金纳米与磁纳米颗粒及其复合物的生物传感和细胞成像研究
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摘要
贵金属纳米颗粒具有独特的表面等离子体共振(surface plasmon resonance, SPR)吸收和散射性质,已被广泛用于生物传感、细胞成像及癌症治疗等生物化学领域。而磁纳米颗粒(MNPs),尤其是超顺磁性四氧化三铁(Fe304)纳米颗粒,也在磁分离、磁驰豫开关、磁治疗以及核磁共振成像(MRI)等生物医学领域引起了人们广泛关注。近年来,复合纳米材料,特别是核壳结构的纳米材料,由于其能克服单一材料存在的稳定性差、修饰较难、功能单一等缺陷,还能复合各种材料的性能,因而具有独特的优良性质。其中,金纳米包覆磁性纳米复合颗粒(Fe3O4@Au)合成简单、易修饰,且具有SPR和磁性双重性质,体现了巨大的应用潜力,已经逐渐成为人们研究的焦点。然而,这些纳米材料的应用仍存在一些问题,例如生物分子如何有效调控金属纳米颗粒SPR性质,使其能更好的应用于生物传感以及疾病诊断和治疗?纳米材料在细胞膜表面是否具有防御病毒功能?多功能纳米材料已有很多报道,但很少能集靶向、多模式成像及多治疗手段于一身。基于此,针对上述存在的问题,本文以金纳米颗粒(AuNPs)、MNPs、以及Fe3O4@Au复合纳米颗粒为代表,拓宽了其在生物传感的应用,分析了生物分子如何有效调控金属纳米颗粒等离子共振性质,以进一步用于癌细胞成像与治疗,并考察了纳米材料修饰的细胞膜是否具有防御病毒功能。具体的研究内容包括以下两部分：
第一部分：基于AuNPs与MNPs在生物传感中的应用。利用AuNPs的SPR吸收性质,以正电AuNPs为探针实现了可视化检测三磷酸腺苷(ATP)与碱性磷酸酶(ALP)；将核酸适配体aptamer)的高选择性与MNPs磁性分离的性质结合,利用银纳米颗粒(AgNPs)的SPR散射性质,建立了高灵敏、高选择性地测定溶菌酶(lysozyme)的方法。考察了生物分子如何有效调控贵金属纳米颗粒SPR性质。具体工作如下：
1.ATP诱导正电AuNPs聚集的光学性质研究及定量检测ATP。实验发现,通过调节ATP浓度,可以有效调控AuNPs在可见区的SPR吸收性质。提出了ATP与AuNPs的作用主要通过两种方式：首先是ATP的磷酸根与AuNPs表面阳离子表面活性剂之间的静电作用,其次是金原子与ATP含N碱基之问的配位作用。基于AuNPs的SPR吸收用于定量检测ATP,方法简单、成本较低、耗时较短、选择性好,检测限达到0.82μM。进一步实验发现,ATP的类似物包括GTP, UTP, CTP, ADP,AMP等,诱导AuNPs聚集程度各不相同,由此可建立了一种简单的可视化分析方法区分ATP类似物。
2.ALP经过脱磷酸化反应使ATP转化为腺苷,建立了一种基于AuNPs的免标记可视化方法检测ALP。该方法的检测范围可以通过加入金属离子动态调节,加入Ca2+或Pb2+可以使其线性范围从100-600unit/L分别调节至5.0-100unit/L及0.2-20unit/L,灵敏度得到极大提高。该方法具有高选择性、高灵敏度、检测范围动态可调的优点,用于检测人血清样品中ALP含量,与临床结果一致。
3. Aptamer偶联MNPs用于lysozyme的富集与高灵敏分析检测。建立了一种基于MNPs与aptamer作为高选择性的分离富集载体,AgNPs作为散射信号探针的方法用于检测lysozyme。首先利用MNPs与aptamer偶联复合物特异性分离并富集lysozyme,再根据其正电荷性质,可与柠檬酸根包被的AgNPs通过静电作用结合,磁性分离上清液中AgNPs强烈的表面等离子共振散射光降低,可用于定量分析lysozyme。磁性分离下层吸附的AgNPs具有强烈的暗场散射光,可用暗场敞射成像对lysozyme进行半定量分析。方法结合了aptamer的高选择性以及lysozyme带正电荷的两个性质,为测定lysozyme设下双重开关,能提高方法的选择性及测定结果的准确性。以具有强散射信号的AgNPs作为信号探针,可以提高方法灵敏度,检测限可低至0.1nM。该方法设计具有普遍适用性,对于复杂样品的测定具有重要意义。
第二部分：MNPs与Fe3O4@Au复合纳米颗粒在细胞成像中的应用。首先,以MNPs为例,考察了在细胞膜表而构建“铁笼子”是否具有防御病毒入侵的功能,拓宽了磁纳米材料在细胞成像及生物医学方而的应用。其次,我们结合了Au与Fe3O4各自优越的性能,制备成复合纳米颗粒,修饰靶向配体,构建了Fe3O4@Au多功能纳米材料用于癌细胞的靶向多模式成像与治疗。具体工作如下：
1.细胞膜表面构建“铁笼子”用于抗病毒入侵。本文使用人喉癌上皮细胞(HEp-2),探讨了细胞膜外形成网状“铁笼子”是否能抑制呼吸道合胞病毒(RSV)的感染。MNPs可通过链霉亲和素与生物素的特异性反应吸附到细胞膜表面,利用颗粒表面修饰DNA的多价效应,通过杂交形成网状“铁笼子”,期望达到抑制病毒入侵的效果。实验采用扫描电镜(SEM)证实了“铁笼子”在细胞膜表面形成。其具有良好的生物相容性,能在一定程度上防御病毒侵染细胞。当病毒侵染MOI值为2时,有“铁笼子”保护的细胞,其细胞存活率能从24.1士4.4%提高到49.0±10.0%。利用免疫荧光显微技术,表明“铁笼子”抑制病毒入侵可能通过以下两种方式：其空间位阻效应阻碍了病毒与细胞膜的结合；降低细胞膜柔韧性,抑制病毒出胞以及在细胞间的扩散。本文利用纳米材料在一定程度上实现抗病毒入侵,为开发新的抗病毒药物以及其它防治病毒性疾病的新方法研究提供了思路。
2.多功能Fe3O4@Au核壳纳米花靶向癌细胞双模式成像与治疗。发展能结合诊断与治疗于一身的多功能纳米材料在分子医学领域有极其重要的意义。本文将五个独特的功能有机地整合到了一个粒径为70nm的Fe3O4@Au纳米花上。Fe304核可作为MRI显影剂；表面包被金壳,使其具有近红外吸收,产生光热效应使细胞温度升高,可用于光热治疗。高温能促进负载的抗癌药物盐酸阿霉素(Dox)快速释放,产生红色荧光,可通过共聚焦荧光显微镜监测其释放过程。颗粒表面偶联aptamer可提高药物的靶向释放。该Fe3O4@Au多功能纳米材料结合了荧光成像与MRI双模式成像方式,可提高癌细胞诊断准确性,并有利于监测药物释放。当纳米材料负载0.8μM Dox时达到的治疗效果,可与单独使用2.0μM Dox时相当。因此,将化疗与光热治疗结合使用,可以减少药物用量,降低非特异性的毒副作用。总之,该多功能纳米材料同时具有靶向、双模式成像与双治疗手段结合的功能,对生物医学领域,尤其是癌症治疗具有潜在的意义。
