Nanodisc Platform for 19F-MRI

用于 19F-MRI 的 Nanodisc 平台

• 批准号: 10746675
• 负责人: Nicholas Oliver Fischer
• 金额: $ 27.29万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-11 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10746675
• 关键词: Affect; Animals; Apolipoproteins; Area; Biodistribution; Biological; Biological Markers; Biopsy; Breast Cancer Model; Cell Culture Techniques; Cell Therapy; Cells; Characteristics; Charge; Cholesterol; Circulation; Clinical; Complex; Contrast Media; Detection; Development; Diameter; Dimensions; Disease; Disease Marker; Drug Delivery Systems; Environment; Fluorine; Fluorocarbons; Formulation; Foundations; Gadolinium; Goals; Hepatocyte; High Density Lipoproteins; Histology; Hydrophobicity; Image; Immune; Immunologic Surveillance; Investigation; Label; Lipid Bilayers; Lipids; Liquid substance; Liver; Longitudinal Studies; Macrophage; Magnetic Resonance Imaging; Membrane; Methods; Microfluidics; Modality; Modeling; Monitoring Clinical Trials; Mus; Noise; Oils; Phagocytes; Phagocytosis; Positioning Attribute; Precision therapeutics; Production; Protons; Radiation therapy; Radioisotopes; Reagent; Reticuloendothelial System; Risk; Sampling; Scaffolding Protein; Signal Transduction; Specificity; Structure; Surface; System; T-Lymphocyte; Techniques; Technology; Testing; Therapeutic; Thick; Tissues; Toxic effect; Toxicity Tests; Tumor Markers; Tumor-associated macrophages; Vaccines; Validation; Water; Work; aqueous; cellular imaging; chelation; clinical imaging; detection sensitivity; disease diagnosis; fluorophore; imaging agent; imaging biomarker; imaging probe; imaging study; improved; innovation; interest; manufacturing scale-up; mimetics; molecular imaging; mouse model; nanodisc technology; nanodisk; nanoemulsion; nanomaterials; nanoparticle; nanosystems; new technology; novel; nuclear imaging; particle; physical property; pilot test; scale up; specific biomarkers; stoichiometry; success; surfactant; targeted biomarker; ultrasound; uptake

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.

19 F MRI在监测细胞治疗的临床试验中显示出有希望的成功，其中小群体的 细胞在1H-MRI（磁共振成像）中显示出较差的对比度，使用19 F-MRI很容易跟踪。 对比度是由预先装入细胞的全氟化碳（PFC）油的纳米乳液提供的。一个主要优点 19 F-MRI的另一个优点是，人体内缺乏天然氟，这使得19 F-MRI具有非常高的噪声对比度 与1H-MRI相比。2通过靶向特定的生物标志物，19 F-MRI在分子成像中的应用具有很大的优势。 虽然这些应用的探针的开发一直是一个难以实现的目标。典型的合成 方法产生相对大的颗粒，> 150 nm，其诱导吞噬细胞的非特异性摄取。 虽然亲和非特异性摄取对于离体标记T细胞和其他免疫细胞是有利的，但它是一种非特异性摄取。 生物标志物成像的决定性限制，因为它可以在发炎组织中产生高背景信号 许多疾病的特征。19 F MRI应该是一个很好的生物标志物检测平台，但有一个 对避免非特异性免疫细胞监视的合适19 F MRI造影剂的关键未满足需求。 理想情况下，造影剂需要<100 nm以避免非特异性摄取。我们建议进行探索性研究， 开发基于纳米盘的创新性新型19 F MRI造影剂。纳米盘尺寸< 50 nm，避免 肝脏清除和逃避免疫监视我们假设结构相似的纳米盘 与在疏水核中携带胆固醇的高密度脂蛋白结合，可能是携带疏水核的理想选择。 全氟化碳。我们的目标是探索在台式（目标1）和微流控（目标2）的合成参数 优化将全氟化碳加载到纳米盘中的方法。在每个目标中，我们将系统地 研究影响纳米盘尺寸和全氟化碳负载的变量。新的纳米盘将 表征组成和尺寸等物理性能，以及每个目标的前3种产品 将在小鼠模型中评价无毒性和生物分布。领先的纳米盘将是 针对肿瘤相关巨噬细胞的生物标志物CD 204进行修饰，并在小鼠乳腺中进行测试。 癌症模型我们是由造影剂（UCD）和纳米盘（LLNL）专家组成的团队，他们理想地 有能力和有条件实现所提出的目标。该项目的成功将增加新的 纳米盘材料不仅有潜力用于靶向19 F MR分子成像，而且有潜力应用于 光声、放射治疗和跟踪药物输送。