本文選題：熒光納米晶　切入點(diǎn)：近紅外熒光　出處：《天津大學(xué)》2016年博士論文　論文類型：學(xué)位論文

【摘要】：隨著納米生物技術(shù)的迅速發(fā)展,近紅外CuInS量子點(diǎn)和NaYF_4上轉(zhuǎn)換納米晶(UCNs)在腫瘤的診斷和治療領(lǐng)域得到了廣泛的關(guān)注。然而,目前制備的CuInS量子點(diǎn)和NaYF_4UCNs表面多為疏水配體,無法直接應(yīng)用于水相生物環(huán)境。鑒于此,本文以CuInS量子點(diǎn)和NaYF_4UCNs為主體,通過表面功能化組裝修飾及編碼微球等技術(shù),構(gòu)建了一系列多功能的腫瘤診療熒光平臺(tái),并初步探索了其在腫瘤細(xì)胞/亞細(xì)胞水平成像、腫瘤可視化治療及腫瘤標(biāo)志物檢測(cè)等領(lǐng)域的應(yīng)用。具體內(nèi)容如下:1.腫瘤微環(huán)境響應(yīng)性CuInS量子點(diǎn)納米探針的構(gòu)建及應(yīng)用�；谀[瘤微環(huán)境的弱酸性特性,本文從分子設(shè)計(jì)角度出發(fā),首先合成出pH敏感的雙親性高分子,即月桂酸和2,3-二甲基馬來酸酐共接枝的聚賴氨酸,并將其與CuInS量子點(diǎn)進(jìn)行多功能組裝,構(gòu)建出一種腫瘤微環(huán)境響應(yīng)而電荷反轉(zhuǎn)的量子點(diǎn)納米探針,用于腫瘤細(xì)胞的靶向成像。結(jié)果證明,該納米探針粒徑均一、非特異性吸附低、穩(wěn)定性好、細(xì)胞毒性低,且具有pH響應(yīng)的電荷反轉(zhuǎn)功能。在正常pH 7.4時(shí)呈負(fù)電性,而在腫瘤微環(huán)境pH 6.8時(shí)迅速反轉(zhuǎn)為正電性,在HeLa細(xì)胞中表現(xiàn)出顯著增強(qiáng)的細(xì)胞攝取,成功實(shí)現(xiàn)對(duì)腫瘤細(xì)胞的靶向熒光成像;2.線粒體靶向高熒光穩(wěn)定性CuInS量子點(diǎn)納米平臺(tái)的構(gòu)建及應(yīng)用。本文以CuInS量子點(diǎn)為核、自行設(shè)計(jì)制備的超支化聚縮水甘油醚衍生物為功能修飾層、膜滲透親脂三苯基膦陽(yáng)離子為線粒體靶向功能分子,構(gòu)建出一種線粒體靶向量子點(diǎn)探針。結(jié)果證明,該探針細(xì)胞毒性低、非特異性吸附少,且能夠?qū)崿F(xiàn)特異性的線粒體靶向成像功能,跟傳統(tǒng)的線粒體染料相比,該量子點(diǎn)探針熒光穩(wěn)定性好,無光漂白淬滅現(xiàn)象。此外,將作用于線粒體的抗癌藥物負(fù)載到該體系中可實(shí)現(xiàn)對(duì)腫瘤細(xì)胞更高效的殺傷;3.腫瘤可視化聯(lián)合治療上轉(zhuǎn)換熒光納米平臺(tái)的構(gòu)建及應(yīng)用。本文以NaYF_4:Yb,ErUCNs為核、阿霉素為化療藥物、酞菁鋅為光敏劑、牛血清白蛋白-聚己內(nèi)酯結(jié)合體為修飾層,構(gòu)建出一種集熒光成像、化療和光動(dòng)力學(xué)治療(PDT)于一體的多功能可視化腫瘤聯(lián)合治療納米平臺(tái)。結(jié)果證明,該體系在980 nm光源輻照下UCNs發(fā)射光能成功激發(fā)酞菁鋅產(chǎn)生活性氧,同時(shí)實(shí)現(xiàn)對(duì)腫瘤細(xì)胞的熒光成像。跟單一的化療或PDT相比,該聯(lián)合治療體系對(duì)HeLa細(xì)胞的殺傷效果顯著增4.多色上轉(zhuǎn)換熒光編碼微球免疫檢測(cè)平臺(tái)的構(gòu)建及應(yīng)用。本文采用高溫油相熱分解法合成了六種顏色的NaYF_4UCNs,并結(jié)合磁性納米顆粒和編碼微球技術(shù)制備出多色上轉(zhuǎn)換熒光編碼微球(UCNMMs)。結(jié)果證明,該UCNMMs熒光穩(wěn)定性優(yōu)異、磁響應(yīng)性好,可實(shí)現(xiàn)快速磁分離;跟傳統(tǒng)的下轉(zhuǎn)換熒光編碼體系相比,UCNMMs免疫檢測(cè)體系具有雙光激發(fā)特性,可成功避免編碼信號(hào)和報(bào)告信號(hào)間的熒光干擾,檢測(cè)靈敏度更高;該體系成功用于鼠IgG的檢測(cè),最低檢測(cè)限為0.01ng/m L。綜上所述,本文成功構(gòu)建了一系列基于CuInS量子點(diǎn)和NaYF_4上轉(zhuǎn)換納米晶的多功能腫瘤診療用熒光納米平臺(tái),極大地推動(dòng)了熒光納米顆粒在腫瘤診斷和治療領(lǐng)域的應(yīng)用和發(fā)展。
[Abstract]:With the rapid development of nano biotechnology, near infrared CuInS quantum dots and NaYF_4 upconversion nanoparticles (UCNs) has received wide attention in the field of diagnosis and treatment of tumors. However, the preparation of CuInS quantum dots and NaYF_4UCNs surface hydrophobic ligands, cannot be applied directly in aqueous biological environment. In view of this, this paper using CuInS quantum dots and NaYF_4UCNs as the main body, through the surface functional group and decoration technology constructs encoding microspheres, tumor diagnosis and treatment of a series of multifunctional fluorescence platform, and explore its subcellular level in tumor cells / tumor imaging, visualization and treatment of tumor marker detection applications. The specific contents are as follows: 1. the tumor microenvironment response of construction and application of CuInS quantum dot nano probe. The weak acid characteristics of the tumor microenvironment based on this paper, from the perspective of molecular design, we synthesized pH sensitive The amphiphilic polymer, namely lauric acid and two 2,3- methyl maleic anhydride grafting poly lysine, and with CuInS quantum dots multifunctional assembly, construct a tumor microenvironment response and quantum dot charge reversal nano probe, for tumor targeted imaging. Results