纳米材料活细胞标记示踪及其生物毒性效应评估
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摘要
纳米科学与生物科学、医学以及环境科学的相互交叉、深度融合催生了纳米生物医学和纳米生物安全研究。本文对纳米材料在活细胞内蛋白质标记成像和示踪中的应用进行了研究,同时用斑马鱼对其生物毒性效应进行了系统评估。主要研究内容如下：
1.构建了基于核酸适配子的纳米生物探针并将其成功用于朊蛋白细胞内在化途径研究。将巯基修饰的核酸适配子偶联到金纳米粒子表面,制备得到细胞型朊蛋白特异性核酸适配子修饰的金纳米粒子光学探针,并将其成功应用到细胞表面朊蛋白的光散射成像和电子透射显微成像分析。通过对核酸适配子修饰的金纳米粒子探针进入细胞的途径及其在细胞内转运命运的进一步研究表明,窖蛋白介导的内吞作用可能是其进入细胞的一个重要途径。核酸适配子修饰的金纳米粒子探针制备简单、成本低廉,可能被广泛应用于生物医学成像领域。
2.发展了一种基于核酸适配子修饰银纳米粒子的新型光学探针。本文将银纳米粒子作为发光元件,核酸适配子作为分子识别元件,构建了细胞内蛋白质的标记成像探针并应用于单颗纳米粒子光谱分析。银纳米粒子用链霉亲和素包被并用核酸适配子功能化后,在细胞培养中显示出良好的生物相容性和稳定性,可同时作为暗场光散射成像和透射电子显微成像的光学探针；不仅如此,银纳米颗粒的超灵敏单粒子散射光谱还可能被潜在的用于细胞内微环境分析。进一步研究表明,窖蛋白介导的内吞作用可能是银纳米探针标记的朊蛋白进入神经瘤母细胞的一个必要途径。核酸适配子修饰的银纳米探针可作为暗场光散射成像和透射电子显微成像的双料成像代理,且具有超灵敏的单粒子光谱,这些优良的性质使其在未来的生物医学成像和疾病探测上具有极大的应用潜质。
3.提出了一种通用而简单的基于多功能核酸适配子介导的活细胞表面蛋白质纳米标记新策略。通过设计使核酸适配子成为综合了靶标识别功能和配体连接功能为一体的双功能代理,成功地实现了活细胞表面靶蛋白的特异性标记和示踪。该策略运用分步标记的方法,先用生物素化的核酸适配子去捕获细胞表面的靶蛋白,然后再用链霉亲和素修饰的纳米探针识别靶蛋白上的生物素,从而实现对活细胞表面靶蛋白的特异性标记。我们应用该标记方法不但实现了多种纳米探针对核仁蛋白的标记及多模式成像,而且还用量子点对朊蛋白在细胞内转运和动力学过程实施了成功的监测。该标记策略操作简单,避免了传统纳米探针复杂的修饰和分离步骤。更为重要的是,我们提出的这一标记策略是一种可通用的蛋白质标记方法。
4.采用水环境暴露和显微注射相结合的方法,系统考察了纳米荧光量子点在斑马鱼体内外的分布情况和毒性效应。研究结果表明,多聚乙二醇修饰的量子点在胚胎卵膜和仔鱼体表的吸附能力弱,表面的电荷对其在卵膜上的吸附能力无明显影响；水环境中的羧基化量子点可在斑马鱼卵膜上大量吸附,也会在仔鱼的口咽腔、鳃、鳍条、排泄孔等部位聚集,并可通过仔鱼的吞咽作用进入消化道。高浓度的羧基化量子点在水环境中暴露会诱导胚胎的畸形发育,这些毒性效应可能是由金属镉的释放所致。心脏显微注射的羧基化量子点会随血液循环进入到斑马鱼的静脉系统,但很少会在内脏中残留,其主要分布于后大脑静脉、眶鼻静脉、心脏壁、腹腔壁、后主静脉、体节动脉及尾部动脉和静脉。羧基化量子点在注射后6天仍大量残存于静脉血管内,不被机体排除,显示出较高的生物吸附能力和体内残存量,具有较高的生物毒性风险。
5.以斑马鱼为模式生物,对石墨烯和多壁碳纳米管的生物毒性效应进行了比较研究。石墨烯是一种新型的碳纳米材料,优良的物理化学性质使其在未来的光热传感、电子传导等领域极具发展潜力,但到目前为止却未见其生物毒性研究报道。研究结果表明,石墨烯的生物毒性较弱,在浓度为50 mg／L才会引起明显的细胞生长抑制和轻微的斑马鱼胚胎孵化延迟效应,但不会导致胚胎内细胞凋亡的增加和严重的胚胎发育畸形。与之相比,多壁碳纳米管具有较强的生物毒性,在浓度为7.6 mg／L就能明显抑制细胞生长；在浓度为50 mg／L时,多壁碳纳米管会在斑马鱼胚胎卵膜表面大量吸附,导致胚胎内细胞凋亡数量明显增加,最终引起胚胎发育畸形。该研究结果提示,石墨烯和碳纳米管在一定条件下都表现出生物毒性效应。同时,石墨烯和多壁碳纳米管虽然具有相似的纳米形态结构,其生物毒性效应却差异较大,这可能是它们与生物体的作用方式和机制不同所致。
Nanomedicine and nanotoxicity are two important cross-disciplinary fields that were derived from the interdisciplinary and integrated from nanotechnology, life science, medicine and environmental science. In this contribution, we focus on the application of nanomaterials to intracellular protein labeling and tracking as well as its biological toxicity assessment. The mainly points are as follows:
1. Aptamer-conjugated gold nanoparticles were developed as optical probes for imaging the internalization pathways of prion protein. By conjugating thiol-modified prion aptamer to the surface of gold nanoparticles, we prepared an aptamer-conjugated nanoparticles probe (Apt-AuNPs) specific to prion protein (PrPC) and then applied the probe for the light scattering imaging and electron transmission microscopic analysis of PrPC in cells. Further investigation showed that caveolin-related endocytosis was likely a necessary pathway for the internalization of PrPC labeled with Apt-AgNPs in human bone marrow neuroblastoma cells (SK-N-SH cells). Owing to its simple preparation and low productive costs, Apt-AuNPs probe offers high promising for further biomedical imaging applications.