总之,本论文具有以下三个创新点：(一)利用生物分子实现了对金属纳米颗粒SPR性质的有效调节。(二)构建了与传统的小分子设计不同的病毒防御系统,以磁纳米颗粒在细胞膜表面形成“铁笼子”抗病毒侵染。(三)制备了同时具有靶向、双成像模式及双治疗手段五个功能的多功能纳米材料。该研究论文拓宽了金属纳米颗粒在化学与生物传感方面的应用,对于将金属纳米颗粒进一步应用于细胞成像及光热治疗领域提供了一定依据,在癌细胞诊断与治疗方面具有一定的临床价值。
Nobel metal nanoparticles, which possess unique surface plasmon resonance (SPR) absorption and scattering properties, have been widely used in biosensing, cell imaging, cancer cell therapy and other biochemical fields. Magnetic nanoparticles, especially superparamagnetic Fe3O4nanoparticles, have received much consideration because of their wide applications in biomedical fields such as magnetic separation, magnetic relaxation switches, magnetic therapy and magnetic resonance imaging (MRI). Recently, nanocomposites, especially core/shell nanoparticles, have been reported to exhibit excellent properties, since they can avoide the limitations of single nanoparticle and have synergistic effects. Among these nanocomposites, gold-coated Fe3O4(Fe3O44@Au) nanoparticles have attracted much attention owing to the advantages such as ease of synthesis and surface modification, unique SPR properties and magnetic properties. However, there are still some problems about the application of nanoparticles. For instance, how can the biomolecules tune the SPR properties of metal nanoparticles when using for cell imaging and cancer therapy? Are the nanoparticles able to protect the host against virus infection? Numbers of multifunctional nanoparticles have been reported, but very few of them offer several functions such as targeting, dual imaging and dual therapy on a single platform. Thus, in this paper, gold nanoparticles (AuNPs), MNPs and Fe3O4@Au nanocomposites were used for further application to solve the above problems. The main contents of this thesis include the following two parts:
Part1. Applications of AuNPs and MNPs in biosensing. Firstly, a colorimetric detection assay based on the SPR absorption of positive-charged gold nanoparticles was established for adenosine triphosphate (ATP) and alkaline phosphatase (ALP), respectively. Secondly, a magnetic nanoparticle-based aptasensor was used for enrichment and highly sensitive determination of lysozyme. At last, we investigated how the biomolecules tune the SPR properties of metal nanoparticles. The details are as follows:
