基于上转换纳米晶FRET的生物检测和PDT应用研究
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摘要
基于荧光共振能量传递(FRET)的生物均相检测简单、灵敏而深受关注。它常用有机染料和量子点(QDs)作为荧光标记。这些传统下转换材料在紫外光或蓝光的激发下,不可避免激发生物样品产生背景光而降低了检测灵敏度。在光动力治疗(PDT)领域,用紫外光或蓝光激发光敏剂,穿透深度浅,PDT效果差。上转换纳米晶(UCNPs)是解决上述难题一个好的选择。它是用低能量的近红外光激发产生高能量的上转换荧光,因此有较低的背景荧光和弱的光损伤,同时生物组织穿透深度大。UCNPs在基于FRET的均相检测和光动力治疗方面有巨大潜力。本论文开展了初步地工作,结果如下:
(1)为了解决上转换纳米晶(UCNPs)生物功能化难的问题,水热和共沉淀相结合制备了NaYF4:Yb3+, Er3+ UCNPs,并包覆二氧化硅壳层。SEM表征包覆前后分别为25 nm和250 nm的单分散粒子。在980nm激光照射下, UCNPs的PBS溶液呈明亮的绿光。荧光光谱和寿命均表明二氧化硅壳层对其发光性质影响很小。圆二色谱表征UCNPs偶联抗体后,抗体二级结构几乎不变。荧光免疫识别的结果进一步验证了UCNPs偶联抗体具有生物的特异性。
(2)相转移得到了小粒径、表面带有氨基基团的水溶性UCNPs,其亲合素化后和生物素化的藻红蛋白构成FRET体系。以生物素检测的实验为例说明这种设计可用于生物分子的定量分析。
(3)在UCNPs为供体的FRET均相检测体系中,弱的供体光强度使FRET信号难于检测,同时生物自发荧光也会产生干扰。为了解决这个问题, 800 nm处有强近红外光的NaYF4:Yb3+,Tm3+ UCNPs作为供体,在784 nm处有表面等离子共振吸收带的金纳米粒子(GNPs)作为受体构建了新型的FRET体系。当体系中加入单纯human IgG,竞争性地争夺与goat antihuman IgG结合位点,破坏FRET。这种荧光信号的变化可用于human IgG的检测。
(4)在基于FRET均相检测中,如果用QDs作为受体,其较大消光系数、宽吸收光谱的特点会增大F?rster半径,提高能量传递的效率。然而宽的吸收光谱同时也引起QDs受体的直接激发。长寿命的镧系荧光标记物作供体的时间分辨的技术虽然可以解决这个问题,但实验本身过于复杂,仪器昂贵。本文用UCNPs作为供体、QDs作受体,构建了一个新型的FRET均相检测体系。由于受体QDs不吸收UCNPs供体的近红外激发光,信号的获得不再需要时间分辨技术。
(5)尽管基于FRET的QDs标记适配子荧光探针是当前研究的热点,但光激活下QDs产生的活性氧会破坏适配子。本实验利用光稳定性更强UCNPs替代QDs设计了新型的适配子荧光探针。硝基四唑氮蓝(NBT)实验表明在光激发下,UCNPs几乎不产生活性氧。一个模式的ATP检测验证了这种设计的可行性。
(6)由于近红外光有强的生物组织穿透性, UCNPs经过二氧化硅包覆掺杂光敏剂后,可用于深层组织的PDT。然而均一薄层二氧化硅的包覆技术难于控制。我们通过简单共价偶联的方式构建了UCNPs藻红蛋白复合体(UCNPs_RPE)作为光敏药物。在红外光的作用下,UCNPs通过FRET敏化藻红蛋白产生单态氧。UCNPs_RPE对H22肝癌细胞明显的抑制效果表明它可能为PDT提供一种新的途径。
Fluorescence resonance energy transfer (FRET)-based analytical methods have gained considerable attention as powerful tools for biological detections because of their simplicity and high sensitivity. There are a number of conventional ?uorescent biolabels used including organic dyes and quantum dots in this system. These conventional down-conversion ?uorescent materials require ultraviolet or blue excitation wavelengths. Many biological samples show auto?uorescence under such conditions, which decreases the sensitivity of detection. For photodynamic therapy (PDT),the visible light needed to activate most photosensitizers cannot pass through a thick tissue, which resulted in the PDT effect is bad. Upconversion nanoparticles (UCNPs) appear as a breakthrough to resolve the problem. It could convert lower-energy near-infrared (NIR) light to higher-energy light through excitation, which can penetrate deep tissues without causing sample damage and avoid auto?uorescence from biological samples. Thus, upconversion materials show potential to be used for FRET based immunoassay and PDT. Around this point, the main results from our experiments are outlined as followings:
(1) In order to achieve biological functions of UCNPs, NaYF4:Yb3+, Er3+ upconversion nanoparticles (UCNPs) were synthesized via the hydrothermal assisted homogeneous precipitation method and then coated with silica. The SEM image demonstrated that the samples were uniform in size distribution with ca. 25 nm, before and ca. 250 nm after silica coating, respectively. The photoluminescence spectra and lifetime measurement showed that the silica shell had hardly effect on the properties of UCNPs fluorescence. The naked eye-visible green fluorescence pattern was acquired from the sample in the PBS buffer excited by 980 nm laser. The UCNPs were linked to the antibodies. The circular dichroism (CD) spectra of pure antibody and bioconjugates were very similar to each other. Finally, the immunofluorescence assay indicated that the UCNPs-antibody bioconjugates had excellent species-specific detection ability.