2. Aptamer adapted silver nanoparticles (Apt-AgNPs) were developed as a novel optical probe for simultaneous intracellular protein imaging and single nanoparticle spectral analysis, wherein AgNPs act as an illuminophore and aptamer as a biomolecule specific recognition unit, respectively. With protein conjugation and aptamer functionalization, AgNPs show satisfactory biocompatibility and stability in cell culture medium. It was found that streptavidin conjugated and aptamer-functionalized AgNPs show satisfactory biocompatibility and stability in cell culture medium, and thus not only can act as a high contrast imaging agent for both dark-field light scattering microscope and TEM imaging but also can inspire supersensitive single nanoparticle spectra for potential intercellular microenvironment analysis. Further investigations showed that caveolae-related endocytosis is likely a necessary pathway for Apt-AgNPs labeled PrPC internalization in human bone marrow neuroblastoma cells (SK-N-SH cells). The integrated capability of Apt-AgNPs to be used as light scattering and TEM imaging agents, along with their potential use for single nanoparticle spectral analysis, makes them a great promise for future biomedical imaging and disease diagnosis.
3. A simple and general strategy for specifically protein labeling with nanoparticles is proposed by employing aptamer not only as the identifier for specifically protein recognizing, but also as a linker for targeting streptavidin conjugate nanoparticles (SA-NPs). In our approach, a cell membrane protein is pre-labeled by biotin modified aptamer (Bio-Apt) added to the medium, and then the biotin group serves as a handle for targeting SA-NPs. To demonstrate the feasibility of our strategy, nucleolin, a biomarker of cancer cells, was first labeling and imaging with three kinds of nanoprobes including gold nanoparticles, silver nanoparticles and quantum dots, respectively. Subsequently, single color and double color labeling with both QDs and fluophores to prion protein (PrPC) in neuroblastoma cells were achieved, and then the intercellular distribution of the PrPC as well as their colocalization with transferrin (Tf) were investigated. We further performed time-lapse imaging of QDs bound to PrPC to addressing the dynamic characteristics analysis of different cellular transportation. This new labeling method is simple in procedure, avoiding any complicated probe modification in comparison to traditional approaches. Furthermore, this strategy is generalizable since not only the sequences of aptamers can be changeable for various proteins recognition but also different types of reporters can in principle use for individual or double signal imaging.
