基于纳米材料的非线性光学生物成像和光介导的癌症治疗研究
发布时间：2019-03-20 21:38
【摘要】：当今社会,癌症严重威胁着人类的健康。开发先进的技术实现快速准确的癌症诊断以及高效的癌症治疗是众多学者研究的焦点。光学生物成像为人类研究肿瘤的发病机理以及肿瘤诊断提供了有力的帮助,而近些年来出现的光介导的肿瘤治疗方法由于其优异的低侵入性和治疗肿瘤的高效性已经吸引了广泛的关注和研究。随着纳米技术的不断发展,具有优异的物理化学特性、易制备、生物兼容性好和易功能化的纳米材料已经被广泛的应用于生物医学领域的研究当中。本文以纳米材料为基础,研究了在纳米颗粒辅助下的非线性光学生物成像和光介导的肿瘤治疗。主要研究内容如下：1.金纳米材料的制备和表征。介绍了几种在后续实验研究中需要用到的金纳米棒的制备方法。同时提出了一种以多巴胺作为还原剂采用一步法(无种子法)制备金纳米棒的方法,这种方法降低了金纳米棒生长液中所需的高浓度的表面活性剂CTAB(从100 mM降至22mM),可以在30分钟完成金纳米棒的生长,并且其纵向表面等离子体共振吸收峰可以在700-1050 nm范围内调节,同时金纳米棒的产率高达80-95%。2.对比分析了1000 nm和760 nm飞秒激光激励下的金纳米棒的多光子发光特性以及在离体组织与活体成像中的应用。1000nm飞秒激光激励的金纳米棒的三光子发光在小鼠脑血管成像中获得了600 μm的成像深度,而760 nm飞秒激光激励的双光子发光成像深度为430 gm。同时在长波长激发下组织的背景噪声大大降低,获得了高对比度的金纳米棒在主要内脏器官和肿瘤组织中的分布成像。3.设计了一种简单的、具有通用性的基于聚多巴胺包覆的金纳米棒的纳米体系,实现了多功能的药物运输与多模式的光介导肿瘤治疗。在聚多巴胺包覆的金纳米棒上分别负载了光动力药物分子亚甲基蓝和化疗药物阿霉素,形成两种纳米体系,这两种纳米体系可以分别实现光动力与光热治疗、化疗与光热治疗的双模式肿瘤治疗。在离体细胞和活体抗肿瘤实验中获得了显著的抗肿瘤协同效应。4.设计了一种基于钛酸钡纳米颗粒的纳米体系,通过在其表面包覆聚合物电解质,大大提高了纳米颗粒在水溶液中的胶体稳定性,并且增强了其标记细胞的能力。此外,我们成功的将光动力药物分子Ce6负载到颗粒表面,利用二次谐波产生和荧光成像证明了聚合物包覆的钛酸钡纳米颗粒可以增强药物进入细胞的能力,最终实现了二次谐波产生成像引导的光动力治疗效果。5.设计了一种基于聚多巴胺纳米球的双药物负载纳米体系,利用聚多巴胺优异的吸附能力将药物分子亚甲基蓝和阿霉素同时负载到纳米球表面,在离体细胞与活体抗肿瘤实验中实现了光动力治疗与化疗协同作用的肿瘤治疗效果。
[Abstract]:In today's society, cancer is a serious threat to human health. The development of advanced technology to achieve rapid and accurate cancer diagnosis and efficient cancer treatment is the focus of many scholars. Optical bio-imaging provides a powerful help for the study of the pathogenesis and diagnosis of tumors in humans. In recent years, light-mediated tumor therapy has attracted extensive attention and research due to its excellent low invasion and high efficiency in the treatment of tumors. With the development of nanotechnology, nano-materials with excellent physical and chemical properties, easy preparation, good biological compatibility and easy to function have been widely used in biomedical research. In this paper, based on nano-materials, nonlinear optical bio-imaging and light-mediated tumor therapy assisted by nano-particles have been studied. The main contents of the study are as follows: 1. Preparation and characterization of gold nanomaterials. Several preparation methods of gold nanorods which need to be used in follow-up experimental research are introduced in this paper. At the same time, a method of preparing gold nanorods by one-step method (seed-free method) with dopamine as reducing agent was proposed. This method reduced the high concentration of surfactant CTAB (from 100 mM to 22mM) required for the growth of gold nanorods. The growth of gold nanorods can be completed in 30 minutes, and the longitudinal surface plasmon resonance absorption peak of gold nanorods can be adjusted in the range of 700 脳 1050 nm, and the yield of gold nanorods is as high as 80 脳 95%. The multi-photon luminescence properties of gold nanorods excited by 1000nm and 760nm femtosecond laser and their applications in tissue and in vivo imaging were compared and analyzed. 1 000 nm femtosecond laser stimulated three-photon luminescence of gold nanorods in mouse brain blood The imaging depth of 600 渭 m was obtained in the tube imaging. The two photon emission imaging depth excited by 760nm femtosecond laser is 430gm.. At the same time, the background noise of the tissues under long wavelength excitation was greatly reduced, and high contrast gold nanorods were obtained for imaging the distribution of gold nanorods in the main internal organs and tumor tissues. 3. A simple and universal nano-system based on polydopamine coated gold nanorods was designed to achieve multi-functional drug transport and multi-mode light-mediated tumor therapy. The photodynamic drug molecule methylene blue and the chemotherapy drug adriamycin were loaded on the gold nanorods coated with dopamine to form two kinds of nano-systems, which can realize photodynamic therapy and photothermal therapy respectively. Dual-mode tumor therapy with chemotherapy and photothermal therapy. In vitro and in vivo antitumor experiments, significant antitumor synergistic effects were obtained. 4. A kind of nano-system based on barium titanate nanoparticles was designed. The colloidal stability of nano-particles in aqueous solution was greatly improved and the ability of labeling cells was enhanced by coating polymer electrolytes on the surface of barium titanate nanoparticles. In addition, we successfully loaded the photodynamic drug molecule Ce6 onto the surface of the particle, using second harmonic generation and fluorescence imaging to prove that the polymer-coated barium titanate nanoparticles can enhance the ability of the drug to enter the cell. Finally, the second harmonic generation imaging-guided photodynamic therapy was achieved. 5. A double drug-loaded nano-system based on polydopamine nanospheres was designed. The drug molecules methylene blue and doxorubicin were loaded onto the surface of the nanospheres at the same time by using the excellent adsorption ability of polydopamine. The synergetic effect of photodynamic therapy and chemotherapy was achieved in the in vitro and in vivo antitumor experiments.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R730.5;TB383.1
