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有力的发现工具，但牺牲会阻止长期的体内研究。 观察自然或病理过程。因此，需要一种形态学的、功能性的、 细胞/分子和定量成像技术，能够纵向可视化的生化和 在小动物疾病模型中的药理学过程。不幸的是，目前的分子光学成像 这些方法倾向于在成像深度和分辨率之间呈现不期望的折衷。无创 光声成像（派），它能够同时进行解剖，功能和分子 因此，在深度处具有高对比度/分辨率的病理可视化产生了显著的兴奋 在临床前成像研究者中。然而，这些最终用户目前缺乏可靠的、可复制的且 经验证的分子派平台，以补充他们的翻译研究。为了满足这一需求，我们建议 通过靶向造影剂的开发和验证实现派的分子敏感性， 信号/图像处理算法，以允许同时、可再现、定量、纵向和 临床前疾病和治疗反应的分子和生理特征的断层成像 问题研究许多可用的分子造影剂缺乏足够的派造影剂用于深度成像和/或重叠 具有血红蛋白吸收的光谱特征，使得难以区分靶向探针与 周围的血。为了解决这些局限性，我们寻求继续开发一种独特的造影剂 基于装载有吲哚菁绿色（ICG）染料的J-聚集体的抗体靶向脂质体。封装 ICG J-聚集体的脂质体隔室产生稳定的造影剂（Lipo-JICG），其提供 对于体内派的高度有利的特性：（i）在~890 nm处的强的、窄的吸光度，其中它可以是 易于从血红蛋白光谱中分离;（ii）由于染料聚集介导的派信号增强 热梯度和吸光度的增加;（iii）实施稳健的半定量派的能力 不干扰重要生理参数（如血氧）成像的分析 饱和度我们令人信服的初步数据表明，靶向Lipo-JICG提供了令人印象深刻的稳定性，线性， PAI信号强度和分子特异性。在这项研究计划中，我们将验证分子- 这种有前途的技术在组织模拟体模，良好表征的细胞培养物， 和卵巢癌原位模型。在这些研究结束后，我们将开始大规模的- Lipo-JICG和图像处理算法的生产和最终用户传播， 分子特异性派平台，用于可靠、可重复且经济实惠的临床前成像。虽然不是 这些研究也为我们的药物的临床翻译提供了基础， 脂质体、ICG和其组成的人源化靶向抗体都已被FDA批准用于 静脉内使用，因此减少了安全性问题并提高了未来临床应用的机会。