多细胞器靶向的近红外光响应载体系统协同用于多药耐药肿瘤治疗

Multidrug resistance (MDR) is a major problem in cancer chemotherapy. Synergistically killing cancer cells through multiorganella-targeting is an efficient strategy to bypass drug-resistant barriers. In this project, we will develop a dual-targeted NIR-responsive drug delivery system for overcoming drug resistance in MDR cancer cells. We anticipate that the drug-loaded system holds such advantages: (1) high stability in blood circulation, intracellular uptake by cancer cells with the assitance of magnetic-targeting ; (2) deshield of the PEG shell triggered by the acidic pH and excess glutathione (GSH) in the cytoplasm, resulting in the mitochondria targeting groups of TPP, and the death of cancer cells will take place by NIR irradiation to interfer the funciton of the mitochondria; (3) meanwhile, the bonding drugs will be released intranuclearly to kill the cancer cells synergistically with NIR. We present a rational design for the multiorganella-targeted drug delivery system, with high intergration of diagnosis, therapy and stimulus-response to overcome the multidrug resistance of tumor, which results in a high efficient cancer treatment.

多重耐药性(MDR)是肿瘤治疗中的一个主要难题，通过多细胞器靶向协同杀死肿瘤细胞是克服多药耐药屏障的有效措施。本项目中，我们将构建一种具有双靶向的近红外光响应载药系统用于克服MDR肿瘤细胞的多药耐药性。我们期望这一载药系统具备以下特征：(1)在血液循环过程中保持高度稳定性，在磁靶向的协助下被肿瘤细胞摄取；(2)在细胞质内的弱酸环境和高浓度谷胱甘肽(GSH)的刺激下脱落外壳聚乙二醇（PEG），暴露出三苯基膦（TPP）从而靶向线粒体，在近红外光照射下干扰线粒体功能从而杀死癌细胞；(3)与此同时，键合药物断裂后进入细胞核作用于DNA，协同近红外光杀死肿瘤核心区细胞。我们通过对纳米载体的合理设计构建出可多细胞器靶向的药物传递系统，并高度整合诊断、治疗及刺激响应三种功能于一体，用于克服肿瘤的多重耐药性，从而实现MDR的高效治疗。

研究化疗和光热疗法协同作用增强肿瘤多药耐药(MDR)的治疗效果。因此，本文设计了一种亚细胞器靶向的近红外响应纳米载药系统Fe3O4@PDA-TPP/S2-PEG-hyd-DOX (缩写为Fe3O4-ATSPD)。作为新的光热制剂，Fe3O4-ATSPD具有良好的光热稳定性和光热转换能力。该纳米药物在血液循环中表现出很高的稳定性，能通过磁靶向增强实体瘤的高通透性和滞留效应(EPR)在肿瘤部位聚积。当纳米药物被MDR肿瘤细胞吞噬后，在溶酶体内较低的pH环境下，Fe3O4-ATSPD可快速释放出抗肿瘤药物DOX，随即扩散进入细胞核破坏DNA，促进细胞凋亡。同时，当近红外光(NIR)照射肿瘤组织时，光热剂聚多巴胺(PDA)产生光热效应，激活线粒体诱导的细胞凋亡途径。本项目设计的亚细胞器靶向的近红外光响应纳米药物系统能通过化疗协同光热治疗显著增强MDR肿瘤的抑制效果，具有高效的诊断和治疗效应。项目实施过程中，发表论文3篇，培养研究生6名。项目负责人与多个高校建立了合作关系。