MAGNETIC NANOSENSORS FOR BIOMEDICAL ANALYSES OF MICROVESICLES

描述(申请人提供)：微囊泡(MVS)是由细胞释放到循环中的磷脂囊泡，是最近出现的一种新的诊断生物标志物。据报道，包括心血管疾病、糖尿病和炎症在内的各种恶性肿瘤的MVS水平升高；MVS似乎也在红细胞老化过程中发挥着不可或缺的作用。然而，发展我们对MV生物学的知识，从而充分利用它们的临床潜力的一个主要障碍是缺乏准确和标准化的MV分析方法。我们最近开发了一种新的、基于纳米技术的诊断平台，称为“DMR”(诊断磁共振)。利用核磁共振原理，DMR设备测量样品的横向弛豫，从而用分子特定的磁性纳米颗粒(MNPs)标记生物目标。通过系统地开发优化的MNPs和基于芯片的微型核磁共振系统，DMR技术现在已经显著进步，可以提供灵敏的、护理点的细胞分子分析。在这些成就的基础上，这项提议的总体目标是调整和进一步推进DMR平台，以便直接从全血中快速检测和多重分析MVS。我们将具体抓好以下几个方面 目标。在目标1中，我们将合成新的磁性纳米试剂和检测方法，以实现对MV靶标的高效和选择性的MNP标记。在目标2中，我们将实现一个集成了复杂微流体的微型核磁共振系统。该系统的设计将使MV分析完全在单个芯片上进行；它将直接从全血中分离MVS，用MNPs标记MVS，并对目标MVS进行核磁共振测量。在目标3中，优化的纳米试剂和设备都将应用于血液产品中红细胞来源的MVS的检测和综合分析。这项研究将促进我们对血液老化生物学的理解，从而提高血液产品质量和输血安全性。我们展望了拟议的DMR-MV技术在生命科学和临床实践中的广阔诊断潜力。通过促进来自不同细胞来源的MVS的快速和定量的分子分析，这项技术可以使疾病早期发现和治疗监测成为可能。反过来，这可以通过提供关于个别患者的细胞/分子签名的有价值的信息，加快在创造个性化治疗方面的进展。 与公共卫生相关：我们建议开发一个新的、基于纳米技术的高度敏感的医疗诊断平台。这项研究是高度协同的，综合了磁性纳米材料、新型生物偶联化学技术和微电子学的优势。开发的平台将用于检测和筛选血液中的微囊，这是血管疾病和输血医学中的一个紧急诊断生物标志物。

DESCRIPTION (provided by applicant): Microvesicles (MVs) are phospholipid vesicles released into the circulation by cells, which have recently emerged as a new diagnostic biomarker. Elevated level of MVs has been reported in various malignancies, including cardiovascular diseases, diabetes, and inflammation; MVs also appear to play an integral role in the erythrocyte aging process. However, a major barrier to advancing our knowledge of MV biology, and thus fully harnessing their clinical potential, has been the lack of accurate and standardized methods for MV analysis. We have recently developed a new, nanotechnology-based diagnostic platform termed "DMR" (diagnostic magnetic resonance). By employing principles of nuclear magnetic resonance (NMR), the DMR device measures the transverse relaxation of samples, whereby biological targets are labeled with molecular-specific magnetic nanoparticles (MNPs). By systematically developing optimized MNPs and chip-based miniature NMR systems, the DMR technology has now significantly advanced so as to provide sensitive, point-of-care molecular analyses of cells. Building upon these achievements, the overall goal of this proposal is to adapt and further advance the DMR platform for rapid detection and multiplexed profiling of MVs directly from whole blood. We will specifically focus on the following aims. In Aim 1, we will synthesize new magnetic nanoagents and assay methods that will allow highly efficient and selective MNP-labeling of MV targets. In Aim 2, we will implement a miniaturized NMR system integrated with sophisticated microfluidics. This system will be designed to enable MV analysis to be performed entirely on a single chip; it will isolate MVs directly from whole blood, label MVs with MNPs, and perform NMR measurements on the targeted MVs. In Aim 3, both the optimized nanoagents and device will be applied to the detection and comprehensive profiling of erythrocyte-derived MVs in blood products. This study will advance our understanding of the biology of blood aging, which could lead to improved blood product quality and transfusion safety. We envision a broad diagnostic potential for the proposed DMR-MV technology in both the life sciences and in clinical practice. By facilitating the rapid and quantitative molecular analysis of MVs from different cellular origins, this technology could enable early disease detection and treatment monitoring. In turn, this could expedite advances in creating personalized treatment by providing valuable information on the cellular/molecular signatures of individual patients. PUBLIC HEALTH RELEVANCE: We propose to develop a new, nanotechnology-based platform for highly sensitive medical diagnosis. The research is highly synergistic, integrating advantages of magnetic nanomaterials, novel bioconjugation chemistry technology, and microelectronics. The developed platform will be applied to detect and screen microvesicles in blood, an emergent diagnostic biomarker in vascular diseases and transfusion medicine.