基于納米材料的非線性光學(xué)生物成像和光介導(dǎo)的癌癥治療研究
發(fā)布時間：2019-03-20 21:38
【摘要】：當(dāng)今社會,癌癥嚴(yán)重威脅著人類的健康。開發(fā)先進的技術(shù)實現(xiàn)快速準(zhǔn)確的癌癥診斷以及高效的癌癥治療是眾多學(xué)者研究的焦點。光學(xué)生物成像為人類研究腫瘤的發(fā)病機理以及腫瘤診斷提供了有力的幫助,而近些年來出現(xiàn)的光介導(dǎo)的腫瘤治療方法由于其優(yōu)異的低侵入性和治療腫瘤的高效性已經(jīng)吸引了廣泛的關(guān)注和研究。隨著納米技術(shù)的不斷發(fā)展,具有優(yōu)異的物理化學(xué)特性、易制備、生物兼容性好和易功能化的納米材料已經(jīng)被廣泛的應(yīng)用于生物醫(yī)學(xué)領(lǐng)域的研究當(dāng)中。本文以納米材料為基礎(chǔ),研究了在納米顆粒輔助下的非線性光學(xué)生物成像和光介導(dǎo)的腫瘤治療。主要研究內(nèi)容如下：1.金納米材料的制備和表征。介紹了幾種在后續(xù)實驗研究中需要用到的金納米棒的制備方法。同時提出了一種以多巴胺作為還原劑采用一步法(無種子法)制備金納米棒的方法,這種方法降低了金納米棒生長液中所需的高濃度的表面活性劑CTAB(從100 mM降至22mM),可以在30分鐘完成金納米棒的生長,并且其縱向表面等離子體共振吸收峰可以在700-1050 nm范圍內(nèi)調(diào)節(jié),同時金納米棒的產(chǎn)率高達80-95%。2.對比分析了1000 nm和760 nm飛秒激光激勵下的金納米棒的多光子發(fā)光特性以及在離體組織與活體成像中的應(yīng)用。1000nm飛秒激光激勵的金納米棒的三光子發(fā)光在小鼠腦血管成像中獲得了600 μm的成像深度,而760 nm飛秒激光激勵的雙光子發(fā)光成像深度為430 gm。同時在長波長激發(fā)下組織的背景噪聲大大降低,獲得了高對比度的金納米棒在主要內(nèi)臟器官和腫瘤組織中的分布成像。3.設(shè)計了一種簡單的、具有通用性的基于聚多巴胺包覆的金納米棒的納米體系,實現(xiàn)了多功能的藥物運輸與多模式的光介導(dǎo)腫瘤治療。在聚多巴胺包覆的金納米棒上分別負載了光動力藥物分子亞甲基藍和化療藥物阿霉素,形成兩種納米體系,這兩種納米體系可以分別實現(xiàn)光動力與光熱治療、化療與光熱治療的雙模式腫瘤治療。在離體細胞和活體抗腫瘤實驗中獲得了顯著的抗腫瘤協(xié)同效應(yīng)。4.設(shè)計了一種基于鈦酸鋇納米顆粒的納米體系,通過在其表面包覆聚合物電解質(zhì),大大提高了納米顆粒在水溶液中的膠體穩(wěn)定性,并且增強了其標(biāo)記細胞的能力。此外,我們成功的將光動力藥物分子Ce6負載到顆粒表面,利用二次諧波產(chǎn)生和熒光成像證明了聚合物包覆的鈦酸鋇納米顆�？梢栽鰪娝幬镞M入細胞的能力,最終實現(xiàn)了二次諧波產(chǎn)生成像引導(dǎo)的光動力治療效果。5.設(shè)計了一種基于聚多巴胺納米球的雙藥物負載納米體系,利用聚多巴胺優(yōu)異的吸附能力將藥物分子亞甲基藍和阿霉素同時負載到納米球表面,在離體細胞與活體抗腫瘤實驗中實現(xiàn)了光動力治療與化療協(xié)同作用的腫瘤治療效果。
[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.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R730.5;TB383.1
，
本文編號：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.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R730.5;TB383.1
，
本文編號：2444654
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