Cerenkov excited luminescence sheet imaging (CELSI)

摘要 临床前成像提供了很好的结构特征，但缺乏分子的空间分辨率。 动物身体深处的特征。这是由于光学散射的基本物理限制。 吸收，尤其是对原位肿瘤，如胰腺或胶质瘤，这些肿瘤生长在 身体的中央。与肿瘤新陈代谢和免疫学最相关的分子示踪剂通常是 在皮下肿瘤中通过皮肤很好地成像，但这些图像非常肤浅或通过 显微成像。没有一种方法可以将1-3厘米的图像成像到具有微磨牙分子敏感性的组织中 到纳摩尔范围。一种新的高分辨率、深层组织成像方法已经发明，在这方面 将进一步开发对亚微摩尔范围内浓度的全身扫描的应用。 新的方法使用了来自直线加速器(LINAC)的兆伏(MV)X射线薄片，该加速器由 多叶准直器，用于诱导切伦科夫激发的发光扫描成像(CELSI)。这些床单 被扫过动物以通过切伦科夫在动物体内定位兴奋，从而允许精确的知识 探测到的光从何而来。利用时间选通的微光探测器阵列捕获发射，使用 这是一种类似于平板照明显微镜的方法。主要的好处是空间分辨率是确定的 由直线加速器光束的大小和位置在其他光学混浊的样品。该设计隐含地允许高 精确的空间定位，我们假设并测试线性校正算法的功能，如 作为空间去卷积和深度相关的衰减校正，与基于非线性扩散的 重建。拟议的项目开发了工作原型系统的基础科学，以及 合作开发一个商业原型系统。切伦科夫发射激发了磷光 或荧光分子，用于直接测量新陈代谢或标记分子记者。首字母 动物研究表明CELSI可以在治疗剂量下以非常低的分子探针实现 浓度(纳摩尔探头为2GY)或II)低辐射剂量，用于中等较高的探头剂量(0.1GY 用微磨牙探头)。很容易实现空间分辨率小于300微米的图像的恢复， 遍及动物的整个身体。有三个参数直接影响图像质量，包括1)Sheet 深度、2)传递剂量和3)探针浓度，以及它们之间的倒数将是定量的 检查以确定可接受的和与生物相关的操作模式。在这项工作中，系统要成像 开发了多只啮齿动物，并在临床直线加速器中对检测灵敏度进行了优化。一个 商业合作伙伴将提供定制的短脉冲直线加速器，用于卓越的信噪比和生产 原型商业系统。代谢和免疫传感探针将针对原位胰腺进行优化 癌症成像，这对于了解肿瘤的反应是关键的，有效地概括了肿瘤的生长和 胰腺内人类疾病的病理生理学。这种全身高分辨率的分子光学成像 对推进原位癌症模型和内脏疾病的研究具有特别的相关性， 用目前的任何分子成像工具都不能很好地分辨。

ABSTRACT Pre-clinical imaging provides wonderful structural features, but is lacking in the spatial resolution for molecular features which are deep into the animal body. This is due to fundamental physical limits on optical scattering & absorption, and is especially problematic for orthotopic tumors, such as pancreas or glioma, which are grown in the middle of the body. The most relevant molecular tracers of tumor metabolism and immunology are often imaged well through the skin in subcutaneous tumors, but these images are highly superficial or achieved with microscopic imaging. There is no method to image 1-3 cm into tissue with molecular sensitivity in the microMolar to nanoMolar range. A new high-resolution, deep-tissue, imaging approach has been invented, and in this application will be further developed for whole body scanning of concentrations in the sub-microMolar range. The new approach uses thin sheets of MegaVolt (MV) x-ray from a linear accelerator (LINAC) shaped by a multileaf collimator, to induce Cherenkov excitation of luminescence for scanned imaging (CELSI). These sheets are swept over the animal to localize the excitation via Cherenkov within the animal, allowing precise knowledge of where the detected light came from. The emission is captured with time-gated low-light detector array, using an approach similar to sheet illumination microscopy. The key benefit is that the spatial resolution is determined by the LINAC beam size and location in an otherwise optically turbid sample. The design implicitly allows high precision spatial localization, and we hypothesize and test the functionality of linear correction algorithms such as spatial deconvolution and depth-dependent attenuation correction, as compared to non-linear diffusion based reconstruction. The proposed project develops the basic science of a working prototype system, as well as a collaboration to develop a commercial prototype system. The Cerenkov emission excites either phosphorescent or fluorescence molecules, which are used to directly measure metabolism or to tag molecular reporters. Initial animal studies showed CELSI could be achieved either i) at therapeutic doses at a very low molecular probe concentration (2Gy with nanoMolar probe) or ii) low radiation doses for moderately higher probe doses (0.1 Gy with microMolar probe). Recovery of images with spatial resolution less than 300 microns is readily achieved, throughout the entire body of an animal. Three parameters directly influence image quality, including 1) sheet depth, 2) delivered dose, and 3) probe concentration, and the reciprocity between these will be quantitatively examined to define acceptable and biologically relevant modes of operation. In this work, the system to image multiple rodents is developed with detection sensitivity being optimized for luminescence in a clinical LINAC. A commercial partner will provide a custom short pulsed LINAC for superior signal-to-noise and production of a prototype commercial system. Metabolic and immune sensing probes will be optimized for orthotopic pancreas cancer imaging, which is critical to understand responses of tumors that effectively recapitulate the growth and pathophysiology of human disease within the pancreas. This full-body high-resolution molecular optical imaging has particular relevance to advancing research into orthotopic cancer models and internal organ diseases, which are not resolved well with any current molecular imaging tools.