基于核酸适配子和纳米颗粒的朊蛋白检测及活细胞标记成像研究
摘要
朊病毒病(prion diseases)是一类致死的神经系统退行性疾病,由细胞型朊蛋白(cellular prion protein, PrPC)经构象转变形成致病型朊蛋白(scrapie prion protein, PrPSc)导致PrPc功能缺陷而引起。上世纪末,疯牛病在欧洲大范围爆发,并跨越物种屏障引起了人的新型克雅氏病,从而引起全世界更多学者对朊蛋白的强烈关注。朊病毒病的诊断尤其是早期诊断对监控该疾病的流行传播具有重大意义,但基于抗体的传统检测方法因抗体制备复杂、不易保存等缺点而难以应用于早期诊断中,因此亟待建立一种简单、快速、灵敏的朊病毒病早期诊断方法。对于已经确诊为朊病毒病的患者,目前尚无有效治疗方法,一般认为首选的治疗手段是阻止PrPc转变为PrPSc,或寻求一种使PrPC结构稳定和使PrPSc结构失稳的药物。另外,研究朊蛋白在细胞内的分布和运转途径对于朊病毒病的诊断和治疗也具有一定的指导意义,而目前在这方面的研究结果都还处于争论之中。
核酸适配子是一类新兴的能与靶物特异性结合的小分子配体,具有抗体无法比拟的优势,因此它逐渐成为抗体替代物在各个领域得到广泛应用。纳米科学与生物科学、医学的相互交叉、深度融合催生了纳米生物医学的研究发展,纳米材料因其独特的物理化学特性在生物医学检测和标记成像领域展现出巨大的潜力。
本文将核酸适配体和纳米材料应用于朊蛋白的构象转变、体外检测、活细胞标记成像研究中,主要内容如下：
1.α,β,γ,δ-四(对磺苯基)卟啉与细胞型朊蛋白的体外作用研究。相关研究表明四吡咯类化合物可抑制PrPSc形成,故本文以α,β,γ,δ-四(对磺苯基)卟啉(TPPS4)作为四吡咯类化合物的代表,主要通过共振光散射光谱,结合紫外-可见光吸收光谱和荧光光谱对TPPS4与PrPC在体外的相互作用进行了表征。结果表明PrPC诱导TPPS4分子发生了J-型聚集,这种J-型聚集体能够很好地与PrPC结合,从而有效地抑制PrPC向PrPSc转变。因此,共振光散射技术可以为研究四吡咯类化合物抑制PrPC向PrPSc转变的机制提供一种新的表征方法；同时,研究结果也暗示四吡咯类化合物在朊病毒病的治疗方面具有很大潜力。
2.基于多壁碳纳米管和荧光染料之间的能量转移检测朊蛋白。根据多壁碳纳米管可作为一种很好的荧光淬灭剂设计了一种单标记的链状分子灯标,TAMRA-aptamer通过π-π堆积作用和静电吸附作用缠绕到碳纳米管侧壁,TAMRA和碳纳米管之间发生能量转移和电子转移,导致荧光淬灭。朊蛋白与aptamer结合使TAMRA远离碳纳米管侧壁,淬灭的荧光得到一定程度的恢复。结果表明,在朊蛋白浓度为4.08-81.67 nM时,恢复的荧光强度和朊蛋白浓度之间呈现很好的线性关系。与传统的抗体检测方法相比,本文所建立的方法简单、灵敏、选择性高。
3.基于二硫化碳锚定核酸适配子修饰的银纳米探针用于细胞内的朊蛋白标记成像。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,用二硫化碳的双巯基将二者牢牢地锚定在一起,制备了一种银纳米光学探针。与常见的单巯基修饰、蛋白质静电吸附相比,双巯基锚定的银纳米探针具有更好的稳定性,不易被细胞内其它巯基化合物取代,也不受pH变化的影响。实验结果表明,该探针在细胞培养中显示出良好的生物相容性、稳定性和选择性,这些优良的特性使其在未来的生物医学成像、病变组织定位等方面具有极大的应用潜力。
Prion diseases, is well known as the causative pathogenic agent of central nervous system (CNS) degenerative disorders, a group of lethal neurodegenerative diseases. In prion diseases, the endogenous form (PrPC) undergoes a conformation rearrangement and generates duplicate copies of the pathological form (PrPSc), accompanied by physiochemical and biochemical defects of prion protein (PrP). At the end of the last century, large-scale mad cow disease, crossing the species barrier, broke out in Europe and caused a new type of human Creutzfeldt-Jakob disease, which created enormous concerns from the scholars around the world. Diagnosis of prion diseases, especially the early diagnosis at the presymptomatic stage is of great significance to control the epidemic spread of the disease. However, the traditional antibody-based detection methods are cumbered for widespread use by expensive, complex preparation and difficult to save. Consequently, it is urgent to establish a simple, rapid and sensitive method for early diagnosis of prion diseases. Until recently, there is no effective treatment for the patients suffering from prion disease, and the generally recognized preferred treatment is to restrain the conformation changes from PrPC to PrPSc, or to find a therapeutic drug which can stabilize the structure of PrPc or destabilize the structure of PrPSc. In addition, it is of great significance to study the distribution and transporting ways of prion protein incellular for the diagnosis and treatment of prion diseases, while the present findings in this area are still in debate.
