Fe@Fe₃O₄纳米粒子在靶向MR/SPECT成像以及光热治疗中的研究

【作者】 王晶；

【导师】 周治国；

【作者基本信息】 上海师范大学 ， 无机化学， 2016， 硕士

【摘要】 随着个体化治疗的发展,基于不同分子成像技术联用的多模式成像,已经被广泛用于临床癌症的诊断,这种诊断模式克服了单模式成像的局限性。在生物成像技术中,核磁共振（MR）成像有着高的空间分辨率和软组织对比度,但是缺乏灵敏度。单光子发射型计算机断层成像仪（SPECT）成像具有高的灵敏度,已经被广泛用于活体的定量分析,但是SPECT成像具有低的空间分辨率和缺乏解剖学的信息。联合MR/SPECT成像能够提供互补的信息达到高灵敏度和分辨率,完成更精准的活体可视化成像。在早期的癌症诊断方面,使用MR/SPECT造影剂能够在生癌组织和正常组织中准确的探测到肿瘤位置得到更清晰的图像。本文设计和制备了一种新颖的多功能纳米诊疗剂材料,对其进行了结构表征和性质研究,并通过MR/SPECT成像引导实现靶向光热治疗一体化。本文主要研究内容概括如下:第一章:简要总结了纳米粒子合成方法、分子成像手段、现阶段肿瘤诊断与治疗方法以及纳米粒子在其中的应用,并阐述了本论文的选题依据和研究内容。第二章:设计和制备了具有良好的分散性、高饱和磁化率、低毒性、高的光热转化效率的Fe@Fe₃O₄纳米粒子。将含有靶向基团RGD的磷脂包裹在MNPs表面,获得了平均水合粒径约为40 nm的一种新型多功能纳米诊疗剂（RGD-PEG-MNPs）,再通过放射性核素¹²⁵I标记,得到成像造影剂(¹²⁵I-RGD-PEG-MNPs),可以实现MR/SPECT成像。在含有高表达的整合素αvβ₃ U87MG肿瘤模型T₂加权成像和SPECT成像信号都高于封闭组。药代动力学和生物分布通过SPECT成像定量分析。实验结果说明RGD-PEG-MNPs展现出卓越的特异性靶向效果和低的网状内皮组织摄取。在尾静脉注射¹²⁵I-RGD-PEG-MNPs的6个小时后,定量分析结果显示在肿瘤位置摄取量达到最大6.75±1.24%ID/g。48小时后,在肝和脾处的摄取量仅为1.11±0.21%和0.16±0.09%ID/g。在MR/SPECT成像引导下,多功能纳米诊疗剂RGD-PEG-MNPs可以实现有效的靶向活体光热治疗。更多还原

【Abstract】 With the development of the personalized medicine, multimodality imaging by use of the combination the different molecular imaging technologies, has widely used in clinical cancer diagnosis to overcome limitations of the single imaging mode. Among the biomedical imaging techniques, magnetic resonance（MR） imaging has the high spatial resolution（several tens of micrometers） and soft tissue contrast, but suffers from limited sensitivity. Single photon emission computed tomography（SPECT） imaging is highly sensitive but is low spatial resolution and lack of the anatomical information. It has been widely used for quantitative in vivo monitoring of living subjects. The combination of MR and SPECT imaging can provide the complementary information with the high sensitivity and high resolution to visualize the molecular events more accurately in vivo. The use of MR/SPECT contrast agents can help to clarify images and detect tumor by enhancing the contrast between cancerous and normal tissues particularly on the early stage of cancer development.In this dissertation, a multifunctional nanotheranostic agent is developed for in vivo MR/SPECT guided highly-effective targeting photothermal therapy（PTT）.Chapter 1. A general introduction to synthesis of nanoparticles, molecular imaging means, tumor diagnosis and theraoy methods are presented. We also describe the applications of nanoparticles in oncology and highlight the new trend of theranostic nanomaterials. Finally, basis and main contents of this dissertation are listed.Chapter 2. We design Fe@Fe₃O₄ nanoparticles that possess a good dispersion, low toxicity, good biocompatibility and high saturation magnetization, high photothermal conversion efficiency. The cyclic c（RGDy K） peptide directly labeled by ¹²⁵ I conjugated PEGylated Fe@Fe₃O₄ nanoparticles（RGD-PEG-MNPs） with the average hydrodynamic diameter of 40 nm as a novel multifunctional platform were developed for targeting MR and SPECT imaging guided photothermal therapy in vivo. On the αvβ₃-positive U87 MG glioblastoma xenograft model, the signals of tumor from T₂-weighted MR and SPECT imaging were much higher than those in the blocking group at 6 h intravenous injection（i.v.） of RGD-PEG-MNPs and ¹²⁵ I radiolabeled RGD-PEG-MNPs, respectively. The pharmacokinetics and biodistribution were analyzed quantitatively by SPECT imaging ex vivo. The facts suggested that RGD-PEG-MNPs should exhibit the excellent targeting property and low reticuloendothelial uptake. At 6 h i.v. injection of ¹²⁵I-RGD-PEG-MNPs, the maximum uptake of 6.75 ± 1.24 % of the percentage injected dose per gram（ID/g） was accumulated in tumor. At 48 h i.v., only 1.11 ± 0.21 % and 0.16 ± 0.09% ID/g of were accumulated in liver and spleen, respectively. With the guidance of MR/SPECT imaging, the multifunctional nanoparticles achieved a good photothermal therapeutic efficacy in vivo.更多还原