含硒金属配合物的靶向设计与抗肿瘤作用机制研究

Chemical drug design based on the biochemical characteristics of cancer cells has become an important strategy for discovery of novel anticancer drugs to enhance the cancer targeting effects and biocompatibility, and decrease toxic side effects. Design of chemical molecules based on cancer cell signaling pathways has become an important strategy for discovery of targeting anticancer strategies. Organic selenium compounds and metal complexes are both promising anticancer drug candidates, whose action mechanisms and drug targets are complementary. Therefore, we combined them together to synthesize selenium-containing metal complexes, and found that the anticancer efficacy was significantly enhanced. However, their cancer targeting effects, safety and action mechanisms need further investigation. In this proposal, we aim to rationally design and develop a series of novel cancer theranostic agents based on selenium-containing metal complexes. Based on the optimization of the chemical structure of selenium-containing ligands and complexes, we will introduce cancer targeting units into the complexes to recognize proteins overexpressed in cancer cell membrane by using bioresponsive disulfide linker. Studies would also be carried out to examine the target-recognition and anticancer activities, cancer imaging property and biodistribution in vitro and in vivo, and the chemical nature of the interaction between the complexes and the cellular targets. We will also elucidate the regulation effects of the complexes on different intracellular signaling pathways and the crosstalk. It is anticipated that the results from this project may provide a good strategy for rational design of the next-generation theranostic selenium-containing metal complexes with specific drug targets and clear action mechanisms.

基于肿瘤细胞的生化特性来进行化学药物设计，可望提高药物的肿瘤靶向性及生物相容性，降低毒副作用，是开发靶向创新药物的有效途径。有机硒及金属配合物均是极具开发前景的抗肿瘤候选药物，且两者作用机制与靶点互补。设计合成含硒金属配合物可望实现两者的强强联合与功能互补，提升肿瘤诊断与治疗效果。在此基础上，本项目将针对肿瘤细胞及其微环境的化学特性进行配合物的功能靶向设计。在优化含硒配体结构的基础上，引入肿瘤细胞特异性膜蛋白靶向识别分子，同时引入能被硫醇类生物分子活化切割的桥梁基团，设计合成新型靶向含硒金属配合物，研究该类配合物对肿瘤细胞的靶向识别作用、抗肿瘤活性、体内成像与分布，探讨配合物与肿瘤靶标之间相互作用的化学本质，阐述靶向配合物对不同信号通路的调控作用，为进一步开发靶点清楚、作用机制明确的新型含硒靶向抗肿瘤药物提供科学依据。

基于肿瘤细胞的生化特性来进行化学药物设计，可望提高药物的肿瘤靶向性及生物相容性 ，降低毒副作用，是开发靶向创新药物的有效途径。有机硒及金属配合物均是极具开发前景的 抗肿瘤候选药物，且两者作用机制与靶点互补。设计合成含硒金属配合物可望实现两者的强强联合与功能互补，提升肿瘤诊断与治疗效果。在此基础上，本项目针对肿瘤细胞及其微环境的化学特性进行配合物的功能靶向设计。在优化含硒配体结构的基础上，引入肿瘤细胞特异性膜蛋白靶向识别分子，同时引入能被硫醇类生物分子活化切割的桥梁基团，设计合成了新型靶向含硒金属配合物和一系列靶向性钌配合物、铱配合物等，系统研究了该类配合物对肿瘤细胞的靶向识别作用、抗肿瘤活性、体内成像与分布，探讨了配合物与肿瘤靶标之间相互作用的化学本质，阐述了靶向配合物对不同信号通路的调控作用；.同时，基于小分子金属配合物生物利用度低等关键挑战，本项目还利用纳米材料的独特理化性质如尺寸小、可控性强且易化学修饰等，设计合成了一系列负载含硒化合物的肿瘤靶向性纳米药物，有效提高了含硒化合物的抗肿瘤活性，且可增强肿瘤细胞的免疫敏感性，有效提高NK细胞的抗肿瘤作用，并与其有机协同，实现对多种肿瘤恶性进展的有效抑制。另外，本项目研究发现功能化纳米硒还可有效改善癌症患者来源免疫细胞如NK细胞、细胞因子诱导的杀伤细胞(CIK)等的免疫功能，且可实现有机协同，改善肿瘤免疫微环境，诱导强有效的抗肿瘤免疫反应，有效抑制多种肿瘤恶性进展。.上述一系列研究为进一步开发靶点清楚、作用机制明确的新型含硒靶向抗肿瘤药物及其联合治疗新策略提供了重要信息，也为临床开发更加安全高效的肿瘤治疗新策略提供了新思路。