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Contrast agents for high-sensitivity ultrasound molecular imaging of tumor angiog

肿瘤血管高灵敏超声分子成像造影剂

基本信息

批准号：
8125232
负责人：
Joshua J. Rychak
金额：
$ 19.57万
依托单位：
TARGESON, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-26 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8125232
关键词：
Acoustics Agar Animal Cancer Model Animals Basic Science Binding Biology Biomedical Research Blocking Antibodies Caliber Chemistry Chloroform Collaborations Computer software Contrast Media Controlled Environment Data Data Set Development Drug Formulations Encapsulated Environment Ethanol Exhibits Frequencies Gases Hindlimb Housing Human Image Imaging Techniques In Vitro Incubated Industry Investigational Therapies Ionizing radiation Ligands Lipids Malignant Neoplasms Malignant neoplasm of prostate Malignant neoplasm of urinary bladder Marketing Measures Methods Microbubbles Microscopy Modeling Molecular Monitor Mus Organic solvent product Performance Phase Phenotype Population Population Control Pre-Clinical Model Preparation Prostate Adenocarcinoma Recombinants Relative (related person)Reproducibility Research Research Contracts Research Personnel Resolution Savings Series Signal Transduction Sorting - Cell Movement Specificity Study Section Surface Techniques Technology Testing Time Tumor Angiogenesis Ultrasonography Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Work angiogenesis anticancer research base bladder Carcinoma cohort cost drug discovery experience imaging modality in vivo molecular imaging molecular marker mouse model novel particle pre-clinical pre-clinical research response success tumor

项目摘要

DESCRIPTION (provided by applicant): Molecular imaging techniques have strong potential in the setting of preclinical research, primarily for drug discovery and basic science in the field of cancer research. In particular, high-frequency ultrasound is a powerful imaging modality for phenotyping and monitoring the response to experimental therapy. Relative to other molecular imaging techniques, ultrasound is portable, does not utilize ionizing radiation, is low cost, and has high spatial and temporal resolution. However, the development of efficacious molecular contrast agents that are active at the high imaging frequencies (15-40 MHz) used in small animal ultrasound imaging has greatly limited the application of this technique. Although ultrasound contrast agents for preclinical imaging are commercially available, the limited performance of these products has restricted the utility of this technique. Gas-encapsulated particles known as microbubbles (MB) are used as contrast agents for ultrasound, and recent research has identified MB diameter as the key determinant for MB activity as a function of imaging frequency. However, current MB formulations tend to be highly polydisperse, and there are currently no high- throughput techniques for manufacturing MB at controlled diameters suitable for commercial-scale manufacture. We propose to develop a low-cost method of producing MB of controlled diameter targeted to VEGFR2. Targeson has developed a lipid-encapsulated MB bearing a ligand against VEGFR2, and this agent has shown utility for imaging tumor angiogenesis at low ultrasound frequencies. We hypothesize that controlled dissolution of the lipid MB shell, by incubation in varying strength organic solvents, will enable us to reduce the mean diameter of this agent. Additionally, we have developed a robust method of gravitational separation that allows us to size-sort MB based upon differential buoyancy. We propose to combine these two methods to produce a series of VEGFR2-targeted MB populations of varying diameter. We will screen these MB preparations for imaging efficacy in vitro using a novel VEGFR2-coated ultrasound flow phantom and a high- frequency ultrasound scanner. We will then work with a commercial partner to test the ability of our size-sorted targeted MB to monitor tumor development in two mouse models of prostate and bladder cancer. PUBLIC HEALTH RELEVANCE: Molecular imaging can enable significant cost and time savings in basic science and drug discovery research. In particular, ultrasound molecular imaging has shown promise as a low-cost, high-throughput modality for imaging molecular markers of angiogenesis in a cancer setting. However, sensitive molecular contrast agents are not available for use at the high ultrasound imaging frequencies typically used for small animal cancer models. We propose to develop an ultrasound contrast agent that is precisely tuned to produce a reproducible and strong ultrasound contrast signal for use with small animal imaging in the preclinical research setting. Success in this project will enable routine use of ultrasound in the molecular imaging field and potentially increase the throughput and efficiency of cancer research.

描述（由申请人提供）：分子成像技术在临床前研究方面具有强大的潜力，主要用于癌症研究领域的药物发现和基础科学。特别是，高频超声是一种强大的成像方式，用于表型分析和监测实验治疗的反应。相对于其他分子成像技术，超声具有便携性、不利用电离辐射、成本低、空间和时间分辨率高等特点。然而，在小动物超声成像中使用的高成像频率（15-40 MHz）下有效的分子造影剂的开发极大地限制了该技术的应用。尽管用于临床前成像的超声造影剂已在市场上销售，但这些产品的有限性能限制了该技术的实用性。被称为微泡 (MB) 的气体封装颗粒被用作超声造影剂，最近的研究已确定微泡直径是微泡活性与成像频率函数关系的关键决定因素。然而，目前的MB配方往往是高度多分散的，并且目前没有高通量技术来以适合商业规模制造的受控直径制造MB。我们建议开发一种低成本方法来生产针对 VEGFR2 的受控直径 MB。 Targeson 开发了一种带有 VEGFR2 配体的脂质封装 MB，该试剂已显示出在低超声频率下对肿瘤血管生成进行成像的实用性。我们假设，通过在不同强度的有机溶剂中孵育，控制脂质 MB 壳的溶解，将使我们能够减小该试剂的平均直径。此外，我们还开发了一种强大的重力分离方法，使我们能够根据不同的浮力对 MB 进行尺寸分类。我们建议结合这两种方法来产生一系列不同直径的 VEGFR2 靶向 MB 群体。我们将使用新型 VEGFR2 涂层超声流模型和高频超声扫描仪筛选这些 MB 制剂的体外成像功效。然后，我们将与商业合作伙伴合作，测试我们按尺寸分类的靶向 MB 监测两种前列腺癌和膀胱癌小鼠模型中肿瘤发展的能力。公共卫生相关性：分子成像可以在基础科学和药物发现研究中显着节省成本和时间。特别是，超声分子成像已显示出作为一种低成本、高通量成像癌症环境中血管生成分子标记物的方式的前景。然而，敏感的分子造影剂不适用于通常用于小动物癌症模型的高超声成像频率。我们建议开发一种超声造影剂，经过精确调整，可产生可重复的强超声造影信号，用于临床前研究环境中的小动物成像。该项目的成功将使超声波在分子成像领域的常规使用成为可能，并有可能提高癌症研究的通量和效率。