基于近红外量子点和上转换纳米晶的肿瘤诊疗平台的初步构建及应用

发布时间：2018-03-18 14:55

本文选题：荧光纳米晶　切入点：近红外荧光　出处：《天津大学》2016年博士论文　论文类型：学位论文

【摘要】：随着纳米生物技术的迅速发展,近红外CuInS量子点和NaYF_4上转换纳米晶(UCNs)在肿瘤的诊断和治疗领域得到了广泛的关注。然而,目前制备的CuInS量子点和NaYF_4UCNs表面多为疏水配体,无法直接应用于水相生物环境。鉴于此,本文以CuInS量子点和NaYF_4UCNs为主体,通过表面功能化组装修饰及编码微球等技术,构建了一系列多功能的肿瘤诊疗荧光平台,并初步探索了其在肿瘤细胞/亚细胞水平成像、肿瘤可视化治疗及肿瘤标志物检测等领域的应用。具体内容如下:1.肿瘤微环境响应性CuInS量子点纳米探针的构建及应用。基于肿瘤微环境的弱酸性特性,本文从分子设计角度出发,首先合成出pH敏感的双亲性高分子,即月桂酸和2,3-二甲基马来酸酐共接枝的聚赖氨酸,并将其与CuInS量子点进行多功能组装,构建出一种肿瘤微环境响应而电荷反转的量子点纳米探针,用于肿瘤细胞的靶向成像。结果证明,该纳米探针粒径均一、非特异性吸附低、稳定性好、细胞毒性低,且具有pH响应的电荷反转功能。在正常pH 7.4时呈负电性,而在肿瘤微环境pH 6.8时迅速反转为正电性,在HeLa细胞中表现出显著增强的细胞摄取,成功实现对肿瘤细胞的靶向荧光成像;2.线粒体靶向高荧光稳定性CuInS量子点纳米平台的构建及应用。本文以CuInS量子点为核、自行设计制备的超支化聚缩水甘油醚衍生物为功能修饰层、膜渗透亲脂三苯基膦阳离子为线粒体靶向功能分子,构建出一种线粒体靶向量子点探针。结果证明,该探针细胞毒性低、非特异性吸附少,且能够实现特异性的线粒体靶向成像功能,跟传统的线粒体染料相比,该量子点探针荧光稳定性好,无光漂白淬灭现象。此外,将作用于线粒体的抗癌药物负载到该体系中可实现对肿瘤细胞更高效的杀伤;3.肿瘤可视化联合治疗上转换荧光纳米平台的构建及应用。本文以NaYF_4:Yb,ErUCNs为核、阿霉素为化疗药物、酞菁锌为光敏剂、牛血清白蛋白-聚己内酯结合体为修饰层,构建出一种集荧光成像、化疗和光动力学治疗(PDT)于一体的多功能可视化肿瘤联合治疗纳米平台。结果证明,该体系在980 nm光源辐照下UCNs发射光能成功激发酞菁锌产生活性氧,同时实现对肿瘤细胞的荧光成像。跟单一的化疗或PDT相比,该联合治疗体系对HeLa细胞的杀伤效果显著增4.多色上转换荧光编码微球免疫检测平台的构建及应用。本文采用高温油相热分解法合成了六种颜色的NaYF_4UCNs,并结合磁性纳米颗粒和编码微球技术制备出多色上转换荧光编码微球(UCNMMs)。结果证明,该UCNMMs荧光稳定性优异、磁响应性好,可实现快速磁分离;跟传统的下转换荧光编码体系相比,UCNMMs免疫检测体系具有双光激发特性,可成功避免编码信号和报告信号间的荧光干扰,检测灵敏度更高;该体系成功用于鼠IgG的检测,最低检测限为0.01ng/m L。综上所述,本文成功构建了一系列基于CuInS量子点和NaYF_4上转换纳米晶的多功能肿瘤诊疗用荧光纳米平台,极大地推动了荧光纳米颗粒在肿瘤诊断和治疗领域的应用和发展。
[Abstract]:With the rapid development of nano biotechnology, near infrared CuInS quantum dots and NaYF_4 upconversion nanoparticles (UCNs) has received wide attention in the field of diagnosis and treatment of tumors. However, the preparation of CuInS quantum dots and NaYF_4UCNs surface hydrophobic ligands, cannot be applied directly in aqueous biological environment. In view of this, this paper using CuInS quantum dots and NaYF_4UCNs as the main body, through the surface functional group and decoration technology constructs encoding microspheres, tumor diagnosis and treatment of a series of multifunctional fluorescence platform, and explore its subcellular level in tumor cells / tumor imaging, visualization and treatment of tumor marker detection applications. The specific contents are as follows: 1. the tumor microenvironment response of construction and application of CuInS quantum dot nano probe. The weak acid characteristics of the tumor microenvironment based on this paper, from the perspective of molecular design, we synthesized pH sensitive The amphiphilic polymer, namely lauric acid and two 2,3- methyl maleic anhydride grafting poly lysine, and with CuInS quantum dots multifunctional assembly, construct a tumor microenvironment response and quantum dot charge reversal nano probe, for tumor targeted imaging. Results show that the nano probe of uniform size, low non-specific adsorption, good stability, low toxicity, and has the function of charge reversal pH response. In 7.4 normal pH was negative, while in the tumor microenvironment of pH 6.8 was quickly reversed positive, showed significantly enhanced cellular uptake in HeLa cells, the successful