本文選題：稀土納米晶 + 熒光性質(zhì)��； 參考：《哈爾濱工業(yè)大學(xué)》2016年博士論文

【摘要】：近些年,稀土納米晶在生物熒光成像和光動(dòng)力治療等醫(yī)學(xué)領(lǐng)域有很廣泛的研究,主要是因?yàn)橄⊥良{米晶具有近紅外光激發(fā)、無(wú)光漂白、無(wú)光閃爍、自體熒光少、光損傷小、光譜豐富、譜帶窄等特點(diǎn)�；谙⊥辽限D(zhuǎn)換納米晶結(jié)合的光敏劑(UCNC-PS)來(lái)開展光動(dòng)力療法是稀土納米晶醫(yī)學(xué)應(yīng)用的主要部分,這主要是由于稀土上轉(zhuǎn)換納米晶的引入將激發(fā)光轉(zhuǎn)移到了近紅外區(qū),有望實(shí)現(xiàn)深組織實(shí)體瘤的治療。然而,UCNC-PS在應(yīng)用中還存在活性氧產(chǎn)生效率低、激發(fā)光功率密度高、治療效果可控性差等問(wèn)題。本文針對(duì)如何提高上轉(zhuǎn)換發(fā)光效率改善UCNC-PS的活性氧產(chǎn)率、增強(qiáng)生物熒光成像的對(duì)比度實(shí)現(xiàn)影像指導(dǎo)的光動(dòng)力治療、以及開發(fā)新型近紅外光激發(fā)的光敏劑實(shí)施高效率的深組織實(shí)體瘤的光動(dòng)力治療等方面開展了研究。研究了環(huán)境對(duì)稀土離子發(fā)光中心熒光性質(zhì)的影響。設(shè)計(jì)并制備了NaYF4/NaYF4:Yb3+,Er3+/Na YF4多層核殼納米結(jié)構(gòu),這種特殊的核殼結(jié)構(gòu)包括三部分,其中心是Na YF4的支撐核,在其外面包覆Na YF4:Yb3+,Er3+發(fā)光薄層,在最外層包覆一層屏蔽殼層,這種結(jié)構(gòu)保證每個(gè)發(fā)光中心受到環(huán)境的作用影響相同,通過(guò)調(diào)節(jié)屏蔽殼層厚度能準(zhǔn)確的探究環(huán)境對(duì)稀土發(fā)光中心的影響。利用上轉(zhuǎn)換熒光光譜和時(shí)間分辨光譜探究了環(huán)境對(duì)稀土發(fā)光中心的熒光性質(zhì)的影響規(guī)律,發(fā)現(xiàn)稀土發(fā)光中心的綠色上轉(zhuǎn)換的熒光強(qiáng)度隨著屏蔽殼層厚度的增加呈e指數(shù)增強(qiáng)的關(guān)系,當(dāng)屏蔽殼層厚度減小到0時(shí),其上轉(zhuǎn)換熒光強(qiáng)度減小到飽和熒光強(qiáng)度的1/356;包覆NaYF4屏蔽殼層厚度在4 nm左右時(shí),外界環(huán)境對(duì)發(fā)光中心的作用減小90%。進(jìn)一步通過(guò)對(duì)發(fā)光中心能級(jí)輻射性質(zhì)的研究闡述了環(huán)境對(duì)發(fā)光中心熒光性質(zhì)影響的原因�；贜aYF_4:Yb3+,Tm3+納米晶開發(fā)近紅外單色的生物熒光探針。通過(guò)變化Tm3+的摻雜濃度對(duì)Na YF4:Yb3+,Tm3+納米晶的光譜進(jìn)行調(diào)節(jié),實(shí)現(xiàn)單色的800nm上轉(zhuǎn)換熒光。利用800 nm和470 nm的上轉(zhuǎn)換熒光的強(qiáng)度比來(lái)衡量800 nm上轉(zhuǎn)換熒光的單色性。通過(guò)對(duì)光譜的分析,發(fā)現(xiàn)800 nm單色性隨著Tm3+摻雜濃度的增加呈e指數(shù)增長(zhǎng),當(dāng)Tm3+摻雜濃度增加到4%時(shí),其熒光強(qiáng)度比可高達(dá)757。進(jìn)一步開展熒光成像研究,探究了Tm3+摻雜濃度與熒光量子產(chǎn)率之間的關(guān)系,當(dāng)Tm3+濃度達(dá)到4%時(shí),470 nm熒光的量子產(chǎn)率已經(jīng)下降到10-7量級(jí),而800 nm熒光的量子產(chǎn)率仍可達(dá)到10-3量級(jí),利用此濃度的納米晶的800nm上轉(zhuǎn)換熒光實(shí)現(xiàn)了高對(duì)比度的熒光成像。提出了一種近紅外光激發(fā)的新型光敏劑NaYF_4納米晶。NaYF_4納米晶具有近紅外光激發(fā),與氧之間能量傳遞效率高的特點(diǎn),因此,NaYF_4納米晶有望實(shí)現(xiàn)高效的深組織光動(dòng)力治療。NaYF_4納米晶中光敏成分是Yb3+,具體的機(jī)制為Yb3+吸收近紅外激發(fā)光,然后將能量傳遞給氧,進(jìn)而產(chǎn)生活性氧。本文利用化學(xué)探針?lè)?yàn)證了NaYb F4納米晶可以產(chǎn)生活性氧,并根據(jù)Yb3+壽命隨氧濃度的響應(yīng),得到了Yb3+與O2之間的能量傳遞速率,發(fā)現(xiàn)二者之間具有較高的能量傳遞速率。同時(shí)也將Na YbF4納米晶作為光敏劑與UCNC-PS進(jìn)行了對(duì)比,結(jié)果表明NaYb F4納米晶具有更高的活性氧產(chǎn)生速率。基于NaYbF_4納米晶開展了光動(dòng)力療法的研究。首先探究了活體光動(dòng)力治療條件,包括藥物的孵育時(shí)間、孵育濃度、光照時(shí)間和光功率密度、藥物毒性等。在此基礎(chǔ)上進(jìn)行了體外的光動(dòng)力治療,發(fā)現(xiàn)NaYF_4納米晶對(duì)PC-9細(xì)胞有很好的殺傷效果,當(dāng)藥物濃度在10μg/m L,光照時(shí)間在0.5 h時(shí),細(xì)胞存活率仍可降低到40%左右。同時(shí),治療條件和細(xì)胞存活率之間存在e指數(shù)關(guān)系,為實(shí)施可控的光動(dòng)力治療提供了實(shí)驗(yàn)依據(jù)。進(jìn)一步通過(guò)流式細(xì)胞術(shù)對(duì)細(xì)胞的死亡機(jī)制進(jìn)行了實(shí)驗(yàn)研究,結(jié)果表明光動(dòng)力治療過(guò)程中細(xì)胞凋亡和壞死均存在。體內(nèi)光動(dòng)力治療結(jié)果表明基于NaYb F4納米晶的光動(dòng)力療法可使腫瘤體積發(fā)生明顯的縮小。