Aptamers, single-stranded oligonucleotides with a length of tens of nucleotides, is capable of binding with the target molecule specificly, taking the advantages that antibodies can not compare with. It has become a substitute of antibodies, and are widely used in various fields. In recent years, the cross-cutting and the deeply integration of nano-science, biological sciences and medicine give birth to the development of biomedical nanotechnology. Because of their unique physical and chemical characteristics, nanomaterials show great potential in the fields of biomedical testing and imaging.
In this manuscript, aptamers and nanoparticles were used in the conformational transition, in vitro testing and in vivo imaging of prion protein. The mainly points are as follows:
1.The interaction study of PrPC andα,β,γ,δ-tetrakis(4-sulfophenyl) porphine(TPPS4) in vitro. It has been reported that tetrapyrrole compounds can inhibit the formation of PrPSc, so we considered TPPS4 as a representation of tetrapyrrole compounds, and principally studied the interaction between Prion Protein and TPPS4 in vitro, mainly through the absorbance, fluorescence and resonance light scattering. The results showed that PrPc induced the J-aggregation of TPPS4, the J-aggregation species can bind well with PrPC, and then inhibit the formation of PrPSc, which suggests that tetrapyrrole compounds may become a potential therapeutic drug for prion diseases.
2. Detection of prion protein based on energy transfer from fluorescent dyes to multi-walled carbon nanotubes. We proposed a molecular marker beacon, with only one end labeled with a fluorophore (TAMRA) acting as the energy donor and multiwalled carbon nanotubes (MWNTs) acting as the energy acceptor. TAMRA-aptamer were adsorbed to the carbon nanotube sidewall byπ-πstacking and electrostatic interaction, then energy transfered from TAMRA to MWNTs, resulting in fluorescence quenching of fluorophore. In the presence of target-PrPc, however, the aptamer can bind with them specificly to form a duplex, leaving the sidewall of the MWCNTs, and thus, the fluorescence is turned on. The results showed that the recovery of fluorescence intensity and concentration of the prion protein showed a good linear relationship at the concentration of 4.08-81.67 nM of prion protein. Compared with the traditional antibody detection methods, the method herein is simple, sensitive and high selective.
3. Carbon disulfide (CS2) anchor-based aptamer modified silver nanoparticles (Ag NPs) probe used for intracellular protein imaging. In this article, Ag NPs-light emitting devices, and aptamers-molecular recognition element, were combinded together by CS2 to prepare a silver nano-optical probe, the dual-thiol of which can firmly anchored to the Ag NPs, while the other end can bind with aptamer. Compared with the common single thiol modification, protein adsorption, dual-thiol anchoring silver nano probe possess better stability, can not be replaced by other cellular sulfhydryl compounds, and are not easily influnced by pH change. Experimental results showed that the probe demonstrated good biocompatibility, stability and selectivity, which make it has great potential applications in the future for biomedical imaging, diseased tissue localization, and so on.
核酸适配子是一类新兴的能与靶物特异性结合的小分子配体,具有抗体无法比拟的优势,因此它逐渐成为抗体替代物在各个领域得到广泛应用。纳米科学与生物科学、医学的相互交叉、深度融合催生了纳米生物医学的研究发展,纳米材料因其独特的物理化学特性在生物医学检测和标记成像领域展现出巨大的潜力。
本文将核酸适配体和纳米材料应用于朊蛋白的构象转变、体外检测、活细胞标记成像研究中,主要内容如下：
1.α,β,γ,δ-四(对磺苯基)卟啉与细胞型朊蛋白的体外作用研究。相关研究表明四吡咯类化合物可抑制PrPSc形成,故本文以α,β,γ,δ-四(对磺苯基)卟啉(TPPS4)作为四吡咯类化合物的代表,主要通过共振光散射光谱,结合紫外-可见光吸收光谱和荧光光谱对TPPS4与PrPC在体外的相互作用进行了表征。结果表明PrPC诱导TPPS4分子发生了J-型聚集,这种J-型聚集体能够很好地与PrPC结合,从而有效地抑制PrPC向PrPSc转变。因此,共振光散射技术可以为研究四吡咯类化合物抑制PrPC向PrPSc转变的机制提供一种新的表征方法；同时,研究结果也暗示四吡咯类化合物在朊病毒病的治疗方面具有很大潜力。
2.基于多壁碳纳米管和荧光染料之间的能量转移检测朊蛋白。根据多壁碳纳米管可作为一种很好的荧光淬灭剂设计了一种单标记的链状分子灯标,TAMRA-aptamer通过π-π堆积作用和静电吸附作用缠绕到碳纳米管侧壁,TAMRA和碳纳米管之间发生能量转移和电子转移,导致荧光淬灭。朊蛋白与aptamer结合使TAMRA远离碳纳米管侧壁,淬灭的荧光得到一定程度的恢复。结果表明,在朊蛋白浓度为4.08-81.67 nM时,恢复的荧光强度和朊蛋白浓度之间呈现很好的线性关系。与传统的抗体检测方法相比,本文所建立的方法简单、灵敏、选择性高。
3.基于二硫化碳锚定核酸适配子修饰的银纳米探针用于细胞内的朊蛋白标记成像。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,用二硫化碳的双巯基将二者牢牢地锚定在一起,制备了一种银纳米光学探针。与常见的单巯基修饰、蛋白质静电吸附相比,双巯基锚定的银纳米探针具有更好的稳定性,不易被细胞内其它巯基化合物取代,也不受pH变化的影响。实验结果表明,该探针在细胞培养中显示出良好的生物相容性、稳定性和选择性,这些优良的特性使其在未来的生物医学成像、病变组织定位等方面具有极大的应用潜力。
