功能纳米荧光探针用于肿瘤细胞成像及诊治研究
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摘要
癌症是严重威胁人类生命和社会发展的重大疾病，是致人死亡的主要原因之一，其发病率呈逐年上升的趋势，因此，癌症的预防和治疗是目前人类医学健康面临的最大挑战。一方面，癌症的早期发现和诊断是预防和治疗癌症的关键，研究表明若能早期发现和做出正确诊断，并采取相应的治疗措施，可极大提高治愈率和生存率。然而，目前的常规诊断方法特异性和灵敏度较低，在肿瘤发生早期较难检测，当确诊时肿瘤细胞已经发生浸润和转移，从而错过治疗的最佳时机。为了尽早发现和诊断癌症，研究者致力于在细胞水平上利用肿瘤标志物的表达来检测和识别肿瘤细胞。另一方面，为了提高癌症的治疗效果，大量研究集中在开发新的药物和治疗方法，但目前化疗还存在许多缺陷，例如化疗药物的毒副作用大、靶向治疗效果差、肿瘤细胞会产生耐药性等，因此迫切需要我们发展可控释放的药物载体并靶向输送药物到肿瘤细胞，降低药物的剂量和毒副作用，增强药物的治疗效果，进而提高化疗的治疗效果。
近年来，随着纳米科技的不断发展，纳米荧光探针已经被广泛应用于化学、生物学、医学等领域，尤其是肿瘤细胞的诊断、成像及治疗。在这些纳米材料中，金纳米粒子有着独特的光学特性和生物亲和性，因此在生物检测、细胞和活体成像、药物输送等方面吸引了人们的广泛关注。尤其是高灵敏度、高选择性对多种肿瘤标志物的检测和成像，是目前研究的热点和难点，而将多组分检测的策略应用于生物模型中，实现动态实时对活细胞内多种物质的同时测定是目前研究的一个巨大挑战。研究表明目前还没有能够同时检测四种或四种以上肿瘤标志物的纳米探针被成功应用在活细胞中进行生物成像，而且大部分多色纳米探针都是检测同一类型的肿瘤标志物，为了更好地避免假阳性结果的出现，发展能同时检测细胞内多种肿瘤标志物及不同类型的肿瘤标志物的探针并用来进行早期癌症的诊断是非常必要且有意义的。另外，当前的药物载体主要集中在单一靶向的药物释放，无法同时实现对肿瘤细胞特异性识别和药物的可控输送，发展多重靶向的药物载体对于特异性识别肿瘤细胞、肿瘤细胞内的可控释放、减少用药量、提高治疗效果有着重要的理论意义和实际价值。
本论文基于细胞内的mRNA、基质金属蛋白酶(MMP)以及细胞表面的受体，利用金纳米粒子、DNA和肽链，设计制备了一系列纳米探针并用于肿瘤细胞的检测、成像、靶向输送及治疗，具体包括：
1.基于金纳米粒子和DNA分子信标设计了一种四色纳米荧光探针，纳米探针组装以后，荧光团的荧光被金纳米粒子猝灭，当遇到目标mRNA后，荧光恢复。首次实现了细胞内四种肿瘤mRNA的同时检测和成像。这个探针具有响应快速、特异性好、抗酶切特性以及好的生物亲和性等优点。该探针可以有效区分乳腺癌细胞、肝癌细胞及正常乳腺细胞和肝细胞，并能评估肿瘤mRNA在细胞中的不同表达水平。相比较传统的单一或者双组分mRNA的检测，该方法可以更有效地避免假阳性结果，从而提高癌症早期诊断的准确性，为癌症诊断提供更加全面可靠的信息。
2.利用分步组装的方式，将DNA分子信标和肽链组装到金纳米粒子表面，制备了一种四色纳米荧光探针。DNA分子信标和肽链上的荧光团可以被金纳米粒子猝灭，当遇到目标mRNA，分子信标会打开，荧光得以恢复；在MMP存在时，肽链会被切断并释放出荧光，从而实现对细胞内mRNA和MMP两种不同类型的肿瘤标志物的同时检测和成像。该探针首次实现了活细胞内不同类型的多种肿瘤标志物的检测和成像，并能够区分正常细胞和肿瘤细胞以及判断不同标志物表达水平的变化，既可以防止假阳性结果的出现，同时也可以提高肿瘤细胞早期诊断的准确性。
3.基于荧光共振能量转移的原理，发展了一种单一波长激发同时检测两种肿瘤标志物的方法。在两个识别不同mRNA的分子信标上，连接可以发生荧光共振能量转移的两个荧光染料(Alexa Fluor488和Cy3)，然后将两个分子信标组装到金纳米粒子表面，设计了一种纳米荧光探针（488nm激发收集Cy3的荧光）。在一种mRNA存在时，不会产生荧光信号，只有当细胞内两种mRNA都过表达时，才能收集到荧光信号，该方法可以在单一波长激发下同时检测细胞内的两种mRNA，有效减少多次激发造成的细胞损伤和背景干扰，还可避免单一检测可能造成的假阳性结果。
4.基于细胞表面的受体和细胞内的mRNA，发展了一种双重靶向的纳米载体。在金纳米粒子表面组装上修饰叶酸的DNA和靶向细胞内mRNA的分子信标，叶酸可以与肿瘤细胞表面的叶酸受体相结合增强细胞对纳米载体的摄取，分子信标茎部的GC序列携带阿霉素分子，当遇到肿瘤细胞中过表达的mRNA时，释放出药物分子，达到双重靶向的目的。实验结果表明纳米载体具有良好的稳定性、抗酶切性质以及生物亲和性，可以有效保护正常细胞并杀死肿瘤细胞，降低药物的用量并能显著增强药物的治疗效果。
Cancer is a major disease that threats human life and social development seriously,is also a leading cause of deaths worldwide. The incidence of cancer is increasing yearby year. Therefore, it is a great challenge to prevent and treat cancer for current publichealth. On the one hand, early detection and diagnosis are critical for prevention andtreatment of cancer. Recent studies have shown that the cure rate and survival ratecould be increased greatly if the cancer can be detected and diagnosed early and thecorresponding treatments are taken. However, the