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（由申请人提供）：虽然癌症是由单个细胞的突变驱动的，但肿瘤是复杂的环境，更像器官而不是简单的细胞簇。最近的研究表明，由于肿瘤具有不同的遗传特征以及肿瘤实质细胞与周围基质细胞之间的相互作用，肿瘤内的微环境具有很大的异质性。这种异质性与肿瘤的恶性程度及其对治疗的抵抗力有关。尽管异质肿瘤微环境很重要，但没有工具可以充分可视化其体内动态。该提案旨在开发一种新的成像技术——超定位超声成像——它依靠高动态相变纳米颗粒来创建肿瘤内分子表达的高分辨率图。这种相变造影剂被称为激光激活纳米探测器（LAND），由脂质单层组成，该脂质单层用封装的染料稳定液体全氟己烷核心。在脉冲激光照射下，LAND 会快速汽化并形成瞬态微泡，从而导致超声成像中的信号增强。当全氟己烷冷却到其沸点 (56 °C) 以下时，LAND 重新凝结成稳定的液滴状态。再凝结的时间是一个随机过程，它取决于液滴尺寸、入射询问超声能量和局部组织环境。因此，高帧率超声成像能够捕获单个再凝结事件。连续超声图像之间的差异揭示了成像系统仅对单个激活的 LAND 的响应。将此响应拟合到成像系统的点扩散函数后，可以比系统的衍射/带宽有限分辨率更高的精度定位 LAND 的精确位置。将 LAND 与分子特异性抗体结合后，可以获得组织中分子表达的高分辨率图谱。该应用程序重点关注 LAND 以及相关超声成像技术的开发和优化。表皮生长因子受体的分子靶向将通过与单克隆抗体的定向缀合来实现。这些颗粒将通过动态光散射、紫外-可见分光光度法和透射电子显微镜进行合成和全面表征。同时，将开发和优化定制超声成像序列，以高灵敏度检测单个 LAND 的再凝结。分辨率的整体改进将在模拟组织模型中得到充分表征。最后，将使用异种移植癌症小鼠模型进行体内研究，以研究该技术的安全性、LANDs 向肿瘤的递送、分子特异性以及超定位超声成像检测异质肿瘤中微小空间变化的能力。最终结果将是一个多功能框架，可用于实时和体内研究肿瘤中的多种分子表达。这具有广泛的意义，从加深我们对癌症进展的理解到临床治疗反应的个性化预测。

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