Preparation and Biomedical Applications of Magnetic Nanoparticle-based High-performance Magnetic Resonance Imaging Contrast Agents

磁共振成像造影剂可以改变组织的弛豫时间，从而改变组织的信号强度，有力地提高了组织的磁共振影像对比度，使得诊断更准确。因此，发展新型高性能磁共振成像造影剂具有重要的现实意义。本论文围绕高性能磁共振成像造影剂这一重大需求，设计合成了多种磁性无机纳米材料，并对其磁共振造影性能及生物应用潜能进行系统研究。 首先，基于高磁性的纳米材料往往可以产生更强的T2造影效果的思路，本论文合成了具高饱和磁化强度和优秀抗氧化性能的Fe5C2纳米颗粒，并对其磁共振造影性能进行研究。结果表明，Fe5C2纳米颗粒可以高效地缩短水质子的T2弛豫时间，是一种潜在的高性能T2磁共振造影剂。 其次，为了更好地理解磁性纳米颗粒中...Magnetic resonance imaging (MRI) contrast agents with the ability to shorten relaxation time of water protons can greatly improve the accuracy and specificity of MRI. Therefore, the search for MRI contrast agents with high efficiency is desirable and of great importance. In this thesis, three kinds of magnetic nanomaterials are exploited to serve as high-performance contrast agents for efficient M...学位：理学博士院系专业：化学化工学院_化学生物学学号：2052011015368

A Biocompatible Gadolinium(Ⅲ)-Poly(Aspartic Acid-Co-Phenylalanine) for Liver Magnetic Resonance Imaging Contrast Agent

一种新型的以天门冬氨酸-苯丙氨酸共聚物为载体的大分子生物相容性材料(AP-EdA-dOTA-gd)被制备出来作为磁共振成像造影剂.首先合成了天门冬氨酸-苯丙氨酸共聚物,之后利用乙二胺将1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(dOTA)连接到共聚物上,最后将钆离子通过配位的作用方式连接到dOTA上,最终得到大分子AP-EdA-dOTA-gd.体外溶血性试验表明AP-EdA-dOTA-gd具有较好的血液相容性.在P H=5.5的组织蛋白酶b的磷酸缓冲液中,AP-EdA-dOTA-gd能够降解.APEdA-dOTA-gd的体外弛豫效率(15.95 MMOl–1·l·S–1)为目前临床应用的gd-dOTA(5.59MMOl–1·l·S–1)的2.9倍.大鼠肝脏成像实验结果表明,AP-EdA-dOTA-gd对于肝组织的成像增强对比度为63.5±6.1%远高于gd-dOTA(24.2±2.9%).A new biocompatible gadolinium(III)-macromolecule(AP-EDA-DOTA-Gd) was developed as a magnetic resonance imaging(MRI) contrast agent.Poly(aspartic acid-cophenylalanine) was synthesized, modified via ethylenediamine, conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid(DOTA) and finally chelated gadolinium(III), yielding gadolinium(III)-based macromolecule(AP-EDA-DOTA-Gd).The hemolytic tests showed the hemocompatibility of this gadolinium(III)-based macromolecular conjugate.In vitro, AP-EDA-DOTA-Gd could be degraded, when it was incubated with cathepsin B in phosphate buffered solution(p H = 5.5).The T1-relaxivity(15.95 mmol–1·L·s–1) of AP-EDA-DOTA-Gd was 2.9 times of that(5.59 mmol–1·L·s–1) of the clinical MRI contrast agent(Gd-DOTA) at 1.5 T and 25 ℃.The liver enhancement of AP-EDA-DOTA-Gd was 63.5±6.1% during the maximum enhancement time(50-80 min), which was much better than that of Gd-DOTA(24.2±2.9%, 10-30 min).AP-EDA-DOTA-Gd was expected to be a potential liver MRI contrast agent.TheNationalNaturalScienceFoundationofChina(20975097and21305134

Engineering on Iron-Oxide-Based Nanoparticles for High-Performance Magnetic Resonance Imaging

第一章，我们简要介绍了MRI的技术背景、MRI造影剂的研究背景以及基于磁性氧化铁纳米材料的合成和生物功能化应用，主要探讨了MRI造影剂材料的研究现状和潜在问题。我们分析了磁性材料（包括分子螯合物配合物类和纳米颗粒类）作为MRI造影剂的关键因素，勾勒出了对于磁性材料的优化设计及其MRI应用的重要切入点。最后，我们简单探讨了氧化铁纳米材料的合成以及表面生物功能化对于其生物医学应用的重要性。 第二章，我们研究了一种独特磁铁矿型超顺磁氧化铁纳米片，这种纳米片可以通过合成调控得到厚度不同的样品，表现出增强的而且具有相互作用性的T1和T2造影性能。我们阐明了氧化铁纳米片中增强的T1造影性能主要与水质子在...In the Chapter one, we briefly introduced the background of magnetic resonance imaging (MRI) technique, the research about MRI contrast agents, and the design of iron-oxide-based nanoparticles as high-performance MRI contrast agents. Besides, we discussed the current status and underlying issues on the research of nanoparticle-based MRI contrast agents. We outlined the key factors influencing MRI ...学位：理学博士院系专业：化学化工学院_化学生物学学号：2052012015348

