Quantitative bioluminescence tomography for pre-clinical radiotherapy

项目总结/摘要 包括我们在内的几个小组已经开始努力开发模拟辐射的小动物辐照器 用于人类治疗的RT疗法。用于引导照射的主要图像模态是锥形束CT（CBCT）， 2010年，我们的CBCT-小动物辐射研究平台（SARRP）商业化。我们的系统， 其他人，是变革性的临床前RT研究，115台机器现在正在使用世界各地的一些 600名调查员虽然CBCT提供了出色的引导能力，但它不太擅长定位软组织 在低图像对比度环境中生长的目标。相比之下，生物发光成像（BLI）提供了强的 成像对比度，因此是用于软组织靶向的有吸引力的解决方案。然而，常用的2D BLI 动物表面不足以引导辐射，因为从内部生物发光的光传输， 肿瘤对不规则躯干和组织光学特性的影响非常敏感。承认这些 限制使我们将3D生物发光断层扫描（BLT）与SARRP集成。我们的第一个BLT 以定位用于照射的光学目标的质心（CoM）。这一进步得到了许多人的欢迎。 然而，SARRP用户实际上很少采用BLT系统。很明显 调查人员需要解决两个关键的未满足的需求，以大大加强他们的研究工作： 1)目标形状的知识是RT的基本需要。没有这样的信息来引导辐射， 正常组织的部分可能被不必要地照射，导致不希望的实验不确定性。是 我们必须将BLT制导技术提升到超越CoM的新的精确的3D目标形状水平 描述;和2）临床实践认识到补充使用功能和 BLI测量细胞活力，因此它是一种理想的成像方式， 监测治疗结果。然而，地面BLI为评估提供的定量信息 目前是有限的，甚至是不准确的。提出了新的重建算法和标定方法 在本申请中，我们将建立一种新定量BLT（QBLT）来满足这一需求。我们假设 QBLT/CBCT引导的小动物辐射系统将为研究人员提供新的能力， 组织目标，定义其形状以进行适形照射，并非侵入性地量化治疗结果。我们的目标 目标1：设计和建造一个独立的QBLT系统，易于适应商业辐射平台; 目标2：优化输入数据，建立目标形状的标定方法和重建算法 目标3：在体内验证QBLT引导的RT并评估其适用性， 治疗评估。这一建议的成功将大大提高小动物的放射治疗 研究功能定位和评估能力超出解剖成像。

PROJECT SUMMARY/ABSTRACT Several groups, including ours, have initiated efforts to develop small-animal irradiators that mimic radiation therapy (RT) for human treatment. The major image modality used to guide irradiation is cone-beam CT (CBCT), and our CBCT-small animal radiation research platform (SARRP) was commercialized in 2010. Our system, and others, were transformative for pre-clinical RT research, and 115 machines are now in use world-wide by some 600 investigators. While CBCT provides excellent guidance capability, it is less adept at localizing soft tissue targets growing in a low image contrast environment. In contrast, bioluminescence imaging (BLI), provides strong image contrast and thus is an attractive solution for soft tissue targeting. However, commonly used 2D BLI on an animal surface is inadequate to guide irradiation, because optical transport from an internal bioluminescent tumor is highly susceptible to the effects of irregular torso and tissue optical properties. Recognition of these limitations led us to integrate 3D bioluminescence tomography (BLT) with SARRP. Our first BLT was designed to localize the center of mass (CoM) of an optical target for irradiation. This advance was received with much intrigue, however there was little practical adoption of the BLT system by SARRP users. It was clear that the investigators required two key unmet needs to be addressed, to significantly enhance their conduct of research: 1) knowledge of target shape is a fundamental need for RT. Without such information to guide radiation, large portions of normal tissue can be irradiated unnecessarily, leading to undesired experimental uncertainties. It is imperative that we advance BLT guidance beyond CoM, to a new and precise level of 3D target shape delineation; and 2) clinical practice recognizes the importance of complementary use of functional and anatomical image for RT. BLI measures cellular viability, thus it is an ideal imaging modality for longitudinally monitoring treatment outcome. However, the quantitative information that surface BLI provides for assessment is currently limited or even inaccurate. With the novel reconstruction algorithm and calibration methods proposed in this application, we will establish a new quantitative BLT (QBLT) to address this need. We hypothesize that the QBLT/CBCT-guided small animal radiation system will provide investigators new capabilities to localize soft tissue target, define its shape for conformal irradiation, and non-invasively quantify treatment outcome. Our aims are: Aim 1: design and construct a standalone QBLT system readily adapted to commercial radiation platform; Aim 2: optimize input data, and develop calibration method and reconstruction algorithm for target shape delineation and quantitative imaging; Aim 3: validate the QBLT-guided RT in vivo and assess its suitability for treatment assessment. The success of this proposal will significantly enhance small animal radiotherapy research with the capabilities of functional targeting and assessment beyond anatomical imaging.