光动力反应中单态氧剂量分布的研究
发布时间：2018-08-04 16:50
【摘要】：光动力疗法是一种利用光动力反应进行疾病诊断和治疗的新技术。光动力治疗效果取决于活性氧特别是单态氧的产量及分布,因光敏剂的靶向性和光照的选择性,适用于个体化精准治疗。目前光动力诊疗技术的临床应用受限于光在生物组织中穿透深度有限、缺乏活性氧分布与产量的精确分析和控制和荧光断层成像分辨率有限等因素。因此本文开展了基于多功能诊疗药物的光动力反应中单态氧剂量分布监测方法的研究。设计并制备了以稀土钆离子(Gd3+)配位的血卟啉单甲醚(HMME)为基础的兼具氧敏感性、光敏性以及磁共振造影(MRI)增强功能的多用途诊疗药物Gd-HMME。利用紫外-可见吸收光谱、傅里叶红外吸收光谱、时间分辨光谱、质谱等测试手段对其进行表征,首次发现Gd-HMME在710 nm的室温磷光发射;研究了溶解氧浓度对Gd-HMME荧光和磷光的影响规律;以1,3-二苯基异苯并呋喃(1,3-diphenylisobenzofuran,DPBF)为单态氧指示剂,利用分光光度法测得甲醇溶液中Gd-HMME的单态氧量子产率为0.4;通过Gd-HMME、Mn-HMME、Sm-HMME和Nd-HMME溶液的MRI成像效果比对,证实Gd-HMME具有优良的MRI造影功能;荧光显微成像表明离子配体和牛血清白蛋白修饰的Gd-HMME具有良好的细胞相容性;基于Gd-HMME的光动力诊疗药物为影像引导光动力治疗的单态氧剂量研究提供了物质基础。研究了溶解氧浓度对Gd-HMME单态氧量子产率的影响并建立了其单态氧量子产率与其磷光强度之间的变化关系。根据速率方程理论分析单态氧产生和被活性氧探针DPBF化学捕获的光物理和光化学过程,建立了光动力反应方程和基于分光光度比较法测量不同溶解氧浓度条件下光敏剂单态氧量子产率方法,同时建立了光敏剂单态氧量子产率与溶解氧浓度和光敏剂磷光强度间的关系模型。测量Gd-HMME在不同溶解氧浓度条件下的单态氧量子产率,证明Gd-HMME三重态量子产率不随O2浓度变化,磷光光谱不仅可以用于测量溶解氧浓度,也可以用于分析单态氧量子产率。此项研究为光动力反应单态氧剂量光谱分析提供了理论依据。提出了基于Gd-HMME磷光光谱的荧光断层成像技术监测分析单态氧产量三维分布和光动力反应进度的方法。采用辐射传输方程的球谐展开计算激发光和Gd-HMME光致发光分布;通过光动力反应动力方程研究Gd-HMME、O2和DPBF间在仿体内的光动力反应过程。通过荧光断层成像重构仿体内光学参数、Gd-HMME浓度和溶解氧浓度分布,利用光动力反应方程计算特定激发光场分布条件下计算单态氧产量、溶解氧浓度、DPBF浓度的空间和时间分布。仿真实验验证了基于Gd-HMME光谱监测分析单态氧产量分布的可行性,在此基础上可利用光动力反应方程计算光动力反应过程的分布。探索了上转换光动力疗法中光场分布和单态氧剂量分布分析方法并建立了光动力反应的计算及重构方法。仿真研究976 nm激光激发Na YF4:Yb/Er@Na Yb F4@Ce6和808 nm激光激发的NaYF4:Yb/Er@Na YF4:Nd@Na YF4@Ce6时,激发光功率度对上转换发光量子产率及分布的影响,研究发现1~10 ms短脉冲高功率密度激发可以获得更大有效深度;同红光直接激发的光动力反应相比,两者均适合血红蛋白含量较高的肝脏疾病治疗,而后者对于含血红蛋白和水都丰富的肾脏组织具治疗优势;利用基于Na YF4:Yb/Er@Na YF4:Nd@Na YF4@Ce6纳米材料中Nd3+离子下转换荧光的荧光断层成像技术重构了纳米粒子及组织光学参数分布,建立了数字仿体中的光动力反应过程的三维重构方法。此研究为组织光学窗口内长波长激发光动力反应单态氧剂量分布测量提供了解决方案。
[Abstract]:Photodynamic therapy is a new technique for the use of photodynamic response to diagnose and treat diseases. The effect of photodynamic therapy depends on the production and distribution of active oxygen, especially mono oxygen. It is suitable for individualized precision treatment because of the targeting and selectivity of photosensitizer. The clinical application of photodynamic diagnosis and treatment is limited to light in birth. The penetration depth of the tissue is limited, the accurate analysis and control of the distribution and production of active oxygen and the limited resolution of the fluorescence tomography are limited. Therefore, this paper has developed a method for monitoring the distribution of mono oxygen dose distribution in the photodynamic response based on multi-functional diagnosis and treatment drugs. The blood of the rare earth gadolinium ion (Gd3+) coordination was designed and prepared. Porphyrin monomethyl ether (HMME) based multipurpose diagnosis and treatment drug Gd-HMME. with both oxygen sensitivity, photosensitivity and magnetic resonance imaging (MRI) enhancement function is characterized by UV visible absorption spectroscopy, Fourier infrared absorption spectroscopy, time resolved spectra, mass spectrometry and other testing methods, and the first discovery of Gd-HMME at room temperature in 710 NM at room temperature The influence of the concentration of dissolved oxygen on the fluorescence and phosphorescence of Gd-HMME was studied. The 1,3- two phenyl isobenzofuran (1,3-diphenylisobenzofuran, DPBF) was a single state oxygen indicator, and the quantum yield of Gd-HMME in the methanol solution was measured by spectrophotometric method by 0.4, and the MRI imaging effect of Gd-HMME, Mn-HMME, Sm-HMME and Nd-HMME solution was compared to the Gd-HMME, Mn-HMME, Sm-HMME and Nd-HMME solutions. It was confirmed that Gd-HMME had excellent MRI contrast function; fluorescence microscopy showed that the ionic ligand and bovine serum albumin modified Gd-HMME had good cytocompatibility, and the photodynamic diagnosis and treatment drugs based on Gd-HMME provided the material basis for the study of the single oxygen dose in the imaging guided photodynamic therapy. The concentration of dissolved oxygen