Nanodisc Platform for 19F-MRI

19F MRI，在监测细胞治疗的临床试验中显示出有希望的成功，在那里，小团体 在1H-MRI(磁共振成像)中显示对比度较低的细胞，使用19F-MRI.1很容易跟踪 对比是通过预装到电池中的全氟碳(PFC)油的纳米乳剂来提供的。一大优势 19F-MRI的缺点是，体内缺乏天然氟，19F-MRI的对比度和噪声比非常高 与1H-MRI相比，在分子成像中使用19F-MRI，通过靶向特定的生物标记物，是非常有意义的 但开发用于这些应用的探测器一直是一个难以实现的目标。典型的合成材料 方法产生相对较大的颗粒，~gt；150 nm，诱导吞噬细胞非特异性摄取。 虽然Avid非特异性摄取有利于体外标记T细胞和其他免疫细胞，但它是一种 决定了生物标志物成像的限制，因为它可以在炎症组织中产生高背景信号 具有许多疾病的特征。19F MRI应该是检测生物标记物的一个很好的平台，但有一个 避免非特异性免疫细胞监视的合适的19F磁共振造影剂的关键需求尚未得到满足。 理想情况下，造影剂的长度应为&lt；100 nm以避免非特异性吸收。我们建议进行探索性研究，以 开发基于纳米盘的新型19F磁共振造影剂。纳米盘的大小为50纳米，避免 清除肝脏，逃避免疫监视。我们假设，结构相似的纳米盘 到高密度脂蛋白，在疏水核心中携带胆固醇，可能是携带疏水的理想 全氟碳化合物。我们的目标是探索台式(目标1)和微流控(目标2)的合成参数 优化将全氟碳化合物装载到纳米盘中的方法。在每个目标中，我们都将系统地 研究影响纳米盘大小和全氟碳负载量的变量。新的纳米盘将是 以物理特性为特征，如组成和尺寸，以及来自每个目标的前3个产品 将在小鼠模型中评估其毒性和生物分布情况。领先的纳米盘将是 针对肿瘤相关巨噬细胞的生物标记物CD204进行了修饰，并在小鼠乳房进行了测试 癌症模型。我们是由造影剂(UCD)和纳米盘(LLNL)专家组成的团队，他们是理想的 做好准备，能够实现拟议的目标。这个项目的成功将增加新奇的东西 纳米盘材料不仅具有靶向~(19)F磁共振分子成像的潜力，而且在 光声、放射治疗和跟踪药物输送。

19F MRI, has shown promising success in clinical trials for monitoring cell therapy, where small groups of cells, showing poor contrast in 1H-MRI (Magnetic Resonance Imaging), are easily tracked using 19F-MRI.1 Contrast is provided by nanoemulsions of perfluorocarbon (PFC) oils pre-loaded into cells. A major advantage of 19F-MRI is that lack of natural fluorine in the body allows for very high contrast-to-noise for 19F-MRI compared to 1H-MRI.2 Use of 19F-MRI in molecular imaging, by targeting specific biomarkers, is of great interest, but the development of probes for these applications has been an elusive goal. Typical synthetic methods produce relatively large particles, > 150 nm, which induce nonspecific uptake by phagocytic cells. While avid nonspecific uptake is advantageous for labeling T cells and other immune cells ex vivo, it is a decided limitation for imaging of biomarkers as it can create high background signal in the inflamed tissues characteristic in many diseases. 19F MRI should be an excellent platform for biomarker detection but there is a critical unmet need for suitable 19F MRI contrast agents that avoid nonspecific immune cell surveillance. Ideally, contrast agents need to be<100 nm to avoid nonspecific uptake. We propose exploratory studies to develop innovative new 19F MRI contrast agents based on nanodiscs. Nanodiscs are < 50 nm in size, avoid liver clearance, and escape immune surveillance. We hypothesize that nanodiscs, which are structurally similar to high density lipoproteins that carry cholesterol in a hydrophobic core, may be ideal for carrying hydrophobic perfluorocarbons. Our aims are to explore synthetic parameters in benchtop (Aim 1) and microfluidic (Aim 2) approaches to optimize loading of perfluorocarbons into nanodiscs. In each aim we will systematically investigate variables that influence nanodisc size and perfluorocarbon loading. New nanodiscs will be characterized for physical properties such composition and dimensions, and the top 3 products from each Aim will be evaluated for lack of toxicity and biodistribution in a mouse model. The leading nanodiscs will be modified for targeting CD204, a biomarker for tumor associated macrophages, and tested in a mouse breast cancer model. We are team composed of contrast agent (UCD) and nanodisc (LLNL) experts who are ideally positioned and well-equipped to carry out the proposed aims. The success of this project would add novel nanodiscs materials with the potential not only for targeted 19F MR molecular imaging, but for applications in photoacoustic, and radiotherapy, and tracking drug delivery.