掺杂型量子点在生物医学检测和疾病诊断方面的应用研究
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摘要
作为一种新型的荧光纳米材料，量子点在生物医学领域的应用受到了国内外学者的广泛关注。量子点的应用范围广是由于它独特的化学性质和光学性质决定的，如发射光谱窄且对称、激发光谱宽且连续、光稳定性强、荧光寿命长等优点。目前，量子点的应用涵盖从生物检测到疾病诊断和治疗等许多方面。
尽管量子点在实际应用中得到了广泛的关注，但同时也出现了很多亟待解决的问题：如何降低量子点中重金属泄露带来的生物毒性，提高量子点在活体成像中的组织穿透能力和降低生物自发荧光的干扰等。本论文将水相合成的两种新型掺杂型量子点应用于生物医学检测、细胞成像及疾病的诊断中。主要内容包括:
论文的第一章中，主要介绍了量子点的性质、合成方法、应用研究及掺杂型量子点的研究进展等，阐明了本论文的研究意义及主要内容。
论文的第二章中，我们首次利用了无镉的Mn:ZnSe量子点制备的靶向光学探针对前列腺癌细胞进行了荧光标记与成像。该光学探针中采用的AMACR是一种高度敏感性和特异性的前列腺癌阳性标记物，与PSA相比具有更高的敏感性和特异性，可作为PSA的补充。Mn:ZnSe量子点可与AMACR抗体结合形成量子点-抗体生物复合物，从而可以对前列腺癌细胞LNCaP进行特异性的长时间的免疫荧光成像。MTT实验结果表明Mn:ZnSe量子点具有良好的生物相容性，对LNCaP细胞的生物毒性非常低。Mn:ZnSe量子点无重金属离子镉，因此具有非常低的生物毒性、优越的光稳定性和非常好的生物适应性，这将使它在生物检测、细胞组织成像甚至是活体研究方面表现出巨大的潜力。
论文的第三章中，我们利用Mn:ZnSe量子点和六个精氨酸的肽链（Arg6）构建的纳米探针，建立了一种能定量检测胰蛋白酶及其抑制剂的新方法。带正电的Arg6通过静电作用可与巯基丙酸修饰的Mn:ZnSe量子点结合，使量子点发生聚集引起其荧光猝灭。胰蛋白酶可以水解Arg6成为小的碎片，抑制量子点的聚集，使量子点荧光恢复，这样就可以通过Mn:ZnSe量子点荧光强度变化来定量检测胰蛋白酶。该纳米探针可用于检测胰蛋白酶的浓度低至40ng mL-1，我们将其用于人体液样品中胰蛋白酶含量的检测，得到满意的结果。该方法可以进行高通量胰蛋白酶及其抑制剂的检测，也可应用于胰腺炎的诊断和治疗。
论文的第四章中，主要利用水相合成法制备的Mn:ZnSe量子点来定量检测对氧磷。我们基于量子点的荧光猝灭和酶的抑制作用建立了一种高灵敏的双酶催化传感器。乙酰胆碱脂酶水解乙酰胆碱生成胆碱，胆碱被胆碱氧化酶氧化生成的过氧化氢可以猝灭Mn:ZnSe量子点的荧光。对氧磷可以和乙酰胆碱脂酶的活性中心体反应来抑制酶催化产生的过氧化氢对量子点的荧光猝灭效应，这样就可以通过Mn:ZnSe量子点荧光强度的变化来定量检测对氧磷。
论文的第五章中，我们利用纤维蛋白原和近红外CuInS_2量子点的复合体系进行高选择性和高灵敏度的凝血酶检测。近红外CuInS_2量子点具有低毒性、组织穿透能力强和无生物自发荧光干扰等优势，非常适用于生物医学检测和组织及活体成像。巯基丙酸修饰的CuInS_2量子点可以与纤维蛋白原表面的氨基通过静电作用形成Fib-CuInS_2复合物，这将导致CuInS_2量子点的荧光强度增强。当凝血酶加入到Fib-CuInS_2复合体系中时，就会催化游离的和结合的纤维蛋白原发生聚合，形成不溶性的纤维状纤维蛋白fibrin-CuInS_2QDs凝集物。离心后上层溶液的荧光强度会随着凝血酶浓度的增加而逐渐降低，通过上层溶液的荧光强度的变化即可实现对凝血酶的检测。这种方法能够检测皮摩尔浓度的凝血酶，在与凝血功能异常有关的疾病和癌症的诊断中具有巨大的潜力。
论文的第六章中，我们开发了一种新型的抗癌药物传输体系（CuInS_2QDs/PGA-DOX复合纳米粒子），该体系是基于L-半胱氨酸修饰的CuInS_2量子点与聚谷氨酸（PGA）的静电相互作用，以及PGA与抗癌药物阿霉素（DOX）之间的共价作用而建立的。DOX可以通过光诱导电子转移过程来猝灭量子点的荧光，当CuInS_2QDs/PGA-DOX复合纳米粒子与羧肽酶作用，或进入肿瘤细胞后，PGA会被水解释放出DOX，这样CuInS_2量子点的荧光就会恢复。此多功能复合纳米粒子不仅可以释放抗癌药物，对癌细胞有靶向性的治疗作用，还可以利用量子点的荧光信号对药物的传输过程进行实时监测，同时可对癌细胞进行荧光成像。
As novel fluorescence nanoparticles, quantum dots (QDs) have been extensiveattention from domestic and foreign scholars in the field of biomedical applications.QDs have some unique spectral properties, such as narrow and symmetricphotoluminescence, broad and intense absorption band, and tunable emission peakpositions. QDs of different sizes with the variable PL can be simultaneously excitedwith a single excitation light source, which endows them with considerableapplications in biomedical labeling, cellular effectors and reporters, light emittingdiodes, lasers