Activatable molecular probes for photoacoustic lifetime imaging

用于光声寿命成像的可激活分子探针

• 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
• 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

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新的无创临床成像特定酶活性的方法。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。利用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。本文提出的方法结合了智能分子剂和三维光声成像技术。PAI提供了一种在超声成像中嵌入光学信息的方法。图像具有高分辨率、高穿透深度以及光学成像的专一性和对比度等特点。我们团队提出的PAI的具体实现依赖于探测激励寿命。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，由两个亚甲基蓝（MB）发色团分子通过肽链连接，将发色团限制为二聚体结构。肽链被设计成在与MMP-2酶相互作用时被切割。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二聚体和游离MB单体，在激发寿命上表现出非常大的差异。MB单体具有稳定的三重态激发态，自然寿命为70毫秒。三态在二聚体结构中被非常有效地淬灭，导致寿命非常短，小于0.040 ms。探针在初始状态和激活状态下寿命的巨大差异为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，这种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，该探针连接到可被MMP-2切割的肽序列。2. 探针表征：测量对MMP-2的敏感性和特异性。3. 在组织模拟幻象中测试成像特征，如穿透深度、灵敏度和对比度。4. 在前列腺癌小鼠模型中测试新的成像系统。该项目将为一项转化研究奠定基础，该研究将侧重于将该技术应用于临床应用，如癌症筛查、治疗计划和治疗监测。