(2) We have developed a feasible surface ligand exchange method for getting water-soluble, small in size and amido-functionalized UCNPs. The construct based on FRET between avidin-conjugated NaYF4: Er3+, Yb3+ UCNPs as donors and biotinylated R-Phycoerythrin as acceptors were employed. A sample model of biotin detection was applied. Such approach enabled the detection and quanti?cation of the biomolecular.
(3) Extensive efforts have been invested in FRET based homogeneous bioaffinity assays utilizing UCNPs as a donor. However, there are some fundamental problems related to fluorescence measurements. Self-fluorescence from biological matrixes and other sample materials and relative weak upconversion emission among the ultraviolet-visible wavelengths region could cause ambiguous or unmeasured emission. To address this problem, we have utilized NaYF4: Yb3+, Tm3+ UCNPs as an energy donor, which can emit intense (NIR) emission around 800 nm ranges, and gold nanoparticales (GNPs) as an energy acceptor, which has a surface plasmon absorption maximum at 784 nm. UCNPs and GNPs were conjugated with goat antihuman IgG and human IgG, respectively. When free human IgG is added, it competitively binds to UCNPs-goat antihuman IgG, and inhibits the FRET process. As a result, the fluorescence change effect was correlated with the concentration of human IgG.
(4) Nowadays, there is a growing interest in the use of QDs in design of LRET-based aptamer luminescent reporters. However, there are concerns regarding the potential photosensitized breakage and damage of aptamer molecules due to the production of reactive oxygen intermediates (ROI) by photoactivated QDs. In this work, we have developed a novel aptamer-based alternative to QDs. Nitroblue tetrazolium (NBT) assay has ?cormned that generation of ROI by photoactivated UCNPs could be completely neglected. The feasibility of this principle in a model ATP assay has been demonstrated.
(5) FRET immunoassays with QDs as energy acceptors are of particular interest because the extremely high-extinction coefficients of the QDs over a broad absorption spectrum enlarged the scope of the recognition events through the increase of the F?rster radius. Large absorptions of the QDs first appeared as a drawback, providing undesired direct excitation of the acceptor. The problem has been recently solved by demonstrating the feasibility of time resolved measurement of sensitized QDs emission in combination with long-lifetime fluorescent lanthanide labels as donors. However, these systems typically require complex experimental setup and expensive pulsed lasers. We have fabricated a FRET-based prototype of molecular recognition switch, utilizing UCNPs as a donor and QDs as an acceptor. As QDs have no absorbance at near-infrared wavelength, it enabled to eliminate problem associated with excitation light in measurement without need for temporal resolution.
