Super-Localization Ultrasound Imaging with Targeted Laser-activated Nanodetectors

使用靶向激光激活纳米探测器进行超定位超声成像

• 批准号: 9267468
• 负责人: Geoffrey P. Luke
• 金额: $ 21.14万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9267468
• 关键词: Address; Antibodies; Area; Back; Body Temperature; Breast Cancer Model; Cancer Model; Cause of Death; Cell Culture Techniques; Cell surface; Cells; Clinic; Complex; Contrast Media; Coupled; Cryoelectron Microscopy; Custom; DNA Sequence Alteration; Development; Diagnosis; Dyes; Encapsulated; Environment; Epidermal Growth Factor Receptor; Event; Exposure to; Gases; Gelatin; Goals; Growth; Heterogeneity; Image; Imagery; Imaging Techniques; Imaging technology; Immunohistochemistry; Individual; Indocyanine Green; Injectable; Kinetics; Lasers; Link; Lipids; Liquid substance; Location; Malignant Neoplasms; Mammography; Maps; Methods; Microbubbles; Microscopy; Modality; Molecular; Molecular Probes; Molecular Target; Monoclonal Antibodies; Mutation; Neoplasm Metastasis; Optics; Organ; Physiologic pulse; Positioning Attribute; Property; Research Personnel; Resistance; Resolution; Signal Transduction; Specificity; Spectrophotometry; Spectrum Analysis; Stochastic Processes; Stromal Cells; System; Techniques; Technology; Temperature; Therapeutic; Time; Tissues; Transmission Electron Microscopy; Ultrasonic Therapy; Ultrasonography; Variant; Xenograft procedure; base; bioimaging; cancer therapy; effective therapy; genetic profiling; high resolution imaging; image processing; imaging system; in vivo; in vivo imaging; irradiation; light scattering; millisecond; molecular imaging; monolayer; mouse model; nanoDroplet; nanoparticle; nanoscale; nanosecond; neoplastic cell; novel therapeutics; particle; perfluorohexane; personalized medicine; phase change; predictive of treatment response; pressure; public health relevance; response; safety study; success; therapy resistant; tool; treatment planning; treatment response; tumor; tumor microenvironment; tumor progression; ultraviolet; vapor; vaporization

 DESCRIPTION (provided by applicant): Although cancer is driven by mutations in individual cells, tumors are complex environments, resembling organs more than simple clusters of cells. Recent studies have shown that the microenvironment within tumors is wildly heterogeneous, owing to tumors with diverse genetic profiles as well as interactions between the tumor parenchymal cells and the surrounding stromal cells. This heterogeneity is linked to the malignancy of tumors and their resistance to therapy. Despite the importance of the heterogeneous tumor microenvironment, there are no tools that can adequately visualize its dynamics in vivo. This proposal seeks to develop a new imaging technology - super-localization ultrasound imaging - which relies on highly dynamic phase-change nanoparticles to create a high resolution map of molecular expressions within tumors. The phase-change contrast agents, termed laser-activated nanodetectors (LANDs), consist of a lipid monolayer stabilizing a liquid perfluorohexane core with an encapsulated dye. Upon irradiation with a pulsed laser, the LANDs undergo a rapid vaporization and a transient microbubble is formed, resulting in an increased signal in ultrasound imaging. As the perfluorohexane cools below its boiling point (56 °C) the LANDs recondense into their stable droplet state. The time of recondensation is a stochastic process, and it depends on the droplet size, incident interrogating ultrasound energy, and the local tissue environment. Therefore, high frame rate ultrasound imaging is able to capture single recondensation events. The difference between successive ultrasound images reveals the response of the imaging system to only a single activated LAND. After fitting this response to the point spread function of the imaging system, the exact position of the LAND can be localized with much greater precision than the system's diffraction/bandwidth limited resolution. After conjugating the LANDs with molecular-specific antibodies, a high-resolution map of the molecular expressions in tissue can be obtained. This application focuses on the development and optimization of the LANDs as well as the associated ultrasound imaging techniques. Molecular targeting to the epidermal growth factor receptor will be achieved via a directional conjugation to a monoclonal antibody. The particles will be synthesized and fully characterized with dynamic light scattering, ultraviolet-visible spectrophotometry, and transmission electron microscopy. Simultaneously, custom ultrasound imaging sequences will be developed and optimized to detect the recondensation of individual LANDs with high sensitivity. The overall improvement in resolution will be fully characterized in tissue-mimicking phantoms. Finally, in vivo studies with a xenograft mouse model of cancer will be used to study the safety of the technique, the delivery of LANDs to the tumor, the molecular specificity, and the ability of super-localization ultrasound imaging to detect small spatial variations in a heterogeneous tumor. The end result will be a versatile framework that can be used to study a wide variety of molecular expressions in tumors in real-time and in vivo. This has broad implications ranging from furthering our understanding of the progression of cancer to personalized prediction of treatment response in the clinic.

 描述（通过应用证明）：腹腔癌是由单个细胞驱动的，是复杂的环境，类似于E的细胞簇，因为肿瘤实质细胞与周围的基质细胞之间的相互作用。它在体内的动力学。土地），由脂质单层稳定液体，并稳定液体曲线，并形成了ulsed激光。 c）重新印记的时间是随机的rocess，它取决于液滴的大小，询问超声波能量和局部组织环境。 Onle激活了对成像系统的响应的响应后，具有更大的先例衍射/带宽有限的位置。在组织中，可以获得相关的超声成像技术的发育和优化具有较高的敏感性的内部降落可以在体内研究肿瘤中的广泛杂质表达。

项目成果

Repeated Acoustic Vaporization of Perfluorohexane Nanodroplets for Contrast-Enhanced Ultrasound Imaging.

• DOI: 10.1109/tuffc.2021.3093828
• 发表时间: 2021-12
• 期刊: IEEE transactions on ultrasonics, ferroelectrics, and frequency control
• 作者: Namen AV;Jandhyala S;Jordan T;Luke GP
• 通讯作者: Luke GP