基于调控多胺稳态的新型四价铂多胺配合物的设计、合成及抗肿瘤转移活性评价

Platinum(IV) antitumor drugs reveal facilitated intravenous-to-oral administration, overcome the resistance and lower toxicity, but they are also vulnerable to sulfur protein to reduce bioavailability. Because polyamine requirements for tumor cells are much higher than normal cells, the polyamine is a good carrier for the targeted tumor cells. Polyamines can also enhance the drug targeting of the nucleus. We previously synthesized platinum(IV)-polyamine complexes. And they showed better activities of anti-tumor growth and metastasis than platinum(IV) core. We suspect that the novel platinum(IV) polyamine complexes realize its tumor targeting by polyamine transport. Moreover, by regulating the polyamine homeostasis, they activated the polyamine oxidase to produce free radicals that depleted glutathione. And thus it can significantly protect the antitumor activities of platinum drugs from deactivating by reducing agent glutathione (sulfur-containing protein). The combination of platinum drugs and DNA was enhanced. In the present study, we optimize the structure to obtain the leading compounds for the platinum(IV) polyamine complexes and explore targeting and targeting mechanism of platinum(IV) polyamine complexes. The project will provide theoretical and experimental basis for further research.

四价铂类抗肿瘤药物具有可口服、克服耐药、毒副作用低等优点，但也存在易被含硫蛋白毒化从而降低生物利用度等缺点，由于肿瘤细胞对多胺的需求远高于正常细胞故多胺成为良好的肿瘤靶向性载体，多胺可同时增强药物对细胞核的靶向性。我们前期合成的新型四价铂多胺配合物表现出比母体铂更强的抗肿瘤生长及转移的活性，推测该类配合物利用多胺载体实现了铂类药物的肿瘤靶向性，并通过调控多胺稳态激活了多胺氧化酶PAO从而使产生的自由基耗竭谷胱甘肽GSH，进而改善铂类药物被还原剂GSH（含硫蛋白）毒化的问题，且增强了铂类药物与DNA的结合。本课题对四价铂多胺配合物进行结构优化获取先导化合物，并通过细胞、动物等模型评价其抗肿瘤作用及分子机制，为该类配合物进一步研发提供理论基础和实验依据。

缺乏靶向性、抗肿瘤转移活性差及免疫抑制是化疗药物联合免疫疗法治疗TNBC面临的主要难题。BRCA1或BRCA2突变细胞对铂药物的高度敏感性导致最近铂药物被重新用于治疗TNBC，然而化疗药物包括铂药物通过上调STAT3下调STAT1/STAT6增加了肿瘤细胞诱导产生M2型巨噬细胞的能力，且与TNBC复发、转移及免疫逃逸密切相关，因此，逆转M2为M1-TAMs将为TNBC的治疗开辟新道路。多胺类似物通过调控多胺稳态消除CSCs并增强免疫，发挥抗肿瘤生长及转移的作用，且血浆中多胺含量已成为TNBC进展的重要标志物。我们合成的新型四价铂多胺配合物表现出比母体铂对TNBC干细胞更强的选择性及抗肿瘤生长转移活性，并首次发现四价铂多胺配合物在增强铂类药物靶向性的同时，通过调节多胺稳态来改变肿瘤细胞内的氧化还原状态，降低铂类药物被含硫蛋白GSH的毒化作用，进而提高肿瘤细胞内有效的铂含量、减少DNA的修复比例、增强铂类药物对先天和获得耐药细胞的作用。同时，四价铂多胺配合物在进入体内后可协同的抑制肿瘤细胞的侵袭和迁移, 通过上调SSAT和PAO下调内源性多胺Put，Spd和Spm的浓度，抑制快速生长的肿瘤细胞，机制探索发现p53/SSAT/β-catenin和PAO/ROS/GSH/GSH-Px途径与四价铂多胺配合物诱导的肿瘤转移抑制有密切关系。并同时靶向M2-TAMs溶酶体，上调其pH值促进其向M1转化。该类配合物利用多胺载体实现了铂药物对TNBC及TNBC干细胞的靶向性，并激活M2-TAMs重塑肿瘤免疫微环境。首次发现肿瘤高多胺微环境及免疫微环境对TNBC及TNBC干细胞的靶向作用，调控M2-TAMs功能及抗肿瘤转移的关系，为解决肿瘤免疫抑制及晚期TNBC患者治疗等提供理论基础和实验依据。