implementation of the tumor cell targeting fluorescence imaging; 2. mitochondrial targeting construction and application of CuInS quantum dot nano platform Gao Yingguang stability. In this paper, using CuInS quantum dots as the core, designed for preparation of hyperbranched polyglycerol derivatives as functional modification layer Three, membrane permeability of lipophilic cationic phenyl phosphine mitochondrial targeting molecule, construct a mitochondrial targeting quantum dot probe. The results proved that the probe with low toxicity, less nonspecific adsorption, and can realize the specificity of mitochondrial targeting imaging function, compared with the traditional mitochondrial dyes, quantum dots fluorescence stability, no photobleaching quenching phenomenon. In addition, anticancer drugs will be applied to the realization of the mitochondrial load to kill tumor cells can be more efficient in the system; construction and application of 3. tumor visualization combined treatment of upconversion fluorescent nano platform. Based on NaYF_4:Yb, ErUCNs as the core, adriamycin chemotherapy drug, phthalocyanine zinc as photosensitizer, bovine serum albumin and polycaprolactone combination as the modification layer, construct a set of fluorescence imaging, chemotherapy and photodynamic therapy (PDT) functions in one visual combined cancer treatment Treatment of nano platform. The results show that the system in 980 nm light under the irradiation of UCNs light emission of zinc phthalocyanine successfully stimulate the production of reactive oxygen species, and fluorescence imaging of tumor cells. Compared with the single chemotherapy or PDT, the killing effect of the combined treatment system of HeLa cells increased significantly in the construction and application of 4. multicolor upconversion fluorescence encoding microsphere immunoassay detection platform. The decomposition of the six colors of NaYF_4UCNs high temperature oil, combined with magnetic nanoparticles and microspheres prepared encoding multicolor fluorescent encoding microspheres (UCNMMs). The result shows that the UCNMMs fluorescent stability is excellent, good magnetic response, which can realize fast magnetic separation; with the traditional conversion fluorescence encoding system in UCNMMs immune detection system with double optical excitation characteristics, successfully avoiding the fluorescence interference signal encoding and reporting between the signals, the detection sensitivity is more The system successfully used to detect high; in IgG, the lowest detection limit of 0.01ng/m L. in summary, we successfully established a series of tumor diagnosis and treatment based on the multi function of CuInS quantum dots and NaYF_4 upconversion nanocrystals with fluorescent nano platform, greatly promoted the development and application of fluorescent nanoparticles in the field of cancer diagnosis and treatment.

【学位授予单位】：天津大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R73-3;TB383.1

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