to Gd-HMME was studied. The relationship between the quantum yield of the single state oxygen and the change of the quantum yield of the single state oxygen and the intensity of the phosphorescence was established. According to the rate equation theory, the photophysical and photochemical processes of the production of mono oxygen and the chemical capture by the active oxygen probe DPBF were analyzed. The photodynamic reaction equation and the spectrophotometric method based on the spectrophotometric method were used to measure the different dissolution. The quantum yield method of single state oxygen quantum yield of photosensitizer was established, and the relationship model between the quantum yield of single oxygen and the concentration of dissolved oxygen and the phosphorescence intensity of photosensitizer was established. The quantum yield of Gd-HMME at different concentration of dissolved oxygen was measured, and the quantum yield of Gd-HMME three heavy state did not change with the concentration of O2, and the phosphorescence spectrum was found. It can be used not only to measure the concentration of dissolved oxygen, but also to analyze the quantum yield of mono oxygen. This study provides a theoretical basis for the analysis of the mono oxygen dose spectrum analysis of the photodynamic reaction. A method for monitoring and analyzing the three dimensional distribution of mono oxygen output and the progress of photodynamic reaction based on the fluorescence tomography of Gd-HMME phosphor spectrum is proposed. The distribution of stimulated luminescence and Gd-HMME photoluminescence was calculated with the spherical harmonic expansion of the radiation transmission equation. The photodynamic reaction process between Gd-HMME, O2 and DPBF was studied through the kinetic equation of photodynamic reaction. The optical parameters of the imitated body were reconstructed by fluorescence tomography, the concentration of Gd-HMME and the distribution of dissolved oxygen concentration, and the calculation of the photodynamic reaction equation. The distribution of mono oxygen production, dissolved oxygen concentration, DPBF concentration and space and time distribution are calculated under the specific excitation light field distribution. The feasibility of analyzing the distribution of mono oxygen yield based on Gd-HMME spectrum monitoring is verified by the simulation experiment. On this basis, the distribution of the photodynamic reaction process can be calculated by the photodynamic reaction equation. The upconversion photodynamic is explored. The distribution of light field and the distribution of single oxygen dose distribution in force therapy and the method of calculation and reconstruction of photodynamic reaction are established. The influence of the excited light power on the quantum yield and distribution of the upconversion luminescence is studied when the 976 nm laser excited the Na YF4:Yb/Er@Na Yb F4@Ce6 and the 808 nm laser excitation NaYF4:Yb/Er@Na YF4:Nd@Na YF4@Ce6. It is found that 1~10 MS short pulse high power density excitation can obtain greater effective depth; compared with the photodynamic response of red light direct excitation, both of them are suitable for liver disease treatment with high hemoglobin content, and the latter has therapeutic advantage for kidney tissue rich in hemoglobin and water, and based on Na YF4:Yb/Er@Na YF4:Nd@Na Y The fluorescence tomography technology of Nd3+ ion converted fluorescence in F4@Ce6 nanomaterials has reconstructed the distribution of optical parameters of nanoparticles and tissues, and established a three-dimensional reconstruction method for the photodynamic reaction in the digital mimic. This study provides a solution to the measurement of the dose distribution of the long wavelength stimulated luminescence in the optical window. Plan.
