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: 10224624
• 负责人: Richard R Bouchard
• 金额: $ 59.97万
• 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/10224624
• 关键词: 3-Dimensional; Address; Algorithms; Anatomy; Animal Disease Models; Animal Model; Animals; Antibodies; Binding; Biochemical; Biodistribution; Blood; Cancer Center; Cell Culture Techniques; Cholesterol; Clinical; Communities; Complement; Contrast Media; Coupled; Data; Detection; Development; Diagnostic Imaging; Disease; Doctor of Medicine; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Dyes; Epidermal Growth Factor Receptor; Evaluation; Foundations; Functional Imaging; Future; Generations; Goals; Gold; 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; Pharmacology; 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; base; bioluminescence imaging; biomarker evaluation; cancer therapy; 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; molecular imaging; molecular marker; mouse model; nanorod; neoplastic cell; novel; optical imaging; personalized medicine; photoacoustic imaging; pre-clinical research; preclinical imaging; preclinical study; prevent; quantitative imaging; response; 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.

项目概要 小动物模型是医学研究中强大的发现工具，但牺牲会阻碍长期的体内研究 观察自然或病理过程。因此，需要一种形态学、功能性、 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出现不希望的权衡。非侵入性 光声成像（PAI），能够同时进行解剖、功能和分子成像 病理可视化在深度上具有高对比度/分辨率，因此引起了极大的兴奋 临床前成像研究人员中。然而，这些最终用户目前缺乏可靠的、可重复的、 经过验证的分子 PAI 平台来补充他们的转化研究。为了满足这一需求，我们建议 通过开发和验证靶向造影剂来实现 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断层扫描成像 研究。许多可用的分子造影剂缺乏足够的 PAI 对比度来进行深度成像和/或重叠 具有血红蛋白吸收的光谱特征，使得很难将目标探针与 周围的血液。为了解决这些限制，我们寻求继续开发独特的造影剂 基于负载有吲哚菁绿 (ICG) 染料 J 聚集体的抗体靶向脂质体。封装 脂质体隔室中的 ICG J-聚集体产生稳定的造影剂 (Lipo-JICG)，它提供 体内 PAI 的非常有利的特性：(i) 在 ~890 nm 处具有强而窄的吸光度，在该处可以 很容易从血红蛋白光谱中分离出来； (ii) 染料聚集介导的 PAI 信号增强 热梯度和吸光度增加； (iii) 实施稳健、半定量 PAI 的能力 不干扰血氧等重要生理参数成像的分析 饱和。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、线性度、 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模拟组织模型、充分表征的细胞培养物中的成像能力， 和卵巢癌的原位模型。在这些研究结束时，我们将能够开始大规模- Lipo-JICG 的生产和最终用户传播以及图像处理算法作为经过充分验证的、 分子特异性 PAI 平台，可实现可靠、可重复且经济实惠的临床前成像。虽然不是 该提案的主要目标，这些研究也为我们的药物的临床转化提供了基础 其组成的脂质体、ICG 和人源化靶向抗体均已获得 FDA 批准 静脉注射使用，从而减少安全问题并提高未来临床使用的机会。