多酸抗肿瘤药物的设计合成及其抗肿瘤活性与MALDI质谱成像研究

Tumor is a serious disease that threatened human life. Polyoxometalates (POMs) in medicine had significant antitumor activity, MALDI imaging mass spectrometry could provide quantitative and spatialized data on the distribution of drugs and their metabolites. This project was aimed at the disadvantages that POMs drug exhibited lower bioactivity and toxic side effects. By the ways of incorporating organic molecules, small biological molecules into the POMs matrix or covering method etc. A series of new POMs drug were designed and synthesized. POMs were characterized by different techniques including the Fourier Transform Infrared (FTIR), nuclear magnetic resonance (NMR) technology, transmission electron microscopy(TEM), etc. MTT assay was used to compare the antitumor activity and cytotoxicity of POMs with Keggin or Dawson structre and their substituted POMs.The intracellular localization of polyoxometalate was studied by using MALDI Imaging Mass Spectrometry and confocal microscopy. Furthermore, fluorescence technology, gel electrophoresis technology and flow cytometry were also used to investigate the anti-tumor effects of new POMs drug.It is expected to synthesize a series of new efficient and low toxicity POMs anti-tumor drugs and explore their anti-tumor mechanism.

肿瘤是当今世界威胁人类生命的一重大疾病，多酸药物具有优异的抗肿瘤活性，MALDI质谱成像技术能提供有关药物及其代谢产物组织分布的定量化和空间化数据。本项目针对传统多酸抗肿瘤药物尚存在的毒副作用较高和生物活性较差等缺点，通过在多酸药物母体分子中引入有机分子、生物小分子或包覆等手段，设计合成出系列新型多酸抗肿瘤药物。利用傅立叶红外光谱、核磁共振技术以及透射电镜等对多酸药物进行表征。应用MTT法比较研究Keggin型、Dawson型多酸药物及其取代多酸药物的抗肿瘤活性和细胞毒性。采用MALDI质谱成像技术和共聚焦显微镜研究多酸有机-无机化合物的细胞内定位情况，进而应用荧光技术、凝胶电泳技术、流式细胞技术深入研究新型多酸药物的抗肿瘤作用机制。预期将合成出系列新型高效低毒多酸抗肿瘤药物，并探明多酸药物抗肿瘤作用机制。

无机多金属氧酸盐（POMs）在生物活性尤其是抗肿瘤和抗病毒方面具有显著表现，有机官能团修饰的POMs能够克服POMs生物体内溶解度低、细胞毒性高等缺陷被认为是一种新型的潜在的抗肿瘤药物。经过4年的努力，本项目成功地设计合成出多种新型多酸抗肿瘤药物，共发表论文14篇（其中SCI/EI收录10篇），授权发明专利4项。取得了以下成果： . 1.以硅钨酸、磷钨酸和磷钼酸为主体，通过取代、包覆等方法对母体多酸进行修饰改性，设计合成出37种不同结构（Keggin型、Dawson型和Preyssler型）的新型取代型多酸药物。为新型多酸药物的研发提供了新思路、新方法。. 2. 通过体外抗肿瘤活性测试初步筛选出3种新型多酸药物。通过皮下瘤模型对1种多酸药物的抗肿瘤活性进行体内实验，治疗8天后抑瘤率可以达到18.67% 。初步研究发现多酸药物通过引起细胞氧化应激诱导细胞凋亡。. 3. 总结了生物系统中纳米材料的MALDI质谱成像方法，并对LDI中金属纳米材料增强离子化效率的机理进行探究，证明了表面等离激元通过热电子转移反应促进LDI过程。初步建立了多酸药物MALDI-MSI方法，为后续探究多酸药物抗肿瘤机制研究提供了方法支持。. 4. 拓展研究了有机硼氮功能分子的构筑及应用，开展了其在癌细胞识别、指纹成像及防伪等方面的工作，高选择性的实现了人体乳腺癌细胞亚细胞器脂滴的精准定位跟踪，对进一步探究多酸抗肿瘤的机制提供了方法保障。