specificity and sensitivity of theconventional diagnostic methods are very low, it is difficult to detect early intumorigenesis. When the cancer was diagnosed, the invasion and metastasis have beenoccurred, thus the best time for treatment was missed. To detect and diagnose thecancer as soon as possible, the researchers devoted to detect and identify cancer cellsusing the expression of tumor markers at the cellular level. On the other hand, toimprove the therapeutic effect for cancer, much attention has been paid on thedevelopment of new drugs and treatments. Nevertheless, there are still manydrawbacks for chemotherapy such as the severe side effects of chemotherapy drugs,poor targeted therapy, drug resistantance for tumor cells, and so on. Hence, there is anurgent need for us to develop nanocarriers for controlled release, to target drugdelivery for tumor cells, to reduce the dose and side effects, to enhance the therapeuticeffect, and to improve the therapeutic effect of chemotherapy.
In recent years, with the development of nanotechnology, fluorescent nanoprobeshave been widely applied in the fields of chemistry, biology and medicine, especiallyfor diagnosis, imaging and treatment of cancer cells. Among these nanomaterials, goldnanoparticles possess unique optical properties and biocompatibility, so it hasattracted widespread attention in biological detection, cellular and in vivo imaging,drug delivery. In particular, it is hot and difficult to detect and image multiple tumormarkers with high sensitivity and high selectivity. The huge challenge in current studyis to apply multi-component strategy for detecting biological models, and determineintracellular multiple tumor markers dynamically and in real time. A variety of studieshave shown that there is no nanoprobe to simultaneously detect four or more tumor markers for biological imaging in living cells. Most of the multicolor nanoprobesdetect tumor markers in the same type. In order to avoid "false positive" resultseffectively, it is very necessary to develop the nanoprobes that can simultaneouslydetect multiple and different types of intracellular tumor markers for early cancerdetection. Moreover, the current drug carriers mainly focus on the single targeted drugrelease can not recognize the tumor cells specifically and release drugs in a controlledmanner. Therefore, the development of multi-targeted drug carriers has importanttheoretical and practical value for specific recognition of tumor cells, controlledrelease in tumor cells, the dosage reduction, the improvement of therapeutic effect.
