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基于碳纳米管的肿瘤细胞电化学传感及凋亡研究
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摘要
肿瘤是严重危害人们身体健康的一类疾病,它的早期诊断和有效治疗是提高肿瘤患者生存率的关键。近年来,以肿瘤细胞及其相关标志物为研究对象的细胞电化学传感器,由于具有选择性好、灵敏度高、分析速度快、成本低等特点,引起了越来越多研究者的兴趣。碳纳米管因其独特的一维、纳米管状结构、优异的热学、电学和力学性质等,在生物传感领域显示出诱人的应用前景。另一方面,细胞凋亡是细胞的一种基本生物学现象,与许多肿瘤疾病的发病机制及化学治疗相关。开展肿瘤细胞凋亡的检测新方法研究,对于肿瘤的发病机理及治疗方法研究具有非常重要的意义。
     本论文正是基于以上研究背景,围绕如何将功能化的碳纳米管应用到肿瘤的早期诊断中,开展了肿瘤细胞电化学传感和细胞凋亡检测的新方法研究。主要包括以下几方面的内容:
     1.明胶稳定的金纳米粒子的合成和羧基化单壁碳纳米管/金复合物的组装用于细胞传感及药物传输
     通过在明胶溶液中原位还原氯金酸这一简便、绿色的合成方法,合成了具有良好生物相容性和亲水性的明胶稳定的金纳米粒子。该纳米粒子有良好的胶体稳定性。利用紫外-可见光谱、透射电子显微镜和原子力显微镜对不同尺寸的金纳米粒子进行了表征。此外,将具有良好生物相容性的纳米金和优良导电性的羧基化单壁碳纳米管(c-SWNTs)相结合,构建了一个新颖的用于HL-60细胞电化学传感的纳米复合物(纳米金-明胶-c-SWNTs).该纳米复合物膜为电极表面HL-60细胞的固定和电化学传感提供了一个生物相容性的界面。固定的细胞呈现出灵敏的伏安响应、良好的生物活性和递增的电子传递阻抗,说明该复合物可用于构建高灵敏的阻抗细胞传感器,其测定范围为1×104-1×107cell mL-1,检测限为5×103cell mL-1。此外,细胞毒性测试、荧光显微镜和电化学实验结果表明,该复合物能有效地促进了阿霉素和HL-60细胞的相互作用,明显地增加癌细胞内的药物沉积量,从而提高了药物治疗的效果。
     2.由贻贝启发的合成碳纳米管/聚多巴胺/叶酸纳米探针用于靶向细胞检测
     利用多巴胺的自身氧化聚合反应,我们在羧基化的多壁碳纳米管(CNTs-COOH)表面原位包覆了一层聚多巴胺(PDA),并进一步通过碳二酰亚胺偶联反应,共价构建了一种新颖的叶酸功能化的纳米探针(CNTs@PDA-FA)。用扫描电子显微镜、高分辨透射电镜和接触角分析仪表征了纳米探针的均一性和生物相容性。该探针同时具有碳纳米管的优异的电化学性能和叶酸分子对肿瘤细胞膜表面叶酸受体的特异性识别能力。进一步利用电化学阻抗技术,我们发展了一种无标记的电化学细胞传感方法,它对高表达叶酸受体的肿瘤细胞,如人宫颈癌HeLa细胞及人白血病HL-60细胞,具有灵敏的电化学响应。由于聚多巴胺修饰层的良好的黏附性能和高的生物分子结合能力,该无标记的电化学传感策略为进一步研究肿瘤细胞膜表面的其它受体-配体的识别反应提供了有力的平台。
     3.用于检测细胞表面糖基和糖蛋白的电化学细胞传感器的设计与应用
     本文设计了一种新颖的电化学免疫传感策略用于检测人宫颈癌HeLa细胞及其表面聚糖和P-糖蛋白(P-gp)的表达水平。首先通过简单的层层组装方法,将氮掺杂的碳纳米管、硫堇和金纳米粒子组装到一起,构建了新型的具有三维结构的细胞传感界面。该界面具有高度的亲水性、良好的生物相容性和稳定性,能有效地促进伴刀豆球蛋白A(ConA)的固定,并使固定的ConA具有高度的稳定性和生物活性。由于ConA对细胞表面甘露糖基的特异性识别作用,构建的ConA/3-D传感界面显现出卓越的捕获细胞的能力。随后利用两步酶联免疫反应将HRP酶引入到细胞传感界面上,通过HRP催化H202氧化硫堇,进一步实现了电化学信号的放大。该细胞电化学传感器具有优异的性能,在8.0×102-2.0×107cells mL-1范围内,电化学信号与HeLa细胞浓度对数呈线性关系,并且在36时计算其检测限为500cells mL-1。此外,利用预先封闭甘露糖或者P-gp结合位点的方法,该传感器可进一步用于估算单个HeLa细胞上的甘露糖残基和P-gp的表达水平,在优化的实验条件下,测得单个细胞表面约含有(4±2)×10m个甘露糖基和8.47×106个P-gp蛋白分子。这一策略为癌细胞及其表面受体的灵敏测定提供了新的途径,为癌症的诊断和治疗提供了帮助。
     4.基于碳氮纳米管和凝集素功能化的量子点/硅球纳米探针的双信号放大策略用于检测早期凋亡细胞
