of this pathway in vitro and in vivo. ②In order to achieve synergistic tumor inhibition, we will construct arsenic nanoparticles (ATO-NPs) targeting PSCs, and combine it with gemcitabine-iron oxide nanoparticles(Gem-IONP-NPs) to treat pancreatic cancer in a subcutaneous tumor model simulating interstitial fibrosis. The ATO-NPs could reduce the degree of tumor tissue fibrosis, break the drug barrier, increase the concentration of gemcitabine in tumor tissue, and finally, ehance the anti-tumor efficacy. And also, we could dynamically track tumor metastasis using Gem-IONP-NPs by MRI. The completion of this project will provide new methods and experimental basis for the comprehensive treatment of pancreatic cancer.