In this dissertation, a variety of nanoprobes were designed and synthesized fortumor cell detection, imaging, targeted delivery and therapy, based on intracellularmRNA, matrix metalloproteinase (MMP) and cell surface receptor. It mainly includesthe following sections:
1. A four-color nanoprobe was devoloped based on the gold nanoparticles andmolecular beacons, that can simultaneously detect and image four kinds of mRNAs inliving cells. The nanoprobe composed of gold nanoparticles functionalized with adense shell of molecular beacons, which can identify multiple intracellular mRNAtranscripts. It shows rapid response, high specificity, nuclease stability and goodbiocompatibility. Intracellular experiments indicated that the nanoprobe couldeffectively distinguish tumor cells from their normal cells, even some mRNAs areoverexpressed in normal cells. Moreover, it can identify the changes of the expressionlevels of mRNA in living cells. The current strategy could provide more accurateinformation for early cancer detection and effectively avoid false positive results.
2. We prepare a four-color nanoprobe using step by step assembly. The molecularbeacons and peptides were assembled on the surface of gold nanoparticles. Thefluorescence of the dye-functionalized molecular beacons and peptides can bequenched by the gold nanoparticles. In the presence of target mRNA，the stem-loopstructure of molecular beacon was opened, recovering the fluorescence. In thepresence of MMP, the peptides were cut and the fluorescence was recovered.Simultaneous detection and imaging for different types of tumor markers ofintracellular mRNA and MMP can be achieved. This is the first time that a nanoprobewas successfully applied for detection and imaging of multiple different types oftumor markers in living cells. The nanoprobe could effectively discriminate normal cells and tumor cells and evaluate the change of expression of different tumor markers.It can prevent "false positive" results and improve the accuracy of early cancerdetection.
3. Based on the mechanism of fluorescence resonance energy transfer (FRET), weintroduce a novel strategy for simultaneous detection of two tumor markers using asingle wavelength excitation. The nanoprobe was prepared based on two molecularbeacons. The molecular beacons were functionalized with two fluorophores (AlexaFluor488and Cy3), in which the FRET can be generated for the two fluorophores. Inthe presence of an mRNA, no fluorescent signal was produced. When the two mRNAwere both overexpressed, fluorescent signal can be detected. The nanoprobe candetect two intracellular mRNAs simultaneously, which can reduce the cell injury andbackground noise of multiple excitation and avoid the "false positive" results causedby detection of a single mRNA.
4. A novel dual-targeted nanocarrier was developed based on cell surface receptorand intracellular mRNA. The gold nanoparticles were modified with a dense shell ofsynthetic oligonucleotides. The folic acid functionalized single-stranded DNA wasdesigned to target the folate receptor on the cancer cell surface and the molecularbeacon was employed as drug carrier for activated release associated with intracellulartumor mRNA. The nanocarrier possesses good stability, nuclease resistance and goodbiocompatibility. Intracellular experiments indicated that the dual-targeted nanocarriercould be preferentially internalized into cancer cells due to the folate receptortargeting and release Dox selectively in cancer cells because of the activated releasewith intracellular mRNA. The nanocarrier could reduce the dosage and greatlyimprove the therapeutic effect of drugs in cancer cells.
