针对肿瘤多药耐药及转移引起化疗失败的科学问题，利用肿瘤细胞线粒体在耐药中起关键作用及磷脂酶D在肿瘤发展转移中的作用，选择线粒体靶向性维生素E琥珀酸酯(TOS)作为配体之一，与亲水性的PEOz形成聚合物胶束材料作为载体，同时包载阿霉素、线粒体靶向分子TOS及磷脂酶D抑制剂FIPI，构建兼具pH敏感性、肿瘤细胞靶向性的新型多功能纳米粒给药系统，实现肿瘤细胞内同步释放抗肿瘤药、磷脂酶D抑制剂和线粒体靶向TOS。评价该体系抗耐药性；探讨耐药肿瘤细胞线粒体作用和磷脂酶D抑制作用的机制及二者相关性。本项目构建的体系在国内外未见报道，其研究结果将为纳米递送系统实现多靶点协同抗肿瘤耐药提供理论依据和实践基础。

Multidrug resistance to chemotherapeutic drugs and cancer metastasis are important reasons for clinical chemotherapy failure. The latest research shows that tocopheryl succinate (TOS) enhances apoptosis by acting on the mitochondrial signaling pathways thereby overcoming multidrug-resistant cancers. Besides, inhibition of phospholipase D (PLD) activity using modern small-molecule inhibitors has been shown to affect survival signaling and invasiveness of glioma tumor cell lines, and to inhibit tumor growth and metastasis in tumor implant models. In our innovative program, lipophilic TOS as a mitochondrial targeting ligand covalently is linked with hydrophilic poly(2-ethyl-2-oxazoline) (PEOz). A novel multifuntional pH-sensitive polymeric nanoparticles composed of TOS, anticancer model drug doxorubicin (DOX) and PLD inhibitor 5-fluoro-2-indolyl des-chlorohalopemide (FIPI) are fabricated, ensuring that anticancer drugs, phospholipase D inhibitor and TOS can be delivered to the tumor region, quickly released from carriers in tumor cells and rapidly escape from endo/lysosomes. We will evaluate reversal of multidrug resistance, mechanism of the effect on mitochondrial function and PLD inhibition. The multifunctional nanoparticle hasn't been reported at home and abroad. Therefore, the results of research will provide a theoretical and pratical basis for multi-target synergistic effect of the constructional multifunctional nano delivery system on tumor multidrug resistance.

针对肿瘤多药耐药及转移引起化疗失败的科学问题，利用肿瘤细胞线粒体在耐药中起关键作用及磷脂酶D在肿瘤发展转移中的作用，选择脂质体为载体平台，同时包载阿霉素、线粒体靶向分子TOS及磷脂酶D抑制剂FIPI，构建兼抗耐药肿瘤细胞、靶向性的新型多功能纳米粒给药系统，实现肿瘤部位释放抗肿瘤药、磷脂酶D抑制剂和线粒体靶向TOS。我们成功构建载有多个成分的纳米脂质体，该脂质体具有理想的体外性质，平均粒径低于150nm，多分散系数低于0.25，表明具有理想的物理稳定性；三种功能成分的包封率均超过85%，表明该载体可同时对三种不同性质的药物实现成功包载，保证了所有成分不受生理环境的影响；TOS的在体外释放条件下几乎不释放，FIPI和Dox的释放具有潜伏期，表明这两种成分在到达肿瘤部位之前，不会因为释放过多而对全身产生不良反应，预示安全性良好；所构建的多功能脂质体可显著提高体外抗耐药肿瘤增殖能力和耐药肿瘤对Dox的摄取能力，表明该脂质体可实现抗耐药功能；能显著提高细胞色素C的释放量，并能显著增强Caspase 3和Caspase 9的活力，表明多功能脂质体可实现TOS的线粒体靶向作用，提高抗耐药能力；此外，该制剂均能显著抑制耐药肿瘤细胞的侵袭和迁移能力，从而验证该制剂具有磷脂酶D抑制功能。总之，该制剂具有理想的抗耐药、线粒体靶向作用以及抗耐药肿瘤细胞侵袭和转移特性，即展现了该纳米制剂的多个功能。本项目构建的体系在国内外未见报道，其研究结果将为纳米递送系统实现多靶点协同抗肿瘤耐药提供理论依据和实践基础。