多维校正方法用于复杂基体中抗癌药及生物分子定量分析

发布时间：2018-06-25 06:17

  本文选题：化学计量学 + 多维校正　； 参考：《湖南大学》2016年硕士论文

【摘要】：近年来,基于多线性成分的多维校正方法受到了分析化学者越来越多的关注,借助于“数学分离”辅助或代替传统的物理化学分离,可以实现在未知干扰共存下感兴趣组分的定量分析。化学计量学中的“二阶优势”为多个目标分析物的同时定量提供了新思路。随着分析仪器以及计算机的快速发展,化学计量学二阶校正方法结合不同仪器产生的复杂数据,可用于不同复杂背景如药物、食品、化妆品以及环境样中感兴趣组分的定量分析,尤其是动态体系下感兴趣组分的定量。目前,许多重大疾病(如癌症、心血管病以及风湿病)治疗的优化尤为重要。因此,本文作者在了解多维校正理论知识基础上,将多维校正方法结合不同的仪器分析用于复杂体系中不同药物和生物大分子的定量分析,并进一步探索了普鲁卡因与人血清白蛋白相互作用的机理。主要内容如下：第二章：二阶校正辅助的HPLC-DAD方法用于快速定量人体血浆中四种酪氨酸激酶抑制剂酪氨酸激酶是细胞生长和分化中至关重要的调节因子。在许多重大疾病如风湿性关节炎和癌症中,均发现其激酶信号调节异常。研究发现,酪氨酸酶介导的信号转导与肿瘤的发生和恶化密切相关。因此,通过阻断激酶信号传导通路可以有效治疗该类疾病。凡德他尼、帕唑帕尼、阿法替尼和达沙替尼是四种不同的酪氨酸激酶抑制剂,已被批准用于甲状腺髓样癌、肾癌、白血病等的治疗。本章利用交替三线性分解(ATLD)结合高效液相色谱二极管阵列检测(HPLC-DAD)方法用于同时定量分析7种不同人体血浆样中凡德他尼、帕唑帕尼、阿法替尼和达沙替尼的含量,发展了一种快速、灵敏、有效的抗癌药物定量方法。第三章：二阶校正方法结合HPLC-DAD定量分析人体体液中三种抗凝药物和利伐沙班片中的活性物质本章采用HPLC-DAD结合ATLD二阶校正方法用于定量分析血浆样和尿液样中的利伐沙班、阿哌沙班和达比加群酯的浓度,并准确定量了利伐沙班片中利伐沙班的实际含量。利伐沙班、阿哌沙班和达比加群酯是新型口服抗凝药,相对于传统的抗凝药物如肝素和低分子肝素、水蛭素、重组水蛭素、阿加曲班和西美加群以及维生素K拮抗剂华法林等,新型抗凝药物不易受食物、药物等影响。本章提出的方法简单、经济、省时、省力,且具有较好的准确性和重复性,可用于常规的利伐沙班质量控制,有望发展成为一种沙班类药物实时的血药浓度的监测方法。第四章：内源荧光结合二阶校正方法用于快速定量分析复杂基质中吲哚美辛含量吲哚美辛,是一种非甾体抗炎药,通过抑制环氧酶的合成减少前列腺素的生成,从而具有解热、镇痛和抗炎功效。本章采用三维荧光结合平行因子分析(PARAFAC)算法策略,实现了人体血浆样、尿液样以及吲哚美辛肠溶片中活性成分的定量分析。即使背景干扰与待分析物的荧光光谱严重重叠,采用化学计量学的“数学分离”代替传统的物理化学分离,实现了感兴趣组分有效定量信息的提取。实验过程简单、快速,可避免复杂的样本预处理,提高了分析结果的准确性。第五章：多维校正方法结合三维血清白蛋白(HSA)作为人体内循环系统中一种常见的可溶性蛋白质,扮演着重要的生化角色,通过研究药物小分子与血清白蛋白的相互作用机理,有助于了解药物的吸收、分布、代谢和排泄。通常情况下,弱结合力使得血浆中游离的药物浓度较高,药物可以快速发挥其药效：强的作用力则导致药物的血药浓度较低,从而导致药物作用时间长,代谢慢。这种行为与不同的药物的化学结构以及给药方式有关。因此,研究药物与HSA的结合机理对药物剂型开发以及药物的药效学具有重要意义。本章提出一种三维荧光结合二阶校正方法用于HSA与普鲁卡因(PRO)动态体系中游离HSA浓度的定量分析,并利用三阶校正方法探索了温度对HSA和PRO相互作用的影响。
[Abstract]:In recent years, multidimensional correction based on multilinear components has attracted more and more attention from analytical chemistry. By means of "mathematical separation" assisting or replacing traditional physical and chemical separation, the quantitative analysis of interesting components can be realized under the coexistence of unknown interference. The "two order advantage" in stoichiometry is a multiple target analysis. With the rapid development of analytical instruments and computers, the two order correction method of chemometrics, combined with complex data produced by different instruments, can be used for quantitative analysis of interesting components in different complex backgrounds, such as drugs, food, cosmetics and environmental samples, especially in dynamic systems. At present, the optimization of the treatment of many major diseases, such as cancer, cardiovascular disease and rheumatism, is particularly important. Therefore, on the basis of knowledge of the theory of multidimensional correction, the author combines the multidimensional correction method with different instruments to analyze the quantitative analysis of different drugs and biological macromolecules in the complex system, and further explores it. The mechanism of the interaction of procaine and human serum albumin. The main contents are as follows: the second chapter: the two order correction assisted HPLC-DAD method is used for the rapid quantitative determination of four tyrosine kinase inhibitors tyrosine kinase in human plasma, which is the key regulator of cell growth and differentiation. In many major diseases such as rheumatic joints It is found that tyrosinase mediated signal transduction is closely related to the occurrence and deterioration of the tumor. Therefore, this type of disease can be effectively treated by blocking the kinase signal transduction pathway. Van derani, palazolani, alafinib and dasatinib are four different tyrosine kinases Inhibitors have been approved for the treatment of medullary thyroid carcinoma, kidney cancer, and leukemia. This chapter uses the alternating three linear decomposition (ATLD) combined with high