基于量子点/多级纳米结构电导阵列超级电容特性的肿瘤标志物传感器研究

Tumor markers (TM) are biochemical substances that reflect the presence of tumors. Precise detection of trace TM is essential for early diagnosis and prognosis of cancers. At present, the determination of TM is mainly based on the multi-procedure and indirect transduction of TM-antibody binding event to detectable signal. However, the direct and reliable single-step detection technology is accounted as an important subject of cancer diagnosis. This project aims to enhance the electrical signal significantly based on the supercapacitive characteristics of quantum dots (QD)/hierarchical nanostructured conductive array (HNCA) composite electrode, thus improving the sensitivity and stability of TM single-step detection. The specific immunoreaction of TM antigen with immobilized antibody, which induces electric-double-layer electrochemical signal change, will endow the TM detection with selectivity. (1) The supercapacitive hierarchical nanostructured conductive array electrode will be designed and prepared to ensure supercapacitance, excellent mass transfer and high electric conductivity. The quantum dots will be composited with hierarchical nanostructured conductive array to further enhance supercapacitance and build a stable electric-double-layer sensing structure. (2) The immobilization of antibody molecules onto quantum dots/hierarchical nanostructured conductive array will be studied so as to construct TM biosensors. The mass transfer and conductive properties of TM at the sensing interface will be investigated. The electrochemical sensing mechanism will be clarified. The influencing factors on sensitivity, selectivity, stability of the fabricated TM sensors will be ascertained. The proposed TM sensors as well as TM determination results will be compared with current clinical assays, such as enzyme-linked immunosorbent assay (ELISA), Electro-chemiluminescence immunoassay (ECLIA), chemiluminescence Immunoassay (CLIA), etc. The research goal is to acquire biosensors with well comprehensive performance for single-step direct detection of human TM level. (3) Finally, the theoretical model of electrochemical quantitative detection of TM will be established to provide the theoretical basis for TM detection, furnishing scientific foundation for the application of electrochemical biosensors in clinical diagnosis and monitoring of cancers.

肿瘤标志物（TM）是反映肿瘤存在的生化物质，精确检测微量TM对癌症早期诊断及预后监测极为重要。TM检测以多步间接法为主，研究直接可靠单步法检测TM是癌症诊断的一个重要课题。本项目拟基于量子点/多级纳米结构电导阵列（QD/HNCA）的超级电容特性显著增强响应电信号，提高检测灵敏度和稳定性；基于TM-抗体特异性结合引起双电层变化，实现TM单步直接选择性检测。（1）设计、制备HNCA电极，使之具有超级电容、优良传质和传导性；研究QD复合HNCA，进一步增大电容，构建稳定双电层结构；（2）研究QD/HNCA固定抗体分子制备TM传感器，研究TM在传感界面的传质与传导，阐明电化学传感机制，探明影响灵敏度、选择性、稳定性的因素，与临床测定方法比较，获得满足人体TM水平检测的综合性能优良的传感器；（3）建立TM电化学定量检测理论模型，提供TM检测理论依据，为电化学生物传感器用于癌症诊断与监测奠定科学基础。

肿瘤标志物（TM）是反映肿瘤存在的生化物质，精确检测微量TM对癌症早期诊断及预后监测极为重要。TM检测以多步间接法为主，研究直接可靠单步法检测TM是癌症诊断的一个重要课题。本项目基于多级纳米结构电导阵列（HNCA）的超级电容特性显著增强响应电信号，提高检测灵敏度和稳定性；基于TM-抗体特异性结合引起双电层变化，实现TM单步直接选择性检测。（1）制备了金多级纳米结构阵列（GHNA），它具有较高的比表面积和良好的生物相容性，并呈现出超级电容器性质。（2）基于双电层理论建立了免疫检测理论模型，制作了GHNA/PA（蛋白质A）传感器尝试检测了免疫球蛋白G（H-IgG），检测水平为pg/mL量级，制作了GHNA/Ab-CEA（癌胚抗原抗体）传感器应用于肿瘤标志物—癌胚抗原（CEA）的检测，传感器操作步骤简化，减少了干扰因素，具有非常低的检测下限（0.08 pg/mL）及良好的选择性和可靠性。人体血清CEA检测结果与常规电化学发光免疫检测方法（ECLI）相一致。（3）采用双重电化学信号放大策略，基于3D金纳米线阵列及聚多巴胺纳米膜的可逆氧化还原反应，放大了电流信号，构建肿瘤标志物-甲胎蛋白（AFP）传感器。从电极电位角度阐释了氧化电流放大机理，并采用循环伏安谱和电化学阻抗谱研究了所构建的免疫传感器的界面动力学特性和机理。传感器具有较宽的线性检测范围（0.1pg/mL~50ng/mL）和较低的检测限（0.01pg/mL），以及良好的选择性、稳定性和重复性，对人血清标本中AFP的检测分析结果与临床检测方法相当。（4）制备了具有信号放大功能和高选择性的多功能纳米标记物（Ab2-PDA-AF），电化学界面动力学分析表明，AF-PDA-Ab2的整体化有利于AF和PDA之间的快速电子转移，电荷转移电阻下降了80%。本AFP免疫传感器的线性检测范围为0.5 pg/mL-1000.0 pg/mL，具有较低的检测限（0.01 pg/mL）。本研究为电化学生物传感器用于癌症诊断与监测奠定了科学基础，研制的肿瘤标志物传感器具有临床检测应用前景。

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