近年来，随着纳米科技的不断发展，纳米荧光探针已经被广泛应用于化学、生物学、医学等领域，尤其是肿瘤细胞的诊断、成像及治疗。在这些纳米材料中，金纳米粒子有着独特的光学特性和生物亲和性，因此在生物检测、细胞和活体成像、药物输送等方面吸引了人们的广泛关注。尤其是高灵敏度、高选择性对多种肿瘤标志物的检测和成像，是目前研究的热点和难点，而将多组分检测的策略应用于生物模型中，实现动态实时对活细胞内多种物质的同时测定是目前研究的一个巨大挑战。研究表明目前还没有能够同时检测四种或四种以上肿瘤标志物的纳米探针被成功应用在活细胞中进行生物成像，而且大部分多色纳米探针都是检测同一类型的肿瘤标志物，为了更好地避免假阳性结果的出现，发展能同时检测细胞内多种肿瘤标志物及不同类型的肿瘤标志物的探针并用来进行早期癌症的诊断是非常必要且有意义的。另外，当前的药物载体主要集中在单一靶向的药物释放，无法同时实现对肿瘤细胞特异性识别和药物的可控输送，发展多重靶向的药物载体对于特异性识别肿瘤细胞、肿瘤细胞内的可控释放、减少用药量、提高治疗效果有着重要的理论意义和实际价值。
本论文基于细胞内的mRNA、基质金属蛋白酶(MMP)以及细胞表面的受体，利用金纳米粒子、DNA和肽链，设计制备了一系列纳米探针并用于肿瘤细胞的检测、成像、靶向输送及治疗，具体包括：
1.基于金纳米粒子和DNA分子信标设计了一种四色纳米荧光探针，纳米探针组装以后，荧光团的荧光被金纳米粒子猝灭，当遇到目标mRNA后，荧光恢复。首次实现了细胞内四种肿瘤mRNA的同时检测和成像。这个探针具有响应快速、特异性好、抗酶切特性以及好的生物亲和性等优点。该探针可以有效区分乳腺癌细胞、肝癌细胞及正常乳腺细胞和肝细胞，并能评估肿瘤mRNA在细胞中的不同表达水平。相比较传统的单一或者双组分mRNA的检测，该方法可以更有效地避免假阳性结果，从而提高癌症早期诊断的准确性，为癌症诊断提供更加全面可靠的信息。
2.利用分步组装的方式，将DNA分子信标和肽链组装到金纳米粒子表面，制备了一种四色纳米荧光探针。DNA分子信标和肽链上的荧光团可以被金纳米粒子猝灭，当遇到目标mRNA，分子信标会打开，荧光得以恢复；在MMP存在时，肽链会被切断并释放出荧光，从而实现对细胞内mRNA和MMP两种不同类型的肿瘤标志物的同时检测和成像。该探针首次实现了活细胞内不同类型的多种肿瘤标志物的检测和成像，并能够区分正常细胞和肿瘤细胞以及判断不同标志物表达水平的变化，既可以防止假阳性结果的出现，同时也可以提高肿瘤细胞早期诊断的准确性。
3.基于荧光共振能量转移的原理，发展了一种单一波长激发同时检测两种肿瘤标志物的方法。在两个识别不同mRNA的分子信标上，连接可以发生荧光共振能量转移的两个荧光染料(Alexa Fluor488和Cy3)，然后将两个分子信标组装到金纳米粒子表面，设计了一种纳米荧光探针（488nm激发收集Cy3的荧光）。在一种mRNA存在时，不会产生荧光信号，只有当细胞内两种mRNA都过表达时，才能收集到荧光信号，该方法可以在单一波长激发下同时检测细胞内的两种mRNA，有效减少多次激发造成的细胞损伤和背景干扰，还可避免单一检测可能造成的假阳性结果。
4.基于细胞表面的受体和细胞内的mRNA，发展了一种双重靶向的纳米载体。在金纳米粒子表面组装上修饰叶酸的DNA和靶向细胞内mRNA的分子信标，叶酸可以与肿瘤细胞表面的叶酸受体相结合增强细胞对纳米载体的摄取，分子信标茎部的GC序列携带阿霉素分子，当遇到肿瘤细胞中过表达的mRNA时，释放出药物分子，达到双重靶向的目的。实验结果表明纳米载体具有良好的稳定性、抗酶切性质以及生物亲和性，可以有效保护正常细胞并杀死肿瘤细胞，降低药物的用量并能显著增强药物的治疗效果。
Cancer is a major disease that threats human life and social development seriously,is also a leading cause of deaths worldwide. The incidence of cancer is increasing yearby year. Therefore, it is a great challenge to prevent and treat cancer for current publichealth. On the one hand, early detection and diagnosis are critical for prevention andtreatment of cancer. Recent studies have shown that the cure rate and survival ratecould be increased greatly if the cancer can be detected and diagnosed early and thecorresponding treatments are taken. However, the specificity and sensitivity of theconventional diagnostic methods are very low, it is difficult to detect early intumorigenesis. When the cancer was diagnosed, the invasion and metastasis have beenoccurred, thus the best time for treatment was missed. To detect and diagnose thecancer as soon as possible, the researchers devoted to detect and identify cancer cellsusing the expression of tumor markers at the cellular level. On the other hand, toimprove the therapeutic effect for cancer, much attention has been paid on thedevelopment of new drugs and treatments. Nevertheless, there are still manydrawbacks for chemotherapy such as the severe side effects of chemotherapy drugs,poor targeted therapy, drug resistantance for tumor cells, and so on. Hence, there is anurgent need for us to develop nanocarriers for controlled release, to target drugdelivery for tumor cells, to reduce the dose and side effects, to enhance the therapeuticeffect, and to improve the therapeutic effect of chemotherapy.
