针对当前癌症治疗多药耐药性的策略，并基于申请人前期工作基础，本项目将以“具有细胞靶向的博来霉素单糖分子(MM)”和“线粒体靶向的TTP”作为切入点，设计出多层次、双细胞器靶向的载药体系。通过将博来霉素三支链单糖分子(TM)键合到高分子载体形成靶向高分子，随后包裹二价顺铂和轴向上含靶向线粒体基团TPP的四价顺铂前药，从而构建TM-NP(Pt(IV)@TPP+Pt(II))的载药体系。TM分子能高效靶向肿瘤细胞，从而通过配体介导的内吞将四价顺铂前药和顺铂运送至细胞内。当四价顺铂前药和二价顺铂进入细胞后，线粒体靶向基团能将四价铂定点靶向运输至线粒体，并还原为二价顺铂作用于线粒体。前述进入细胞的顺铂，又能靶向细胞核。因此通过二价顺铂靶向细胞核和线粒体靶向的四价顺铂可用来双重调控耐药相关基因的表达，增强诱导耐药癌细胞凋亡作用, 提高癌细胞的化疗敏感性，在现有研究的基础上，进一步改善化疗药物的耐药性。

Multiple drug resistance (MDR) that relies on many different mechanisms still remains a major challenge for cancer chemotherapy. We attempt to conduct a comprehensive investigation based on our previous studies and published literatures to explore possible strategies that are potential to overcome MDR in cancer cells. Therefore, in this project, we focus on two approaches, i.e., the use of cell surface receptor-specific ligands and mitochondrial-targeting moieties. Previous studies, including ours, have demonstrated that several types of monosaccharides could specifically bind to cancer cells and mitochondria could be targeted by TPP moiety. We herein will fabricate novel hybrid drug delivery nanoplatforms that can implement dual cell organelle targeting. We will exploit a trimeric bleomycin-branched monosaccharides (TBM) as a ligand to modify the surface of PEG-PLA polymeric carrier that encapsulate Pt(IV)@TPP and Pt(II) to generate TM-NP(Pt(IV)@TPP+Pt(II)). This dual organelle-targeting delivery system is expected to be able to recognize tumor cells via the binding events between TM and receptors. Subsequently, the nanoparticles will be transported to mitochondria by utilizing the TPP group. This dual organelle-targeting strategy will allow us to regulate the expression of related genes by targeting mitochondria, and, thereby, enhance the killing capacity of cisplatin in drug-resistant cancer cells. Eventually, the targeted delivery system will increase therapeutic efficacy and overcome MDR. We also envision that this novel multifunctional drug delivery system will provide a new insight into the precision cancer therapy.