Preliminary chemical investigation of NSF—Characterization and structure analyses of the substituted products of phosphate and phosphite with gadolinium aminopolycarboxylates

以钆离子为中心的多氨多羧酸螯合物由于其独特的电子结构和磁学性能被广泛应用于核磁共振成像(MagneticResonanceImaging,MRI)中作为造影剂。自1984年首次应用造影剂二乙三胺五乙酸钆（Gd-DTPA）进行脑肿瘤的增强显像研究以来，人们对钆基造影剂进行大量的研发和临床研究。通常，钆基造影剂都具有很高的热力学稳定性和动力学惰性以保证安全，然而研究表明，对于一些肾功能障碍的患者，钆基造影剂注射入体内后可能会与体内的可溶性无机磷酸盐、金属离子和其它成分发生复杂的反应最终生成磷酸钆复合生物微粒，进而引起一种危险的疾病：肾源性系统纤维化。因此，对于钆基螯合物造影剂与磷酸类无机小分子的反...Gadolinium polyaminocarboxylates were widely used in Magnetic Resonance Imaging as contrast agents due to their unique electron structure and magnetic properties. Since the first gadolinium based contrast agent (GBCA) Gd-DTPA was clinical used in 1984, the GBCAs have been broadly investigated and clinically tested. Generally, the Gd3+ was coordinated by the chelating ligand to obtain thermodynamic...学位：工学博士院系专业：化学化工学院_工业催化学号：2062012015346

The Experimental Study of Magnetic Resonance Immunoimaging Using Anti human Lung Cancer Monoclonal Antibodies Coated Superparamagnetic Iron Oxied Nanoparticle

目的：探讨标记抗人肺癌单抗的超顺磁性氧化铁微粒（SPIO）进行磁共振免疫显像的可能性。材料与方法：将采用fE（Ⅲ）与fE（Ⅱ）混合液在碱性条件下制备SPIO微粒；将粒径4.5nM±3.4nM的SPIO微粒标记到抗人肺癌单抗（MCAbS）上；观察静注SPIO—MCAbS定向改变载瘤裸鼠（n＝4）Mr信号强度的可能性。结果：SPIO—MCAbSMr成像能有效地降低全部瘤靶的Mr信号。结论：磁共振免疫成像是一种有发展前景的肿瘤靶向显像新途径Objective: To investigate the possibility of MR immunoimaging using monoclonal antibodies against human lung cancer (McAbs) labelled with superparamagnetic iron oxide nanoparticle (SPIO).Materials and Methods:SPIO with a mean diameter of 4.5nm±3.4nm, was synthesized by reaction of Fe(Ⅲ) and Fe(Ⅱ) with dextran under the alkaline condition.The McAbs coupled convalently to SPIO was achieved with the potassium periodate method.Then the McAbs—SPIO was injected intravenously in nude mice hosted human lung cancer (n=4).Results:The MR contrast agent of SPIO—McAbs can selectively reduce the signal intensities of the tumor targets.Conclusion: The data indicate MR immunoimaging may become a new approach For speciFic imaging of tumors.国家自然科学基

Polypeptide Micelle-based Theranostic Nanoplatform for Overcoming Cancer Multidrug Resistance

癌症是全球范围内导致人口死亡的一个重要原因，在各种癌症中，胃癌是一 种较为高发的癌症，特别是在发展中国家。在发展中国家中，胃癌是造成男性死 亡的第三大死因。由于胃癌容易产生潜在的淋巴结转移，单纯的手术切除通常不 是很有效。因而，临床治疗过程中，常在手术切除肿瘤病灶后，常利用化学疗法 对晚期或是已经发生转移的胃癌进行治疗。化学疗法在癌症的治疗中已经得到广 泛的应用，但化学治疗的同时，也产生了一个新的问题，即癌细胞在经过化疗药 物治疗后，出现了耐药性。为了解决癌细胞对化疗药物耐药的问题，临床常选用 联用其他化学治疗药物或者增加化疗药物用量的方法，但这种方式并不能从根本 上解决耐药性...Cancer is the leading cause of death worldwide, and stomach cancer is one of the most frequently diagnosed ones. In less developed countries, stomach cancer is the third most frequently diagnosed cancer among men and the leading cause of cancer death. Owning to the suspected lymph nodes metastasis, sole surgical resection is usually not very effective. Therefore, chemotherapy has been widely used ...学位：医学硕士院系专业：公共卫生学院_流行病与卫生统计学学号：3272013115055

Preparation and Applications of Carbon Nanomaterials with Amino-groups Modified in One-step Process

