纳米壳层稳定的铁纳米粒子的构建及其在肿瘤双靶向核磁共振成像与光热治疗中的研究

Tumor, which is one of a global public health problem, threats to human health seriously. It has attracted the entire society’s attention. To solve the disadvantages of the theranostic agent, such as the complicated synthetic procedure and weak targeting property, the project aims to synthesize multi-functional nanoshell stabilized Fe nanoparticles with a high temperature decomposition approach. By the self-assembly, lipids are coated on the surface of stabilized Fe nanoparticles to endow the water solubility and further conjugation. The RGD with the active targeting property and Zn-DPA complex with the apoptotic targeting property are conjugated on their surface to perform the dual-targeting property. On the xenografted golima model, magnetic resonance imaging (MRI) and photo-thermal therapy for tumor are performed simultaneously by use of the good magnetic and photo-thermal property of Fe nanoparticles. Furthermore, the amplification effect of the dosage of nanoparticles, the enhancement of targeting ability of nanoparticles and MRI signal, the improvement of photothermal therapy for tumor will be investigated by means of the apoptotic targeting property triggered by the near-infraed laser. The project will not only promote the investigation of the nanoparticulated theranostic agents, but also favor their clinical transformation.

肿瘤，作为全球性的公共卫生问题之一，严重威胁着人类的健康，已经引起了全社会的广泛关注。本项目利用肿瘤诊疗一体化技术，针对目前诊疗一体化试剂存在合成工艺复杂与靶向性不足的问题，采用分步高温热解法构建纳米壳层稳定的铁纳米粒子，充分发挥Fe纳米粒子同时具备优良的磁学性质和光热转换的特性，实现纳米粒子的核磁共振成像(MRI)和光热转换；通过纳米粒子与磷脂的自组装，进一步修饰对肿瘤具有主动靶向性的多肽RGD和凋亡靶向性的二-(2，2’-二吡啶)甲基胺-锌(Zn-DPA)配合物，实现纳米粒子的双重靶向功能；建立移植性小鼠脑胶质瘤模型，通过尾静脉注射纳米粒子，以MRI为监测手段，系统研究近红外激光触发的肿瘤细胞凋亡靶向性对纳米粒子在肿瘤中剂量的放大效应，对肿瘤的靶向能力和MRI信号的增强作用以及肿瘤光热治疗效果的提高。本项目的开展，将有助于推动纳米粒子在肿瘤诊疗领域的应用，促进纳米诊疗试剂的临床转化。

本项目针对诊疗一体化试剂的系统集成与肿瘤靶向的这一关键科学问题，围绕铁基纳米粒子的诊疗一体化主要开展了以下工作：(1) 通过多肽RGD的修饰，实现Fe@Fe3O4纳米粒子的主动靶向肿瘤光热治疗，并通过多肽的放射性标记，详细研究了纳米粒子的血液动力学与生物分布；考虑到Fe3O4的纳米酶特性，进一步开展了Fe@Fe3O4纳米粒子在核磁共振成像引导的超声促进的化学动力学治疗中的应用；(2) 利用具有凋亡靶向能力的二-(2，2’-二吡啶)甲基胺-锌(ZnDPA)对Fe@Fe3O4纳米粒子的修饰，在小鼠凋亡靶向模型建立的基础上，实现了肿瘤的凋亡靶向放大光热治疗，同时，利用ZnDPA修饰的Zn0.4Co0.6Fe2O4@Zn0.4Mn0.6Fe2O4纳米粒子实现了凋亡靶向放大的磁热治疗； (3)利用张力炔基修饰的Fe@Fe3O4纳米粒子的 EPR效应预靶向纳米粒子，通过张力促进的Click反应与叠氮修饰的花菁染料，实现了花菁染料的靶向放大的光声成像；(5)以Fe@Fe3O4为模板，利用Kirkendall效应合成了超小空心结构的Fe3O4纳米粒子，实现了Fe3O4纳米粒子的T1加权的核磁共振成像与肾代谢；(6) 在Fe@Fe3O4纳米粒子研究的基础上，开展了Fe@Fe3O4@Cu2-xS复合纳米粒子的化学动力学治疗以及Fe@Fe5Ge2纳米粒子的核磁共振成像引导的光动力学治疗。本项目的开展，为铁基纳米粒子在肿瘤诊疗领域的应用与临床转化奠定了基础。