PEG-Branch-Nitroxide Nanostructured Organic MRI Contrast Agents

PEG-支链-氮氧化物纳米结构有机 MRI 造影剂

• 批准号: 8772541
• 负责人: Jeremiah Allen Johnson
• 金额: $ 18.53万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8772541
• 关键词: Acute; Animals; Architecture; Biodistribution; Biological; Biological Assay; Blood; Body Weight; Cancer cell line; Charge; Chemicals; Child; Clinical; Contrast Media; Data; Development; Diffusion; Drug Delivery Systems; Drug Kinetics; Electrons; Ethylene Glycols; Fluorescence; Future; Goals; Half-Life; Histology; Image; Imaging Techniques; Immune system; In Vitro; Inbred BALB C Mice; Injection of therapeutic agent; Kidney; Kinetics; Label; Lead; Length; Libraries; Magnetic Resonance Imaging; Measurement; Measures; Methods; Molecular; Molecular Sieve Chromatography; Mus; Nanostructures; New Agents; Newborn Infant; Non-Small-Cell Lung Carcinoma; Nude Mice; Organ; Organic Synthesis; Oxidative Stress; Particle Size; Patient Agents; Patients; Performance; Physiological; Play; Polymer Chemistry; Preparation; Procedures; Property; Protocols documentation; Reagent; Reducing Agents; Renal function; Resistance; Role; Serum; Solubility; Structure; Structure-Activity Relationship; Surface; Therapeutic; Therapeutic Agents; Time; Tissue Sample; Tissues; Toxic effect; Translations; Tumor-Derived; Variant; Vertebral column; Water; Work; Xenograft Model; base; copolymer; cytotoxicity; density; design; established cell line; ethylene glycol; fluorescence imaging; hydrophilicity; immunogenicity; in vivo; in vivo imaging; innovation; light scattering; liver transplantation; mouse model; nano; nanoparticle; nanostructured; next generation; novel; novel strategies; particle; polymerization; professor; public health relevance; research study; scaffold; subcutaneous; theranostics; tumor; water solubility; whole animal imaging

DESCRIPTION (provided by applicant): Over 10 million magnetic resonance imaging (MRI) procedures are performed each year; a significant fraction require the use of a paramagnetic Gd (III) contrast enhancement agent. Gd (III) agents are not suitable for patients with impaired kidney function, newborn children, or for patients that require liver transplants. Paramagnetic organic radical contrast agents (ORCAs) could provide suitable alternatives to Gd (III) agents, but several technological hurdles inhibit their development. We propose the synthesis of a novel class of nanostructured ORCAs that will be suitable for translation to clinical imaging applications. These materials will be constructed from branched macromonomers that carry poly (ethylene glycol) (PEG) and reduction resistant spirocyclohexyl nitroxide domains. Parallel ring opening metathesis polymerization (ROMP) of these macromonomers will yield a library of novel nanostructured branched-brush ORCAs with controlled sizes, high water solubility, fluorescent labels, and homogeneous structures. These materials represent a synergistic intersection between nanostructures developed by the Johnson lab and the current state-of-the-art dendritic ORCAs developed by Rajca. We will characterize the nitroxide quenching kinetics for all ORCAs in the presence of biologically relevant reducing agents; the MRI relaxivities will be measured for all new agents. The results will allow for correlation of relaxivity with nanostructure, and will guide the development of next generation ORCAs. In this study, the top ORCA candidates based on low high solubility, high relaxivity, high resistance to reduction, and low in vitro toxicity will be studied in vivo using mouse models. We will study the toxicity, biodistribution, and MRI contrast enhancement. Ex vivo biodistribution will be quantified by whole animal fluorescence imaging and EPR spectral analysis of organ homogenates. We will explore passive targeting to tumors with leaky vasculature using a mouse xenograft model. The key innovations of this proposal are the synthetic approach and the new nanostructures, which work synergistically to allow for rapid synthesis of ORCAs with ideal architectures for MRI applications. Specifically, the placement of nitroxides near the nanostructure core will provide adequate steric shielding for imaging at long times, but sufficient access to water for high relaxivity. Importantly, the method is versatile; it can be extended to dual-modal imaging, and ultimately development of combined drug delivery and imaging platforms (theranostics). Taken as a whole, the results of this proposal will lead to a new class of ORCAs for MR imaging, and new synthetic concepts for the preparation of nanostructures for biomedical applications.

描述（由申请人提供）：每年进行超过 1000 万次磁共振成像 (MRI) 手术；很大一部分需要使用顺磁性 Gd (III) 对比增强剂。 Gd (III) 药物不适合肾功能受损的患者、新生儿或需要肝移植的患者。顺磁有机自由基造影剂 (ORCA) 可以提供 Gd (III) 造影剂的合适替代品，但一些技术障碍阻碍了其发展。我们建议合成一类新型纳米结构 ORCA，适合转化为临床成像应用。这些材料将由带有聚乙二醇（PEG）和抗还原螺环己基硝基氧结构域的支化大分子单体构建。这些大分子单体的平行开环复分解聚合（ROMP）将产生一个新型纳米结构支化刷状 ORCA 库，这些 ORCA 具有可控的尺寸、高水溶性、荧光标记和均质结构。这些材料代表了约翰逊实验室开发的纳米结构与 Rajca 开发的当前最先进的树突状 ORCA 之间的协同交叉。我们将表征在生物相关还原剂存在下所有 ORCA 的硝基氧猝灭动力学；将测量所有新药物的 MRI 弛豫度。结果将允许弛豫率与纳米结构相关联，并将指导下一代 ORCA 的开发。在本研究中，将使用小鼠模型对基于低高溶解度、高弛豫性、高还原抗性和低体外毒性的顶级 ORCA 候选物进行体内研究。我们将研究毒性、生物分布和 MRI 对比度增强。离体生物分布将通过整个动物荧光成像和器官匀浆的 EPR 光谱分析来量化。我们将使用小鼠异种移植模型探索被动靶向具有渗漏脉管系统的肿瘤。该提案的关键创新在于合成方法和新的纳米结构，它们协同工作，可以快速合成具有 MRI 应用理想架构的 ORCA。具体来说，将硝基氧放置在纳米结构核心附近将为长时间成像提供足够的空间屏蔽，但又可以充分接触水以获得高弛豫率。重要的是，该方法是通用的；它可以扩展到双模式成像，并最终开发组合药物输送和成像平台（治疗诊断学）。总的来说，该提案的结果将带来一类用于 MR 成像的新型 ORCA，以及用于制备生物医学应用纳米结构的新合成概念。