and sensors. QDs have some disadvantages, such as the intrinsictoxicity from any leakage of cadmium, strong self-quenching caused by their smallensemble Stokes shift and sensitivity to thermal, chemical, and photochemicaldisturbances. In this paper, we focus on the application of QDs in a wide range ofbiological assays, imaging of cells and tissues, and even in vivo investigations,summarized as follows:
In the chapter1, we described the optical properties of QDs, the biomedicalapplication, the toxicity of QDs and research progress of doped QDs. Finally, weprovided the significance and contents of this dissertation.
In chapter2, we report the successful use of non-cadmium-based Mn-dopedZnSe d-dots (Mn:ZnSe) as highly efficient and nontoxic optical probes for humanprostate cancer cells imaging. Mn:ZnSe d-dots are directly prepared in aqueoussolution. The α-methylacyl-CoA racemase (AMACR) is overexpressed in prostatecancers; the presence of antibodies specific for AMACR is more sensitive andspecific than serum PSA levels in distinguishing patients with prostate cancers.Mn:ZnSe d-dots were linked to anti-AMACR to form Mn:ZnSe d-dots-anti-AMACRbioconjugates for the direct prostate cancer cells imaging. Mn:ZnSe d-dots exhibitedfavorable cytocompatibility to LNCaP cells with high concentration and long-timeincubation. Furthermore, cellular imaging results demonstrated that Mn:ZnSe d-dotswere remarkably efficacious for high-specificity cell imaging. Mn:ZnSe d-dots as non-cadmium-based safe and efficient optical imaging nanoprobes could therefore beused for targeting imaging and treatment of cancers in the early stage.
In the chapter3, a novel optical nanoprobe (Mn:ZnSe d-dots-Arg6) for trypsindetection and its inhibitor screening has been constructed successfully based on thefluorescence quenching and recovery of Mn:ZnSe d-dots. Mn:ZnSe d-dots wouldaggregate in the presence of positively charged Arg6(six arginine residues) due toelectrostatic interactions that result in the fluorescence quenching. Arg6can behydrolyzed into small fragments in the presence of trypsin, and accordingly, theaggregation of Mn:ZnSe d-dots can be prohibited, which lead to the fluorescencerecovery. Additionally, the optical nanoprobe can be employed for screening theinhibitors of trypsin. The optical nanoprobe was successfully applied for thedetermination of trypsin in human serum and urine samples with good accuracy andsatisfactory recovery.
