Efficient Synthesis of Modular Fluorinated Brush- Arm Star Polymers for 19F MRI

用于 19F MRI 的模块化氟化刷臂星形聚合物的高效合成

• 批准号: 9794649
• 负责人: Jessica Lamb
• 金额: $ 5.29万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2020-07-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9794649
• 关键词: Address; Adopted; Alkynes; Architecture; Arthrography; Attention; Azides; Biochemical; Biodistribution; Blood Circulation; Carboxylic Acids; Chemistry; Clinic; Clinical; Complex; Contrast Media; Copper; Data; Development; Diagnostic; Diagnostic Imaging; Drug Delivery Systems; Drug Kinetics; Emulsions; Evaluation; Female; Fluorine; Fluorocarbon Polymers; Fluorocarbons; Future; Health; Heterogeneity; Image; In Vitro; Inbred BALB C Mice; Industry; Investigation; Kilogram; Label; Libraries; Literature; Magnetic Resonance; Magnetic Resonance Imaging; Maximum Tolerated Dose; Metals; Molecular; Mus; Nature; Near-infrared optical imaging; Particle Size; Pharmaceutical Preparations; Polymers; Production; Property; Relaxation; Renal clearance function; Reproducibility; Research; Series; Signal Transduction; Solubility; Structure; System; Techniques; Time; Tissues; Toxic effect; Translating; Variant; aqueous; arm; attenuation; base; biological systems; catalyst; cytotoxicity; ethylene glycol; image guided; imaging agent; immunogenicity; improved; in vivo; interest; nanoparticle; novel; particle; polymerization; preclinical trial; small molecule; theranostics; tool; tumor; water solubility

PROJECT SUMMARY/ABSTRACT MRI is a powerful, non-invasive tool for studying biological systems in vivo. Because the clinically used 1H MRI suffers from a large background signal, 19F MRI has garnered attention in recent years. There have been a variety of small molecule and polymeric contrast agents developed for 19F MRI, but none have been routinely adopted. Fluorinated small molecules have poor aqueous solubility, necessitating emulsions that can be polydisperse and have poor reproducibility. Polymeric contrast agents suffer from low fluorine content, short spin-spin relaxation times (causing signal attenuation), and complex syntheses. Recently, the Johnson group has developed a brush-arm star polymer (BASP) platform that can deliver a high concentration of organic radical contrast agents to tumors for 1H MRI in vivo. BASPs are relatively non-toxic and can be readily produced on kilogram scale, prompting their current evaluation in preclinical trials in mice. In this proposal, we aim to create a series of novel fluorinated BASPs (F-BASPs) with well-defined particle size, polydispersity, and fluorine content. Poly(ethylene glycol) will be used to impart water solubility and high fluorine concentrations will be achieved through the use of a “triple-click” branched macromonomer base, which contains three pendant alkyne moieties to which fluorine tags can be tethered using copper-catalyzed click chemistry. The particles will be fully characterized by NMR, GPC, DLS, and TEM while being evaluated in vitro for toxicity, solubility, and suitability for MRI using phantoms. The most promising F-BASP will then be evaluated in vivo, including toxicity, pharmacokinetics, biodistribution, and, ultimately, 19F MRI in mice. The modularity of this system will allow us to readily address the typical challenges of 19F MRI contrast agents – such as aggregation, solubility, and fluorine concentration – in a synthetically straight forward manner. The development of these F-BASPs will provide the groundwork for metal-free, easily synthesized contrast agents to make 19F MRI viable for clinical use.

项目摘要/摘要 磁共振成像是研究活体生物系统的一种强大的、非侵入性的工具。因为临床上使用的核磁共振氢谱 19F磁共振成像具有背景信号大的特点，近年来引起了人们的关注。曾经有过一次 各种小分子和聚合物造影剂被开发用于19F MRI，但没有一种是常规的 领养的。含氟小分子在水中的溶解性很差，因此需要乳剂 多分散，重现性差。聚合物造影剂氟含量低，短小 自旋-自旋弛豫时间(导致信号衰减)和复杂的合成。最近，约翰逊集团 开发了一种刷臂星形聚合物(BASP)平台，可以提供高浓度的有机自由基 ~1H磁共振活体肿瘤造影剂。BASP相对无毒，可以很容易地在 公斤尺度，促使他们目前在小鼠的临床前试验中进行评估。在这份提案中，我们的目标是创建 一系列具有良好粒度、多分散性和氟离子的新型氟化碱(F-BASP) 内容。将使用聚乙二醇来提高水的溶解性，并将使用高浓度的氟 通过使用“三次点击”支化大分子单体碱来实现，它含有三个侧链的炔烃 可以使用铜催化的点击化学将氟标签拴在其上的部分。粒子将被完全 用核磁共振、凝胶渗透色谱、差示扫描量热仪和透射电子显微镜进行表征，同时在体外进行毒性、溶解性和适合性评估 使用幻影进行核磁共振检查。然后将对最有希望的F-BASP进行体内评估，包括毒性， 药代动力学，生物分布，并最终在小鼠身上进行19F磁共振成像。该系统的模块化将使我们能够 轻松解决19F磁共振造影剂的典型难题--例如聚集性、溶解度和氟 全神贯注--以一种综合直白的方式。这些F-BASP的开发将提供 为无金属、易于合成的造影剂奠定基础，使19F MRI能够用于临床。