Prion diseases, is well known as the causative pathogenic agent of central nervous system (CNS) degenerative disorders, a group of lethal neurodegenerative diseases. In prion diseases, the endogenous form (PrPC) undergoes a conformation rearrangement and generates duplicate copies of the pathological form (PrPSc), accompanied by physiochemical and biochemical defects of prion protein (PrP). At the end of the last century, large-scale mad cow disease, crossing the species barrier, broke out in Europe and caused a new type of human Creutzfeldt-Jakob disease, which created enormous concerns from the scholars around the world. Diagnosis of prion diseases, especially the early diagnosis at the presymptomatic stage is of great significance to control the epidemic spread of the disease. However, the traditional antibody-based detection methods are cumbered for widespread use by expensive, complex preparation and difficult to save. Consequently, it is urgent to establish a simple, rapid and sensitive method for early diagnosis of prion diseases. Until recently, there is no effective treatment for the patients suffering from prion disease, and the generally recognized preferred treatment is to restrain the conformation changes from PrPC to PrPSc, or to find a therapeutic drug which can stabilize the structure of PrPc or destabilize the structure of PrPSc. In addition, it is of great significance to study the distribution and transporting ways of prion protein incellular for the diagnosis and treatment of prion diseases, while the present findings in this area are still in debate.
Aptamers, single-stranded oligonucleotides with a length of tens of nucleotides, is capable of binding with the target molecule specificly, taking the advantages that antibodies can not compare with. It has become a substitute of antibodies, and are widely used in various fields. In recent years, the cross-cutting and the deeply integration of nano-science, biological sciences and medicine give birth to the development of biomedical nanotechnology. Because of their unique physical and chemical characteristics, nanomaterials show great potential in the fields of biomedical testing and imaging.
In this manuscript, aptamers and nanoparticles were used in the conformational transition, in vitro testing and in vivo imaging of prion protein. The mainly points are as follows:
1.The interaction study of PrPC andα,β,γ,δ-tetrakis(4-sulfophenyl) porphine(TPPS4) in vitro. It has been reported that tetrapyrrole compounds can inhibit the formation of PrPSc, so we considered TPPS4 as a representation of tetrapyrrole compounds, and principally studied the interaction between Prion Protein and TPPS4 in vitro, mainly through the absorbance, fluorescence and resonance light scattering. The results showed that PrPc induced the J-aggregation of TPPS4, the J-aggregation species can bind well with PrPC, and then inhibit the formation of PrPSc, which suggests that tetrapyrrole compounds may become a potential therapeutic drug for prion diseases.
2. Detection of prion protein based on energy transfer from fluorescent dyes to multi-walled carbon nanotubes. We proposed a molecular marker beacon, with only one end labeled with a fluorophore (TAMRA) acting as the energy donor and multiwalled carbon nanotubes (MWNTs) acting as the energy acceptor. TAMRA-aptamer were adsorbed to the carbon nanotube sidewall byπ-πstacking and electrostatic interaction, then energy transfered from TAMRA to MWNTs, resulting in fluorescence quenching of fluorophore. In the presence of target-PrPc, however, the aptamer can bind with them specificly to form a duplex, leaving the sidewall of the MWCNTs, and thus, the fluorescence is turned on. The results showed that the recovery of fluorescence intensity and concentration of the prion protein showed a good linear relationship at the concentration of 4.08-81.67 nM of prion protein. Compared with the traditional antibody detection methods, the method herein is simple, sensitive and high selective.
3. Carbon disulfide (CS2) anchor-based aptamer modified silver nanoparticles (Ag NPs) probe used for intracellular protein imaging. In this article, Ag NPs-light emitting devices, and aptamers-molecular recognition element, were combinded together by CS2 to prepare a silver nano-optical probe, the dual-thiol of which can firmly anchored to the Ag NPs, while the other end can bind with aptamer. Compared with the common single thiol modification, protein adsorption, dual-thiol anchoring silver nano probe possess better stability, can not be replaced by other cellular sulfhydryl compounds, and are not easily influnced by pH change. Experimental results showed that the probe demonstrated good biocompatibility, stability and selectivity, which make it has great potential applications in the future for biomedical imaging, diseased tissue localization, and so on.
引文
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