一种通过巨噬细胞转运，共载自杀基因/无机催化粒子纳米递送系统的构建及其抗肿瘤作用的研究

The tumor-targeting capability of nano-system is based on EPR effect which doesn’t work in humans. In this work we design a novel multi-fuctional nano-system which is selected delivered to hypoxic region of tumor by macrophages. In order to attenuate hypoxia, MnO2 is a core part of nano-system to catalyse decomposition of endogenous H2O2 to O2. In addition, cationic PEI polymer could trigger anti-immune response of TAM and increase sensitivity of tumor chemotherapy. More importantly, the suicide gene is also induced in our system to transform the pro-drug into cytotoxic drug. I this research, we will evaluate the targeting ability of macrophage and transporting process of this system. The anti-tumor effect of suicide gene therapy will be assessed. Furthermore, we are try to explore the mechanism of the chemotherapy sensitization of hypoxic attenuation and transformation of TAM. Currently, the anti-tumor multifunctional nanoparticles mediated by macropahges are barely reported. This research is prone to open a promising way for comprehensive treatment of tumor.

纳米靶向制剂对肿瘤组织特异型分布所依赖EPR效应难以在人类中实现，给临床应用带来诸多困难。本课题在前期基础上，构建一种多功能能纳米载体，以无机催化粒子MnO2为核心，外周负载聚甘露糖修饰的PEI和表达自杀基因的DNA，利用巨噬细胞对肿瘤组织低氧环境的亲和性，将吞噬的纳米载体转运至肿瘤组织微环境。通过MnO2催化内源性H2O2分解产生O2，PEI促进肿瘤相关巨噬细胞的转化，增加肿瘤组织对化疗药物的敏感性，同时表达自杀基因，转化前药为细胞毒性药物，发挥抗肿瘤作用。本研究将考察递送系统靶向巨噬细胞的特性，以及对肿瘤组织转运的过程。考察自杀基因疗法的抗癌治疗效果。探索改善肿瘤组织低氧和转化肿瘤相关巨噬细胞对于化疗增敏的机制。目前，巨噬细胞介导的多功能能纳米药系统治疗肿瘤的研究，国内外未见报道。本研究有望为肿瘤综合治疗开辟新途径。

EPR效应是当前许多纳米靶向制剂对肿瘤组织特异型分布的理论依据，但是在人体中难以实现，给临床应用带来诸多困难。本课题在前期基础上，构建一种多功能能活细胞载体，以无机催化粒子MnO2为核心，周围负载聚牛血清白蛋白BSA，利用BSA疏水性空腔包载化疗药物多西他赛.在体外与巨噬细胞共孵育后回输至体内，利用巨噬细胞对肿瘤组织低氧环境的亲和性，将吞噬的纳米载体转运至肿瘤组织微环境。通过MnO2催化内源性H2O2分解产生O2，同时促进肿瘤相关巨噬细胞的转化，增加肿瘤组织对化疗药物的敏感性，纳米粒携带的多西他赛发挥抗肿瘤协同作用。本研究考察了MnO2/BSA/DTX纳米粒对巨噬细胞的生物相容性，载药巨噬细胞对肿瘤组织转运的过程，对巨噬细胞表型的影响，载药巨噬细胞在体外和体内实验中对肿瘤生长的抑制作用。