Cerenkov excited luminescence sheet imaging (CELSI)

摘要 临床前成像提供了极好的结构特征，但缺乏分子水平的空间分辨率。 深入动物体内的特征。这是由于光学散射的基本物理限制& 这对于原位肿瘤如胰腺或神经胶质瘤来说是特别成问题的，因为它们生长在肿瘤细胞中。 身体的中间。肿瘤代谢和免疫学最相关的分子示踪剂通常是 在皮下肿瘤中，通过皮肤成像良好，但这些图像非常浅表，或通过 显微成像在微摩尔中，没有方法以分子灵敏度成像1-3 cm的组织 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， 将进一步开发用于次微摩尔浓度范围内的全身扫描的应用。 这种新方法使用来自线性加速器（LINAC）的兆伏（MV）x射线薄片， 多叶准直器，以诱导用于扫描成像（CELSI）的发光的切伦科夫激发。这些床单 扫过动物，通过切伦科夫在动物体内定位兴奋， 探测到的光来自哪里。使用时间选通低光检测器阵列捕获发射， 一种类似于薄片照明显微镜的方法。关键的好处是空间分辨率是确定的 由LINAC光束的大小和位置，否则光学混浊的样品。该设计隐含地允许高 精确的空间定位，我们假设和测试线性校正算法的功能， 作为空间去卷积和深度相关衰减校正，与基于非线性扩散的 重建拟议的项目开发了一个工作原型系统的基础科学，以及 合作开发商业原型系统。切伦科夫发射激发磷光 或荧光分子，其用于直接测量代谢或标记分子报告物。初始 动物研究表明，CELSI可以i）在治疗剂量下以非常低的分子探针 浓度（使用纳摩尔探针为2戈伊）或ii）低辐射剂量，用于适度较高的探针剂量（0.1戈伊 微摩尔探针）。容易实现空间分辨率小于300微米的图像的恢复， 在动物的整个身体里。三个参数直接影响图像质量，包括1）纸张 深度，2）递送剂量，和3）探针浓度，并且这些之间的相互作用将被定量地确定。 检查以确定可接受的和生物学相关的操作模式。在这项工作中，系统图像 开发了多种啮齿动物，其中检测灵敏度针对临床LINAC中的发光进行了优化。一 一个商业合作伙伴将提供一个定制的短脉冲直线加速器，用于上级信噪比和生产 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，这是至关重要的了解反应的肿瘤，有效地重演的增长， 胰腺内人类疾病的病理生理学。这种全身高分辨率分子光学成像 对于推进原位癌症模型和内部器官疾病的研究具有特别的意义， 用任何现有的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.