1. Optical investigations on ATP-induced aggregation of positive-charged AuNPs and further application for ATP determination. It was found that the SPR absorption of AuNPs over a visible region can be tunable by ATP. Mechanism investigations showed that the aggregation of the AuNPs is likely induced by two interaction modes. One is the electrostatic interaction between the phosphate anions associated with the ATP and AuNPs owing to the cationic surfactant on the surfaces of AuNPs, and the other is the interaction between gold atom and nitrogen-containing bases. With the changes of SPR absorption of AuNPs, a new method for the determination of ATP has been developed with the detection limit of0.82μM. The proposed method is simple, rapid, and highly selective. Further investigations showed that other analogs of ATP, such as GTP, UTP, CTP, A DP, AMP and so on, can be visually distinguished by AuNPs based on the different affinity with AuNPs.
2. A simple and label-free colorimetric assay was developed for detecting ALP. ATP induces the aggregation of cetyltrimethylammonium bromide (CTAB)-capped AuNPs and ALP stimulates the disaggregation of AuNPs by converting ATP into adenosine through an enzymatic dephosphorylation reaction. Hence, the presence of ALP can be visually observed (gray-to-red color change) and monitored by the shift of the SPR absorption band of AuNPs. Furthermore, the dynamic range of the method can be varied by addition of different metal ions (e.g.100-600unit/L to5.0-100unit/L and0.2-20unit/L in the presence of Ca2+and Pb2+, respectively). The feasibility of this sensitive and specific assay with a tunable dynamic range was demonstrated to be consistent even in human serum samples.
3. Magnetic nanoparticle-based aptasensor for enrichment and highly sensitive determination of lysozyme. In this report, lysozyme was firstly enriched and separated by aptamer conjugated MNPs, and then silver nanoparticles (AgNPs) with strong light scattering signals, were absorbed by positive charged lysozyme through electrostatic interaction. The light scattering signal of AgNPs in the supernatant after magnetic separation was gradually reduced with the increasing concentration of lysozyme. In addition, after magnetic separation, since the lysozyme on the MNPs can enrich numbers of AgNPs, which showed strong dark-field light scattering, lysozyme can also be semi-quantified by dark-field light scattering images. The proposed method took advantage of both the high selectivity of aptamer and the positive charge of lysozyme; hence the selectivity and accuracy for lysozyme determination can be greatly improved, with the detection limit of0.1nM. This design is universal, and it has the potential to be used in analysing complex samples.
