利用合成致死性原理构建Pt(IV)和PARP抑制剂复合体系精准治疗高级浆液性卵巢癌

合成致死是指两个非致死基因同时失活导致细胞死亡的现象。卵巢癌化疗金标准顺铂易耐药，尤以高级浆液性卵巢癌(HGSOC)为最。本项目拟借“合成致死”原理来指导设计新型四价铂载药体系精准治疗HGSOC肿瘤。具体策略是：1)合成新型高效低毒四价铂；2)制备含PARP抑制剂、四价铂、BRCA1/2基因干扰元件的非靶向和MUC1抗体靶向的纳米粒子；3)根据HGSOC三种类型设计不同的纳米粒子进行治疗，以实现不同分子分型的同一类肿瘤以及处于不同进展阶段的同一肿瘤治疗手段的不同；4)纳米粒子进入癌细胞后，释放出铂造成大量DNA损伤、释放PARP抑制剂抑制PARP酶活性、释放基因干扰元件干扰BRCA1/2基因，使PARP和BRCA1/2同时失活，导致细胞合成致死，最终克服肿瘤耐药。本项目旨在运用“合成致死”的概念，设计集四价铂、PARP抑制剂、基因治疗、MUC1抗体靶向于一体的共载体，对肿瘤实现精准治疗。

Synthetic lethality refers to the phenomenon that simultaneous shut-down of two non-lethal genes results in the death of cells. The gold standard of ovarian cancer chemotherapy is cisplatin, which can develop drug resistance very easily, especially for high-grade serous ovarian cancers(HGSOC). Here, we propose to use the concept of "synthetic lethality" to construct a Pt(IV) prodrugs loaded drug delivery platform for precise nanomedicine. The specific strategy is to : i) synthesize highly potent but low toxic Pt(IV) prodrugs; ii) prepare a MUC1 antibody targeted and untargeted drug delivery nanoparticles with Pt(IV) prodrugs, PARP inhibitors, BRCA1/2 gene interfering units; iii) different nanoparticles were designed and administered to HGSOC cancers according to their three genotypes; iv) after entering the cells, the nanoparticles can release toxic Pt(II) which will stimulate the cells to produce tremendous DNA single strand breaks, release PARP inhibitors to inhibit DNA repair via PARP inhibition and the released BRCA1/2 gene interfering units can shut down BRCA1/2 gene, which will eventually result in " synthetic lethality", death of cells and finally overcoming drug resistance. This study provides with a new concept of adopting " synthetic lethality" to guide constructing a composite nano-delivery platform with Pt(IV) prodrugs, PARP inhibitors, gene therapy and MUC1 antibody targeting for precise cancer therapy.