In the chapter4, we report a sensitive and selective method for detection oforganophosphorus compounds (OPs) based on Mn:ZnSe d-dots-enzyme-hydrogenperoxide (H_2O_2) fluorescence quenching system. Acetylcholine esterase (AChE) canhydrolyze acetylcholine (ACh) to choline. Subsequently, choline oxidase (ChOx)oxidizes choline to generate H2O2. The enzyme-generated H2O2can quench thefluorescence of Mn:ZnSe d-dots. When paraoxon are introduced in solution, it caninteract with the active centers of AChE and decrease the enzyme activity. This leadsto the decrease of the H2O2production and then the fluorescence quenching rate ofMn:ZnSe d-dots. The proposed biosensor has been employed for quick determinationof paraoxon in tap water and milk samples with satisfactory reproducibility andaccuracy. This nano-biosensor was proved to be sensitive, rapid, simple and toleranceof most interfering substances.
In the chapter5, we describes a novel, simple method for the highly sensitive andselective detection of thrombin using fibrinogen (Fib) and CuInS_2quantum dots (QDs)as biosensing probes. Water-soluble near-infrared CuInS_2QDs capped bymercaptopropionic acid (MPA) was directly synthesized by hydrothermal method.Addition of fibrinogen to CuInS_2QDs solution led to the formation of Fib-CuInS_2
QDs complex, and resulting in the enhancement of photoluminescence intensity. Oncethrombin was introduced into the Fib-CuInS_2QDs system, it catalyzed thepolymerization of the free and conjugated fibrinogen species to form insolublefibrillar fibrin-CuInS_2QDs agglutinates. After centrifugation, the PL intensity of thesupernatants decreased upon increasing the concentration of thrombin. The proposedapproach provides a simple and fast-responding procedure, which might hold apromising potential for application in the diagnosis of diseases associated withcoagulation abnormalities and cancers.
In the chapter6, we reported a new anticancer drug release system based on cationic CuInS_2quantum dots (QDs) and anionic poly(L-glutamic acid) conjugated with anticancer drugdoxorubicin (QDs/PGA-DOX). Water-soluble near-infrared (NIR) CuInS_2QDs capped byL-cysteine was directly synthesized by hydrothermal method. DOX can quench thephotoluminescence (PL) of CuInS_2QDs through photoinduced electron transfer process. AfterQDs/PGA-Dox nanoparticles are exposed to carboxypeptidase or are taken up by cancer cells, thePGA is hydrolysed to release the Dox, inducing the activation of QDs fluorescence to “turn-on”state. The multifunctional nanoparticles can deliver Dox to targeted cancer cells and monitor theDox release, which concurrently images the cancer cells. Thus, these tumor-targetingmultifunctional QDs/PGA-DOX nanoparticles will hold great potential in terms ofclinical application to cancer therapy.