show that the nano probe of uniform size, low non-specific adsorption, good stability, low toxicity, and has the function of charge reversal pH response. In 7.4 normal pH was negative, while in the tumor microenvironment of pH 6.8 was quickly reversed positive, showed significantly enhanced cellular uptake in HeLa cells, the successful implementation of the tumor cell targeting fluorescence imaging; 2. mitochondrial targeting construction and application of CuInS quantum dot nano platform Gao Yingguang stability. In this paper, using CuInS quantum dots as the core, designed for preparation of hyperbranched polyglycerol derivatives as functional modification layer Three, membrane permeability of lipophilic cationic phenyl phosphine mitochondrial targeting molecule, construct a mitochondrial targeting quantum dot probe. The results proved that the probe with low toxicity, less nonspecific adsorption, and can realize the specificity of mitochondrial targeting imaging function, compared with the traditional mitochondrial dyes, quantum dots fluorescence stability, no photobleaching quenching phenomenon. In addition, anticancer drugs will be applied to the realization of the mitochondrial load to kill tumor cells can be more efficient in the system; construction and application of 3. tumor visualization combined treatment of upconversion fluorescent nano platform. Based on NaYF_4:Yb, ErUCNs as the core, adriamycin chemotherapy drug, phthalocyanine zinc as photosensitizer, bovine serum albumin and polycaprolactone combination as the modification layer, construct a set of fluorescence imaging, chemotherapy and photodynamic therapy (PDT) functions in one visual combined cancer treatment Treatment of nano platform. The results show that the system in 980 nm light under the irradiation of UCNs light emission of zinc phthalocyanine successfully stimulate the production of reactive oxygen species, and fluorescence imaging of tumor cells. Compared with the single chemotherapy or PDT, the killing effect of the combined treatment system of HeLa cells increased significantly in the construction and application of 4. multicolor upconversion fluorescence encoding microsphere immunoassay detection platform. The decomposition of the six colors of NaYF_4UCNs high temperature oil, combined with magnetic nanoparticles and microspheres prepared encoding multicolor fluorescent encoding microspheres (UCNMMs). The result shows that the UCNMMs fluorescent stability is excellent, good magnetic response, which can realize fast magnetic separation; with the traditional conversion fluorescence encoding system in UCNMMs immune detection system with double optical excitation characteristics, successfully avoiding the fluorescence interference signal encoding and reporting between the signals, the detection sensitivity is more The system successfully used to detect high; in IgG, the lowest detection limit of 0.01ng/m L. in summary, we successfully established a series of tumor diagnosis and treatment based on the multi function of CuInS quantum dots and NaYF_4 upconversion nanocrystals with fluorescent nano platform, greatly promoted the development and application of fluorescent nanoparticles in the field of cancer diagnosis and treatment.

【學(xué)位授予單位】：天津大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R73-3;TB383.1

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