近年来，碳纳米材料的合成、性质与应用研究倍受关注。但由于碳纳米材料表面具有疏水性，不适合在水溶液体系中使用。为了扩展碳纳米材料的应用范围，必须对碳纳米材料的表面进行修饰和改性。目前，对碳纳米材料的表面进行修饰和改性主要采用共价修饰和非共价修饰两种方法。一般对碳纳米材料表面修饰和改性都是在材料合成之后进行，但这种改性方法往往会造成碳纳米材料结构的破坏，从而影响碳纳米材料的性能。如何在材料合成的过程中同步完成对碳纳米材料的表面修饰和改性是改善碳纳米材料性质和拓宽其应用领域的重要方向。本文尝试用十氯代芘、八氯苊烯、六氯代苯和六溴代苯作为碳源反应物，在溶剂热条件下发生脱氯反应，在不同反应条件下分别制备...The application of carbon materials has been slowed due to their insolubility and incompatibility, which can be improved through surface modification. Functional-group-mediated covalent-modification has been utilized in CNTs . The use of covalent chemistry to link DNA to CNTs is also expected to provide excellent stability, accessibility, and selectivity compared with noncovalent bonding. In gener...学位：理学博士院系专业：化学化工学院材料科学与工程系_无机化学学号：B20043600

Microwave Synthesis of Upconversion Luminescence and Magnetic Nanomaterials and Their Application in Biosensing

摘要 本论文以稀土掺杂上转换发光纳米晶和尖晶石型铁氧体磁性纳米粒子这两类纳米材料为研究主体，力图从制备方法、结构与性能关系及其在生物医学检测等几方面都有所创新性的研究。主要内容概括如下： 第一章，综述了微波加热的原理及其在无机纳米材料可控合成中的优势与应用，上转换发光的基本原理、磁性纳米材料的磁学特性以及这两类材料在生物医学中的应用研究进展。 第二章，结合微波加热与“乙醇/水”溶剂体系，发展了一种快速、便捷的NaGdF4:Yb,Er/Tm/Ho上转换发光/顺磁性纳米晶制备方法。通过对照实验，证实微波加热不仅非常显著地把传统热传导加热条件下所需的数小时保持时间缩短到5min以内，而且产物的...Abstract In this thesis, rare earth doped upconversion luminescence nanoparticles (UCNPs) and spinel ferrite magnetic nanoparticles (MNPs) are choosen as research objects. The project mainly focuses on the preparation process, the relationship between structure & properties and the application in biomedical detection. The main contents are as follow. In the first chapter, the mechanism of microw...学位：理学博士院系专业：材料学院_高分子化学与物理学号：2072011015349

Recent advances in biological-environment-responsive smart MRI contrast agents

随着生物医学领域的不断发展,人们对于在分子机理层面上研究生物体系中新陈代谢、疾病的发生和发展等过程的需求日益增长.磁共振成像因拥有其他成像方法所; 不具备的非侵入式、深层次的空间分辨能力,为生物体系分子层面的检测提供了有力的工具.分子层面的磁共振成像检测离不开生物环境智能响应磁共振造影剂的使; 用.生物环境智能响应磁共振造影剂的造影能力会随着特定生物环境变化而发生改变.此类造影剂使得人们可以根据磁共振图像上信号的改变分析得到生物体特定位; 置的pH、离子浓度、酶活力等相关信息.近20年来,生物环境智能响应磁共振造影剂得到了长足的发展.本文将按不同的响应对象分类总结近几年此类造影剂的; 研究进展,并对一些重要的研究成果进行较为详细的阐述和对比,分析目前生物环境智能响应磁共振造影剂研究中存在的困难和解决方案,最后对本领域的进一步发; 展进行展望.With the rapid advancement in biology and medicine, there is an urgent; need to study metabolisms in lives and mechanisms of diseases at; molecular levels. Magnetic resonance imaging (MRI), which is capable of; non-invasive and three-dimensional deep imaging, is a powerful tool to; meet this demand. Environment-responsive contrast agents, whose contrast; abilities change once stimulated, are necessary for this purpose. With; the use of these responsive contrast agents, related biological; information, such as pH, concentration of ions, activity of enzymes,; could be easily extracted and analyzed from MR images. Considerable; progress has been made in the field of biological-environment-responsive; smart MRI contrast agents over the two decades. In this review, we; describe achievements in recent years, discuss several representative; works in detail, summarize current difficulties that have been met and; possible solutions that have been formulated, and finally look into the; promising future of biological-environment-responsive smart MRI contrast; agents.科技部973项目; 国家自然科学基金; 霍英东教育基

Fe3O4复合TiO2纳米粒子及其制备方法以及在磁共振成像造影剂中的应用

本发明涉及Fe3O4复合TiO2纳米粒子及其制备方法以及在磁共振成像造影剂中的应用。其中，Fe3O4复合TiO2纳米粒子的制备方法包括步骤：将三价铁的化合物与二价铁的化合物溶入还原性酸的水溶液中；在前述溶液中滴加四价钛盐溶液，反应制得Fe3O4复合TiO2纳米粒子溶胶。与现有技术相比，本发明所提供的Fe3O4复合TiO2纳米粒子的制备方法操作简单、制备成本低、反应过程无需N2保护，产物具有粒径分布均匀、尺寸可控、水溶性好、生物相容性好、无毒等优点。由本发明所提供的制备方法所制备的Fe3O4复合TiO2纳米粒子是一种具有超顺磁性和光催化活性双重性质的复合纳米材料，可以应用于磁共振成像造影剂中