基于氮氧化物的纳米磁共振成像造影剂的合成与表征

发布时间：2018-04-07 16:57

本文选题：MRI造影剂　切入点：凝胶造影剂　出处：《浙江大学》2014年硕士论文

【摘要】：肿瘤的早期准确诊断是其成功治疗的关键。磁共振成像(MRI)由于其高度的软组织分辨能力和无辐射伤害,成为临床上最重要的医学成像技术之一,在肿瘤的早期诊断和治疗监测方面发挥重要的作用。但是MRI的灵敏度不高,经常需要使用造影剂增强MRI的对比度,以提高MRI检测疾病的灵敏度和准确度。目前临床上使用的和研究的造影剂都缺乏针对肿瘤的特异性,在肿瘤和正常组织中都发挥造影作用,因此成像效果不够理想。开发一种肿瘤特异性的造影剂是增加MRI检测疾病灵敏度的关键。肿瘤具有与正常组织不同的生理特性,为设计开发肿瘤特异性造影剂提供了基础。其中,肿瘤具有与正常组织不同的pH环境,使得设计开发pH响应型MRI造影剂成为可能,而其厌氧的环境,可用来设计开发厌氧响应的MRI造影剂。本论文首先简要介绍了肿瘤影像诊断的方法、MRI及其工作原理、磁共振造影剂的研究进展,特别重点介绍了高分子造影剂和生物响应磁共振造影剂方面的研究进展,并提出研制一种分子结构稳定,有较长血液半衰期,高的弛豫率以及具有肿瘤微环境响应功能的纳米凝胶造影剂(NGCA)。通过合成一种含有造影剂分子的疏水性交联剂(HDA-DTPA-Gd3+),将它与甲基丙烯酸二乙基氨基乙酯(DEAMA)以及聚乙二醇羟甲基苯乙烯(VBPEG)进行微乳液聚合,然后经过双氧水处理后,制备了一种内含MRI造影剂(HDA-DTPA-Gd3+)以及厌氧和酸性响应基团(氧化DEAMA),外含亲水性保护基团NGCA。比较了不同配方和制备条件,发现当单体组成为VBPEG (3%)、DEAMA (57%)、 HDA-DTPA-Gd3+(40%)时制备的NGCA在pH=7.4时能形成尺寸为34 nm的稳定纳米颗粒氧化后其粒径变为66nm。NGC A的弛豫率(r1)随pH值的降低在pH 6.8-6之间从5.3增加到11.5 mM-1s-1,达到小分子造影剂DTPA-Gd3+(Magnevist(?)) r的2.6倍,而氧化后的NGCA(ONGCA)比NGCA具有更高的r1值,表明ONGCA具有肿瘤微环境(pH和厌氧)响应能力。动物体内成像实验表明,ONGCA能够在较低剂量下有效增强肿瘤成像,清晰显示肿瘤的边界。同时,我们意外地发现NGCA对正常细胞和癌细胞的毒性都比较大,而ONGC A对癌细胞有较大的毒性,但是对正常细胞的毒性较小。结果表明我们初步制备出了一种能够对肿瘤pH和厌氧环境作出响应的NGCA,而且具有体外抗肿瘤效果。它有望成为一种诊疗一体化的造影剂。后续工作包括NGCA的厌氧响应机理以及NGCA抗癌动物实验需要进一步的研究。
[Abstract]:Early and accurate diagnosis of tumor is the key to its successful treatment.Magnetic resonance imaging (MRI) has become one of the most important medical imaging techniques because of its high soft tissue resolution and no radiation injury. It plays an important role in the early diagnosis and monitoring of tumor treatment.However, the sensitivity of MRI is not high, it is often necessary to use contrast agent to enhance the contrast of MRI in order to improve the sensitivity and accuracy of MRI detection of disease.At present, the contrast agents used and studied in clinic are lack of tumor specificity and play an important role in both tumor and normal tissues, so the imaging effect is not satisfactory.The development of a tumor-specific contrast agent is the key to increase the sensitivity of MRI for disease detection.Tumor has different physiological characteristics from normal tissue, which provides a basis for the design and development of tumor specific contrast agent.Among them, tumor has different pH environment from normal tissue, which makes it possible to design and develop pH responsive MRI contrast agent, while its anaerobic environment can be used to design and develop anaerobic MRI contrast agent.In this paper, we first briefly introduce the methods of tumor imaging diagnosis and its working principle, the research progress of magnetic resonance contrast agent, especially the research progress of polymer contrast agent and biological response magnetic resonance imaging agent.A novel nanogel contrast agent with stable molecular structure, long blood half-life, high relaxation rate and tumor microenvironmental response was proposed.A hydrophobic crosslinking agent (HDA-DTPA-Gd3) containing contrast agent was synthesized. It was polymerized with diethylaminoethyl methacrylate (DEAMA) and polyethylene glycol hydroxymethyl styrene (VBPEG) by microemulsion polymerization, and then treated with hydrogen peroxide.A MRI contrast agent (HDA-DTPA-Gd3) and anaerobic and acidic responsive groups (oxidized DEAMAA, with hydrophilic protective group NGCA) were prepared.Different formulations and preparation conditions were compared.To the small molecular contrast agent DTPA-Gd3 Magnevistella) r, 2. 6 times,The oxidized NGCA ONGCA had a higher R1 value than that of NGCA, indicating that ONGCA had the ability to respond to tumor microenvironment pH and anaerobic.In vivo imaging experiments show that ONGCA can effectively enhance tumor imaging at lower doses and clearly show tumor boundary.At the same time, we accidentally found that NGCA is more toxic to both normal cells and cancer cells, while ONGC A is more toxic to cancer cells, but less toxic to normal cells.The results showed that NGCA, which could respond to tumor pH and anaerobic environment, had been prepared and had antitumor effect in vitro.It is expected to become an integrated diagnostic and therapeutic contrast agent.The following work includes the anaerobic response mechanism of NGCA and NGCA anti-cancer animal experiments need further study.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R445.2

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