精准、双靶向胃癌线粒体NitDOX/GMBP1纳米探针构建及其多向协同抗MDR作用研究

Poor targeting and multidrug resistance (MDR) are the major and key factors which results in the inhibition effects of chemotherapeutic drugs in gastric cancer. In this project, accurate nanoprobe with targeting molecule of gastric cancer and mitochondria drugs as well as combination the advantages of carrier PET/MRI technology were integrated together to improve the effect of anti-MDR. GMBP1 was labeled with 18F radio isotope to form the target of gastric cancer. Fe / Fe3O4 and NitDOX were both loaded by TPGS-PLGA carrier to form the target of mitochondria. The two targets were further to construct the drug loaded nano probe of the target of mitochondrial of gastric cancer. These nano probes were analyzed and characterized by different physical and chemical methods. Then the influence of performance evaluation indicators and imaging, mitochondrial function and MDR related molecules were further analyzed by in vivo and in vitro experiments. Simultaneously, the advantage of PET-MRI technology was coupled to monitor anti -MDR effects. The cooperative anti-MDR effects and the mechanism of the drug loaded nano probe of the target of mitochondrial of gastric cancer were confirmed when compared with the target of gastric cancer nano probe and the target of mitochondrial nano probe. Based on the new perspective, the chemotherapeutic drug were directly oriented to the mitochondria to avoid the traditional chemotherapy resistance through the new nano probe. It will provide effective intervention strategies for the effects of cooperative anti-MDR in chemotherapy of gastric cancer. Additionally, for accurate diagnosis and treatment of cancer, the new ideas and theoretical basis were also applied to get the effects of cooperative anti-MDR. In short, this project will indicate the important academic significance and good application prospect in the future.

靶向性差，同时产生胃癌细胞的多药耐药性(MDR)是制约胃癌化疗疗效的关键环节。本项目将胃癌及线粒体双靶向结合构建精准的纳米载药探针，并与PET/MRI技术的优势集成在一起多向协同抗MDR。拟将GMBP1进行Al18F标记形成胃癌靶向，TPGS-PLGA共载的Fe/ Fe3O4和NitDOX形成线粒体靶向，构建胃癌线粒体靶向新型纳米载药探针并进行不同表征分析，体内外实验进行性能评估及成像、线粒体功能、MDR相关分子的影响，耦合PET-MRI的优势互补监测抗MDR 疗效，并与胃癌靶向、线粒体靶向探针效应比较，确定胃癌线粒体靶向载药探针的协同抗MDR效应及分子机制。这一新型探针将从一个全新的视角将化疗药物直接作用在线粒体中，有效避开传统化学治疗的抵抗机制，为胃癌化疗中的协同抗MDR提供有效干预策略，为肿瘤精准诊疗中多向协同抗MDR的研究提供新思路及理论依据，具有重要的学术意义和良好的应用前景。

胃癌的死亡率位居各种恶性肿瘤的前列。手术对大部分胃癌患者有效，但大多数胃癌患者就诊时已处于中、晚期，且目前胃癌治疗使用的药物靶向性差，毒副作用强，易产生耐药性，成为制约胃癌化疗疗效的关键难题。化疗药物靶向治疗或抗耐药性药物成为胃癌治疗中亟待解决的关键科技问题。因此本项目研究集中在两部分：1.胃癌线粒体靶向探针Al18F-NOTA-GMBP1-TPGS-PLGA@Fe/ Fe3O4 NitDOX靶向胃癌细胞，抗耐药性作用机制的研究：首先，成功构建了胃癌线粒体靶向新型纳米载药探针并进行不同表征分析，然后利用体内外实验研究表明确定了胃癌线粒体靶向载药探针的协同抗MDR效应。这一新型探针将从一个全新的视角将化疗药物直接作用在线粒体中，有效避开传统化学治疗的抵抗机制，为胃癌化疗中的协同抗MDR提供有效干预策略，为肿瘤精准诊疗中多向协同抗MDR的研究提供新思路及理论依据，具有重要的学术意义和良好的应用前景；2.甘草甙抗胃癌细胞顺铂耐药的作用机制研究。在这项研究中，甘草甙在治疗顺铂耐药性胃癌细胞时，可以抑制其增殖和迁移。顺铂和甘草甙联合治疗可以通过诱导G0 / G1细胞周期阻滞以抑制胃癌细胞的增殖，这伴随着细胞周期蛋白D1，细胞周期蛋白A和细胞周期蛋白依赖性的降低激酶4和p53和p21的增加。此外，甘草甙与顺铂联合治疗可通过增加caspase-8 / -9 / -3和PARP以及LC3B和Beclin 1的表达诱导细胞凋亡。此项研究表明顺铂的和甘草甙相结合应用于耐药性胃癌的治疗具有潜在的应用价值。