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Technology Development for Detection of Circulating Disease Biomarkers from Liquid Biopsies Using Multifunctional Nanomaterials

机译：使用多功能纳米材料从液体活检中检测循环疾病生物标志物的技术开发

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摘要

Despite the advance health care, devastating health conditions such as cancer and infectious diseases that affect populations worldwide are too often not diagnosed until morbid symptoms become apparent in the late phase. Obtaining an early and accurate diagnosis that reveal a hidden lethal threat before the disease becomes complicated may dramatically reduce the severity of its impact on the patient's life and increase the probability of survival. For example, in the case of ovarian cancer, which is the fifth most common malignancy and the fifth leading cause of cancer mortality in women in the US, the 5-year relative survival is 45%. If the diagnosis is made in stages III and IV when the cancer is well established and spreading, 17% of the women survive at five years. However, if ovarian cancer is found (and treated) before the cancer has spread outside the ovary, the survival rate can reach 93%. The sad fact is only 15% of all ovarian cancers are found at this early stage, whereas the vast majority, 70%, are detected in stages three and four. There is therefore an apparent need for the development of highly sensitive and specific noninvasive diagnostic assays for early detection, prognostic evaluation, and recurrence monitoring. This uneasy task, however, is hindered by three existing major limitations; (1) lack of an easy, inexpensive and noninvasive serial sampling method that can replace medical procedures, which is like colonoscopy for colon cancer or mammography for breast cancer. Second, lack of definitive molecular biomarkers for specific diseases as an alternative to protein biomarkers, like PSA for prostate cancer and (3) lack of a rapid multi-marker detection platform with high sensitivity and excellent specificity.;Liquid biopsy, a simple non-invasive blood test, is an emerging novel technology has the potential to overcome these restrictions. Because of its non-invasive nature, liquid biopsy can be serially collected to provide a personalized global snapshot of the total tumor burden at certain time points as well as identify specific mutations that arise during therapy. This potential in large part is driven by the fact that dying tumor cells or pathogens release their genetic materials into body fluids such as blood, urine, and saliva, and the load of circulating cell-free biomarkers are treasure trove for molecular diagnostics as they represent physiological or disease states. These biomarkers could be from whole cancer cells (CTC), to exosomes 'vesicles' containing tumor material, to proteins and peptides, to fragments of circulating cell free nucleic acids; cfDNA and cfRNA (mRNAs, lncRNAs, miRNAs).;MicroRNAs (miRNAs) are small non-coding RNAs that act as master regulators of many cellular processes. Because aberrant miRNA expression is an early event in tumorigenesis, circulating miRNAs might reflect tumor status and predict therapy response as noninvasive diagnostic biomarkers. They have been isolated from most of the body fluids and are highly stable in the circulation system, which makes miRNAs attractive diagnostic markers. As several miRNAs may be simultaneously involved in disease progression and development, it is inadequate to generate any meaningful or conclusive information for clinical diagnostics using only a single marker. Therefore having a platform capable of performing multiplexed biological detection is an