复合磁性纳米氧化物的制备与肝癌靶向诊疗一体化的研究

For malignant tumor especially hepatic carcinoma, early stage diagnose and treatment definitely increase the long-term disease-free survival. Magnetic nanomaterials had drawn broad attention for their magnetic property performing excellent in cancer theranostics, whereas the component dependent activity of their own has been rarely reported. The applicant synthesized a novel water-soluble paramagnetic manganese oxide (MnO) nanocrystal for T1 magnetic resonance imaging (MRI), and found it could induce autophagy in multiple tumor cells including hepatic carcinoma cell to enhance the cancer curative effect. On this basis, in this project we propose to design and synthesize a series of advanced core-shell structural MnO-FION-PEG-Tf magnetic oxide nanocomposites. Using microwave heating method, manganese oxide nanocrystals with well T1 MRI ability would be synthesized in situ on the surface of magnetosome-like ferrimagnetic iron oxide nanocubes (FION) with great T2 MRI ability to obtain MnO-FION magnetic nanocomposites. Then, tumor targeted molecule transferrin (Tf) would be conjugated. We propose to optimize the MR imaging and magnetic hyperthermia performances via regulation of the size and component ratio of these magnetic nanocomposites. Magnetic targeting and transferrin targeting should contribute synergistically to enhance the diagnosis sensitivity of hepatic carcinoma, meanwhile manganese oxide component should induce hepatic tumor cells autophagy which would enhance magnetic hyperthermia to kill hepatic tumor. As a result, with the controlled synthesis and systematical biological research, sensitive MR diagnosis and drug-free therapy of hepatic carcinoma can be achieved synergistically in this project.

恶性肿瘤尤其是肝癌的早期诊断和治疗是提高其治愈率的有效手段。磁性纳米生物材料用于肿瘤诊疗一体化研究受到广泛关注，但主要是基于其磁性能，对磁性纳米材料自身的生物活性的研究报道还比较少见。申请人前期研发了一种水溶性顺磁性一氧化锰（MnO）T1型纳米磁共振造影剂，并发现其可以通过诱导肿瘤细胞自噬对肿瘤治疗增敏。在此基础上，本课题拟采用微波加热法，在具有优异的T2型磁共振成像性能和磁热疗性能的四氧化三铁纳米立方体（FION）表面原位合成MnO纳米粒，然后偶联肿瘤靶向分子转铁蛋白（Tf），构建一系列核壳结构的MnO-FION-PEG-Tf磁性纳米复合物，并通过对其尺寸和组分的可控调节实现磁共振成像和磁热疗性能的优化。在磁靶向与转铁蛋白靶向下，该复合磁性纳米材料可以通过T1/T2型双模式磁共振成像提高肝癌诊断灵敏度，同步可进行自噬增敏的肿瘤磁热疗，从而实现非化疗性的肝癌诊疗一体化。

恶性肿瘤尤其是肝癌的早期诊断和治疗是提高其治愈率的有效手段。磁性纳米生物材料用于肿瘤诊疗一体化研究受到广泛关注。在本项目的支持下，相关课题顺利开展，按照研究计划制定的目标已经完成一系列磁性氧化物材料的合成制备，设计搭建了高频磁热治疗及成像装置一台，完成了氧化铁-氧化锰磁性复合氧化物（FMN）的合成以及磁共振成像、肿瘤磁热疗的研究，其T2性能达到273 mM-1s-1。200 µg Fe /mL的FMN水溶液在35KA/m的交变磁性强度下其温度可以在10分钟内从37度升到50度左右，已经在用于肿瘤诊疗的新型磁性纳米氧化物的合成与研究上达到了本项目制定的研究计划。此外本项目还在磁性纳米材料的自噬性能上进行了初步的研究。本项目在生物材料与肿瘤诊疗方向取得一系列研究成果，其中本课题主持人作为共同第一作者发表自然子刊论文一篇Nature Biomedical Engineering，并被Nature Biomedical Engineering以News&Views形式全文点评。项目主持人作为共同通讯作者在生物医学和生物材料领域发表SCI论文6篇，包括Biomaterials 1篇，ACS Applied Materials & Interfaces 3篇，Nanoscale 1篇，Biomaterials Science 2篇（Front Cover 1篇）。申请中国发明专利4项，其中1项授权，相关工作展现出良好的应用转化潜力。