[Abstract]:In recent years, rare earth nanocrystals have been widely studied in biomedical fields such as bioluminescence imaging and photodynamic therapy, mainly because the rare earth nanocrystals have near infrared light excitation, no light bleaching, light scintillation, less autofluorescence, less light damage, rich spectrum and narrow band, and so on. The photosensitizer based on the nanocrystalline binding of rare earth (UCNC-PS) To carry out photodynamic therapy is the main part of the application of rare earth nanocrystalline medicine. This is mainly due to the introduction of rare earth's upconversion nanocrystals to transfer the excited luminescence to the near infrared region. It is expected to realize the treatment of deep tissue solid tumor. However, UCNC-PS still has low active oxygen production efficiency, high excitation light power density and therapeutic effect in the application. In this paper, the research on how to improve the efficiency of up conversion luminescence efficiency to improve the active oxygen yield of UCNC-PS, enhance the contrast of bioluminescence imaging to realize photodynamic therapy guided by image, and develop a new type of near infrared light stimulated photosensitizer to implement high efficiency photodynamic therapy for deep tissue solid tumor. The effects of the environment on the fluorescence properties of the rare earth ion luminescence center were investigated. The NaYF4/NaYF4:Yb3+, Er3+/Na YF4 multilayer nuclear shell nanostructures were designed and prepared. The special nuclear shell structure consists of three parts. The center is the support core of Na YF4, which covers the outer layer of Na YF4:Yb3+, Er3+ and the outer layer of a layer of shielding shell. The influence of environment on the luminescence center of rare earth can be accurately explored by adjusting the thickness of shielding shell. Using up conversion fluorescence spectrum and time resolved spectrum, the law of environment to the luminescence of rare earth luminescence center is explored, and the green on the luminescent center of rare earth is found. The fluorescence intensity of the converted shell is e exponentially enhanced with the increase of the shielding shell thickness. When the shielding shell thickness is reduced to 0, the upconversion fluorescence intensity decreases to 1/356 of the saturated fluorescence intensity. When the thickness of the coated NaYF4 shielding shell is about 4 nm, the effect of the external environment on the luminescent center is reduced by 90%. further through the luminescence center. The effect of energy level radiation on the fluorescence properties of the luminescent center is explained. Based on the NaYF_4:Yb3+, Tm3+ nanocrystals, the near-infrared monochromatic bioluminescence probe is developed. By changing the doping concentration of Tm3+, the spectra of Na YF4:Yb3+ and Tm3+ nanocrystals are regulated to realize the single color upconversion fluorescence of 800nm. 800 nm and 470 nm are used. The intensity ratio