尽管量子点在实际应用中得到了广泛的关注，但同时也出现了很多亟待解决的问题：如何降低量子点中重金属泄露带来的生物毒性，提高量子点在活体成像中的组织穿透能力和降低生物自发荧光的干扰等。本论文将水相合成的两种新型掺杂型量子点应用于生物医学检测、细胞成像及疾病的诊断中。主要内容包括:
论文的第一章中，主要介绍了量子点的性质、合成方法、应用研究及掺杂型量子点的研究进展等，阐明了本论文的研究意义及主要内容。
论文的第二章中，我们首次利用了无镉的Mn:ZnSe量子点制备的靶向光学探针对前列腺癌细胞进行了荧光标记与成像。该光学探针中采用的AMACR是一种高度敏感性和特异性的前列腺癌阳性标记物，与PSA相比具有更高的敏感性和特异性，可作为PSA的补充。Mn:ZnSe量子点可与AMACR抗体结合形成量子点-抗体生物复合物，从而可以对前列腺癌细胞LNCaP进行特异性的长时间的免疫荧光成像。MTT实验结果表明Mn:ZnSe量子点具有良好的生物相容性，对LNCaP细胞的生物毒性非常低。Mn:ZnSe量子点无重金属离子镉，因此具有非常低的生物毒性、优越的光稳定性和非常好的生物适应性，这将使它在生物检测、细胞组织成像甚至是活体研究方面表现出巨大的潜力。
论文的第三章中，我们利用Mn:ZnSe量子点和六个精氨酸的肽链（Arg6）构建的纳米探针，建立了一种能定量检测胰蛋白酶及其抑制剂的新方法。带正电的Arg6通过静电作用可与巯基丙酸修饰的Mn:ZnSe量子点结合，使量子点发生聚集引起其荧光猝灭。胰蛋白酶可以水解Arg6成为小的碎片，抑制量子点的聚集，使量子点荧光恢复，这样就可以通过Mn:ZnSe量子点荧光强度变化来定量检测胰蛋白酶。该纳米探针可用于检测胰蛋白酶的浓度低至40ng mL-1，我们将其用于人体液样品中胰蛋白酶含量的检测，得到满意的结果。该方法可以进行高通量胰蛋白酶及其抑制剂的检测，也可应用于胰腺炎的诊断和治疗。
论文的第四章中，主要利用水相合成法制备的Mn:ZnSe量子点来定量检测对氧磷。我们基于量子点的荧光猝灭和酶的抑制作用建立了一种高灵敏的双酶催化传感器。乙酰胆碱脂酶水解乙酰胆碱生成胆碱，胆碱被胆碱氧化酶氧化生成的过氧化氢可以猝灭Mn:ZnSe量子点的荧光。对氧磷可以和乙酰胆碱脂酶的活性中心体反应来抑制酶催化产生的过氧化氢对量子点的荧光猝灭效应，这样就可以通过Mn:ZnSe量子点荧光强度的变化来定量检测对氧磷。
论文的第五章中，我们利用纤维蛋白原和近红外CuInS_2量子点的复合体系进行高选择性和高灵敏度的凝血酶检测。近红外CuInS_2量子点具有低毒性、组织穿透能力强和无生物自发荧光干扰等优势，非常适用于生物医学检测和组织及活体成像。巯基丙酸修饰的CuInS_2量子点可以与纤维蛋白原表面的氨基通过静电作用形成Fib-CuInS_2复合物，这将导致CuInS_2量子点的荧光强度增强。当凝血酶加入到Fib-CuInS_2复合体系中时，就会催化游离的和结合的纤维蛋白原发生聚合，形成不溶性的纤维状纤维蛋白fibrin-CuInS_2QDs凝集物。离心后上层溶液的荧光强度会随着凝血酶浓度的增加而逐渐降低，通过上层溶液的荧光强度的变化即可实现对凝血酶的检测。这种方法能够检测皮摩尔浓度的凝血酶，在与凝血功能异常有关的疾病和癌症的诊断中具有巨大的潜力。
论文的第六章中，我们开发了一种新型的抗癌药物传输体系（CuInS_2QDs/PGA-DOX复合纳米粒子），该体系是基于L-半胱氨酸修饰的CuInS_2量子点与聚谷氨酸（PGA）的静电相互作用，以及PGA与抗癌药物阿霉素（DOX）之间的共价作用而建立的。DOX可以通过光诱导电子转移过程来猝灭量子点的荧光，当CuInS_2QDs/PGA-DOX复合纳米粒子与羧肽酶作用，或进入肿瘤细胞后，PGA会被水解释放出DOX，这样CuInS_2量子点的荧光就会恢复。此多功能复合纳米粒子不仅可以释放抗癌药物，对癌细胞有靶向性的治疗作用，还可以利用量子点的荧光信号对药物的传输过程进行实时监测，同时可对癌细胞进行荧光成像。
As novel fluorescence nanoparticles, quantum dots (QDs) have been extensiveattention from domestic and foreign scholars in the field of biomedical applications.QDs have some unique spectral properties, such as narrow and symmetricphotoluminescence, broad and intense absorption band, and tunable emission peakpositions. QDs of different sizes with the variable PL can be simultaneously excitedwith a single excitation light source, which endows them with considerableapplications in biomedical labeling, cellular effectors and reporters, light emittingdiodes, lasers and sensors. QDs have some disadvantages, such as the intrinsictoxicity from any leakage of cadmium, strong self-quenching caused by their smallensemble Stokes shift and sensitivity to thermal, chemical, and photochemicaldisturbances. In this paper, we focus on the application of QDs in a wide range ofbiological assays, imaging of cells and tissues, and even in vivo investigations,summarized as follows:
In the chapter1, we described the optical properties of QDs, the biomedicalapplication, the toxicity of QDs and research progress of doped QDs. Finally, weprovided the significance and contents of this dissertation.