(6) Because NIR light can penetrate thick tissue, UCNPs which are then coated with a thin layer of silica incorporating photosensitizer were used for PDT. However, it is difficult to make uniform and thin silica coatings on UCNPs. We construct UCNPs_RPE (UCNPs_R-Phycoerythrin) bioconjugates through a simple covalent coupling. After exposed to NIR light, the UCNPs convert NIR light to visible light which activates the RPE to produce reactive singlet oxygen to kill cancer cells. The inhibition effects on the hepatocarcinoma H22 cells show that the design will provide a new way to PDT.
(1)为了解决上转换纳米晶(UCNPs)生物功能化难的问题,水热和共沉淀相结合制备了NaYF4:Yb3+, Er3+ UCNPs,并包覆二氧化硅壳层。SEM表征包覆前后分别为25 nm和250 nm的单分散粒子。在980nm激光照射下, UCNPs的PBS溶液呈明亮的绿光。荧光光谱和寿命均表明二氧化硅壳层对其发光性质影响很小。圆二色谱表征UCNPs偶联抗体后,抗体二级结构几乎不变。荧光免疫识别的结果进一步验证了UCNPs偶联抗体具有生物的特异性。
(2)相转移得到了小粒径、表面带有氨基基团的水溶性UCNPs,其亲合素化后和生物素化的藻红蛋白构成FRET体系。以生物素检测的实验为例说明这种设计可用于生物分子的定量分析。
(3)在UCNPs为供体的FRET均相检测体系中,弱的供体光强度使FRET信号难于检测,同时生物自发荧光也会产生干扰。为了解决这个问题, 800 nm处有强近红外光的NaYF4:Yb3+,Tm3+ UCNPs作为供体,在784 nm处有表面等离子共振吸收带的金纳米粒子(GNPs)作为受体构建了新型的FRET体系。当体系中加入单纯human IgG,竞争性地争夺与goat antihuman IgG结合位点,破坏FRET。这种荧光信号的变化可用于human IgG的检测。
(4)在基于FRET均相检测中,如果用QDs作为受体,其较大消光系数、宽吸收光谱的特点会增大F?rster半径,提高能量传递的效率。然而宽的吸收光谱同时也引起QDs受体的直接激发。长寿命的镧系荧光标记物作供体的时间分辨的技术虽然可以解决这个问题,但实验本身过于复杂,仪器昂贵。本文用UCNPs作为供体、QDs作受体,构建了一个新型的FRET均相检测体系。由于受体QDs不吸收UCNPs供体的近红外激发光,信号的获得不再需要时间分辨技术。
(5)尽管基于FRET的QDs标记适配子荧光探针是当前研究的热点,但光激活下QDs产生的活性氧会破坏适配子。本实验利用光稳定性更强UCNPs替代QDs设计了新型的适配子荧光探针。硝基四唑氮蓝(NBT)实验表明在光激发下,UCNPs几乎不产生活性氧。一个模式的ATP检测验证了这种设计的可行性。
(6)由于近红外光有强的生物组织穿透性, UCNPs经过二氧化硅包覆掺杂光敏剂后,可用于深层组织的PDT。然而均一薄层二氧化硅的包覆技术难于控制。我们通过简单共价偶联的方式构建了UCNPs藻红蛋白复合体(UCNPs_RPE)作为光敏药物。在红外光的作用下,UCNPs通过FRET敏化藻红蛋白产生单态氧。UCNPs_RPE对H22肝癌细胞明显的抑制效果表明它可能为PDT提供一种新的途径。
Fluorescence resonance energy transfer (FRET)-based analytical methods have gained considerable attention as powerful tools for biological detections because of their simplicity and high sensitivity. There are a number of conventional ?uorescent biolabels used including organic dyes and quantum dots in this system. These conventional down-conversion ?uorescent materials require ultraviolet or blue excitation wavelengths. Many biological samples show auto?uorescence under such conditions, which decreases the sensitivity of detection. For photodynamic therapy (PDT),the visible light needed to activate most photosensitizers cannot pass through a thick tissue, which resulted in the PDT effect is bad. Upconversion nanoparticles (UCNPs) appear as a breakthrough to resolve the problem. It could convert lower-energy near-infrared (NIR) light to higher-energy light through excitation, which can penetrate deep tissues without causing sample damage and avoid auto?uorescence from biological samples. Thus, upconversion materials show potential to be used for FRET based immunoassay and PDT. Around this point, the main results from our experiments are outlined as followings:
(1) In order to achieve biological functions of UCNPs, NaYF4:Yb3+, Er3+ upconversion nanoparticles (UCNPs) were synthesized via the hydrothermal assisted homogeneous precipitation method and then coated with silica. The SEM image demonstrated that the samples were uniform in size distribution with ca. 25 nm, before and ca. 250 nm after silica coating, respectively. The photoluminescence spectra and lifetime measurement showed that the silica shell had hardly effect on the properties of UCNPs fluorescence. The naked eye-visible green fluorescence pattern was acquired from the sample in the PBS buffer excited by 980 nm laser. The UCNPs were linked to the antibodies. The circular dichroism (CD) spectra of pure antibody and bioconjugates were very similar to each other. Finally, the immunofluorescence assay indicated that the UCNPs-antibody bioconjugates had excellent species-specific detection ability.
