Fluorescence lifetime-based tumor contrast enhancement using exogenous probes

可以针对非特定背景增强肿瘤对比度的成像技术可以 显著影响肿瘤学中的诊断和外科应用。荧光光学成像是 正在接受疾病诊断和手术治疗的评估，使用的探头优先 在肿瘤中积聚，或被抗体结合以标记肿瘤特异性受体。在那里有 是分子靶向近红外荧光研究的重大进展 探针背景荧光的非特异性积累仍然是一个主要困惑 这降低了检测肿瘤的敏感性和特异性。即使当探头清除很快时， 与肿瘤的荧光相比，组织的自发荧光意义重大。现有临床 光学成像系统主要使用基于荧光强度的成像。荧光 强度强烈依赖于组织衰减和实验因素，如激发光 强度，因此不能区分肿瘤结合的探针和非特异性的探针或组织 绝对尺度上的自发荧光。我们的临床前和临床研究表明 注射肿瘤靶向探针的受试者肿瘤和正常组织的荧光寿命为 在典型条件下，不受实验参数的影响。我们已经证明了 与正常分类相比，这种FLT对比度显著提高了肿瘤分类的准确性 使用FDA批准的近红外荧光染料吲哚青绿进行基于强度的成像 (ICG)。在这一令人兴奋的发现的基础上，这项提议的目标是有力地验证荧光 寿命作为ICG用于口腔癌肿瘤识别的对比机制。我们将开发一种 用于术中成像和手术标本同时成像的便携式时域成像系统 使用临床前模型绘制和优化系统。随后，我们将对系统进行验证 通过头颈部临床研究对术中影像和标本边缘进行评估 肿瘤手术患者全身注射ICG，并确定剂量和注射时间 与正常分类相比，为肿瘤分类提供最佳准确度的点。这项提议还将导致 寿命对比的未来应用，以提高其他癌症中肿瘤检测的准确性，使用 ICG和目前正在开发的新型癌症靶向探针。

Imaging techniques that can enhance tumor contrast against non-specific background can significantly impact diagnostic and surgical applications in oncology. Fluorescence optical imaging is being evaluated for disease diagnosis and surgical treatment, using probes that either preferentially accumulate in tumors, or are antibody conjugated to label tumor-specific receptors. While there has been a significant progress in the development of molecularly targeted near infrared fluorescent probes, background fluorescence from non-specific probe accumulation remains a major confound that reduces sensitivity and specificity for tumor detection. Even when the probe clearance is rapid, tissue autofluorescence can be significant compared to the tumor fluorescence. Existing clinical optical imaging systems primarily employ fluorescence intensity-based imaging. Fluorescence intensity strongly depends on tissue attenuation and experimental factors such as excitation light intensity, and therefore cannot distinguish tumor bound probe from non-specific probe or tissue autofluorescence on an absolute scale. Our preclinical and clinical studies indicate that the fluorescence lifetimes of tumor and normal tissue in subjects injected with cancer targeted probes are distinct and independent of experimental parameters under typical conditions. We have shown that this FLT contrast dramatically improves the accuracy for tumor vs. normal classification compared to intensity-based imaging using the FDA-approved near infrared fluorescent dye, Indocyanine green (ICG). Building on this exciting finding, the goal of this proposal is to robustly validate fluorescence lifetime as a contrast mechanism for tumor identification in oral cancers using ICG. We will develop a portable time domain imaging system for concurrent intraoperative imaging and surgical specimen mapping and optimize the system using preclinical models. Subsequently, we will validate the system for intraoperative imaging and specimen margin assessment using clinical studies in head and neck cancer surgery patients systemically injected with ICG, and determine the dosage and injection time points that provide optimal accuracy for tumor vs normal classification. This proposal will also lead to future applications of lifetime contrast to enhance accuracy of tumor detection in other cancers, using ICG and novel cancer targeted probes currently under development.