In chapter2, we report the successful use of non-cadmium-based Mn-dopedZnSe d-dots (Mn:ZnSe) as highly efficient and nontoxic optical probes for humanprostate cancer cells imaging. Mn:ZnSe d-dots are directly prepared in aqueoussolution. The α-methylacyl-CoA racemase (AMACR) is overexpressed in prostatecancers; the presence of antibodies specific for AMACR is more sensitive andspecific than serum PSA levels in distinguishing patients with prostate cancers.Mn:ZnSe d-dots were linked to anti-AMACR to form Mn:ZnSe d-dots-anti-AMACRbioconjugates for the direct prostate cancer cells imaging. Mn:ZnSe d-dots exhibitedfavorable cytocompatibility to LNCaP cells with high concentration and long-timeincubation. Furthermore, cellular imaging results demonstrated that Mn:ZnSe d-dotswere remarkably efficacious for high-specificity cell imaging. Mn:ZnSe d-dots as non-cadmium-based safe and efficient optical imaging nanoprobes could therefore beused for targeting imaging and treatment of cancers in the early stage.
In the chapter3, a novel optical nanoprobe (Mn:ZnSe d-dots-Arg6) for trypsindetection and its inhibitor screening has been constructed successfully based on thefluorescence quenching and recovery of Mn:ZnSe d-dots. Mn:ZnSe d-dots wouldaggregate in the presence of positively charged Arg6(six arginine residues) due toelectrostatic interactions that result in the fluorescence quenching. Arg6can behydrolyzed into small fragments in the presence of trypsin, and accordingly, theaggregation of Mn:ZnSe d-dots can be prohibited, which lead to the fluorescencerecovery. Additionally, the optical nanoprobe can be employed for screening theinhibitors of trypsin. The optical nanoprobe was successfully applied for thedetermination of trypsin in human serum and urine samples with good accuracy andsatisfactory recovery.
In the chapter4, we report a sensitive and selective method for detection oforganophosphorus compounds (OPs) based on Mn:ZnSe d-dots-enzyme-hydrogenperoxide (H_2O_2) fluorescence quenching system. Acetylcholine esterase (AChE) canhydrolyze acetylcholine (ACh) to choline. Subsequently, choline oxidase (ChOx)oxidizes choline to generate H2O2. The enzyme-generated H2O2can quench thefluorescence of Mn:ZnSe d-dots. When paraoxon are introduced in solution, it caninteract with the active centers of AChE and decrease the enzyme activity. This leadsto the decrease of the H2O2production and then the fluorescence quenching rate ofMn:ZnSe d-dots. The proposed biosensor has been employed for quick determinationof paraoxon in tap water and milk samples with satisfactory reproducibility andaccuracy. This nano-biosensor was proved to be sensitive, rapid, simple and toleranceof most interfering substances.
In the chapter5, we describes a novel, simple method for the highly sensitive andselective detection of thrombin using fibrinogen (Fib) and CuInS_2quantum dots (QDs)as biosensing probes. Water-soluble near-infrared CuInS_2QDs capped bymercaptopropionic acid (MPA) was directly synthesized by hydrothermal method.Addition of fibrinogen to CuInS_2QDs solution led to the formation of Fib-CuInS_2
QDs complex, and resulting in the enhancement of photoluminescence intensity. Oncethrombin was introduced into the Fib-CuInS_2QDs system, it catalyzed thepolymerization of the free and conjugated fibrinogen species to form insolublefibrillar fibrin-CuInS_2QDs agglutinates. After centrifugation, the PL intensity of thesupernatants decreased upon increasing the concentration of thrombin. The proposedapproach provides a simple and fast-responding procedure, which might hold apromising potential for application in the diagnosis of diseases associated withcoagulation abnormalities and cancers.
In the chapter6, we reported a new anticancer drug release system based on cationic CuInS_2quantum dots (QDs) and anionic poly(L-glutamic acid) conjugated with anticancer drugdoxorubicin (QDs/PGA-DOX). Water-soluble near-infrared (NIR) CuInS_2QDs capped byL-cysteine was directly synthesized by hydrothermal method. DOX can quench thephotoluminescence (PL) of CuInS_2QDs through photoinduced electron transfer process. AfterQDs/PGA-Dox nanoparticles are exposed to carboxypeptidase or are taken up by cancer cells, thePGA is hydrolysed to release the Dox, inducing the activation of QDs fluorescence to “turn-on”state. The multifunctional nanoparticles can deliver Dox to targeted cancer cells and monitor theDox release, which concurrently images the cancer cells. Thus, these tumor-targetingmultifunctional QDs/PGA-DOX nanoparticles will hold great potential in terms ofclinical application to cancer therapy.
引文
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