Molecular Photoacoustic Imaging for Diagnostics and Therapy Monitoring

用于诊断和治疗监测的分子光声成像

• 批准号: 10631940
• 负责人: Richard R Bouchard
• 金额: $ 60.33万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631940
• 关键词: 3-Dimensional; Acceleration; Address; Algorithms; Anatomy; Animal Disease Models; Animal Model; Animals; Antibodies; Binding; Biochemical; Biodistribution; Blood; Cancer Center; Cell Culture Techniques; Cholesterol; Clinical; Commercial grade; Communities; Complement; Contrast Media; Coupled; Data; Detection; Development; Diagnostic Imaging; Disease; Doctor of Medicine; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Dyes; Encapsulated; Epidermal Growth Factor Receptor; Evaluation; Foundations; Functional Imaging; Future; Generations; Goals; Hemoglobin; Image; Imaging Device; Imaging Techniques; Imaging technology; Indocyanine Green; Label; Letters; Lighting; Liposomes; Malignant neoplasm of ovary; Mediating; Medical; Medical Research; Modeling; Molecular; Molecular Target; Monitor; Morphology; Neoplasms; Optics; Outcome; Oxygen; Pathologic Processes; Pathology; Penetration; Phospholipids; Physiologic pulse; Physiological; Positioning Attribute; Process; Production; Property; Protocols documentation; Quality Control; Reproducibility; Research Personnel; Research Proposals; Resolution; Safety; Sensitivity and Specificity; Signal Transduction; Silicon Dioxide; Specificity; System; Technology; Therapeutic; Tissues; Toxic effect; Translational Research; Translations; Validation; Visualization; absorption; bioluminescence imaging; biomarker evaluation; cancer therapy; cellular imaging; clinical translation; contrast imaging; detection limit; drug discovery; fundamental research; image processing; imaging approach; imaging capabilities; imaging modality; imaging platform; imaging system; improved; in vivo; industry partner; interest; large scale production; millimeter; molecular imaging; molecular marker; monomer; mouse model; nanoGold; nanorod; neoplastic cell; novel; optical imaging; personalized medicine; pharmacologic; photoacoustic imaging; pre-clinical research; preclinical imaging; preclinical study; prevent; quantitative imaging; scale up; tomography; tool; treatment response

PROJECT SUMMARY Small-animal models are powerful discovery tools in medical research, but sacrificing prevents long-term, in vivo observation of natural or pathological processes. As such, there is a need for a morphologic, functional, cellular/molecular, and quantitative imaging technique capable of longitudinal visualization of biochemical and pharmacological processes in small-animal disease models. Unfortunately, current molecular optical imaging approaches tend to present an undesirable trade-off between imaging depth and resolution. Non-invasive photoacoustic imaging (PAI), which is capable of simultaneous anatomical, functional, and molecular visualization of pathology with high contrast/resolution at depth, has thus generated significant excitement among preclinical imaging researchers. However, these end-users currently lack a reliable, reproducible, and validated molecular PAI platform to complement their translational research. To address this need, we propose enabling the molecular sensitivity of PAI through the development and validation of targeted contrast agents and signal/image processing algorithms to allow simultaneous, reproducible, quantitative, longitudinal, and tomographic imaging of molecular and physiological signatures of disease and therapy response in preclinical studies. Many available molecular contrast agents lack adequate PAI contrast for deep imaging and/or overlap with spectral features of hemoglobin absorption, making it difficult to differentiate a targeted probe from surrounding blood. To address these limitations, we seek to continue development of a unique contrast agent based on antibody-targeted liposomes loaded with J-aggregates of indocyanine green (ICG) dye. Encapsulation of ICG J-aggregates in a liposomal compartment results in a stable contrast agent (Lipo-JICG), which provides highly advantageous properties for in vivo PAI: (i) a strong, narrow absorbance at ~890 nm, where it can be readily unmixed from hemoglobin spectra; (ii) enhancement of PAI signal due to dye-aggregation-mediated increases in thermal gradients and absorbance; (iii) the ability to implement robust, semi-quantitative PAI analysis that does not interfere with imaging of important physiological parameters such as blood oxygen saturation. Our compelling preliminary data show that targeted Lipo-JICG provides impressive stability, linearity, PAI-signal intensity and molecular specificity. During this research proposal, we will validate the molecular- imaging capabilities of this promising technology in tissue-mimicking phantoms, well-characterized cell cultures, and orthotopic models of ovarian cancer. At the conclusion of these studies, we will be in position to start mass- production and end-user dissemination of Lipo-JICG and image processing algorithms as a fully validated, molecularly specific PAI platform for reliable, reproducible, and affordable preclinical imaging. Although not the principle objective of this proposal, these studies also provide a foundation for clinical translation of our agent as the liposomes, ICG, and humanized-targeted antibodies of which it is composed have all been FDA cleared for i.v. use, therefore reducing safety concerns and improving the chances for future clinical utilization.

项目摘要 小动物模型是医学研究中强大的发现工具，但牺牲可以阻止长期体内 观察自然或病理过程。因此，需要形态学，功能， 细胞/分子和定量成像技术，能够纵向可视化生化和 小动物疾病模型中的药理过程。不幸的是，当前的分子光学成像 方法往往会在成像深度和分辨率之间表现出不良的权衡。非侵入性 光声成像（PAI），能够同时解剖，功能和分子 在深度处具有高对比度/分辨率的病理学的可视化，因此引起了显着的兴奋 在临床前成像研究人员中。但是，这些最终用户目前缺乏可靠，可重现的，并且 验证了分子PAI平台，以补充其转化研究。为了满足这种需求，我们提出 通过开发和验证靶向对比剂和验证PAI的分子敏感性 信号/图像处理算法允许同时，可重复，定量，纵向和 临床前疾病和治疗反应的分子和生理特征的层析成像 研究。许多可用的分子对比剂缺乏足够的PAI对比度，用于深度成像和/或重叠 具有血红蛋白吸收的光谱特征，因此很难区分目标探针与 周围的血。为了解决这些限制，我们试图继续开发独特的对比代理 基于靶向抗体的脂质体，该脂质体装有吲哚烷绿（ICG）染料的J凝集剂。封装 脂质体室中的ICG J-聚集物导致稳定的对比剂（Lipo-JICG），该剂提供了 体内PAI的高优势性能：（i）在〜890 nm处具有强大的狭窄吸光度 很容易从血红蛋白光谱中脱颖而出； （ii）由于染料聚集介导的PAI信号的增强 热梯度和吸光度增加； （iii）实施强大的半定量PAI的能力 分析不会干扰重要的生理参数（例如血氧）的成像 饱和。我们引人注目的初步数据表明，针对性的脂肪jicg具有令人印象深刻的稳定性，线性， PAI信号强度和分子特异性。在这项研究建议中，我们将验证分子 - 这种有前途的技术在模拟组织的幻影，特征良好的细胞培养物中的成像能力， 和卵巢癌的原位模型。这些研究结束时，我们将有能力开始质量 生产和最终用户传播Lipo-JICG和图像处理算法作为充分验证的， 可靠，可重复和负担得起的临床前成像的分子特异性PAI平台。虽然不是 该提案的主要目的，这些研究还为我们的代理人的临床翻译奠定了基础 脂质体，ICG和人性化靶向抗体的组成均已清除 I.V.使用，因此减少了安全问题，并提高了未来临床利用的机会。