Microscale Radionuclide S-values for αRPT

摘要/摘要-项目2 标记有α粒子发射体的放射性药物(rpt)独特地满足各种治疗条件 癌症处于晚期。α粒子有很高的线性能量转移(~100keV/m)，因此很短 组织范围(~50-80m)。因此，它们只需1-3个颗粒就可以杀菌肿瘤细胞， 相比之下，需要1000秒的β粒子穿越。此外，他们不容易感染 化学抗性，并且对辐射抗性的敏感性最小。在开发针对特定患者的 对于RPT的治疗计划，一个主要目标是确保正常组织和 器官接近毒性阈值，但仍低于阈值。器官α粒子剂量学评价 潜在的毒性风险可以通过MIRD方案执行，但理想情况下必须在空间尺度上应用 这与驱动毒性的特定细胞群体有关，也与 发射的阿尔法粒子。MIRD方案规定，可以计算对目标区域的吸收剂量 作为源区时间综合活动的产物(即放射性核素衰变的总数)和 放射性核素S值(源区每次衰变对靶区的吸收剂量)。传统上， MIRD将源区域和目标区域定义为整个器官(肝或肾)或可能的器官子区域(例如， 肝叶或肾皮质)。然而，考虑到阿尔法粒子的射程，理想情况下，源和目标区域 在更微观的层面上进行定义。因此，项目2的主要目标是开发一个全面的库 支持骨髓、肾脏、肝脏、肺、唾液中RPT值的微尺度S 腺体、泪腺和小肠。Aim 1将在这两个组织中开发基于几何的模型 人类和小鼠；我们之前已经发表了针对骨髓和肾脏的此类模型。在AIM 2、我们将开发用于微尺度S数值计算的新一代三维组织模型-基于 这些相同组织的高质量系列组织学图像的广泛资料库。这些型号(鼠标和 人类)将跨多个ROI(量化器官内变异性)和多个个体构建 (量化患者间的变异性)。先前的研究已经表明，实验室小鼠并不是一个健壮的前 RPT致骨髓毒性的临床模型。因此，在AIM 3中，研究将集中在微型骨骼上 骨髓S-在小型猪高物种模型中的价值。此外，猪肾脏的微型模型将 被开发为允许物种间外推。目标4的研究将集中于验证我们的目标2和3 关于组织体积变化和组织毛细血管潜在失血的模型。理解 这些变化将允许对它们在体内的状态进行更准确的建模。

Abstract / Summary – Project 2 Radiopharmaceuticals labeled with alpha-particle emitters (RPT) uniquely satisfy various conditions for therapy of cancer in its advanced stages. Alpha particles have high linear-energy transfer (~100 keV / m) and thus short tissue ranges (~50-80 m). Resultantly, they can sterilize tumor cells with as few as 1-3 particle traversals, in contrast to the requirement of 1000s of beta-particle traversals. Furthermore, they are not susceptible to chemoresistance, and are minimally susceptible to radioresistance. In the development of patient-specific treatment planning for RPT, one primary objective is to ensure that the radiation dose to normal tissues and organs approaches, but remains below, thresholds for toxicity. Assessment of alpha-particle dosimetry of organs at potential toxicity risk can be performed via the MIRD schema, but it ideally must be applied at a spatial scale that is pertinent to the specific cell populations which drive toxicity, and that is relevant to the ranges of the emitted alpha particles. The MIRD schema states that the absorbed dose to a target region may be computed as the product of the time-integrated activity in a source region (i.e., total number of radionuclide decays) and the radionuclide S-value (absorbed dose to the target region per decay in the source region). Traditionally, the MIRD defines source and target regions as whole organs (liver or kidney) or perhaps organ subregions (e.g., liver lobe or renal cortex). Given the ranges of alpha particles, however, source and target regions would ideally be defined at a more microscale level. The main goal of Project 2 is thus to develop a comprehensive library of microscale S-values which will support RPT in the following organs: bone marrow, kidneys, liver, lungs, salivary glands, lacrimal glands, and small intestine. Aim 1 will develop geometric-based models of these tissues in both the human and mouse; we have previously published such models for both bone marrow and kidneys. In Aim 2, we will develop a new generation of 3D tissue models for microscale S-value computation based upon an extensive library of high-quality serial histology images of these same tissues. These models (both mouse and human) will be constructed across multi-ROIs (quantifying intra-organ variability) and multiple individuals (quantifying inter-patient variability). Prior studies have indicated that the laboratory mouse is not a robust pre- clinical model for RPT induced marrow toxicity. Consequently, in Aim 3 studies will focus on microscale bone marrow S-values in the higher-species model of the mini-pig. Also, a microscale model of the porcine kidney will be developed to allow for inter-species extrapolation. Aim 4 studies will focus on validating our Aim 2 and 3 models with respect to tissue volume changes and potential loss of blood in the tissue capillaries. Understanding these changes will allow more accurate modeling of their in-vivo state.