Aptameric Modulation of Relaxivity in MRI Contrast Agents

描述(申请人提供)：该项目的目标是开发下一代高灵敏度、靶向性和生物响应性的核磁共振造影剂适体调节剂。这些新试剂将在体内提供其他成像模式无法获得的额外结构和功能信息。在接下来的两年里，我们将通过以下三个目标提供金属离子络合物(例如Gd3+DOTA)与其基于寡核苷酸的受体(适配子)之间三种不同类型相互作用的初步表征：阴目标1我们将研究连接到Gd3+造影剂上的小分子与结合到这些分子上的适配子相互作用时发生的驰豫变化。我们将首先分离与磁共振造影剂结合的寡核苷酸受体，然后研究适体结合对松弛能力的影响。阴靶3我们将针对携带多种造影剂的支架分离适体。在后续的研究中，我们将通过几种可能的机制来表征这些适配子增强松弛能力的能力。在这个项目的最后，我们将提供几种改变磁共振造影剂弛豫度的方法的初步结果。基于适配子的方法是灵活的；单个适配子可以很容易地被工程成低聚和高度组织化的结构，并可以使其对其他识别过程敏感。因此，这个项目的主要意义在于，我们将为受体和代谢成像开辟全新的场所。 公共卫生相关性：我们的目标是提供高灵敏度、靶向性和生物响应性的基于寡核苷酸(适配子)的磁共振造影剂调节剂。在代谢和受体成像的背景下，这些调节器将提供当前成像模式所不具备的结构和功能信息。我们将重点展示三种不同类型的相互作用，通过这些相互作用，适体调节剂被预测可以增强MRI造影剂的弛豫性能。我们基于适体的方法的一个重要优势是它的灵活性；例如，利用DNA纳米技术的原理，单个受体可以很容易地被设计成寡聚和高度组织化的结构，并可以对其他识别过程敏感。

DESCRIPTION (provided by applicant): The goal of this project is to develop the next generation of highly-sensitive, targeted, and bio- responsive aptameric modulators of MRI contrast agents. These new reagents would provide in vivo additional structural and functional information, not otherwise available through other imaging modalities. Over the next two years we will provide initial characterization of three different types of interactions between metal ion complexes (e.g., Gd3+DOTA) and their oligonucleotide-based receptors (aptamers), through the following three aims: yIn Aim 1 we will study changes in relaxivity that occur when small molecules attached to gadolinium contrast agents interact with aptamers binding to those molecules. yIn Aim 2 we will first isolate oligonucleotide receptors binding to MRI contrast agents, and then study the impact of aptamer binding on relaxivity. yIn Aim 3 we will isolate aptamers against scaffolds carrying multiple contrast agents. In a follow- up study we will characterize the ability of these aptamers to enhance relaxivity by several possible mechanisms. At the end of this project we will provide preliminary results for several approaches to modify the relaxivity of MRI contrast agents. The approaches based on aptamers are flexible; individual aptamers can be readily engineered into oligomeric and highly-organized structures, and can be made sensitive to other recognition processes. Thus, the main significance of this project is that we will open completely new venues for receptor and metabolic imaging. PUBLIC HEALTH RELEVANCE: Our goal is to provide highly-sensitive, targeted, and bio-responsive oligonucleotide-based (aptameric) modulators of MRI contrast agents. In the context of metabolic and receptor imaging these modulators will provide structural and functional information not available with current imaging modalities. We will focus on demonstrating three different types of interactions through which aptameric modulators are predicted to enhance the relaxivity of MRI contrast agents. An important advantage of our approach based on aptamers is in its flexibility; for example, individual receptors can be readily engineered into oligomeric and highly-organized structures using principles of DNA nanotechnology, and can be made sensitive to other recognition processes.