Nonlinear Interferometric Vibrational Imaging of Cancer

描述（由申请人提供）：生物医学成像的趋势是在疾病最有可能治愈的最早时间点检测和可视化疾病，如癌症。为此目的，分子成像技术正在开发几乎所有的成像模式。光学分子成像不仅提供了高成像分辨率的潜力，而且还提供了获得分子灵敏度的多种方法。我们开发了一种光学分子成像技术，称为非线性干涉振动成像（NIVI）。该技术基于分子的振动共振频率对分子的三维空间分布进行成像。利用相干反斯托克斯拉曼散射（汽车）的非线性光学信号探测分子的振动共振。利用汽车的相干性，我们使用外差干涉检测进行深度分辨相干门控，利用光学相干断层扫描（OCT）中发现的许多原理。在该项目的R21阶段，我们将把NIVI的成像能力扩展到与癌症相关的生物分子。我们将提高检测的灵敏度，通过拒绝非共振信号，通常产生的水在生物环境中，显着贡献的背景噪声，并将实施光谱域检测，同时检测多个拉曼频率。在进入R33阶段之前，我们将通过建立生物大分子的灵敏度检测限，并根据分子组成和分类从大鼠乳腺肿瘤模型中区分肿瘤和正常组织，来证明NIVI的生物学应用。通过展示NIVI在生物分子诊断中的潜在用途，我们将在R33阶段将该技术推向体内成像。为了实现这一点，我们将构建一个超宽带NIVI仪器，利用飞秒脉冲整形技术，以快速刺激特定分子中的多个振动共振。我们将建立这种技术的灵敏度下限，以及量化的分辨率在相似的分子振动可以区分。最后，为了证明我们的系统的实时分子成像能力，我们将进行细胞，组织和体内动物研究，使用一个良好的特征致癌物诱导的大鼠乳腺肿瘤模型。在整个致癌过程中，肿瘤将在体内成像，以表征其变化的分子组成，并量化DMA的浓度和空间分布。这项研究将建立NIVI作为一种独特的体内非线性光学分子成像技术，用于区分和空间映射与癌症相关的分子分布。

DESCRIPTION (provided by applicant): The trend in biomedical imaging is to detect and visualize diseases such as cancer at their earliest time-points, when the disease is most likely to be cured. Molecular imaging techniques are being developed across virtually all imaging modalities for this purpose. Optical molecular imaging offers the potential for not only high imaging resolution, but also multiple approaches for obtaining molecular sensitivity. We have developed an optical molecular imaging technique called Nonlinear Interferometric Vibrational Imaging (NIVI). This technique images the three-dimensional spatial distribution of molecules based on their vibrational resonance frequencies. Molecular vibrational resonances are detected by the nonlinear optical signals from Coherent Anti-Stokes Raman Scattering (CARS). Taking advantage of the coherent nature of CARS, we perform depth-resolved coherence-gating using heterodyne interferometric detection, leveraging many of the principles found in optical coherence tomography (OCT). For the R21 phase of this project, we will extend the imaging capabilities of NIVI to biological molecules associated with cancer. We will improve the sensitivity of detection by rejecting nonresonant signals that are commonly generated from water in biological environments and significantly contribute to background noise, and will implement spectral-domain detection to detect multiple Raman frequencies simultaneously. Before advancing to the R33 phase, we will demonstrate the biological application of NIVI by establishing sensitivity detection limits for biological macromolecules, and by differentiating neoplastic from normal tissue from a rat mammary tumor model based on molecular composition and classification. By demonstrating the potential use of NIVI for biomolecular diagnostics, we will advance this technology toward in vivo imaging in the R33 phase. To accomplish this, we will construct an ultra-broadband NIVI instrument that utilizes femtosecond pulse-shaping techniques to rapidly stimulate multiple vibrational resonances in specific molecules. We will establish the lower sensitivity limits of this technique as well as quantify the resolution at which similar molecular vibrations can be differentiated. Finally to demonstrate the real-time molecular imaging capabilities of our system, we will perform cell, tissue, and in vivo animal studies using a well-characterized carcinogen-induced rat mammary tumor model. Throughout carcinogenesis, tumors will be imaged in vivo to characterize their changing molecular composition and quantify the concentration and spatial distribution of DMA. This research will establish NIVI as a unique in vivo nonlinear optical molecular imaging technique for distinguishing and spatially mapping the distribution of molecules associated with cancer.