     通过层层静电组装的方法制备了核壳结构的SiO2@CdTe QDs纳米复合物,并以聚烯丙基胺盐酸盐作为连接剂,将伴刀豆球蛋白A非共价组装到纳米复合物表面,构建了一种新型的凝集素功能化的纳米探针。该探针同时具有凝集素对细胞表面甘露糖基的特异性识别能力和量子点/二氧化硅纳米复合物的多标记电化学信号放大功能,可以作为一种细胞电化学传感器的标记物。为了构建细胞传感器的基底,我们将碳氮纳米管和金胶组装到电极表面,用于膜联蛋白Ⅴ (Annexin Ⅴ)的固定。利用Annexin Ⅴ能特异性的识别并结合凋亡细胞暴露在细胞膜外表面的磷脂酰丝氨酸,将早期凋亡细胞捕获到传感界面上,并进一步结合凝集素纳米探针,我们发展了一种快速识别和灵敏检测早期凋亡细胞的电化学分析检测方法。这种方法快速简便、灵敏度高、选择性好,在细胞凋亡的检测中具有潜在的应用价值。
     5.功能化碳纳米管/量子点纳米探针用于Caspase3激活和抑制的检测
     将碳纳米管/量子点纳米探针的信号放大作用与半胱氨酸蛋白酶3(Caspase3)对DEVD肽段的特异性识别与酶解相结合,研制出一种检测Caspase3活性与抑制作用的电化学传感器。首先利用LBL静电组装的方法合成了CNTs/PDDA/CdTe QDs纳米复合物,随后通过碳二酰亚胺偶合反应,共价偶联了链亲和素(SA)得到功能化的纳米探针。然后设计了一种Biotin标记的含有DEVD肽段的多肽,这种多肽可以特异性的识别激活的Caspase3。组装到电极上的多肽被凋亡细胞裂解液中的Caspase3切割后,多肽末端的Biotin分子从电极表面脱落下来。随后利用量子点纳米探针,我们可以检测电极上剩余Biotin分子的比例。由于Biotin分子的剩余量与Caspase3的活性成反比,因此通过电化学检测QDs的信号,可以间接反映细胞裂解液中Caspase3的活性。此外,该传感器也为检测Caspase3抑制剂及评估抗癌药物的药效提供了一个有力的平台。
     6.基于热电极体系的竞争型免疫传感器用于人白介素6的检测
     通过一步化学还原法合成了聚多巴胺功能化的金纳米粒子,并利用超声方法将其组装到石墨烯表面制备了石墨烯/金胶纳米复合物。该复合物同时具有了石墨烯的高负载特性、金胶的良好生物相容性以及聚多巴胺与蛋白质分子的高结合能力,因此有望成为一种新的生物分子的固定载体。我们以石墨烯/金胶复合物为传感器的基底,结合量子点功能化的碳纳米管探针作为生物标记物,构建了一种新型的竞争型电化学免疫传感器用于人白介素6的检测。该传感器结合了石墨烯/金胶的高效固载生物分子能力和碳纳米管/量子点探针的多标记信号放大特性,因此具有很高的灵敏度。更重要的是,我们将丝网印刷热电极引入到免疫传感器的信号测定中去,通过简便的提高电极表面的温度,实现了待测金属离子的快速有效富集,显著增强了电化学信号,从而进一步提高了传感器的灵敏度。该电化学免疫分析方法的检测范围是0.1-100pg mL-1,检测限是0.033pg mL-1。这种新型的免疫传感器具有较高选择性与稳定性,能够应用于实际血清样品的检测,在临床方面具有一定的应用前景。
Cancer is a class of diseases, which could seriously affect the health of human body. Early detection of cancer greatly increases the chances for successful treatment. Recently, electrochemical cytosensor has attracted increasing attention in the detection of cancer cells and related biomarkers, which offers distinctive advantages of high sensitivity and selectivity, rapid response, and low cost. Carbon nanotubes have shown attractive prospect in the biosensing field due to their unique one-dimensional, nano tubular structure, unusual thermal, electrical and mechanical properties. On the other hand, apoptosis is an important biological process that is associated with pathogeny and chemotherapy response for a variety of diseases. It is beneficial to develop highly sensitive and convenient detection approach for apoptosis diagnosis.