indispensable tool for accurate clinical diagnostics.;To overcome these limitations, this research project exploits the unique tools provided by DNA nanotechnology, which combines two emerging fields---nano-graphene, MoS2, MNcy5.5, and AuNPs as two/three-dimensional nanoparticles in biomedicine and the role of blood-based circulating disease biomarkers (DNA/RNA) in cancer and infectious diseases---to address the challenges in diagnosis, prognosis and therapeutics. Taking advantage of controllable and programmable features of oligonucleotides, in our laboratory, two different multiplexed biomarker detection methods were developed by utilizing nanomaterials as a capture nanoplatform, DNA/RNA as circulating diseases-specific biomarkers and biofluids as minimally invasive sources.;The first multi-marker detection approach is to engineer water-soluble two-dimensional nanoassemblies and develop methodologies to detect circulating miRNAs and DNAs in human body fluids for the state-of-the art diagnostics. Nano-graphene oxide in this approach serves as a highly stable and functional template with extraordinary ssDNA adsorption capacity and fast and ultra-efficient fluorescence quenching capability lead us to engineer a fluorescently silent nano-platform. As a first application, we demonstrate the successful utilization of nano-graphene oxide based nanoplatform for the simultaneous detection of circulating prostate cancer biomarkers from various body fluids including blood, urine, and saliva. Later, we advanced nGO-based detection nanoplatform to an easily tunable and very highly controllable stimuli-responsive nano-device by attaching thermo-responsive polymers to advance its applications and minimize the drawbacks. (Abstract shortened by ProQuest.).
机译：尽管提供了先进的医疗保健，但直到晚期病态症状变得明显之前，往往无法诊断出影响世界各地人口的破坏性健康状况，例如癌症和传染病。在疾病变得复杂之前，尽早进行准确的诊断以揭示潜在的致命威胁，可以显着降低其对患者生命的影响的严重程度，并提高生存率。例如，就卵巢癌而言，它是美国女性中第五大最常见的恶性肿瘤，是癌症死亡率的第五大诱因，其5年相对生存率为45％。如果在癌症已充分建立并扩散的第三和第四阶段做出诊断，则有17％的妇女可以存活5年。但是，如果在癌扩散到卵巢外之前发现（并治疗）了卵巢癌，则存活率可以达到93％。可悲的事实是，在这个早期阶段仅发现所有卵巢癌的15％，而绝大多数（70％）在第三和第四阶段被发现。因此，显然需要开发用于早期检测，预后评估和复发监测的高度敏感和特异性的非侵入性诊断测定法。但是，现有的三个主要局限性阻碍了这项艰巨的任务。 （1）缺乏一种简单，便宜且无创的连续采样方法，可以代替医疗程序，例如结肠镜检查用于结肠癌或乳房X线照相术用于乳腺癌。其次，缺乏针对特定疾病的确定性分子生物标记物来替代蛋白质生物标记物，例如前列腺癌的PSA；（3）缺乏具有高灵敏度和出色特异性的快速多标记物检测平台。侵入式血液测试，是一种新兴的新颖技术，具有克服这些限制的潜力。由于其无创性，可以连续收集液体活检，以在某些时间点提供总肿瘤负荷的个性化全局快照，并识别治疗期间出现的特定突变。这种潜力在很大程度上由以下事实驱动：垂死的肿瘤细胞或病原体将其遗传物质释放到体液中，例如血液，尿液和唾液，循环中的无细胞生物标志物的负载是分子诊断的宝库，因为它们代表了生理或疾病状态。这些生物标志物可能来自整个癌细胞（CTC），包含肿瘤物质的外泌体“囊泡”，蛋白质和肽，循环中的无细胞核酸片段。 cfDNA和cfRNA（mRNA，lncRNA，miRNA）。； MicroRNA（miRNA）是小的非编码RNA，可充当许多细胞过程的主要调控因子。由于异常的miRNA表达是肿瘤发生中的早期事件，因此循环的miRNA可能反映肿瘤状态并预测作为无创诊断生物标志物的治疗反应。它们已从大多数体液中分离出来，并在循环系统中高度稳定，这使miRNA成为有吸引力的诊断标记。由于几种miRNA可能同时参与疾病的发展和发展，因此仅使用单个标记物就无法为临床诊断生成任何有意义或结论性的信息。因此，拥有一个能够执行多重生物学检测的平台对于准确的临床诊断是必不可少的工具。为了克服这些限制，本研究项目利用了DNA纳米技术提供的独特工具，该工具结合了两个新兴领域-纳米石墨烯MoS2 ，MNcy5.5和AuNPs作为生物医学中的二维/三维纳米粒子以及基于血液的循环疾病生物标记物（DNA / RNA）在癌症和传染病中的作用-以应对诊断，预后和治疗方面的挑战。利用寡核苷酸的可控和可编程特性，在我们的实验室中，通过利用纳米材料作为捕获纳米平台，DNA / RNA作为循环疾病特异性生物标志物以及生物流体作为微创来源，开发了两种不同的多重生物标志物检测方法。标记检测方法是设计水溶性二维纳米组件并开发方法以检测人体液中循环的miRNA和DNA，以进行最新的诊断。采用这种方法的纳米氧化石墨烯可作为高度稳定且功能强大的模板，具有出色的ssDNA吸附能力以及快速超高效的荧光猝灭能力，这使我们设计出了无荧光的纳米平台。作为第一个应用程序，我们证明了基于氧化石墨烯的纳米平台在从各种体液（包括血液，尿液和唾液）中同时检测循环前列腺癌生物标记物的成功利用。后来，我们通过将热响应性聚合物连接到先进的基于nGO的检测纳米平台，将其发展为易于调节且高度可控的刺激响应性纳米设备，以提高其应用范围并最大程度地减少弊端。 （摘要由ProQuest缩短。）。

著录项

  • 作者

    Balcioglu, Mustafa.;

  • 作者单位

    State University of New York at Albany.;

  • 授予单位 State University of New York at Albany.;
  • 学科 Biochemistry.;Analytical chemistry.;Materials science.
  • 学位 Ph.D.
  • 年度 2018
  • 页码 233 p.
  • 总页数 233
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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