of upconversion fluorescence is measured to measure the monochromatic property of the upconversion fluorescence of 800 nm. Through the analysis of the spectrum, it is found that the monochromatic of 800 nm increases exponentially with the increase of Tm3+ doping concentration. When the Tm3+ doping concentration increases to 4%, the fluorescence intensity is up to 757. to further develop the fluorescence imaging study, exploring the Tm3+ doping concentration and fluorescence. When the Tm3+ concentration reaches 4%, the quantum yield of the 470 nm fluorescence has been reduced to 10-7, while the quantum yield of the 800 nm fluorescence can still reach 10-3. A high contrast fluorescence image is realized by using the 800nm up conversion fluorescence of the nanocrystalline in this concentration. A new type of photosensitivity excited by near infrared light is proposed. NaYF_4 nanocrystalline.NaYF_4 nanocrystals have the characteristics of near infrared light excitation and high energy transfer efficiency between oxygen and oxygen. Therefore, NaYF_4 nanocrystalline is expected to achieve efficient deep tissue photodynamic treatment of.NaYF_4 nanocrystalline photosensitive component is Yb3+, the specific mechanism for Yb3+ absorption near infrared excitation, and then transfer energy to oxygen, and then produce life. NaYb F4 nanocrystals can produce living oxygen by chemical probe, and the energy transfer rate between Yb3+ and O2 is obtained according to the response of Yb3+ life with oxygen concentration. It is found that there is a high energy transfer rate between the two and the Na YbF4 nanocrystals are also compared with UCNC-PS as photosensitizers. NaYb F4 nanocrystals have higher ROS production rate. Based on NaYbF_4 nanocrystals, the study of photodynamic therapy was carried out. First, the conditions of active photodynamic therapy were explored, including incubation time, incubation concentration, light time, light power density and drug toxicity. On this basis, photodynamic therapy in vitro was carried out and N was found. AYF_4 nanocrystals have a good killing effect on PC-9 cells. When the drug concentration is 10 mu g/m L and the light time is 0.5 h, the cell survival rate can still be reduced to about 40%. At the same time, the relationship between the treatment conditions and the cell survival rate is e index, which provides the experimental basis for the implementation of the controlled photodynamic therapy. The mechanism of cell death was experimentally investigated. The results showed that both apoptosis and necrosis existed during photodynamic therapy. Photodynamic therapy in vivo showed that photodynamic therapy based on NaYb F4 nanocrystals could significantly reduce tumor volume.

【學(xué)位授予單位】：哈爾濱工業(yè)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：TB383.1;R73-36

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