Part2. Applications of MNPs and Fe3O4@Au in cell imaging. At first, we investigated whether an "iron cage" formed by DNA crosslinking on cell membranes can be used for inhibition of viral fusion and entry. Then by making use of the unique properties of Au and Fe3O4, we prepared a Fe3O4@Au nanorose with five different functions, which can be used for targeted dual molecular imaging (MRI/optical imaging) and dual therapy (photothermal/chemotherapy). The details are as follows:
1. Inhibition viral entry and spread by crosslinking an "iron cage" on cell membranes. In this report, an "iron cage" was formed on the cell membrane of Human epidermoid cancer cell (HEp-2cell) to investigate whether it can inhibit respiratory syncytial virus (RSV) infection. MNPs modified with DNA probes wereattached on the cell membranes through the strong affinity between streptavidin and biotin, and then an "iron cage" was formed through the hybridization of DNA probes. Scanning electron microscope (SEM) was used to demonstrate the formation of "iron cage" on cell membrane. The "iron cage" was nontoxic to the cells under the conditions studied. If cells were infected by RSV at multiplicity of infection (MOI) of2, the cell viability can be improved from24.1±4.4%to49.0±10.0%once protected by "iron cage". The results from immunofluorescence imaging technique indicated that RSV infection may be inhibited by "iron cage" through two ways. One is by blocking the attachment of the virus to the cells as a result of the steric effect; the other is by altering mechanical properties of membrane lipid bilayers to less fusogenic, so that the cell-to-cell viral spread is inhibited. This research implicated the possibility of designing nanoparticles for alternative antiviral therapy and it may also provide some valuable information for developing antiviral drugs.
2. Gold-coated Fe3O4nanoroses with five unique functions for cancer cell targeting, imaging and therapy. The development of nanomaterials that combine diagnostic and therapeutic functions within a single nanoplatform is extremely important for molecular medicine. Here, five different functions were synergistically integrated into a single platform by a Fe3O4@Au nanorose of about70nm in diameter. The inner Fe3O4core functions as an MRI agent, while the photothermal effect is achieved through near-infrared absorption by the gold shell, causing a rapid rise in temperature and also resulting in a facilitated release of the anticancer drug doxorubicin (Dox) carried by the nanoroses. Dox release is monitored by its fluorescent under confocal fluorescence microscope. Aptamers immobilized on the surfaces of the nanoroses enable efficient and selective drug delivery, imaging and photothermal effect with high specificity. The combination of dual-modality MRI and optical imaging has the potential to improve the specificity of cancer cell diagnosis and facilitate therapeutic drug monitoring. The results showed that0.8μM of Dox released from nanorose-sgc8-Dox was sufficient to reach the same killing efficiency with2.0μM of free Dox. Hence, it minimized the nonspecific toxicity and side effects based on a lower dosage of chemotherapy drugs when combined with photothermal therapy. We demonstrate the Fe3O4@Au nanoroses with five distinct functions, which integrate aptamer-based targeting, MRI, optical imaging, photothermal therapy and chemotherapy into one single probe. It is expected that this versatile theranostic system will have wide biomedical applications and may be particularly useful for cancer therapy.
In summary, this research offers three attractive features. Firstly, the SPR properties of metal nanoparticles over a visible region can be tunable by biomolecules. Secondly, a new strategy for inhibition viral entry and spread by crosslinking an "iron cage" on cell membranes was proposed, which is different to the traditional small molecules. At last, a multifunctional nanomaterial with five distinct functions was prepared, which can be used for targeting, MRI, optical imaging, photothermal therapy and chemotherapy to cancer cells. Overall, this thesis broadens the application of metal nanoparticles in chemical and biosensing, and provides the scientific basis for their further application in cell imaging and photothermal therapy, which is significant for clinic cancer cell diagnosis and therapy.