，
本文编号：2444654
[Abstract]:In today's society, cancer is a serious threat to human health. The development of advanced technology to achieve rapid and accurate cancer diagnosis and efficient cancer treatment is the focus of many scholars. Optical bio-imaging provides a powerful help for the study of the pathogenesis and diagnosis of tumors in humans. In recent years, light-mediated tumor therapy has attracted extensive attention and research due to its excellent low invasion and high efficiency in the treatment of tumors. With the development of nanotechnology, nano-materials with excellent physical and chemical properties, easy preparation, good biological compatibility and easy to function have been widely used in biomedical research. In this paper, based on nano-materials, nonlinear optical bio-imaging and light-mediated tumor therapy assisted by nano-particles have been studied. The main contents of the study are as follows: 1. Preparation and characterization of gold nanomaterials. Several preparation methods of gold nanorods which need to be used in follow-up experimental research are introduced in this paper. At the same time, a method of preparing gold nanorods by one-step method (seed-free method) with dopamine as reducing agent was proposed. This method reduced the high concentration of surfactant CTAB (from 100 mM to 22mM) required for the growth of gold nanorods. The growth of gold nanorods can be completed in 30 minutes, and the longitudinal surface plasmon resonance absorption peak of gold nanorods can be adjusted in the range of 700 脳 1050 nm, and the yield of gold nanorods is as high as 80 脳 95%. The multi-photon luminescence properties of gold nanorods excited by 1000nm and 760nm femtosecond laser and their applications in tissue and in vivo imaging were compared and analyzed. 1 000 nm femtosecond laser stimulated three-photon luminescence of gold nanorods in mouse brain blood The imaging depth of 600 渭 m was obtained in the tube imaging. The two photon emission imaging depth excited by 760nm femtosecond laser is 430gm.. At the same time, the background noise of the tissues under long wavelength excitation was greatly reduced, and high contrast gold nanorods were obtained for imaging the distribution of gold nanorods in the main internal organs and tumor tissues. 3. A simple and universal nano-system based on polydopamine coated gold nanorods was designed to achieve multi-functional drug transport and multi-mode light-mediated tumor therapy. The photodynamic drug molecule methylene blue and the chemotherapy drug adriamycin were loaded on the gold nanorods coated with dopamine to form two kinds of nano-systems, which can realize photodynamic therapy and photothermal therapy respectively. Dual-mode tumor therapy with chemotherapy and photothermal therapy. In vitro and in vivo antitumor experiments, significant antitumor synergistic effects were obtained. 4. A kind of nano-system based on barium titanate nanoparticles was designed. The colloidal stability of nano-particles in aqueous solution was greatly improved and the ability of labeling cells was enhanced by coating polymer electrolytes on the surface of barium titanate nanoparticles. In addition, we successfully loaded the photodynamic drug molecule Ce6 onto the surface of the particle, using second harmonic generation and fluorescence imaging to prove that the polymer-coated barium titanate nanoparticles can enhance the ability of the drug to enter the cell. Finally, the second harmonic generation imaging-guided photodynamic therapy was achieved. 5. A double drug-loaded nano-system based on polydopamine nanospheres was designed. The drug molecules methylene blue and doxorubicin were loaded onto the surface of the nanospheres at the same time by using the excellent adsorption ability of polydopamine. The synergetic effect of photodynamic therapy and chemotherapy was achieved in the in vitro and in vivo antitumor experiments.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R730.5;TB383.1
，
本文编号：2444654
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