In recent years, with the development of nanotechnology, fluorescent nanoprobeshave been widely applied in the fields of chemistry, biology and medicine, especiallyfor diagnosis, imaging and treatment of cancer cells. Among these nanomaterials, goldnanoparticles possess unique optical properties and biocompatibility, so it hasattracted widespread attention in biological detection, cellular and in vivo imaging,drug delivery. In particular, it is hot and difficult to detect and image multiple tumormarkers with high sensitivity and high selectivity. The huge challenge in current studyis to apply multi-component strategy for detecting biological models, and determineintracellular multiple tumor markers dynamically and in real time. A variety of studieshave shown that there is no nanoprobe to simultaneously detect four or more tumor markers for biological imaging in living cells. Most of the multicolor nanoprobesdetect tumor markers in the same type. In order to avoid "false positive" resultseffectively, it is very necessary to develop the nanoprobes that can simultaneouslydetect multiple and different types of intracellular tumor markers for early cancerdetection. Moreover, the current drug carriers mainly focus on the single targeted drugrelease can not recognize the tumor cells specifically and release drugs in a controlledmanner. Therefore, the development of multi-targeted drug carriers has importanttheoretical and practical value for specific recognition of tumor cells, controlledrelease in tumor cells, the dosage reduction, the improvement of therapeutic effect.
In this dissertation, a variety of nanoprobes were designed and synthesized fortumor cell detection, imaging, targeted delivery and therapy, based on intracellularmRNA, matrix metalloproteinase (MMP) and cell surface receptor. It mainly includesthe following sections:
1. A four-color nanoprobe was devoloped based on the gold nanoparticles andmolecular beacons, that can simultaneously detect and image four kinds of mRNAs inliving cells. The nanoprobe composed of gold nanoparticles functionalized with adense shell of molecular beacons, which can identify multiple intracellular mRNAtranscripts. It shows rapid response, high specificity, nuclease stability and goodbiocompatibility. Intracellular experiments indicated that the nanoprobe couldeffectively distinguish tumor cells from their normal cells, even some mRNAs areoverexpressed in normal cells. Moreover, it can identify the changes of the expressionlevels of mRNA in living cells. The current strategy could provide more accurateinformation for early cancer detection and effectively avoid false positive results.
2. We prepare a four-color nanoprobe using step by step assembly. The molecularbeacons and peptides were assembled on the surface of gold nanoparticles. Thefluorescence of the dye-functionalized molecular beacons and peptides can bequenched by the gold nanoparticles. In the presence of target mRNA，the stem-loopstructure of molecular beacon was opened, recovering the fluorescence. In thepresence of MMP, the peptides were cut and the fluorescence was recovered.Simultaneous detection and imaging for different types of tumor markers ofintracellular mRNA and MMP can be achieved. This is the first time that a nanoprobewas successfully applied for detection and imaging of multiple different types oftumor markers in living cells. The nanoprobe could effectively discriminate normal cells and tumor cells and evaluate the change of expression of different tumor markers.It can prevent "false positive" results and improve the accuracy of early cancerdetection.
3. Based on the mechanism of fluorescence resonance energy transfer (FRET), weintroduce a novel strategy for simultaneous detection of two tumor markers using asingle wavelength excitation. The nanoprobe was prepared based on two molecularbeacons. The molecular beacons were functionalized with two fluorophores (AlexaFluor488and Cy3), in which the FRET can be generated for the two fluorophores. Inthe presence of an mRNA, no fluorescent signal was produced. When the two mRNAwere both overexpressed, fluorescent signal can be detected. The nanoprobe candetect two intracellular mRNAs simultaneously, which can reduce the cell injury andbackground noise of multiple excitation and avoid the "false positive" results causedby detection of a single mRNA.
4. A novel dual-targeted nanocarrier was developed based on cell surface receptorand intracellular mRNA. The gold nanoparticles were modified with a dense shell ofsynthetic oligonucleotides. The folic acid functionalized single-stranded DNA wasdesigned to target the folate receptor on the cancer cell surface and the molecularbeacon was employed as drug carrier for activated release associated with intracellulartumor mRNA. The nanocarrier possesses good stability, nuclease resistance and goodbiocompatibility. Intracellular experiments indicated that the dual-targeted nanocarriercould be preferentially internalized into cancer cells due to the folate receptortargeting and release Dox selectively in cancer cells because of the activated releasewith intracellular mRNA. The nanocarrier could reduce the dosage and greatlyimprove the therapeutic effect of drugs in cancer cells.
引文
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