第一部分：基于AuNPs与MNPs在生物传感中的应用。利用AuNPs的SPR吸收性质,以正电AuNPs为探针实现了可视化检测三磷酸腺苷(ATP)与碱性磷酸酶(ALP)；将核酸适配体aptamer)的高选择性与MNPs磁性分离的性质结合,利用银纳米颗粒(AgNPs)的SPR散射性质,建立了高灵敏、高选择性地测定溶菌酶(lysozyme)的方法。考察了生物分子如何有效调控贵金属纳米颗粒SPR性质。具体工作如下：
1.ATP诱导正电AuNPs聚集的光学性质研究及定量检测ATP。实验发现,通过调节ATP浓度,可以有效调控AuNPs在可见区的SPR吸收性质。提出了ATP与AuNPs的作用主要通过两种方式：首先是ATP的磷酸根与AuNPs表面阳离子表面活性剂之间的静电作用,其次是金原子与ATP含N碱基之问的配位作用。基于AuNPs的SPR吸收用于定量检测ATP,方法简单、成本较低、耗时较短、选择性好,检测限达到0.82μM。进一步实验发现,ATP的类似物包括GTP, UTP, CTP, ADP,AMP等,诱导AuNPs聚集程度各不相同,由此可建立了一种简单的可视化分析方法区分ATP类似物。
2.ALP经过脱磷酸化反应使ATP转化为腺苷,建立了一种基于AuNPs的免标记可视化方法检测ALP。该方法的检测范围可以通过加入金属离子动态调节,加入Ca2+或Pb2+可以使其线性范围从100-600unit/L分别调节至5.0-100unit/L及0.2-20unit/L,灵敏度得到极大提高。该方法具有高选择性、高灵敏度、检测范围动态可调的优点,用于检测人血清样品中ALP含量,与临床结果一致。
3. Aptamer偶联MNPs用于lysozyme的富集与高灵敏分析检测。建立了一种基于MNPs与aptamer作为高选择性的分离富集载体,AgNPs作为散射信号探针的方法用于检测lysozyme。首先利用MNPs与aptamer偶联复合物特异性分离并富集lysozyme,再根据其正电荷性质,可与柠檬酸根包被的AgNPs通过静电作用结合,磁性分离上清液中AgNPs强烈的表面等离子共振散射光降低,可用于定量分析lysozyme。磁性分离下层吸附的AgNPs具有强烈的暗场散射光,可用暗场敞射成像对lysozyme进行半定量分析。方法结合了aptamer的高选择性以及lysozyme带正电荷的两个性质,为测定lysozyme设下双重开关,能提高方法的选择性及测定结果的准确性。以具有强散射信号的AgNPs作为信号探针,可以提高方法灵敏度,检测限可低至0.1nM。该方法设计具有普遍适用性,对于复杂样品的测定具有重要意义。
第二部分：MNPs与Fe3O4@Au复合纳米颗粒在细胞成像中的应用。首先,以MNPs为例,考察了在细胞膜表而构建“铁笼子”是否具有防御病毒入侵的功能,拓宽了磁纳米材料在细胞成像及生物医学方而的应用。其次,我们结合了Au与Fe3O4各自优越的性能,制备成复合纳米颗粒,修饰靶向配体,构建了Fe3O4@Au多功能纳米材料用于癌细胞的靶向多模式成像与治疗。具体工作如下：
1.细胞膜表面构建“铁笼子”用于抗病毒入侵。本文使用人喉癌上皮细胞(HEp-2),探讨了细胞膜外形成网状“铁笼子”是否能抑制呼吸道合胞病毒(RSV)的感染。MNPs可通过链霉亲和素与生物素的特异性反应吸附到细胞膜表面,利用颗粒表面修饰DNA的多价效应,通过杂交形成网状“铁笼子”,期望达到抑制病毒入侵的效果。实验采用扫描电镜(SEM)证实了“铁笼子”在细胞膜表面形成。其具有良好的生物相容性,能在一定程度上防御病毒侵染细胞。当病毒侵染MOI值为2时,有“铁笼子”保护的细胞,其细胞存活率能从24.1士4.4%提高到49.0±10.0%。利用免疫荧光显微技术,表明“铁笼子”抑制病毒入侵可能通过以下两种方式：其空间位阻效应阻碍了病毒与细胞膜的结合；降低细胞膜柔韧性,抑制病毒出胞以及在细胞间的扩散。本文利用纳米材料在一定程度上实现抗病毒入侵,为开发新的抗病毒药物以及其它防治病毒性疾病的新方法研究提供了思路。
2.多功能Fe3O4@Au核壳纳米花靶向癌细胞双模式成像与治疗。发展能结合诊断与治疗于一身的多功能纳米材料在分子医学领域有极其重要的意义。本文将五个独特的功能有机地整合到了一个粒径为70nm的Fe3O4@Au纳米花上。Fe304核可作为MRI显影剂；表面包被金壳,使其具有近红外吸收,产生光热效应使细胞温度升高,可用于光热治疗。高温能促进负载的抗癌药物盐酸阿霉素(Dox)快速释放,产生红色荧光,可通过共聚焦荧光显微镜监测其释放过程。颗粒表面偶联aptamer可提高药物的靶向释放。该Fe3O4@Au多功能纳米材料结合了荧光成像与MRI双模式成像方式,可提高癌细胞诊断准确性,并有利于监测药物释放。当纳米材料负载0.8μM Dox时达到的治疗效果,可与单独使用2.0μM Dox时相当。因此,将化疗与光热治疗结合使用,可以减少药物用量,降低非特异性的毒副作用。总之,该多功能纳米材料同时具有靶向、双模式成像与双治疗手段结合的功能,对生物医学领域,尤其是癌症治疗具有潜在的意义。
总之,本论文具有以下三个创新点：(一)利用生物分子实现了对金属纳米颗粒SPR性质的有效调节。(二)构建了与传统的小分子设计不同的病毒防御系统,以磁纳米颗粒在细胞膜表面形成“铁笼子”抗病毒侵染。(三)制备了同时具有靶向、双成像模式及双治疗手段五个功能的多功能纳米材料。该研究论文拓宽了金属纳米颗粒在化学与生物传感方面的应用,对于将金属纳米颗粒进一步应用于细胞成像及光热治疗领域提供了一定依据,在癌细胞诊断与治疗方面具有一定的临床价值。
Nobel metal nanoparticles, which possess unique surface plasmon resonance (SPR) absorption and scattering properties, have been widely used in biosensing, cell imaging, cancer cell therapy and other biochemical fields. Magnetic nanoparticles, especially superparamagnetic Fe3O4nanoparticles, have received much consideration because of their wide applications in biomedical fields such as magnetic separation, magnetic relaxation switches, magnetic therapy and magnetic resonance imaging (MRI). Recently, nanocomposites, especially core/shell nanoparticles, have been reported to exhibit excellent properties, since they can avoide the limitations of single nanoparticle and have synergistic effects. Among these nanocomposites, gold-coated