4. In vivo biodistribution and toxic effects of functionalized QDs in developing zebrafish was systemic investigated through the aquatic exposure and microinjection. Quantum dots are widely explored for biomedical applications, but there is very limited information regarding their in vivo biodistribution and biocompatibility, especially in aquatic animals. Our results demonstrate that multi-PEGylated QDs show weak adsorption capability both on the surface of egg membrane and larval body, and the surface charge of QDs have no effect on such adsorption. However, carboxylated quantum dots which exposure in aquatic environment, can not only adsorbed on the embryonic chorion in large numbers, but also effectively accumulated in the tissues of larvae, distributing in oropharyngeal cavity, gills, fins and anus. Furthermore, QDs can move easily into the digestive canal through the role of larval swallowing. High concentrations of carboxylated quantum dots exposure can induce abnormal embryonic development that may be caused by the release of metal cadmium. When introduced into the circulation system by heart microinjection, carboxylated quantum dots will be transported into the venous system through blood circulation of zebrafish, mainly distributing in the intravenous after brain, nasal orbital vein, heart, abdominal wall, spinal vein, as well as tail artery and vein. What is more important, a large number of carboxylated quantum dots still residue within the vein and were not cleaned out by the body at 6 days after the injection, showed a high adsorption capacity and in vivo biological residue, suggesting the high potential in biological toxicity.
5. A comparative study of nano-toxicological effect to graphene and mutli-walled carbon nanotubes (MCNTs) was achieved through model organisms exposed methods. Graphene is a new type of carbon nanomaterials that has stimulated great interest due to their superior mechanical, electrical, and thermal properties. However, no special toxic assessment of graphene, so far, has been reported as far as we know. Our results demonstrate that graphene would cause obvious cell growth inhibition and slight hatching delay of zebrafish embryo at a concentration of 50 mg/L, but can not lead to increased apoptosis in embryonic and serious fetal malformations, showing a moderate toxicity. In comparison to mild toxicological effect of graphene, MCNTs exhibits acute toxicity to organisms. MCNTs can obviously inhibit cell growth at the concentration of 7.6 mg/L, and heavy accumulate in embryonic chorion at 50 mg/L, resulting in significantly increasing of apoptosis in embryo that eventually lead to fetal malformation. These results demonstrate that both graphene and MCNTs have shown toxic effect under certain condition. It is worth noting that graphene and MCNTs, while having a similar nano-morphology, exhibit quite different toxic effects, this may be derived from their distinctive interaction mode to the organisms.
