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

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.

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。

通过高分子递送金属铂类药物和增敏化疗药物的基因药物是提高化疗药物疗效、降低毒性、克服肿瘤耐药的重要策略。针对高级别浆液性卵巢癌在临床上经铂类药物治疗后容易产生耐药的特点，本项目拟设计合成一类肿瘤微环境敏感的高分子载体材料，并利用这些载体材料负载新型四价铂前药，以及可引起合成致死效应的靶向药物/基因药物，最终形成复合纳米药物。同时，本项目构建了诸多病人来源的肿瘤模型包括病人来源的肿瘤细胞（PDC）、类器官（PDO）、异种移植瘤模型（PDX），这些模型被用到体外、体内水平筛选上述复合纳米药物，取得了一系列研究成果。本项目为克服高级别浆液性卵巢癌铂耐药提供了解决问题的新思路，同时也为肿瘤靶向治疗提供了新的策略。在本项目的资助下，本项目组研究人员共在国内外学术期刊尚发表学术论文14篇，申请中国专利4项，授权中国专利2项；参加国内和国际学术会议20次；合作培养博士研究生5名，硕士研究生5名，博士后2名。