Fe3O4(Fe3O44@Au) nanoparticles have attracted much attention owing to the advantages such as ease of synthesis and surface modification, unique SPR properties and magnetic properties. However, there are still some problems about the application of nanoparticles. For instance, how can the biomolecules tune the SPR properties of metal nanoparticles when using for cell imaging and cancer therapy? Are the nanoparticles able to protect the host against virus infection? Numbers of multifunctional nanoparticles have been reported, but very few of them offer several functions such as targeting, dual imaging and dual therapy on a single platform. Thus, in this paper, gold nanoparticles (AuNPs), MNPs and Fe3O4@Au nanocomposites were used for further application to solve the above problems. The main contents of this thesis include the following two parts:
Part1. Applications of AuNPs and MNPs in biosensing. Firstly, a colorimetric detection assay based on the SPR absorption of positive-charged gold nanoparticles was established for adenosine triphosphate (ATP) and alkaline phosphatase (ALP), respectively. Secondly, a magnetic nanoparticle-based aptasensor was used for enrichment and highly sensitive determination of lysozyme. At last, we investigated how the biomolecules tune the SPR properties of metal nanoparticles. The details are as follows:
1. Optical investigations on ATP-induced aggregation of positive-charged AuNPs and further application for ATP determination. It was found that the SPR absorption of AuNPs over a visible region can be tunable by ATP. Mechanism investigations showed that the aggregation of the AuNPs is likely induced by two interaction modes. One is the electrostatic interaction between the phosphate anions associated with the ATP and AuNPs owing to the cationic surfactant on the surfaces of AuNPs, and the other is the interaction between gold atom and nitrogen-containing bases. With the changes of SPR absorption of AuNPs, a new method for the determination of ATP has been developed with the detection limit of0.82μM. The proposed method is simple, rapid, and highly selective. Further investigations showed that other analogs of ATP, such as GTP, UTP, CTP, A DP, AMP and so on, can be visually distinguished by AuNPs based on the different affinity with AuNPs.
2. A simple and label-free colorimetric assay was developed for detecting ALP. ATP induces the aggregation of cetyltrimethylammonium bromide (CTAB)-capped AuNPs and ALP stimulates the disaggregation of AuNPs by converting ATP into adenosine through an enzymatic dephosphorylation reaction. Hence, the presence of ALP can be visually observed (gray-to-red color change) and monitored by the shift of the SPR absorption band of AuNPs. Furthermore, the dynamic range of the method can be varied by addition of different metal ions (e.g.100-600unit/L to5.0-100unit/L and0.2-20unit/L in the presence of Ca2+and Pb2+, respectively). The feasibility of this sensitive and specific assay with a tunable dynamic range was demonstrated to be consistent even in human serum samples.
