多功能纳米诊疗剂的构建及其在肿瘤的成像与治疗中的应用研究

发布时间：2017-12-27 07:15

本文关键词：多功能纳米诊疗剂的构建及其在肿瘤的成像与治疗中的应用研究　出处：《吉林大学》2017年硕士论文　论文类型：学位论文

【摘要】：自从集诊断与治疗于一体的“诊疗”概念被提出以来,设计和构建多功能的诊疗剂就成为了癌症诊断与治疗研究领域中的热点。近年来,随着纳米科技的飞速发展,一系列的无机纳米复合材料被应用于癌症的成像、治疗以及药物传输,如介孔硅纳米粒子、上转换纳米粒子、半导体量子点、磁性纳米粒子等。在本论文中,我们设计并构建了两类基于稀土掺杂的上转换发光纳米材料(UCNPs)和四氧化三锰的多功能纳米诊疗剂,并深入系统的研究了其在癌症诊断与治疗中的潜在应用性。主要研究内容概括如下:1、稀土掺杂的上转换发光纳米材料以其独特的优势,如良好的光稳定性,高的化学稳定性,窄带隙发射,无背景荧光的干扰以及低毒性等,在生物医学方面展现了广泛的潜在应用性。传统的以Yb~(3+)作为敏化剂的UCNPs,由于水分子对其激发光(980 nm)具有强吸收而产生过热效应,极大阻碍了UCNPs在生物医学方面的应用。针对该问题,我们设计合成了Nd~(3+)敏化的稀土上转换纳米粒子,用水分子吸收较弱的808 nm近红外光作为激发光源,可以有效避免激光辐照对正常组织的热损伤。由于Nd~(3+)和Yb~(3+)高的原子序数可以作为计算机断层扫描(CT)的造影剂,由此该诊疗剂可以实现上转换荧光和CT的双重模式的成像,同时,在UCNPs表面用聚丙烯酸(PAA)修饰,进一步与黑色素多巴胺(PDA)结合,既实现了高效率的光热治疗,也增加了材料本身的生物相容性。因此,PDA@UCNPs纳米诊疗剂可以实现上转换荧光和CT的双重成像模式引导的光热治疗,实现肿瘤诊疗的一体化策略。2、由于固有的优异磁学性质,锰(Mn)基纳米材料有望成为新第一代核磁共振成像(MRI)的造影剂。与传统的钆(Gd~(3+))造影剂相比,锰(Mn)基纳米材料具有更低的生物毒性。然而,目前已报道的锰(Mn)基纳米材料的弛豫率仍无法另人满意,因此,急需设计合成具有高弛豫率、低毒性的新型锰(Mn)基MRI造影剂。在此,我们设计并合成了具有超高弛豫率的Mn_3O_4纳米粒子作为T1-MRI造影剂,并在其表面包覆多巴胺(PDA),有效地提高了材料的生物相容性,降低了其本身的生物毒性。同时,利用PDA表面的丰富基团,实现了对抗癌药物的负载。此外,我们在PDA表面通过双氨基聚乙二醇(NH_2-PEG-NH_2)进一步与具有细胞靶向的叶酸(FA)相结合,最终合成的FA-Mn_3O_4@PDA@PEG纳米粒子,实现了T1-MRI引导靶向的化疗/热疗协同进行的肿瘤治疗。
[Abstract]:Since the concept of "diagnosis and treatment" has been put forward since the integration of diagnosis and treatment, the design and construction of multifunctional diagnostic agents has become a hot topic in the field of cancer diagnosis and treatment. In recent years, with the rapid development of nanotechnology, a series of inorganic nanocomposites have been applied to cancer imaging, treatment and drug delivery, such as mesoporous silica nanoparticles, upconversion nanoparticles, semiconductor quantum dots, magnetic nanoparticles and so on. In this paper, we designed and constructed two kinds of multifunctional nano diagnostic agents based on rare earth doped upconversion luminescent nanomaterials (UCNPs) and four oxidized manganese three, and systematically studied their potential applications in cancer diagnosis and treatment. The main research contents are as follows: the conversion of luminescent nano material with its unique advantages in 1, rare earth doped, such as good light stability, high chemical stability, narrow bandgap emission, no background fluorescence interference and low toxicity, shows a potential wide application in biomedicine. The traditional UCNPs with Yb~ (3+) as sensitizer is overheated due to the strong absorption of water molecules to its excitation (980 nm), which greatly hinders the application of UCNPs in biomedicine. Aiming at this problem, we designed and synthesized Nd~ (3+) sensitized rare-earth upconversion nanoparticles, which absorbs 808 nm near infrared light with water molecules as excitation source, which can effectively avoid thermal damage to normal tissues irradiated by laser. The Nd~ (3+) and Yb~ (3+) high atomic number can be used as computed tomography (CT) contrast agent, dual mode imaging, thus the treatment agent can realize upconversion fluorescence and CT at the same time, on the surface of UCNPs with polyacrylic acid (PAA) modification, and further dopamine melanin (PDA) combined, not only realizes the efficient photothermal therapy, also increased the biocompatibility of the material itself. Therefore, the PDA@UCNPs nano diagnosis agent can realize the light and heat treatment guided by double imaging mode of upconversion fluorescence and CT, and realize the integration strategy of tumor diagnosis and treatment. 2. Due to its inherent excellent magnetic properties, manganese (Mn) - based nanomaterials are expected to be the contrast agents for the first generation NMR imaging (MRI). Manganese (Mn) - based nanomaterials have lower biotoxicity than conventional gadolinium (Gd~ (3+)) contrast agents. However, the reported Mn (Mn) based nano material relaxation rate is still not satisfying. Therefore, synthesis of new manganese high relaxivity and low toxicity design need (Mn) based MRI contrast agent. Here, we have designed and ultra high relaxivity Mn_3O_4 nanoparticles as T1-MRI contrast agent was synthesized and coated on the surface of dopamine (PDA), can effectively improve the biocompatibility of the material, reduce the toxicity of its own. At the same time, the load of anticancer drugs was realized by using the rich groups of the PDA surface. In addition, we have further synthesized FA-Mn_3O_4@PDA@PEG nanoparticles with PDA, which is combined with cell targeted folic acid (FA) on the surface of NH_2-PEG-NH_2 through the double amino polyethylene glycol (FA).
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R730;TQ421.7

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