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.

项目总结/摘要 MRI是一种强大的，非侵入性的工具，用于研究体内生物系统。因为临床上使用的1H MRI 由于19 F MRI具有较大的背景信号，近年来受到了广泛关注。已经有 各种小分子和聚合物造影剂开发用于19 F MRI，但没有一个常规 领养的氟化的小分子具有差的水溶性，需要可以在水中溶解的乳液。 多分散且再现性差。聚合物造影剂的缺点是氟含量低， 自旋-自旋弛豫时间（导致信号衰减）和络合物合成。最近，约翰逊集团 开发了一种刷臂星星聚合物（BASP）平台，可以提供高浓度的有机自由基 用于体内1H MRI的肿瘤造影剂。BASP是相对无毒的，并且可以容易地在 公斤规模，促使他们目前在小鼠临床前试验中的评估。在这份提案中，我们的目标是创造 一系列具有明确粒度、多分散性和氟含量的新型氟化BASP（F-BASP）， 内容聚（乙二醇）将被用来赋予水溶性和高氟浓度将被用于 通过使用含有三个侧链炔的“三点击”支化大分子单体基础来实现 可以使用铜催化的点击化学将氟标签连接到其上的部分。粒子将完全 通过NMR、GPC、DLS和TEM进行表征，同时在体外评价毒性、溶解度和适用性 用于使用体模的MRI。最有前途的F-BASP将在体内进行评估，包括毒性， 药物代谢动力学，生物分布，并最终在小鼠中的19 F MRI。该系统的模块化将使我们能够 容易解决19 F MRI造影剂的典型挑战-例如聚集、溶解度和氟 浓度-在一个综合直线前进的方式。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19 F MRI可用于临床。