光動力反應(yīng)中單態(tài)氧劑量分布的研究
發(fā)布時間：2018-08-04 16:50
【摘要】：光動力療法是一種利用光動力反應(yīng)進(jìn)行疾病診斷和治療的新技術(shù)。光動力治療效果取決于活性氧特別是單態(tài)氧的產(chǎn)量及分布,因光敏劑的靶向性和光照的選擇性,適用于個體化精準(zhǔn)治療。目前光動力診療技術(shù)的臨床應(yīng)用受限于光在生物組織中穿透深度有限、缺乏活性氧分布與產(chǎn)量的精確分析和控制和熒光斷層成像分辨率有限等因素。因此本文開展了基于多功能診療藥物的光動力反應(yīng)中單態(tài)氧劑量分布監(jiān)測方法的研究。設(shè)計(jì)并制備了以稀土釓離子(Gd3+)配位的血卟啉單甲醚(HMME)為基礎(chǔ)的兼具氧敏感性、光敏性以及磁共振造影(MRI)增強(qiáng)功能的多用途診療藥物Gd-HMME。利用紫外-可見吸收光譜、傅里葉紅外吸收光譜、時間分辨光譜、質(zhì)譜等測試手段對其進(jìn)行表征,首次發(fā)現(xiàn)Gd-HMME在710 nm的室溫磷光發(fā)射;研究了溶解氧濃度對Gd-HMME熒光和磷光的影響規(guī)律;以1,3-二苯基異苯并呋喃(1,3-diphenylisobenzofuran,DPBF)為單態(tài)氧指示劑,利用分光光度法測得甲醇溶液中Gd-HMME的單態(tài)氧量子產(chǎn)率為0.4;通過Gd-HMME、Mn-HMME、Sm-HMME和Nd-HMME溶液的MRI成像效果比對,證實(shí)Gd-HMME具有優(yōu)良的MRI造影功能;熒光顯微成像表明離子配體和牛血清白蛋白修飾的Gd-HMME具有良好的細(xì)胞相容性;基于Gd-HMME的光動力診療藥物為影像引導(dǎo)光動力治療的單態(tài)氧劑量研究提供了物質(zhì)基礎(chǔ)。研究了溶解氧濃度對Gd-HMME單態(tài)氧量子產(chǎn)率的影響并建立了其單態(tài)氧量子產(chǎn)率與其磷光強(qiáng)度之間的變化關(guān)系。根據(jù)速率方程理論分析單態(tài)氧產(chǎn)生和被活性氧探針DPBF化學(xué)捕獲的光物理和光化學(xué)過程,建立了光動力反應(yīng)方程和基于分光光度比較法測量不同溶解氧濃度條件下光敏劑單態(tài)氧量子產(chǎn)率方法,同時建立了光敏劑單態(tài)氧量子產(chǎn)率與溶解氧濃度和光敏劑磷光強(qiáng)度間的關(guān)系模型。測量Gd-HMME在不同溶解氧濃度條件下的單態(tài)氧量子產(chǎn)率,證明Gd-HMME三重態(tài)量子產(chǎn)率不隨O2濃度變化,磷光光譜不僅可以用于測量溶解氧濃度,也可以用于分析單態(tài)氧量子產(chǎn)率。此項(xiàng)研究為光動力反應(yīng)單態(tài)氧劑量光譜分析提供了理論依據(jù)。提出了基于Gd-HMME磷光光譜的熒光斷層成像技術(shù)監(jiān)測分析單態(tài)氧產(chǎn)量三維分布和光動力反應(yīng)進(jìn)度的方法。采用輻射傳輸方程的球諧展開計(jì)算激發(fā)光和Gd-HMME光致發(fā)光分布;通過光動力反應(yīng)動力方程研究Gd-HMME、O2和DPBF間在仿體內(nèi)的光動力反應(yīng)過程。通過熒光斷層成像重構(gòu)仿體內(nèi)光學(xué)參數(shù)、Gd-HMME濃度和溶解氧濃度分布,利用光動力反應(yīng)方程計(jì)算特定激發(fā)光場分布條件下計(jì)算單態(tài)氧產(chǎn)量、溶解氧濃度、DPBF濃度的空間和時間分布。仿真實(shí)驗(yàn)驗(yàn)證了基于Gd-HMME光譜監(jiān)測分析單態(tài)氧產(chǎn)量分布的可行性,在此基礎(chǔ)上可利用光動力反應(yīng)方程計(jì)算光動力反應(yīng)過程的分布。探索了上轉(zhuǎn)換光動力療法中光場分布和單態(tài)氧劑量分布分析方法并建立了光動力反應(yīng)的計(jì)算及重構(gòu)方法。仿真研究976 nm激光激發(fā)Na YF4:Yb/Er@Na Yb F4@Ce6和808 nm激光激發(fā)的NaYF4:Yb/Er@Na YF4:Nd@Na YF4@Ce6時,激發(fā)光功率度對上轉(zhuǎn)換發(fā)光量子產(chǎn)率及分布的影響,研究發(fā)現(xiàn)1~10 ms短脈沖高功率密度激發(fā)可以獲得更大有效深度;同紅光直接激發(fā)的光動力反應(yīng)相比,兩者均適合血紅蛋白含量較高的肝臟疾病治療,而后者對于含血紅蛋白和水都豐富的腎臟組織具治療優(yōu)勢;利用基于Na YF4:Yb/Er@Na YF4:Nd@Na YF4@Ce6納米材料中Nd3+離子下轉(zhuǎn)換熒光的熒光斷層成像技術(shù)重構(gòu)了納米粒子及組織光學(xué)參數(shù)分布,建立了數(shù)字仿體中的光動力反應(yīng)過程的三維重構(gòu)方法。此研究為組織光學(xué)窗口內(nèi)長波長激發(fā)光動力反應(yīng)單態(tài)氧劑量分布測量提供了解決方案。
[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.
【學(xué)位授予單位】：哈爾濱工業(yè)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R454.2
本文編號：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.
【學(xué)位授予單位】：哈爾濱工業(yè)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R454.2
【相似文獻(xiàn)】
相關(guān)博士學(xué)位論文 前1條
1 王鵬;光動力反應(yīng)中單態(tài)氧劑量分布的研究[D];哈爾濱工業(yè)大學(xué);2016年
，本文編號：2164499
本文鏈接：http://sikaile.net/yixuelunwen/swyx/2164499.html
最近更新
教材專著
