Synthesis of Metal-Free Magnetic Resonance Imaging Contrast Agents

无金属磁共振成像造影剂的合成

• 批准号: 9317484
• 负责人: ANDRZEJ RAJCA
• 金额: $ 29.92万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-07 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9317484
• 关键词: Affect; Biodistribution; Biological Assay; Biological Markers; Cell Line; Chelating Agents; Clinic; Clinical; Contrast Media; Dendrimers; Development; Dose; Drug Design; Drug Kinetics; Early Diagnosis; Effectiveness; Electron Spin Resonance Spectroscopy; Electrons; Evaluation; Excretory function; Extracellular Space; Fibroblasts; Fibrosis; Filtration; Fluorescence; Fluorescence Spectroscopy; Fluorescent Probes; Foundations; Gadolinium; General Population; Generations; Goals; Histologic; Human; Imaging Techniques; Impairment; In Vitro; Injectable; Ions; Kidney; Knowledge; Label; Life; MRI Scans; Magnetic Resonance Imaging; Metals; Modernization; Modification; Molecular; Mus; New Agents; Noise; Organ; Organic Synthesis; Oxidation-Reduction; Patients; Plasma; Polyethylene Glycols; Property; Radial; Relaxation; Renal function; Reporting; Resistance; Risk; Risk Factors; Rotation; Signal Transduction; Solubility; Structure; Testing; Time; Toxic effect; United States National Institutes of Health; Vascular Permeabilities; Water; Work; base; bioimaging; clinical imaging; contrast enhanced; cytotoxicity; density; design; disease diagnosis; drug discovery; experimental study; flexibility; frontier; high resolution imaging; hydrophilicity; imaging properties; imaging study; improved; in vivo; molecular size; nitroxyl; organic base; polypropyleneimine; public health relevance; scaffold; success; tool; toxic metal; tumor; tumor xenograft; water solubility

DESCRIPTION (provided by applicant): The overall goal of this project is the development of biostable organic radicals as contrast agent (CA) for magnetic resonance imaging (MRI). Such metal-free, organic-based CAs will provide a breakthrough in contrast-enhanced MRI while avoiding the risk associated with toxic metal ions. While the agents would especially benefit patients with impaired kidney function, who are at increased risk of developing nephrogenic systemic fibrosis (NSF) following administration of paramagnetic gadolinium chelates (GBCAs) for MRI procedures, the new agents may also benefit the general population. The objective of the proposed work is to synthesize organic radical contrast agents (ORCAs) that provide high quality in vivo MR images. The long-standing obstacle in the development of a practical ORCA for MRI is the design and synthesis of paramagnetic organic compounds of moderate molecular size that possess sufficiently long in vivo lifetime, high 1H water relaxivity (r1), and high water solubility. We propose a design strategy to prepare ORCAs from nitroxide radicals that are highly resistant to reduction and exploit prior knowledge about dendrimers and PEGylation, particularly their applications to drug design, to achieve agents with optimized MRI properties. The proposed project has three specific aims. Specific aim 1: optimize 1H water relaxivity r1 (at 3 Tesla) and hydrophilicity of ORCAs to achieve molecular r1 = 10 mMs, at least twice that of the clinical CAs (molecular r1 ≈ 5 mM‾¹s‾¹). The ORCAs are derived from nitroxides conjuated to a generation 4 polypropylenimine (PPI-G4) dendrimer through PEGylation with long linear and/or branched PEG chains. The proposed work will provide a foundation for specific aim 2: optimize molecular size of the ORCAs with molecular r1 ≥ 10 mM‾¹s‾¹ to achieve agents with th radii 1 nm ≤ rSE ≤ 2 nm that would undergo efficient renal filtration/excretion. In vitro toxicty and water relaxivity of the ORCAs, as well as the properties that affect molecular r1, such as rotational correlation time and electron spin relaxation time, will be determined, to identify the four best ORCAs. Specific aim 3: evaluate effectiveness of ORCAs for in vivo MRI. Lowest effective dose, time course, and tumor vascular permeability (transfer constant Ktrans) for the four selected ORCAs will be determined at the clinical field of 3 Tesla by MRI of normal mice and by dynamic contrast enhanced (DCE) MRI of mice bearing tumor xenografts. Preliminary toxicity of the ORCA will be evaluated by histological examination. The most effective ORCA will be selected, labeled with a fluorescence probe, and then subjected to ex vivo biodistribution studies by electron paramagnetic resonance and fluorescence spectroscopy. These studies will determine suitability of ORCA for further development towards human use. Development of metal-free MRI contrast agents based on biostable organic radicals will expand the frontier of biomedical imaging. Modularity of organic synthesis enables efficient structural modifications for specific property tuning (redox, solubility, and toxicity). Such organic-based agents will improve early detection and diagnosis of diseases.

描述（由适用提供）：该项目的总体目标是开发可生物稳定的有机自由基作为对比剂（CA）进行磁共振成像（MRI）。这种无金属有机的CAS将在对比增强的MRI上取得突破，同时避免与有毒金属离子相关的风险。虽然药物特别受益于肾功能受损的患者，他们在服用顺磁性gadolinium樱桃（GBCA）的MRI手术后，患有肾病全身性纤维化（NSF）的风险增加，但新药物也可能使一般人群受益。拟议工作的目的是合成在体内MR图像中提供高质量的有机根治对比剂（ORCA）。用于MRI的实用孔的长期障碍是中等分子大小的顺磁性有​​机化合物的设计和合成，其体内寿命足够长，高1H水松弛度（R1）和高水位 可溶。我们提出了一种设计策略，以从硝基自由基中制备逆戟鲸，这些逆逆戟鲸对减少和探索对树突聚合物和pegylation的先验知识，尤其是它们在药物设计中的应用，以实现具有优化的MRI特性的试剂。拟议的项目具有三个具体目标。具体目标1：优化1H水弛豫性R1（在3 tesla）和逆戟鲸的亲水性以实现分子R1 = 10 mms，至少是临床CAS（分子R1 r1〜5mm‾s‾s）的两倍。逆戟鲸源自与长线性和/或分支的PEG链的Pegylation通过Pegylation通过Pegylation衍生成4代聚丙烯亚胺（PPI-G4）树枝状聚合物。拟议的工作将为特定目标2提供基础：优化具有分子R1≥10mm‾击的逆戟鲸的分子大小，以实现用Radii 1nm≤rse≤2nm的剂量，从而经历有效的肾脏过滤/排泄。将确定兽人的体外毒性和水的松弛性，以及影响分子R1的特性，例如旋转相关时间和电子自旋松弛时间，以识别四个最佳逆戟鲸。特定目标3：评估逆戟鲸对体内MRI的有效性。通过正常小鼠的MRI，将确定四个选定的逆通孔的有效剂量，时间病程和肿瘤血管通透性（转移常数KTRAN），并通过正常小鼠的MRI和带有肿瘤内groft术的小鼠的动态对比度增强（DCE）MRI确定。 ORCA的初步毒性将通过组织学检查评估。最有效的ORCA将被选择，用荧光探针标记，然后通过电子顺磁共振和荧光光谱法进行离体生物分布研究。这些研究将确定Orca对进一步发展人类使用的适用性。基于可生物稳定有机自由基的无金属MRI对比剂的开发将扩大生物医学成像的前沿。有机合成的模块化可以为特定性质调整（氧化还原，可溶性和毒性）进行有效的结构修饰。这样的基于有机的药物将改善疾病的早期检测和诊断。