【作者】 刘建华；

【导师】 施展；

【作者基本信息】 吉林大学 ， 无机化学， 2019， 博士

【摘要】 近年来,纳米生物材料因其优异的医学成像性质及治疗效果引起了无机纳米材料研究人员的广泛关注。纳米生物材料一般应用于医学成像诊断及肿瘤治疗。如何通过绿色、便捷、低成本的方法构建高质量纳米生物材料逐渐受到学者们的重视。医学成像诊断方面,由于PET/CT检查费用昂贵,荧光成像及光声成像的组织穿透力低,我们选取了目前临床最常用的两种检查方法,CT成像及MR成像。肿瘤治疗方面,由于放射治疗具有辐射等原因,我们选取了起效作用快的光热治疗。我们分别合成出PEG-WO3-x、Fe3O4@Mn O2-PAA、Co-P-PEG等纳米粒子,在此基础上,对其进行表征、毒性分析、CT成像或MR成像、光热治疗等研究,探讨其在医学影像诊疗中的应用。第一章是绪论部分,论文介绍了纳米生物材料的合成方法、表面修饰方法、在医学成像及肿瘤治疗方面的研究进展以及选题目的和意义。第二章,我们选择溶剂热方法合成了高水溶性聚丙烯酸(PAA)修饰的Fe3O4@Mn O2纳米粒子。该纳米粒子具有核-壳结构,其核心的Fe3O4能够使磁共振T2加权成像信号明显降低,外周纳米壳Mn O2在肿瘤组织内的酸性环境下可以分解出顺磁性Mn2+离子,从而能够使磁共振T1加权成像信号明显升高。纳米粒子内在的T2加权MR成像能力能够提供肿瘤的解剖信息,其肿瘤酸性环境p H响应T1加权MR成像效果可以进一步提高肿瘤病变检出的敏感性。此外,Fe3O4@Mn O2-PAA纳米粒子在近红外区展现出优异的吸收能力,能够用于肿瘤的光热治疗。这种p H响应T1/T2双模态MR成像引导下的肿瘤光热治疗为纳米诊疗剂的研发提供一种新思路。第三章,我们通过高温热解法合成氧化钨纳米粒子,并用聚乙二醇(PEG)进行表面修饰从而合成PEG-WO3-x。与临床商用碘离子(碘原子序数53)CT造影剂相比,该纳米粒子(钨原子序数74)的CT成像效果较好。在探讨纳米粒子应用于瘤内CT成像及血液循环CT成像的基础上,我们首次将PEG-WO3-x用于胃肠道CT成像,并通过三维后处理清晰显示了胃肠道的轮廓。此外PEG-WO3-x纳米粒子在近红外区具有较强的吸收能力,其吸光值优于常见的近红外热疗试剂,因此可以作为性能优良的光热诊疗试剂。我们把PEG-WO3-x用于CT成像引导下的肿瘤光热治疗,并取得了良好的效果,为进一步的消化系统疾病CT成像及肿瘤光热治疗研究奠定了基础。第四章,我们利用高温热解法合成了PEG修饰的磷化钴纳米粒子Co-P-PEG。该纳米粒子形貌均一、分散均匀,细胞毒性及组织毒性较低。研究发现Co-P-PEG能够实现T2加权MR成像,具有较好的荷瘤小鼠肿瘤内MR成像能力,以及尾静脉注射纳米粒子肿瘤部位富集MR成像效果。此外,Co-P-PEG具备较强的近红外光吸收能力,可以对肿瘤细胞进行光热治疗。该纳米粒子在MR成像引导下肿瘤光热治疗领域具有很大的应用潜力。第五章,我们选择简单、绿色的微波辅助溶剂热法合成了聚乙烯亚胺(PEI)修饰Ba Gd F5纳米粒子。PEI-Ba Gd F5纳米粒子呈球形、表面光滑、分布均匀,粒径约30nm,具有较低的细胞毒性及体内毒性。体外成像结果表明PEI-Ba Gd F5纳米粒子具有较好的CT成像效果及T1加权MR成像能力,小鼠体内成像结果显示,注入纳米粒子24小时后,其肝脏CT成像及T1加权MR成像效果优于其他脏器,结果表明该纳米粒子具有肝脏富集的特点,具备肝脏CT及MR双模态成像的潜力。最后一章总结,对本论文研究的纳米生物材料从可控合成、表面修饰、医学CT成像、MR成像,以及肿瘤的光热治疗等方面进行了归纳。更多还原