3. Magnetic nanoparticle-based aptasensor for enrichment and highly sensitive determination of lysozyme. In this report, lysozyme was firstly enriched and separated by aptamer conjugated MNPs, and then silver nanoparticles (AgNPs) with strong light scattering signals, were absorbed by positive charged lysozyme through electrostatic interaction. The light scattering signal of AgNPs in the supernatant after magnetic separation was gradually reduced with the increasing concentration of lysozyme. In addition, after magnetic separation, since the lysozyme on the MNPs can enrich numbers of AgNPs, which showed strong dark-field light scattering, lysozyme can also be semi-quantified by dark-field light scattering images. The proposed method took advantage of both the high selectivity of aptamer and the positive charge of lysozyme; hence the selectivity and accuracy for lysozyme determination can be greatly improved, with the detection limit of0.1nM. This design is universal, and it has the potential to be used in analysing complex samples.
Part2. Applications of MNPs and Fe3O4@Au in cell imaging. At first, we investigated whether an "iron cage" formed by DNA crosslinking on cell membranes can be used for inhibition of viral fusion and entry. Then by making use of the unique properties of Au and Fe3O4, we prepared a Fe3O4@Au nanorose with five different functions, which can be used for targeted dual molecular imaging (MRI/optical imaging) and dual therapy (photothermal/chemotherapy). The details are as follows:
1. Inhibition viral entry and spread by crosslinking an "iron cage" on cell membranes. In this report, an "iron cage" was formed on the cell membrane of Human epidermoid cancer cell (HEp-2cell) to investigate whether it can inhibit respiratory syncytial virus (RSV) infection. MNPs modified with DNA probes wereattached on the cell membranes through the strong affinity between streptavidin and biotin, and then an "iron cage" was formed through the hybridization of DNA probes. Scanning electron microscope (SEM) was used to demonstrate the formation of "iron cage" on cell membrane. The "iron cage" was nontoxic to the cells under the conditions studied. If cells were infected by RSV at multiplicity of infection (MOI) of2, the cell viability can be improved from24.1±4.4%to49.0±10.0%once protected by "iron cage". The results from immunofluorescence imaging technique indicated that RSV infection may be inhibited by "iron cage" through two ways. One is by blocking the attachment of the virus to the cells as a result of the steric effect; the other is by altering mechanical properties of membrane lipid bilayers to less fusogenic, so that the cell-to-cell viral spread is inhibited. This research implicated the possibility of designing nanoparticles for alternative antiviral therapy and it may also provide some valuable information for developing antiviral drugs.
2. Gold-coated Fe3O4nanoroses with five unique functions for cancer cell targeting, imaging and therapy. The development of nanomaterials that combine diagnostic and therapeutic functions within a single nanoplatform is extremely important for molecular medicine. Here, five different functions were synergistically integrated into a single platform by a Fe3O4@Au nanorose of about70nm in diameter. The inner Fe3O4core functions as an MRI agent, while the photothermal effect is achieved through near-infrared absorption by the gold shell, causing a rapid rise in temperature and also resulting in a facilitated release of the anticancer drug doxorubicin (Dox) carried by the nanoroses. Dox release is monitored by its fluorescent under confocal fluorescence microscope. Aptamers immobilized on the surfaces of the nanoroses enable efficient and selective drug delivery, imaging and photothermal effect with high specificity. The combination of dual-modality MRI and optical imaging has the potential to improve the specificity of cancer cell diagnosis and facilitate therapeutic drug monitoring. The results showed that0.8μM of Dox released from nanorose-sgc8-Dox was sufficient to reach the same killing efficiency with2.0μM of free Dox. Hence, it minimized the nonspecific toxicity and side effects based on a lower dosage of chemotherapy drugs when combined with photothermal therapy. We demonstrate the Fe3O4@Au nanoroses with five distinct functions, which integrate aptamer-based targeting, MRI, optical imaging, photothermal therapy and chemotherapy into one single probe. It is expected that this versatile theranostic system will have wide biomedical applications and may be particularly useful for cancer therapy.
In summary, this research offers three attractive features. Firstly, the SPR properties of metal nanoparticles over a visible region can be tunable by biomolecules. Secondly, a new strategy for inhibition viral entry and spread by crosslinking an "iron cage" on cell membranes was proposed, which is different to the traditional small molecules. At last, a multifunctional nanomaterial with five distinct functions was prepared, which can be used for targeting, MRI, optical imaging, photothermal therapy and chemotherapy to cancer cells. Overall, this thesis broadens the application of metal nanoparticles in chemical and biosensing, and provides the scientific basis for their further application in cell imaging and photothermal therapy, which is significant for clinic cancer cell diagnosis and therapy.
引文
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