本文關(guān)鍵詞：環(huán)境響應(yīng)型近紅外熒光探針在腫瘤診療中的應(yīng)用研究　出處：《中國(guó)科學(xué)院深圳先進(jìn)技術(shù)研究院》2016年碩士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 七甲川菁染料 pH探針 近紅外熒光成像 光聲成像 光穩(wěn)定性

【摘要】：細(xì)胞內(nèi)的pH值在許多細(xì)胞生理過(guò)程中起著關(guān)鍵作用。正常生理?xiàng)l件下,細(xì)胞液中H+的濃度約為40 nm/L(7.40),變動(dòng)在0.1-0.2個(gè)pH單位就可能導(dǎo)致生理功能紊亂,產(chǎn)生疾病如炎癥、阿爾茨海默病、癌癥等。研究表明,腫瘤的pH值低于正常組織的pH值。因此,可視化檢測(cè)腫瘤pH,對(duì)實(shí)現(xiàn)腫瘤的準(zhǔn)確檢測(cè)和治療是非常重要的。熒光成像具有如非入侵式、低能量非離子福射、高的靈敏度和選擇性等多個(gè)優(yōu)點(diǎn),而廣泛用于活體內(nèi)pH檢測(cè)。近紅外熒光染料如的最大發(fā)射峰位于近紅外區(qū)(650-900 nm),具有組織穿透深、散射弱并可以可以避免背景熒光的干擾,因此以近紅外熒光染料為熒光團(tuán)的pH探針?lè)浅＿m合用于腫瘤pH檢測(cè)。本文首先合成七甲川菁染料母體,通過(guò)對(duì)中位氯的親核取代反應(yīng),我們合成五例中位二元氨取代的以七甲川菁染料為母體的pH熒光探針。然在此基礎(chǔ)上,探究其對(duì)腫瘤pH微環(huán)境檢測(cè)的應(yīng)用�；谠O(shè)計(jì)合成的一系列不同的中位氨取代的七甲川菁染料,我們探究這些染料分子在不同pH溶液中的光譜性質(zhì),發(fā)現(xiàn)其吸收光譜、熒光光譜都隨pH值的改變而產(chǎn)生明顯的變化,說(shuō)明可以用作pH探針。所合成的近紅外熒光染料1a-5a中探針3a的pKa為6.4,很適合用于腫瘤早起檢測(cè)和成像,故而篩選出探針3a繼續(xù)探討用于腫瘤的診療應(yīng)用研究。由于探針?lè)肿?a的吸收光強(qiáng)度表現(xiàn)出明顯的pH依賴,所以我們探究其在不同pH溶液中680 nm和760 nm處光聲信號(hào)。結(jié)果表明,760 nm/680 nm光聲信號(hào)比率表現(xiàn)出明顯的pH依賴的光聲信號(hào)變化性,在pH5.5-7.8范圍內(nèi)表現(xiàn)出很好的線性關(guān)系。同時(shí)探針?lè)肿?a生物組織模型光聲成像中,探針?lè)肿?a在同一pH值溶液中穿透不同厚度豬肉組織時(shí),其光聲信號(hào)強(qiáng)度比例沒(méi)有明顯變化,說(shuō)明可以實(shí)現(xiàn)準(zhǔn)確的腫瘤微酸環(huán)境pH檢測(cè),說(shuō)明探針?lè)肿?a是一個(gè)很好的光聲pH成像探針。動(dòng)物實(shí)驗(yàn)表明,探針?lè)肿?a有很好的光熱治療效果�？偟膩�(lái)說(shuō),我們?cè)O(shè)計(jì)篩選出一例熒光-光聲雙模pH敏感成像探針,能夠?qū)崿F(xiàn)更準(zhǔn)確的腫瘤微環(huán)境pH檢測(cè)。同時(shí),在熒光-光聲成像的引導(dǎo)下,實(shí)現(xiàn)更準(zhǔn)確的光熱治療。眾所周知,近紅外染料菁染料光穩(wěn)定性差和水溶性差阻礙其在生物中的應(yīng)用。針對(duì)近紅外染料菁染料的缺陷,我們將合成的近紅外pH探針包裹在三嵌段多肽聚合物PE G5000-PLL30-PLLeu40中。實(shí)驗(yàn)表明近紅外探針CP包裹在多肽膠束后,穩(wěn)定性有了顯著提高。染料包裹前后的光漂白特性和光穩(wěn)定性表明,僅僅光照60s后,游離的近紅外探針CP的熒光幾乎完全淬滅,可以非常明顯地看出溶液的顏色已經(jīng)完全褪去。而將染料包裹在納米顆粒(DNPs),在高能量的光照之后,溶液的熒光強(qiáng)度僅僅下降了約25%,而溶液的褪色也幾乎無(wú)法用肉眼觀察到。這些現(xiàn)象再次證實(shí)了菁染料的光穩(wěn)定性差,而包裹到納米膠束中后,穩(wěn)定性明顯提高�？偟膩�(lái)說(shuō),我們?cè)O(shè)計(jì)合成了一例pH響應(yīng)型納米探針,菁染料的穩(wěn)定性和水溶性有明顯提高,能夠用來(lái)檢測(cè)細(xì)胞內(nèi)pH變化,在腫瘤早期診斷和成像有較好的應(yīng)用前景。
[Abstract]:The intracellular pH plays a key role in many cellular processes. Under normal physiological conditions, the cell sap concentration of H+ is about 40 nm/L (7.40), the change in the 0.1-0.2 pH unit may cause physiological function disorder, cause diseases such as inflammation, Alzheimer's disease, cancer and so on. The study shows that the tumor the pH value is lower than the normal tissue pH value. Therefore, the visual detection of tumor pH, is very important for accurate detection and treatment of tumor. Fluorescence imaging has such as non-invasive, low energy ion radiation, high sensitivity and selectivity and many other advantages, and is widely used for in vivo detection of pH. Infrared fluorescence emission peak as in near infrared region (650-900 nm), with deep tissue penetration, weak scattering and fluorescent background interference can be avoided, so the pH probe near infrared fluorescent dye fluorophore is very suitable for tumor pH Detection. This paper firstly synthesized seven methine cyanine dye precursor, through nucleophilic substitution reaction of chlorinated, we synthesized five cases of two yuan to seven amine substituted methine cyanine dyes as pH fluorescent probes. Then based on the