Biogenic Gas Nanostructures As Molecular Imaging Reporters For Ultrasound

生物气体纳米结构作为超声分子成像记者

• 批准号: 8892182
• 负责人: Mikhail Shapiro
• 金额: $ 31.81万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8892182
• 关键词: Acoustics; Address; Antibodies; Area; Biodistribution; Biological; Biological Models; Biomedical Engineering; Biomedical Research; Biophysics; Blood; Blood Circulation; Blood Vessels; Cancer Immunology Science; Cardiovascular Diseases; Cell Line; Cell Proliferation; Cells; Characteristics; Charge; Chemicals; Clinical; Code; Communicable Diseases; Contrast Media; Detection; Development; Diagnosis; Diagnostic; Disease; Engineering; Event; Frequencies; Future; Gases; Gene Cluster; Gene Expression; Genes; Genetic; Genetic Engineering; Green Fluorescent Proteins; Health; Hydration status; Image; Imaging technology; Immune System Diseases; In Vitro; Inferior vena cava structure; Label; Liver; Malignant Neoplasms; Mammalian Cell; Methods; Microbubbles; Microcirculation; Modeling; Modification; Molecular; Nanostructures; Nanotechnology; Nature; Nerve Degeneration; Neurology; Play; Property; Proteins; Reporter; Reporter Genes; Research; Role; Scheme; Shapes; Stream; Structure; Surface; Technology; Time; Tissues; Toxic effect; Translations; Ultrasonography; Vesicle; Water; Work; base; bioimaging; cellular engineering; cellular imaging; clinical application; contrast imaging; design; disease diagnosis; imaging agent; imaging modality; in vivo; in vivo imaging; intravenous administration; malignant breast neoplasm; microorganism; migration; molecular imaging; nanometer; nanoscale; nanosized; neoplastic cell; non-invasive imaging; physical property; pre-clinical; targeted imaging; tumor

DESCRIPTION (provided by applicant): Ultrasound is among the most widely used non-invasive imaging modalities in biomedicine, but plays a surprisingly small role in molecular imaging due to a lack of suitable molecular imaging agents. Although conventional microbubble contrast agents are gaining acceptance in non-invasive diagnosis of certain cardiovascular diseases and cancers, they have limited utility as labels of specific cells and tissues outside the bloodstream because their micron size typically confines them to the blood stream. As a result, ultrasound has yet to fulfill its full potential to enable convenient, rapid molecular imaging in biomedical research and potential clinical areas including cancer, immunology, neurology and infectious disease. We propose to address this need by borrowing from nature. Specifically, we will develop molecular imaging agents based on a unique class of genetically encoded gas nanostructures known as gas vesicles (GVs). Expressed by aquatic microorganisms as a means to control buoyancy, GVs are hollow protein-shelled compartments 50-500 nanometers in size that exclude water but are permeable to gas. Unlike artificial micro bubbles, GVs are not pressurized and allow gases to freely exchange with the surrounding medium. This results in a very stable nanoscale configuration enabling a broader range of potential molecular imaging applications. In preliminary results, we have demonstrated that GVs from multiple species produce stable ultrasound contrast that is readily detected in vitro, inside cells and in vivo. The fact that GVs are genetically en- coded provides an unprecedented opportunity of engineering their properties at the genetic level to optimize their acoustics, biodistribution and targeting fo specific applications. In addition, there is the potential of adapting GVs as reporter genes - for the first time combining the ability of ultrasound to image at depth in vivo with the ability of genetic reporters to directly visualize cellular events such as gene expression. To address our hypothesis that GVs can serve as versatile molecular imaging reporters for ultrasound, we propose to develop this new class of molecular imaging agents by (1) understanding GVs' genetically en- coded acoustic properties through physical characterization and modeling, (2) using a genetic engineering plat- form to optimize GVs' acoustic, biological and targeting properties, (3) demonstrating the ability of these nanostructures to target and image extravascular tumor cells in vivo and (4) expressing GV-forming genes in mammalian cells. Successful completion of this project will result in a transformative advance in molecular imaging with ultrasound: a fundamentally new class of stable, nanosized, genetically tunable, molecularly targetable extra- vascular imaging agents, with immediate relevance in biomedical research and the potential for future clinical translation. In addition, this work will stimulate advances in biophysics, molecular and cellular engineering and imaging technology that will contribute more generally to biomedical imaging and bioengineering research.

描述（由申请人提供）：超声是生物医学中使用最广泛的非侵入性成像方式之一，但由于缺乏合适的分子成像剂，在分子成像中起着令人惊讶的小作用。尽管常规的微气泡对比剂在某些心血管疾病和癌症的非侵入性诊断中获得了接受，但它们作为特定细胞和组织的标签有限 血液是因为它们的微米大小通常将它们限制在血液中。结果，超声检查尚未满足其在生物医学研究和潜在临床领域的方便，快速分子成像的全部潜力，包括癌症，免疫学，神经病学和传染病。我们建议通过从自然中借钱来满足这一需求。具体而言，我们将根据一类遗传编码的气体纳米结构（GVS）开发分子成像剂。通过水生微生物作为控制浮力的一种手段，GVS是空心蛋白壳室的大小50-500纳米，可排除水但可渗透到气体中。与人造微气泡不同，GV不会加压，并允许气体与周围介质自由交换。这会导致非常稳定的纳米级构型，从而实现了更广泛的潜在分子成像应用。在初步结果中，我们证明了来自多种物种的GV会产生稳定的超声对比度，在体外，内部细胞和体内很容易检测到。这 GV是遗传编码的事实，为在遗传水平上进行工程性能提供了前所未有的机会，以优化其声学，生物分布和针对特定的应用程序。此外，有可能将GVS调整为报告基因 - 首次将超声在体内深度图像形象的能力与遗传记者直接可视化基因表达等细胞事件的能力。为了解决我们的假设，即GV可以用作超声的多功能分子成像记者，我们建议通过（1）通过（1）通过物理表征和建模来开发GVS的遗传性循环特性（2）使用遗传工程型的遗传学典型效果（3），并以（1）为基础的生物学来开发这种新的分子成像剂（1）遗传性的遗传性特性，以实现遗传工程效果（3）。纳米结构在体内靶向和图像血管外肿瘤细胞和（4）在哺乳动物细胞中表达GV形成基因的纳米结构。该项目的成功完成将导致超声进行分子成像的变革性进步：从根本上进行新的稳定，纳米化，遗传性可调性，可调，分子靶向的外血管外成像剂，并在生物医学研究中立即相关，并且具有生物医学研究的相关性，并具有未来临床翻译的潜力。此外，这项工作将刺激生物物理学，分子和细胞工程和成像技术的进步，这些技术将对生物医学成像和生物工程研究更加普遍。