     Based on the electrochemical technology, this dissertation presents an exploration of the use of functionalized carbon nanotubes in cytosensing and apoptosis diagnosis. The main results were summarized as follows:
     1. Synthesis of Gelatin-Stabilized Gold Nanoparticles and Assembly of Carboxylic Single-walled Carbon Nanotubes/Au Composites for Cytosensing and Drug Uptake
     Gelatin-Stabilized gold nanoparticles with hydrophilic and biocompatible were prepared with a simple and "green" route by reducing in situ tetrachloroauric acid in gelatin. The nanoparticles showed the excellent colloidal stability. UV-vis spectra, transmission electron microscopy, and atomic force microscopy revealed the formation of well-dispersed AuNPs with different sizes. By combining the biocompatibility of AuNPs and excellent conductivity of carboxylic single-walled carbon nanotubes, a novel nanocomposite was designed for the immobilization and cytosensing of HL-60cells at electrodes. The immobilized cells showed sensitive voltammetric response, good activity and increased electron-transfer resistance. It can be used as a highly sensitive impedance sensor for HL-60cells ranging from1×104to1×107cell mL-1with a limit of detection of5×103cell mL-1. Moreover, the nanocomposite could effectively facilitate the interaction of Adriamycin with HL-60cells and remarkably enhance the permeation and drug uptake of anticancer agents in the cancer cells, which could readily lead to the induction of the cell death of leukemia cells.
     2. Mussel-Inspired Preparation of Carbon Nanotube/Polydopamine/Folic Acid Nanocomposites for Targeted Cell Detection
     This paper reported a facile approach for surface modification of carboxylic multi-walled carbon nanotubes through self oxidative polymerization of dopamine. The obtained nanocomposite was further conjugated with folic acid by a carbodiimide coupling reaction. This nanoprobe incorporated both the excellent electronic property of carbon nanotube and the specific recognition ability of folic acid for folate receptor on tumor cell membrane. Scanning electron microscopy, transmission electron microscopy and contact angle analysis revealed that the novel nanoprobe was uniform and biocompatible. With the help of electrochemical impedance technology, an electrochemical label-free method was developed to detect folate receptor positive tumor cells by making use of the interaction between folic acid and its receptor over-expressed on tumor cell membrane. The proposed cytosensor showed an excellent analytical performance for the detection of folate receptor positive tumor cells, such as human cervical cancer cells and human promyelocytic leukemia cells. This strategy offers great promise to extend its application in studying the interaction between ligand and cell-surface receptor.
     3. Design and Implementation of Electrochemical Cytosensor for Evaluation of Cell Surface Carbohydrate and Glycoprotein
     A new strategy for assessing cell surface carbohydrates and P-glycoprotein (P-gp) expression status and quantifying the cell numbers with electrochemical immunoassay was designed. In order to construct the base of the cytosensor, a novel3-D architecture was initially fabricated by combining nitrogen-doped carbon nanotubes, thionine, and gold nanoparticles via a simple layer-by-layer method. The formed architecture provided an effective matrix for Concanavalin A (ConA) binding and made the immobilized ConA hold high stability and bioactivity. On the basis of the specific recognition of cell surface mannosyl groups to ConA, the ConA/3-D architecture interface showed a predominant capability for cell capture. By coupling with another signal amplification based on a enzymatic catalytic reaction of HRP toward the oxidation of thionine by the H2O2, which was induced by two-step immunoreactions, the proposed cytosensor showed an excellent analytical performance for the detection of HeLa cells ranging from8.0×102to2.0×107cells mL-1with a limit of detection of500cells mL-1. Moreover, with the use of pre-blocking procedures, the mannosyl groups and P-gp on single HeLa cell could be further detected to be (4×2)×1010molecules of mannose moieties and8.47×106molecules of P-gp. This strategy offers great promise for sensitive detection of cancer cells and cell surface receptors, thus may help improve cancer diagnosis and treatment.
