胰腺癌是目前预后最差的实体肿瘤。化疗已成为胰腺癌治疗最常用且有效的手段之一。耐药性是胰腺癌临床化疗失败的主要原因。本项目以克服胰腺癌化疗的耐药性为目标，针对一氧化氮（NO）和吉西他滨体内传递的关键科学问题，拟利用超分子聚合物特有的“即插即用”（Plug-and-Play）特性，将谷胱甘肽（GSH）响应的长半衰期NO供体和吉西他滨共价键合到客体分子上，与负载了磁共振造影剂钆（Gd）的主体分子进行“乐高积木”式自组装，构筑具有磁共振诊断功能的超分子纳米前药载体，实现NO和吉西他滨的共传递；研究NO和吉西他滨在GSH还原环境下的药物释放增速效应；探索NO对胰腺癌化疗的增敏效应并研究其分子机制；评价不同NO和吉西他滨比例的纳米载体在抑制肿瘤细胞增殖上的协同增效作用，获得最佳“协同指数”和最好“耐药指数”；建立原位胰腺癌模型，研究超分子纳米载体的抗肿瘤效果，为耐药性胰腺癌治疗手段的突破提供新方法。

Pancreatic cancer is one of the most lethal malignancies. Most of patients have tumors that cannot be surgically resected. Chemotherapy is one of the best options for pancreatic cancer treatment. However, because of the drug resistance of pancreatic cancer, chemotherapy has a very high rate of failure. In order to reverse the drug resistance of pancreatic cancer chemotherapy, this proposal focuses on the development of supramolecular prodrug nanocarriers for the co-delivery of nitric oxide (NO) and gemcitabine. Taking advantage of the “plug and play” property of supramolecular polymers, supramolecular multifunctional drug nanocarriers will be constructed by host-guest interaction of NO and gemcitabine conjugated guest molecules and Gd conjugated host molecules. The glutathione (GSH) triggered release of NO and gemcitabine will be studied. NO is expected to overcome the drug resistance in gemcitabine-resistant pancreatic cancer cells. The possible mechanism will be well studied by real-time PCR, Western Blot, and ELISA. The supramolecular prodrug nanocarriers are capable of simultaneously encapsulating and delivering NO and gemcitabine into the same pancreatic cancer cells after systemic administration to synergistically inhibit the growth of gemcitabine-resistant pancreatic tumors. The novel drug nanocarriers will provide a new strategy for more efficient treatment of pancreatic cancer.