performance liquid chromatography diode array detection (HPLC-DAD) method for the simultaneous quantitative analysis of the contents of van der tadoni, parazazoli, alafinii and dasatinib in 7 different human plasma samples. A rapid, sensitive and effective quantitative method for anticancer drugs. The third chapter: the two order correction method combined with HPLC-DAD for quantitative analysis of three anticoagulants in human body fluid and the active substance in Rivaroxaban tablets. This chapter uses HPLC-DAD combined with ATLD two order correction method for quantitative analysis of lefal Shaaban and artha in blood samples and urine samples. The concentration of the class and dabiaga group and accurate quantitative determination of the actual content of lefal Shaaban in Rivaroxaban tablets. Lev Shaaban, ABO Shaaban and dabiaga are new oral anticoagulants, relative to the traditional anticoagulants such as heparin and low molecular weight heparin, hirudin, recombinant hirudin, acataban and simeg group, and vitamin K antagonists. Hua Falin and so on, the new anticoagulant drugs are not easy to be affected by food and medicine. The method proposed in this chapter is simple, economical, time-saving, laborsaving, and has good accuracy and repeatability. It can be used for the conventional Lev Shaaban quality control. It is expected to develop into a method of monitoring the concentration of blood drugs in the real time of Shaaban drugs. The fourth chapter: endogenous fluorescent junction The combined two order correction method is used for the rapid quantitative analysis of indomethacin in complex matrix. It is a nonsteroidal anti-inflammatory drug, which reduces the production of prostaglandins by inhibiting the synthesis of epoxide, and thus has antipyretic, analgesic and anti-inflammatory effects. This chapter uses a three dimensional fluorescence binding parallel factor analysis (PARAFAC) algorithm. The quantitative analysis of the active components in human plasma, urine and Indometacin Enteric-coated Tablets. Even if the background interference and the fluorescence spectrum of the analyte are seriously overlapped, the chemometrics "mathematical separation" is used instead of the traditional physical and chemical separation to achieve the extraction of effective quantitative information of the interesting components. The experimental process is simple and rapid. It can avoid complex sample pretreatment and improve the accuracy of analysis results. The fifth chapter: multidimensional correction method combined with three dimensional serum albumin (HSA) as a common soluble protein in the internal circulation system, plays an important biochemical role, and helps to study the interaction mechanism between small drug molecules and serum albumin. To understand the absorption, distribution, metabolism, and excretion of drugs. Generally, the weak junction force makes the concentration of free drugs in the plasma higher, and the drug can give full play to its efficacy: the strong force leads to the lower concentration of the drug, which leads to the long time and slow metabolism of the drug. This behavior and the chemical structure of different drugs It is of great significance to study the mechanism of combination of drugs and HSA for the development of drug dosage forms and pharmacodynamics. In this chapter, a three-dimensional fluorescence combined two order correction method is proposed for quantitative analysis of free HSA concentration in the dynamic system of HSA and procaine (PRO), and the temperature is explored by using the three order correction method. The effect on the interaction of HSA and PRO.
【学位授予单位】：湖南大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R917
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本文编号：2064946