1.构建了基于核酸适配子的纳米生物探针并将其成功用于朊蛋白细胞内在化途径研究。将巯基修饰的核酸适配子偶联到金纳米粒子表面,制备得到细胞型朊蛋白特异性核酸适配子修饰的金纳米粒子光学探针,并将其成功应用到细胞表面朊蛋白的光散射成像和电子透射显微成像分析。通过对核酸适配子修饰的金纳米粒子探针进入细胞的途径及其在细胞内转运命运的进一步研究表明,窖蛋白介导的内吞作用可能是其进入细胞的一个重要途径。核酸适配子修饰的金纳米粒子探针制备简单、成本低廉,可能被广泛应用于生物医学成像领域。
2.发展了一种基于核酸适配子修饰银纳米粒子的新型光学探针。本文将银纳米粒子作为发光元件,核酸适配子作为分子识别元件,构建了细胞内蛋白质的标记成像探针并应用于单颗纳米粒子光谱分析。银纳米粒子用链霉亲和素包被并用核酸适配子功能化后,在细胞培养中显示出良好的生物相容性和稳定性,可同时作为暗场光散射成像和透射电子显微成像的光学探针；不仅如此,银纳米颗粒的超灵敏单粒子散射光谱还可能被潜在的用于细胞内微环境分析。进一步研究表明,窖蛋白介导的内吞作用可能是银纳米探针标记的朊蛋白进入神经瘤母细胞的一个必要途径。核酸适配子修饰的银纳米探针可作为暗场光散射成像和透射电子显微成像的双料成像代理,且具有超灵敏的单粒子光谱,这些优良的性质使其在未来的生物医学成像和疾病探测上具有极大的应用潜质。
3.提出了一种通用而简单的基于多功能核酸适配子介导的活细胞表面蛋白质纳米标记新策略。通过设计使核酸适配子成为综合了靶标识别功能和配体连接功能为一体的双功能代理,成功地实现了活细胞表面靶蛋白的特异性标记和示踪。该策略运用分步标记的方法,先用生物素化的核酸适配子去捕获细胞表面的靶蛋白,然后再用链霉亲和素修饰的纳米探针识别靶蛋白上的生物素,从而实现对活细胞表面靶蛋白的特异性标记。我们应用该标记方法不但实现了多种纳米探针对核仁蛋白的标记及多模式成像,而且还用量子点对朊蛋白在细胞内转运和动力学过程实施了成功的监测。该标记策略操作简单,避免了传统纳米探针复杂的修饰和分离步骤。更为重要的是,我们提出的这一标记策略是一种可通用的蛋白质标记方法。
4.采用水环境暴露和显微注射相结合的方法,系统考察了纳米荧光量子点在斑马鱼体内外的分布情况和毒性效应。研究结果表明,多聚乙二醇修饰的量子点在胚胎卵膜和仔鱼体表的吸附能力弱,表面的电荷对其在卵膜上的吸附能力无明显影响；水环境中的羧基化量子点可在斑马鱼卵膜上大量吸附,也会在仔鱼的口咽腔、鳃、鳍条、排泄孔等部位聚集,并可通过仔鱼的吞咽作用进入消化道。高浓度的羧基化量子点在水环境中暴露会诱导胚胎的畸形发育,这些毒性效应可能是由金属镉的释放所致。心脏显微注射的羧基化量子点会随血液循环进入到斑马鱼的静脉系统,但很少会在内脏中残留,其主要分布于后大脑静脉、眶鼻静脉、心脏壁、腹腔壁、后主静脉、体节动脉及尾部动脉和静脉。羧基化量子点在注射后6天仍大量残存于静脉血管内,不被机体排除,显示出较高的生物吸附能力和体内残存量,具有较高的生物毒性风险。
5.以斑马鱼为模式生物,对石墨烯和多壁碳纳米管的生物毒性效应进行了比较研究。石墨烯是一种新型的碳纳米材料,优良的物理化学性质使其在未来的光热传感、电子传导等领域极具发展潜力,但到目前为止却未见其生物毒性研究报道。研究结果表明,石墨烯的生物毒性较弱,在浓度为50 mg／L才会引起明显的细胞生长抑制和轻微的斑马鱼胚胎孵化延迟效应,但不会导致胚胎内细胞凋亡的增加和严重的胚胎发育畸形。与之相比,多壁碳纳米管具有较强的生物毒性,在浓度为7.6 mg／L就能明显抑制细胞生长；在浓度为50 mg／L时,多壁碳纳米管会在斑马鱼胚胎卵膜表面大量吸附,导致胚胎内细胞凋亡数量明显增加,最终引起胚胎发育畸形。该研究结果提示,石墨烯和碳纳米管在一定条件下都表现出生物毒性效应。同时,石墨烯和多壁碳纳米管虽然具有相似的纳米形态结构,其生物毒性效应却差异较大,这可能是它们与生物体的作用方式和机制不同所致。
Nanomedicine and nanotoxicity are two important cross-disciplinary fields that were derived from the interdisciplinary and integrated from nanotechnology, life science, medicine and environmental science. In this contribution, we focus on the application of nanomaterials to intracellular protein labeling and tracking as well as its biological toxicity assessment. The mainly points are as follows:
1. Aptamer-conjugated gold nanoparticles were developed as optical probes for imaging the internalization pathways of prion protein. By conjugating thiol-modified prion aptamer to the surface of gold nanoparticles, we prepared an aptamer-conjugated nanoparticles probe (Apt-AuNPs) specific to prion protein (PrPC) and then applied the probe for the light scattering imaging and electron transmission microscopic analysis of PrPC in cells. Further investigation showed that caveolin-related endocytosis was likely a necessary pathway for the internalization of PrPC labeled with Apt-AgNPs in human bone marrow neuroblastoma cells (SK-N-SH cells). Owing to its simple preparation and low productive costs, Apt-AuNPs probe offers high promising for further biomedical imaging applications.
