Activatable MR Imaging Probes

可激活 MR 成像探头

• 批准号: 8179525
• 负责人: Peter D Caravan
• 金额: $ 28.36万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-07 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8179525
• 关键词: Acids; Affinity; Binding; Biochemical Reaction; Biological; Calcium; Cells; Chemistry; Clinical; Complex; Development; Diffusion; Dimensions; Dissociation; Electrodes; Electronics; Elements; Environment; Gene Activation; Haptens; Human; Hydration status; Hypoxia; Image; In Vitro; Injection of therapeutic agent; Ions; Islets of Langerhans; Libraries; Magnetic Resonance; Magnetic Resonance Imaging; Manganese; Measurement; Measures; Modeling; Molecular; Mus; Names; Neurons; Normal tissue morphology; Organism; Oryctolagus cuniculus; Oxidants; Oxidation-Reduction; Oxygen; Penetration; Perfusion; Permeability; Positron-Emission Tomography; Property; Reducing Agents; Relative (related person); Relaxation; Reporter Genes; Reporting; Resolution; Signal Transduction; Stimulus; Structure; System; Technology; Time; Tissues; Translating; Translations; Variant; Water; base; blood oxygen level dependent; design; gadolinium oxide; imaging probe; improved; in vivo; insight; iron oxide; light microscopy; man; millimeter; nanoparticle; oxidation; response; sensor; tumor

DESCRIPTION (provided by applicant): Activatable MR Imaging Probes Activatable magnetic resonance (MR) imaging probes offer the potential to provide unprecedented biological insights. MR probes responsive to Ca2+ flux, Zn2+ flux, reporter genes, enzymatic activity, pO2, and pH have been reported. Potential applications of such probes include direct imaging of neuronal currents, pancreatic islet viability, gene activation, and key elements of the heterogeneous tumor microenvironment. MR allows the interrogation of intact, opaque organisms in three dimensions at cellular resolution (~10 5m) on high field systems and sub millimeter resolution on clinical scanners. The deep tissue penetration and high resolution make MR make it possible to directly translate findings from cells to mice to humans. The fundamental limitation of activatable MR probes that stifles their translation is the difficulty in distinguishing "active" from "inactive" probe. In MRI primarily water is imaged and the probe is detected indirectly by its effect on the water signal. This effect depends on probe concentration and the probe's relaxivity. Relaxivity is dependent on a number of molecular factors including the hydration state of the probe and its rotational diffusion rate. It is possible to design activatable or "smart" probes where the relaxivity changes in response to an environmental stimulus, e.g. the probe is transformed via enzymatic reaction from a low relaxivity state to a high relaxivity state, or the probe's relaxivity changes upon binding an analyte, e.g. calcium. Although relaxivity can be exquisitely sensitive to a stimulus, the MR signal change depends on both relaxivity and probe concentration: two unknowns. In vitro, where concentration does not change, these probes act as elegant sensors. However in vivo, the probe concentration is unknown and changes with time. Relative to normal tissue, concentrations may be higher in diseased tissue due to increased endothelial permeability, or lower because of poor perfusion. Signal change could be a result of distribution of inactive probe or could be due to probe activation. Currently there is no practical way to distinguish active from inactive probe. We propose activatable probes that are completely MR silent in the "off" state. In this way, any change in MR signal after probe injection must be due to activation of the probe. We propose a new paradigm for activatable MR probes based on the reduction-oxidation (redox) chemistry of manganese. Divalent manganese (Mn2+) is a potent MR relaxation agent but Mn3+ is generally a poor relaxor. We will prepare stable manganese complexes that can reversibly convert from a truly MR-off state (Mn3+) to a MR-on state (Mn2+) in the presence of an environmental stimulus. With development of a tunable redox core, it is possible to design probes sensitive to pH, enzymatic activity, ion flux, or specific haptens. In this application we will focus on developing an MR oxygen sensor for hypoxia imaging, where MR signal is only generated in hypoxic regions. We will validate this hypoxia probe in mouse and rabbit tumor models by comparing to direct pO2 electrode measurements, a positron emission tomography hypoxia probe, and blood oxygen level dependent MR. PUBLIC HEALTH RELEVANCE: Project Narrative This goal of this project is to develop a magnetic resonance imaging probe that can be used to noninvasively identify and quantify regions of low oxygen levels in tumors (hypoxia). Characterizing hypoxic tumors may be valuable in guiding the choice of therapy that a patient receives.

描述（由申请人提供）：可激活的MR成像探针可激活的磁共振（MR）成像探针提供了提供前所未有的生物学见解的潜力。 MR探针响应Ca2+通量，Zn2+通量，报告基因，酶活性，PO2和pH值。此类探针的潜在应用包括直接成像神经元电流，胰岛活力，基因激活以及异质肿瘤微环境的关键元素。 MR允许在高场系统和临床扫描仪上的细胞分辨率（〜10 5m）和临床扫描仪的次毫米分辨率上询问完整的不透明生物（〜10 5M）。深层组织穿透和高分辨率使MR使直接将发现从细胞转化为小鼠为人类成为可能。 扼杀其翻译的可激活MR探针的基本局限性很难区分“活跃”和“无活性”探针。在MRI中，主要是水的成像，并通过对水信号的影响间接检测到探针。这种效果取决于探针浓度和探针的松弛性。松弛性取决于许多分子因子，包括探针的水合态及其旋转扩散率。可以设计可激活或“智能”探针，其中放松性会因环境刺激而变化，例如探针通过酶促反应从低松弛态转化为高宽松态，或者在结合分析物（例如钙。尽管松弛性可以对刺激非常敏感，但MR信号的变化取决于放松性和探针浓度：两个未知数。在体外，集中度不会改变，这些探针充当优雅的传感器。然而，在体内，探针浓度尚不清楚，并且随时间变化。相对于正常组织，由于内皮渗透性增加，患病组织中的浓度可能更高，或者由于灌注不良而较低。信号变化可能是由于探针分布的结果，也可能是由于探针激活引起的。当前，没有实际方法可以区分活动性探针。 我们提出了在“关闭”状态下完全沉默的可激活探针。这样，探针注射后MR信号的任何变化都必须是由于探针的激活。我们提出了一种基于锰的还原氧化（氧化还原）化学的新范式，用于可激活的MR探针。二价锰（MN2+）是一种有效的MR松弛剂，但MN3+通常是较差的松弛剂。我们将准备稳定的锰配合物，可以在存在环境刺激的情况下从真正的MR-OFF状态（MN3+）转换为MR-ON状态（MN2+）。随着可调氧化还原芯的发展，可以设计对pH，酶活性，离子通量或特定触觉敏感的探针。在此应用中，我们将集中于为缺氧成像开发MR氧气传感器，其中MR信号仅在低氧区域产生。我们将通过与直接的PO2电极测量，正电子发射断层扫描探针和血氧水平依赖性MR进行比较来验证小鼠和兔肿瘤模型中的低氧探针。 公共卫生相关性：项目叙述这个项目的目标是开发一种磁共振成像探针，该探针可用于非侵入性地识别和量化肿瘤低氧水平的区域（缺氧）。表征低氧肿瘤可能在指导患者接受的治疗选择方面很有价值。