Activatable molecular probes for photoacoustic lifetime imaging

用于光声寿命成像的可激活分子探针

基本信息

批准号：
8668056
负责人：
Shai Ashkenazi
金额：
$ 17.48万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8668056
关键词：
Animals Atherosclerosis Basic Science Binding Cell Culture Techniques Cell Line Chronic Cleaved cell Clinical Clinical Data Contrast Media Contrast Sensitivity Degenerative polyarthritis Development Disease Disease Progression Environment Enzyme Activation Enzymes Exhibits Extracellular Matrix FDA approved Family Fiber Optics Fluorescence Foundations Functional Imaging Gelatinase A Goals Human Image Imaging Device Imaging Techniques In Vitro Inflammation Label Lead Lighting Link Malignant Neoplasms Malignant neoplasm of prostate Matrix Metalloproteinases Measures Methods Methylene blue Molecular Molecular Conformation Molecular Probes Monitor Neoplasm Metastasis Optics Outcome Oxygen Penetration Peptides Physicians Play Research Resolution Rheumatoid Arthritis Role Screening for cancer Sensitivity and Specificity Signal Transduction Solutions Specificity Structure System Techniques Technology Testing Three-Dimensional Imaging Tissues Translational Research Translations Triplet Multiple Birth Ultrasonography Work base cancer diagnosis cancer therapy chromophore clinical application design dimer drug development enzyme activity fluorescence imaging imaging probe implementation research improved in vivo light scattering millimeter minimally invasive molecular imaging monomer mouse model nervous system disorder non-invasive imaging novel optical imaging photoacoustic imaging pre-clinical pressure protein aminoacid sequence public health relevance research and development research study response stem subcutaneous treatment planning triplet state tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): The ultimate goal of the project is developing a new method for non-invasive clinical imaging of activity of specific enzymes. Enzymes of the matrix metalloproteinase (MMP) family are known to play a significant role in progression of cancer, atherosclerosis, and other inflammation related disease. The ability to identify a specific enzyme and localize its activity using 3D imaging would help physicians to better understand disease progression and response to treatment. The method proposed here combines a smart molecular agent and a 3D photoacoustic imaging (PAI) technique. PAI provides a way to embed optical information on ultrasound imaging. The images feature high resolution and high penetration depth along with the specificity and contrast of optical imaging. The specific implementation of PAI that our team proposes relies on probing excitation lifetime. The technique is termed photoacoustic lifetime imaging (PALI). We propose designing a molecular probe that consists of two methylene blue (MB) chromophore molecules linked by a peptide chain that confines the chromophores to a dimer configuration. The peptide link is designed to be cleaved upon interaction with MMP-2 enzyme. This would result in breaking the MB dimer and releasing two MB monomers. The two states of the probe, MB dimer vs. free MB monomers, exhibit a very drastic difference in excitation lifetime. MB monomers have a stable triplet excited state that has a natural lifetime of 70 ms. The triplet state is very effectively quenched in a dimer configuration resulting in a very short lifetime of less than 0.040 ms. This extreme difference in lifetime between the probe in its initial state and its activated state provie an effective contrast mechanism for PALI imaging. Moreover, the activated state of the probe is clearly distinct from any other tissue component because of the extremely long excitation lifetime of the chromophores. This mechanism would therefore generate high image contrast for functional imaging of enzyme activity. The research plan entails the following steps: 1. Probe Synthesis: Synthesize and test a molecular probe consisting of MB pair tethered to a peptide sequence that can be cleaved by MMP-2. 2. Probe Characterization: Measure sensitivity and specificity to MMP-2. 3. Testing imaging features such as penetration depth, sensitivity, and contrast in tissue-mimicking phantoms. 4. Testing the new imaging system in vivo in mice models of prostate cancer. The project will lay the groundwork for a translational research that would focus on implementing the technique in clinical applications such as cancer screening, treatment planning, and treatment monitoring.

描述（由申请人提供）：该项目的最终目标是开发一种对特定酶活性进行非侵入性临床成像的新方法。已知基质金属蛋白酶 (MMP) 家族的酶在癌症、动脉粥样硬化和其他炎症相关疾病的进展中发挥重要作用。使用 3D 成像识别特定酶并定位其活性的能力将有助于医生更好地了解疾病进展和对治疗的反应。这里提出的方法结合了智能分子代理和 3D 光声成像 (PAI) 技术。 PAI 提供了一种在超声成像中嵌入光学信息的方法。这些图像具有高分辨率和高穿透深度以及光学成像的特异性和对比度。我们团队提出的 PAI 的具体实现依赖于探测激发寿命。该技术被称为光声寿命成像（PALI）。我们建议设计一种分子探针，该探针由两个亚甲蓝（MB）发色团分子组成，这些分子通过肽链连接，将发色团限制为二聚体构型。肽键设计为在与 MMP-2 酶相互作用时被裂解。这将导致 MB 二聚体断裂并释放两个 MB 单体。探针的两种状态（MB 二聚体与游离 MB 单体）在激发寿命方面表现出非常巨大的差异。 MB 单体具有稳定的三重激发态，自然寿命为 70 毫秒。三重态在二聚体配置中被非常有效地猝灭，导致寿命非常短，小于 0.040 ms。探针在初始状态和激活状态之间的寿命差异为 PALI 成像提供了有效的对比机制。此外，由于发色团的激发寿命极长，探针的激活状态明显不同于任何其他组织成分。因此，该机制将为酶活性的功能成像产生高图像对比度。研究计划包括以下步骤： 1. 探针合成：合成并测试由MB对组成的分子探针，该探针与可被MMP-2切割的肽序列相连。 2. 探针表征：测量 MMP-2 的敏感性和特异性。 3. 测试成像特征，例如组织模拟体模的穿透深度、灵敏度和对比度。 4. 在前列腺癌小鼠模型中测试新的体内成像系统。该项目将为转化研究奠定基础，重点是在癌症筛查、治疗计划和治疗监测等临床应用中实施该技术。