摘要
Pancreatic cancer remains one of the most lethal malignancies worldwide. The combination of the first-line standard agent gemcitabine(GEM) with the molecular-targeted drug erlotinib(Er) has emerged as a promising strategy for pancreatic cancer treatment. However, the clinical benefit from this combination is still far from satisfactory due to the unfavorable drug antagonism and the fibrotic tumor microenvironment. Herein, we propose a membrane-camouflaged dual stimuliresponsive delivery system for the co-delivery of GEM and Er into pancreatic cancer cells and tissues to block the antagonism, as well as reshapes profibrotic tumor microenvironment via simultaneous delivery of small interference RNA(siRNA) for synergistic pancreatic cancer treatment. This “all-in-one”delivery system exhibits sensitive GSH and pH-dependent drug release profiles and enhances the inhibitory effects on the proliferation and migration of tumor cells in vitro. Excitingly, the systemic injection of such a biomimetic drug co-delivery system not only resulted in superior inhibitory effects against orthotopic pancreatic tumor and patient-derived tumor(PDX), but also greatly extended the survival rate of tumor-bearing mice. Our findings provide a promising therapeutic strategy against pancreatic cancer through the enhanced synergistic effect of target therapy, chemotherapy and anti-fibrotic therapy, which represents an appealing way for pancreatic cancer treatment.
基金
the National Key Research and Development Program of China (No.2018YFA0901800)
Natural Science Foundation of Zhejiang Province (Distinguished Young Scholar Program,No.LR21H300002,China)
National Natural Science Foundation of China (Nos.81573003 and 32000992)
Chinese Society of Clinical Oncology (CSCO) oncology research foundation (Nos.Y-XD2019-243 and Y-Roche2019/2-0042)
Joint Foundation of Zhejiang Natural Science FoundationZhejiang Society for Mathematical Medicine (LSY19H160005,China)
the Chinese Postdoctoral Science Foundation (2018M642469)
Scientific Research Fund of Zhejiang Provincial Education Department (Y202148347,China)。
