肿瘤耐药是成功治愈癌症的主要障碍之一, 将抗肿瘤药物靶向传输至维持细胞存活的能量工厂-线粒体的策略，被视为是未来克服肿瘤耐药一个重大的突破口。本项目以先前的研究成果“具有靶向功能的平阳霉素单糖分子”和线粒体靶向多肽序列（MTS）为切入点，通过将平阳霉素单糖分子键合到修饰了MTS的DOX上，构建MM-MTS-DOX键合物的双重靶向载药体系。该载药体系既靶向细胞表面又靶向线粒体. 该体系通过首先将DOX靶向人乳腺癌细胞表面，通过配体介导的内吞运输Dox至细胞内，继而利用线粒体靶向多肽靶向阿霉素于线粒体中，从而改变Dox的作用靶点，且通过靶向线粒体调控耐药相关基因表达，增强DOX诱导耐药癌细胞凋亡作用，阻滞细胞周期来克服肿瘤细胞的耐药。通过进一步开展体外实验，该项目旨在证实该该体系能将DOX传输至细胞内并靶向线粒体，从而克服耐药。该项目的成功实施必将为临床上肿瘤的耐药难题提供新的解决思路

Caused by many different mechanisms, Multiple drug resistance (MDR) is a major challenge for cancer chemotherapy . Targeted delivery of anticancer drugs to mitochondria, the energy factory to sustain the cell viability, has been considered as a great promising strategy to prevent or inhibit the MDR effect of cancer cells. In our previous reports, we have demonstrated that certain monosaccharide molecule（MM）could recognize cancer cells and mitochondria could be targeted by specific polypeptide sequence. Based on the above hypothesis, a MM-MTS-DOX（MTS，mitochondria targeted signal) multifunctional drug delivery can actively target cancer cell membrane and mitochondria. This system is able to targeted deliver DOX to human breast cancer cells, cure cancer cells and decrease the cytotoxicity and side effects of DOX. Therefore, this project will bind MM ligand to DOX functionalized with MTS to fabricate MM-MTS-DOX targeted drug delivery system. In vitro experiments will be performed to test and verify the capability of this targeted drug delivery system for delivering DOX to the mitochondria of cancer cells. With this system, we desire to regulate the expression of related genes by targeting mitochondria and enhance killing capacity of DOX for drug-resistant cancer cells and inhibit cell cycle. Thus the targeted delivery system will increase therapeutic efficacy and overcome MDR. Furthermore, this novel drug delivery system targeting mitochondria will provide new insights for targeted cancer therapy.

肿瘤耐药是成功治愈癌症的主要障碍之一, 将抗肿瘤药物靶向传输至维持细胞存活的能量工厂-线粒体的策略，被视为是未来克服肿瘤耐药一个重大的突破口。本项目以先前的研究成果“具有靶向功能的平阳霉素单糖分子”和线粒体靶向多肽序列（MTS）为切入点，通过将平阳霉素单糖分子键合到修饰了MTS的DOX上，构建MM-MTS-DOX键合物的双重靶向载药体系。我们基本完成了研究计划要点。通过体外细胞毒性试验，我们发现MTS-DOX和MM-MTS-DOX比游离的DOX 大大增加了MCF-7/DOX细胞株耐药治疗效果，MTS-DOX其IC50大约7.5 μg/mg， MTS-DOX IC50大约8.6 μg/mg，而游离的DOX的IC50大于100 μg/mg。然而MM-MTS-DOX键合物的双重靶向载药体系没有明显改善肿瘤治疗效果，提高疗效，克服耐药性。接下来我们将继续评估其载药体系细胞内的摄取和耐药机制。同时我们重新设计新的sugar-PEG-PLA（DOX-MTS）双重靶向载药体系，期望此双重靶向载药体系可以明显改善肿瘤治疗效果，克服耐药性。