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 MRI是用于研究体内生物系统的强大，无创的工具。因为临床使用1H MRI 近年来，有19F MRI的背景信号受到了较大的信号。有一个 为19F MRI开发的各种小分子和聚合物对比剂，但没有常规 采用。氟化的小分子的水溶性不足，必要的乳液可以是 多分散且可重复性差。聚合物对比剂的氟含量低，短 自旋旋转松弛时间（引起信号衰减）和复杂的合成。最近，约翰逊集团 已经开发了一个刷臂星形聚合物（BASP）平台，该平台可以提供高浓度的有机自由基 在体内对比肿瘤1H MRI。 BASP相对无毒，可以很容易地产生 千克尺度，促使他们在小鼠的临床前试验中进行当前的评估。在此提案中，我们旨在创建 一系列具有明确定义的粒径，多分散性和氟的新型氟化BASP（F-BASP） 内容。聚（乙二醇）将用于赋予水溶性，高氟浓度将是 通过使用“三键”分支的宏观工程学库来实现，其中包含三个吊坠炔烃 氟标签可以使用铜催化的点击化学束缚的部分。颗粒将完全 以NMR，GPC，DLS和TEM为特征，同时在体外评估毒性，可溶性和适用性 用于使用幻影的MRI。然后，最有希望的F-BASP将在体内进行评估，包括毒性， 药代动力学，生物分布，最终在小鼠中进行19F MRI。该系统的模块化将使我们能够 容易解决19F MRI对比剂的典型挑战 - 例如聚集，可溶性和氟 浓度 - 以合成的直截了当的方式。这些F-BASP的开发将提供 无金属，易于合成的对比剂的基础工作，使19F MRI可用于临床使用。