     4. Dual Amplification Strategy for Sensitive Detection of Early Apoptotic Cells based on Nitrogen-doped Carbon Nanotubes and Quantum Dot-Labeled Silica Nanosphere
     A novel lectin functionalized nanoprobe was designed by noncovalent assembly of ConA on CdTe quantum dot (QD)-labeled silica nanosphere with poly(allylamine hydrochloride) as a linker. This nanoprobe incorporated both the specific recognition ability of ConA for cell-surface mannosyl groups and the electrochemical signal amplification property of multi-labeled SiO2@QDs nanocomposites, and was further used as a label in cytosensor. In order to construct the base of the cytosensor, a novel3-D architecture was initially fabricated by combining nitrogen-doped carbon nanotubes and gold nanoparticles via a simple layer-by-layer method. The formed architecture provided an effective matrix for Annexin Ⅴ binding and made the immobilized Annexin V hold high stability and bioactivity, offering the possibility of sensitivity enhancement. On the basis of the specific recognition between Annexin V and phosphatidylserine on the early apoptotic cell membrane, the Annexin V/3-D architecture interface showed a predominant capability for early apoptotic cell capture. By coupling with SiO2@QDs-ConA nanoprobe and electrochemical stripping analysis, a novel electrochemical method for cytosensing was then developed for detection of early apoptotic cells. This facile method showed excellent sensitivity and selectivity, revealing great potential in cell apoptosis analysis.
     5. Electrochemical Sensing for Caspase3Activity and Inhibition Using Quantum Dot Functionalized Carbon Nanotube Labels
     This work constructed a novel electrochemical sensing platform for sensitive determination of caspase3activity and inhibition by combining the site-specific recognition and cleavage of the DEVD-peptide with quantum dots as signal amplification. A signaling probe composed of CdTe QDs, carbon nanotubes, and streptavidin was first prepared via the layer-by-layer assembly approach. Then, a smart, caspase-3-responsive, and biotinylated DEVD peptide was designed and immobilized on the gold electrode surface, which could be specifically recognized and cleaved by active caspase3in the apoptotic cell lysates. Using the QDs-based nanoprobes, an electrochemical biosensor was then developed for monitoring the caspase3activity and inhibition during cell apoptosis. This electrochemical strategy exhibited attractive advantages of ease of performance, high sensitivity and specificity. It presents a significant tool for efficient screening of the potential caspase3inhibitors and anticancer drugs, suggesting promising applications in cancer research.
     6. Ultrasensitive Detection of Human Interleukin6Using a Competitive Immunosensor Based on a Disposable Electrically Heated Screen-printed Carbon Electrode
     A facile one-step chemical reduction method was developed to prepare the polydopamine functionalized gold nanoparticle, followed by ultrasonically assembled on the surface of graphene nanosheets. The resulting hybrid material incorporated both the high-binding capability of graphene nanosheets, favorable biocompatibility of gold nanoparticles, and high protein affinity of polydopamine, which thus offered a promising template for biomolecule immobilization and biosensor fabrication. A novel competitive electrochemical immunoassay was then proposed by combining the RGO-AuNPs platform with quantum dots functionalized carbon nanotube labels for the sensitive detection of human interleukin6. Enhanced sensitivity was obtained by combining the advantages of high-binding capability of graphene nanocomposite with the QDs-based signal amplification. More importantly, an electrically heated screen-printed carbon electrode was induced in the detection procedure of the immunosensor, and further improved the sensitivity. The immunosensor exhibited a wide linear response to IL-6ranging from0.1to100pg mL-1with a detection limit of0.033pg mL-1. The proposed method showed good precision, acceptable stability and reproducibility, and could be used for the detection of IL-6in real samples, which possessed promising application in clinical research.
引文
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