matrix, to explore the application of tumor microenvironment of pH detection. Seven methine cyanine dyes based on the design and synthesis of a series of different substituted in ammonia, we explore the spectral properties of these dyes in solution of different pH, found that the absorption spectra, fluorescence spectra with the change of pH value and produce significant changes that can be used as a pH probe. Near infrared fluorescent dye 1a-5a the synthesis of the probe 3a pKa is 6.4, it is suitable for early tumor detection and imaging, and screened for 3A probe to continue to explore the diagnosis and therapy of tumor research. As the probe molecule absorption of 3A light intensity showed significant pH dependence, so we explore In different pH solution of 680 nm and 760 nm of photoacoustic signal. The results showed that 760 nm/680 nm ratio of photoacoustic signal showing the photoacoustic signal was pH dependent, showed a good linear relationship in the range of pH5.5-7.8. At the same time the probe molecule 3A biological tissue model of photoacoustic imaging, probe molecular 3a in the same pH value through different thickness of pork in the solution, the photoacoustic signal intensity ratio did not change significantly, that can achieve accurate detection of the tumor micro environment of pH, indicating that the probe molecule 3a is a good photoacoustic imaging probe pH. Animal experiments show that the probe molecule 3A photothermal therapeutic effect very good. In general, we screened a case design of photoacoustic pH sensitive fluorescence dual-mode imaging probe, can achieve more accurate detection of tumor microenvironment of pH. At the same time, the fluorescence and photoacoustic imaging guided light heat treatment more accurately . as everyone knows, the near infrared cyanine dye dye light stability and poor water solubility hinder its application in biology. Aiming at the limitation of near infrared dye cyanine dyes, we will probe the synthesis of near infrared pH package in the three block of PE polypeptide polymer G5000-PLL30-PLLeu40. Experiments show that the near infrared probe CP wrapped in polypeptide micelles after and stability are greatly improved. Show that the dye package before and after photobleaching properties and light stability, just after 60s light, near infrared fluorescent probe CP free almost completely quenched, can clearly see the color of the solution has been completely faded. The dye entrapped in nanoparticles (DNPs), after high energy light, fluorescence intensity of the solution only decreased by about 25%, and the solution of the fade is almost impossible to see with the unaided eye. These phenomena proved photostability of cyanine dyes, and the package to nano micelles In the middle, the stability is obviously improved. In general, we have designed and synthesized a pH responsive nanoprobe. The stability and water solubility of cyanine dye has been significantly improved. It can be used to detect intracellular pH changes. It has a good application prospect in early diagnosis and imaging of tumors.

【學(xué)位授予單位】：中國(guó)科學(xué)院深圳先進(jìn)技術(shù)研究院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類號(hào)】：R730.4;O657.3

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