【Abstract】 In recent years,nanobiomaterials have attracted a great deal of attention due to their excellent medical imaging and therapy.Theyare used extensivelyinmedical imaging and therapy.Synthesis of excellent nanobiomaterials with simple and quick methods has attracted considerable attention.In area of medical imaging,PET/CT examination is expensive.The penetrating ability of fluorescence imaging and photoacoustic tomography is low.Therefore,we decided to use CT imaging and MR imaging for medical imaging of nanobiomaterials.In the area of tumor treatment,because of radiation exposure by radiation therapy,we used phototherapy for tumor treatment.PEG-WO3-x,Fe3O4@Mn O2-PAA,Co-P-PEG were synthesized and characterized.In the first chapter,the synthesismethod,surface modification methods,and current advances of nanobiomaterials are introduced in detail.In the second chapter,we synthesized highly water-soluble Fe3O4@Mn O2-PAA nanoparticles through a simple and green microwave-assisted hydrothermal method.The nanoparticles showed core-shell structure.The core of Fe3O4 exhibited enhanced MR T2 image,and the shell of Mn O2 exhibited enhanced MR T1 imaging when existingin tumor tissue because of the Mn2+.MR T2 imaging of the Fe3O4@Mn O2-PAA nanoparticles provided the anatomical information,and the p H response MR T1 imaging could improve the diagnosis of tumor.Furthermore,Fe3O4@Mn O2-PAA nanoparticles exhibited excellent absorption in near infrared region,and could be used for phototherapy.The p H-responsive dual-model MR-guided tumor eradication by photothermal therapy provided new idea for theranostic in transition-metal based nanobiomaterials.In the third chapter,the PEG-WO3-x was synthesized via a fast and facile high-temperature solvothermal method with PEG as the surfactant.Compared to clinical iodinated(53)contrast of CT imaging,this nanoparticle(W 74)exhibited excellent CT imaging.Besides CT imaging within tumor and blood circle,we applied PEG-WO3-x for digestive tract CT imaging first time,the postpross with 3 D imaging showed counter of stomach.Furthermore,PEG-WO3-x nanoparticles exhibited excellent absorption in near infrared region,and could be used for phototherapy.PEG-WO3-x could be used for CT-guided tumour eradication by photothermal therapy.In the fourth chapter,we synthesized highly water-soluble Co-P-PEG nanoparticles through high-temperature solvothermal method.The nanoparticles exhibited excellent uniform morphology and dispersion,low cytotoxicity and tissue toxicity.Co-P-PEG showed excellent MR T2 imaging both within tumor and blood circle.Furthermore,Co-P-PEG nanoparticles exhibited excellent absorption in near infrared region,and could be used for MR-guided phototherapy.In the fifth chapter,the monodisperse and water-soluble PEI-Ba Gd F5 were synthesized via an environmentally friendly,fast and facile microwave-assisted method.The PEI-Ba Gd F5 nanoparticles exhibited features with spherical,smooth surface and uniform distribution.The diameter of particle size is about 30 nm,with low cytotoxicity and tissue toxicity.The PEI-Ba Gd F5 nanoparticles exhibited excellent CT imaging and MR T1 imaging.24 hours after intravenous injection of nanoparticles,the liver exhibited excellent CT imaging and MR T1 imaging,which indicated the ability of targeted hepatic imaging with dual-model MR and CT imaging.The last chapter is asummary ofthe synthesis,surface modification methods,medical imaging and tumor treatment with nanobiomaterials.更多还原