(2) We have developed a feasible surface ligand exchange method for getting water-soluble, small in size and amido-functionalized UCNPs. The construct based on FRET between avidin-conjugated NaYF4: Er3+, Yb3+ UCNPs as donors and biotinylated R-Phycoerythrin as acceptors were employed. A sample model of biotin detection was applied. Such approach enabled the detection and quanti?cation of the biomolecular.
(3) Extensive efforts have been invested in FRET based homogeneous bioaffinity assays utilizing UCNPs as a donor. However, there are some fundamental problems related to fluorescence measurements. Self-fluorescence from biological matrixes and other sample materials and relative weak upconversion emission among the ultraviolet-visible wavelengths region could cause ambiguous or unmeasured emission. To address this problem, we have utilized NaYF4: Yb3+, Tm3+ UCNPs as an energy donor, which can emit intense (NIR) emission around 800 nm ranges, and gold nanoparticales (GNPs) as an energy acceptor, which has a surface plasmon absorption maximum at 784 nm. UCNPs and GNPs were conjugated with goat antihuman IgG and human IgG, respectively. When free human IgG is added, it competitively binds to UCNPs-goat antihuman IgG, and inhibits the FRET process. As a result, the fluorescence change effect was correlated with the concentration of human IgG.
(4) Nowadays, there is a growing interest in the use of QDs in design of LRET-based aptamer luminescent reporters. However, there are concerns regarding the potential photosensitized breakage and damage of aptamer molecules due to the production of reactive oxygen intermediates (ROI) by photoactivated QDs. In this work, we have developed a novel aptamer-based alternative to QDs. Nitroblue tetrazolium (NBT) assay has ?cormned that generation of ROI by photoactivated UCNPs could be completely neglected. The feasibility of this principle in a model ATP assay has been demonstrated.
(5) FRET immunoassays with QDs as energy acceptors are of particular interest because the extremely high-extinction coefficients of the QDs over a broad absorption spectrum enlarged the scope of the recognition events through the increase of the F?rster radius. Large absorptions of the QDs first appeared as a drawback, providing undesired direct excitation of the acceptor. The problem has been recently solved by demonstrating the feasibility of time resolved measurement of sensitized QDs emission in combination with long-lifetime fluorescent lanthanide labels as donors. However, these systems typically require complex experimental setup and expensive pulsed lasers. We have fabricated a FRET-based prototype of molecular recognition switch, utilizing UCNPs as a donor and QDs as an acceptor. As QDs have no absorbance at near-infrared wavelength, it enabled to eliminate problem associated with excitation light in measurement without need for temporal resolution.
(6) Because NIR light can penetrate thick tissue, UCNPs which are then coated with a thin layer of silica incorporating photosensitizer were used for PDT. However, it is difficult to make uniform and thin silica coatings on UCNPs. We construct UCNPs_RPE (UCNPs_R-Phycoerythrin) bioconjugates through a simple covalent coupling. After exposed to NIR light, the UCNPs convert NIR light to visible light which activates the RPE to produce reactive singlet oxygen to kill cancer cells. The inhibition effects on the hepatocarcinoma H22 cells show that the design will provide a new way to PDT.
引文
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