【学位授予单位】：哈尔滨工业大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R454.2
本文编号：2164499
[Abstract]:Photodynamic therapy is a new technique for the use of photodynamic response to diagnose and treat diseases. The effect of photodynamic therapy depends on the production and distribution of active oxygen, especially mono oxygen. It is suitable for individualized precision treatment because of the targeting and selectivity of photosensitizer. The clinical application of photodynamic diagnosis and treatment is limited to light in birth. The penetration depth of the tissue is limited, the accurate analysis and control of the distribution and production of active oxygen and the limited resolution of the fluorescence tomography are limited. Therefore, this paper has developed a method for monitoring the distribution of mono oxygen dose distribution in the photodynamic response based on multi-functional diagnosis and treatment drugs. The blood of the rare earth gadolinium ion (Gd3+) coordination was designed and prepared. Porphyrin monomethyl ether (HMME) based multipurpose diagnosis and treatment drug Gd-HMME. with both oxygen sensitivity, photosensitivity and magnetic resonance imaging (MRI) enhancement function is characterized by UV visible absorption spectroscopy, Fourier infrared absorption spectroscopy, time resolved spectra, mass spectrometry and other testing methods, and the first discovery of Gd-HMME at room temperature in 710 NM at room temperature The influence of the concentration of dissolved oxygen on the fluorescence and phosphorescence of Gd-HMME was studied. The 1,3- two phenyl isobenzofuran (1,3-diphenylisobenzofuran, DPBF) was a single state oxygen indicator, and the quantum yield of Gd-HMME in the methanol solution was measured by spectrophotometric method by 0.4, and the MRI imaging effect of Gd-HMME, Mn-HMME, Sm-HMME and Nd-HMME solution was compared to the Gd-HMME, Mn-HMME, Sm-HMME and Nd-HMME solutions. It was confirmed that Gd-HMME had excellent MRI contrast function; fluorescence microscopy showed that the ionic ligand and bovine serum albumin modified Gd-HMME had good cytocompatibility, and the photodynamic diagnosis and treatment drugs based on Gd-HMME provided the material basis for the study of the single oxygen dose in the imaging guided photodynamic therapy. The concentration of dissolved oxygen to Gd-HMME was studied. The relationship between the quantum yield of the single state oxygen and the change of the quantum yield of the single state oxygen and the intensity of the phosphorescence was established. According to the rate equation theory, the photophysical and photochemical processes of the production of mono oxygen and the chemical capture by the active oxygen probe DPBF were analyzed. The photodynamic reaction equation and the spectrophotometric method based on the spectrophotometric method were used to measure the different dissolution. The quantum yield method of single state oxygen quantum yield of photosensitizer was established, and the relationship model between the quantum yield of single oxygen and the concentration of dissolved oxygen and the phosphorescence intensity of photosensitizer was established. The quantum yield of Gd-HMME at different concentration of dissolved oxygen was measured, and the quantum yield of Gd-HMME three heavy state did not change with the concentration of O2, and the phosphorescence spectrum was found. It can be used not only to measure the concentration of dissolved oxygen, but also to analyze the quantum yield of mono oxygen. This study provides a theoretical basis for the analysis of the mono oxygen dose spectrum analysis of the photodynamic reaction. A method for monitoring and analyzing the three dimensional distribution of mono oxygen output and the progress of photodynamic reaction based on the fluorescence tomography of Gd-HMME phosphor spectrum is proposed. The distribution of stimulated luminescence and Gd-HMME photoluminescence was calculated with the spherical harmonic expansion of the radiation transmission equation. The photodynamic reaction process between Gd-HMME, O2 and DPBF was studied through the kinetic equation of photodynamic reaction. The optical parameters of the imitated body were reconstructed by fluorescence tomography, the concentration of Gd-HMME and the distribution of dissolved oxygen concentration, and the calculation of the photodynamic reaction equation. The distribution of mono oxygen production, dissolved oxygen concentration, DPBF concentration and space and time distribution are calculated under the specific excitation light field distribution. The feasibility of analyzing the distribution of mono oxygen yield based on Gd-HMME spectrum monitoring is verified by the simulation experiment. On this basis, the distribution of the photodynamic reaction process can be calculated by the photodynamic reaction equation. The upconversion photodynamic is explored. The distribution of light field and the distribution of single oxygen dose distribution in force therapy and the method of calculation and reconstruction of photodynamic reaction are established. The influence of the excited light power on the quantum yield and distribution of the upconversion luminescence is studied when the 976 nm laser excited the Na YF4:Yb/Er@Na Yb F4@Ce6 and the 808 nm laser excitation NaYF4:Yb/Er@Na YF4:Nd@Na YF4@Ce6. It is found that 1~10 MS short pulse high power density excitation can obtain greater effective depth; compared with the photodynamic response of red light direct excitation, both of them are suitable for liver disease treatment with high hemoglobin content, and the latter has therapeutic advantage for kidney tissue rich in hemoglobin and water, and based on Na YF4:Yb/Er@Na YF4:Nd@Na Y The fluorescence tomography technology of Nd3+ ion converted fluorescence in F4@Ce6 nanomaterials has reconstructed the distribution of optical parameters of nanoparticles and tissues, and established a three-dimensional reconstruction method for the photodynamic reaction in the digital mimic. This study provides a solution to the measurement of the dose distribution of the long wavelength stimulated luminescence in the optical window. Plan.
【学位授予单位】：哈尔滨工业大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R454.2
【相似文献】
相关博士学位论文 前1条
1 王鹏;光动力反应中单态氧剂量分布的研究[D];哈尔滨工业大学;2016年
，本文编号：2164499
本文链接：https://www.wllwen.com/yixuelunwen/swyx/2164499.html
