双重靶向介孔有机硅纳米药物抑制自噬诱导营养缺乏的Kras突变胰腺癌铁死亡及机制研究

The pathobiological barriers and the up-regulation of autophagy and anti-apoptosis caused by Kras mutation are the important factors leading to the poor efficacy of chemotherapy for pancreatic cancer. Therefore, the development of a new drug delivery system which can carry targeted groups, autophagy inhibitors and ferroptosis inducers may be an effective way to improve the efficacy of chemotherapy for pancreatic cancer. In this study, a highly organic/inorganic hybrid periodic mesoporous silica (PMOs) drug delivery system was used to load PTP polypeptide and KrasG12D siRNA, with double targeting effect. And design disulfide bond hybrids that are sensitive to the reduction of pancreatic cancer microenvironment. In addition, the autophagy inhibitor ATG4B siRNA was coupled to PMOs to prepare a drug delivery system that could accurately and rapidly release drugs across biological barriers in pancreatic cancer tissues. And it can induce ferroptosis in "hungry" pancreatic cancer cells. Furthermore, the biological effects of the drug delivery system are investigated in vitro, and its efficacy in vivo was evaluated in situ pancreatic cancer and postoperative models. At the same time, the mechanism of ferroptosis in nutritional deficient pancreatic cancer induced by the drug delivery system is studied. This study is expected to improve the chemotherapy efficacy of Kras-mutant pancreatic cancer and enrich the variety of chemotherapeutic drugs for Kras-mutant pancreatic cancer, which may provide a new idea for drug development targeting Kras-mutant pancreatic cancer.

病理生物学屏障的存在及Kras突变引起的细胞自噬上调和抗细胞凋亡是导致胰腺癌化疗疗效不佳的重要因素，因此，研发可携带靶向基团、自噬抑制剂和铁死亡诱导剂的新型载药系统可能是提高胰腺癌化疗疗效的有效途径。本研究拟应用介孔有机硅 (PMOs) 纳米载药系统，负载具有双重靶向作用的PTP多肽和KrasG12D siRNA，并设计对胰腺癌微环境还原敏感的二硫键杂化，将自噬抑制剂ATG4B siRNA偶联到PMOs上，制备能跨生物学屏障在胰腺癌组织中精准快速释放药物并可诱导“饥饿”的胰腺癌细胞铁死亡的纳米载药系统。体外考察该载药系统的生物学效应，并在原位胰腺癌及术后模型上评估其在体内疗效，同时研究该载药系统诱导营养缺乏的胰腺癌铁死亡的作用机制。本研究有望提高Kras突变胰腺癌化疗疗效、丰富Kras突变胰腺癌化疗药物种类，可能为靶向Kras突变胰腺癌的药物研发提供新思路。

铁死亡和自噬是程序性细胞死亡的两种典型形式，在肿瘤治疗中起着重要作用。然而，铁死亡与自噬的合理结合用于协同肿瘤治疗仍然具有很大的挑战性。本项目中，我们提出了一种有效的纳米医学策略，以实现自噬增强的铁死亡，有效地治疗癌症，该策略是基于负载海藻糖的mSiO2@MnOx-mPEG (TreMMM)纳米载体的构建，具有良好的生物相容性。纳米载体具有高的谷胱甘肽(GSH)消耗效率，从而通过灭活谷胱甘肽过氧化物酶4(GPX4)诱导癌细胞铁死亡。随后，由于GSH耗竭和pH敏感性引起的TreMMM降解有助于海藻糖释放诱导自噬，通过NCOA4介导的铁蛋白降解促进/增强铁死亡。这种自噬增强铁死亡策略在体内和体外都有显著的抗肿瘤作用。因此，通过纳米药物设计，合理结合GSH消耗诱导的铁死亡和海藻糖诱导的自噬，为肿瘤治疗提供了新的有效策略。