2. Aptamer adapted silver nanoparticles (Apt-AgNPs) were developed as a novel optical probe for simultaneous intracellular protein imaging and single nanoparticle spectral analysis, wherein AgNPs act as an illuminophore and aptamer as a biomolecule specific recognition unit, respectively. With protein conjugation and aptamer functionalization, AgNPs show satisfactory biocompatibility and stability in cell culture medium. It was found that streptavidin conjugated and aptamer-functionalized AgNPs show satisfactory biocompatibility and stability in cell culture medium, and thus not only can act as a high contrast imaging agent for both dark-field light scattering microscope and TEM imaging but also can inspire supersensitive single nanoparticle spectra for potential intercellular microenvironment analysis. Further investigations showed that caveolae-related endocytosis is likely a necessary pathway for Apt-AgNPs labeled PrPC internalization in human bone marrow neuroblastoma cells (SK-N-SH cells). The integrated capability of Apt-AgNPs to be used as light scattering and TEM imaging agents, along with their potential use for single nanoparticle spectral analysis, makes them a great promise for future biomedical imaging and disease diagnosis.
3. A simple and general strategy for specifically protein labeling with nanoparticles is proposed by employing aptamer not only as the identifier for specifically protein recognizing, but also as a linker for targeting streptavidin conjugate nanoparticles (SA-NPs). In our approach, a cell membrane protein is pre-labeled by biotin modified aptamer (Bio-Apt) added to the medium, and then the biotin group serves as a handle for targeting SA-NPs. To demonstrate the feasibility of our strategy, nucleolin, a biomarker of cancer cells, was first labeling and imaging with three kinds of nanoprobes including gold nanoparticles, silver nanoparticles and quantum dots, respectively. Subsequently, single color and double color labeling with both QDs and fluophores to prion protein (PrPC) in neuroblastoma cells were achieved, and then the intercellular distribution of the PrPC as well as their colocalization with transferrin (Tf) were investigated. We further performed time-lapse imaging of QDs bound to PrPC to addressing the dynamic characteristics analysis of different cellular transportation. This new labeling method is simple in procedure, avoiding any complicated probe modification in comparison to traditional approaches. Furthermore, this strategy is generalizable since not only the sequences of aptamers can be changeable for various proteins recognition but also different types of reporters can in principle use for individual or double signal imaging.
4. In vivo biodistribution and toxic effects of functionalized QDs in developing zebrafish was systemic investigated through the aquatic exposure and microinjection. Quantum dots are widely explored for biomedical applications, but there is very limited information regarding their in vivo biodistribution and biocompatibility, especially in aquatic animals. Our results demonstrate that multi-PEGylated QDs show weak adsorption capability both on the surface of egg membrane and larval body, and the surface charge of QDs have no effect on such adsorption. However, carboxylated quantum dots which exposure in aquatic environment, can not only adsorbed on the embryonic chorion in large numbers, but also effectively accumulated in the tissues of larvae, distributing in oropharyngeal cavity, gills, fins and anus. Furthermore, QDs can move easily into the digestive canal through the role of larval swallowing. High concentrations of carboxylated quantum dots exposure can induce abnormal embryonic development that may be caused by the release of metal cadmium. When introduced into the circulation system by heart microinjection, carboxylated quantum dots will be transported into the venous system through blood circulation of zebrafish, mainly distributing in the intravenous after brain, nasal orbital vein, heart, abdominal wall, spinal vein, as well as tail artery and vein. What is more important, a large number of carboxylated quantum dots still residue within the vein and were not cleaned out by the body at 6 days after the injection, showed a high adsorption capacity and in vivo biological residue, suggesting the high potential in biological toxicity.
5. A comparative study of nano-toxicological effect to graphene and mutli-walled carbon nanotubes (MCNTs) was achieved through model organisms exposed methods. Graphene is a new type of carbon nanomaterials that has stimulated great interest due to their superior mechanical, electrical, and thermal properties. However, no special toxic assessment of graphene, so far, has been reported as far as we know. Our results demonstrate that graphene would cause obvious cell growth inhibition and slight hatching delay of zebrafish embryo at a concentration of 50 mg/L, but can not lead to increased apoptosis in embryonic and serious fetal malformations, showing a moderate toxicity. In comparison to mild toxicological effect of graphene, MCNTs exhibits acute toxicity to organisms. MCNTs can obviously inhibit cell growth at the concentration of 7.6 mg/L, and heavy accumulate in embryonic chorion at 50 mg/L, resulting in significantly increasing of apoptosis in embryo that eventually lead to fetal malformation. These results demonstrate that both graphene and MCNTs have shown toxic effect under certain condition. It is worth noting that graphene and MCNTs, while having a similar nano-morphology, exhibit quite different toxic effects, this may be derived from their distinctive interaction mode to the organisms.
引文
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