靶向PGR阳性乳腺癌的多功能钌配合物合成及其抗肿瘤机制研究

项目名称： 靶向PGR阳性乳腺癌的多功能钌配合物合成及其抗肿瘤机制研究

项目编号： No.21501074

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 环境科学、安全科学

项目作者： 吕高超

作者单位： 江苏省原子医学研究所

项目金额： 20万元

中文摘要： 乳腺癌已成为危害女性健康的主要癌症之一。目前，临床上的辅助化疗药物靶向性低，存在较大副作用，对晚期患者效果不明显。因此，如何设计合成具有高活性和肿瘤靶向性的抗癌药物，成为目前该领域研究的重点和难点。前期实验结果表明，N-杂环卡宾-钌(ΙΙ)类(NHC-Ru(ΙΙ))配合物对乳腺癌细胞(MDA-MB-231)表现出较高的抑制活性。本项目将进一步研究和拓展合成具有高活性、靶向性和荧光显像的多功能NHC-Ru(ΙΙ)类配合物。首先，通过对NHC配体的修饰，提高配合物的抗肿瘤活性；然后，利用孕酮对孕酮受体阳性(PGR+)乳腺癌细胞的高选择性，与配合物结合，实现对PGR+乳腺癌的靶向性；最后，以香豆素为荧光探针，实时检测配合物在细胞内的释放和分布。同时，研究此类配合物与可能靶点硫氧还蛋白还原酶(TrxR)的作用以及由此引起细胞凋亡的信号通路，阐明该类配合物的抗肿瘤机制，为新药开发提供必要的研究基础。

中文关键词： 乳腺癌；N-杂环卡宾；钌配合物；靶向性；作用机制

英文摘要： Breast cancer is the most common cause of death in women. Currently, the major challenges in cancer chemotherapy involve delivery of potent drugs selectively to the pathological cells without exposing the toxic effects of the drugs to the normal tissue and the no obvious effect for advanced patients. Therefore, it is currently the focus and difficulty to design and synthesis of targeted and highly activity anticancer drugs. The preliminary experimental results of us demonstrated that N-heterocyclic carbene ruthenium (NHC-Ru(ΙΙ)) complexes showed high cytotoxicity against MDA-MB-231 cell lines. The project will further research on the synthesis of multi-functional NHC-Ru(ΙΙ) complexes as anticancer agents. Firstly, it is aimed to improve the cytotoxicity of the NHC-Ru(ΙΙ) complexes by the modification of the NHC precursors. Secondly, the progesterone will be used to promote the targeting of the drugs to progesterone receptor positive (PGR+) breast cancer cells. Lastly, coumarin as the fluorescent probe will be connected with the NHC-Ru complexes in purpose of the real-time detection of the release and distribution of the complexes in cancer cells. Meanwhile, the project will focus on the mechanism of NHC-Ru(ΙΙ) complexes action including the interaction of the NHC-Ru(ΙΙ) complexes with the possible target thioredoxin reductase (TrxR) and the apoptosis signal pathways.

英文关键词： Breast Cancer;N-Heterocyclic Carbene;Ruthenium Complexes;Targeting;Mechanism Action