Microscale Radionuclide S-values for αRPT

摘要/摘要-项目2 用α粒子发射体标记的放射性药物（α-粒子发射体）独特地满足用于治疗的各种条件 癌症晚期的症状α粒子具有高的线性能量转移（~100 keV /μ m）， 组织范围（~50-80 μ m）。因此，它们可以在1-3个粒子穿过的情况下杀灭肿瘤细胞， 与1000次β粒子穿越的要求形成对比。此外，它们不易受 化学抗性，并且对辐射抗性的敏感性最低。在开发患者特异性 在制定放射治疗计划时，一个主要目标是确保对正常组织的辐射剂量， 器官接近但仍低于毒性阈值。器官α粒子剂量学评估 可以通过MIRD方案进行潜在毒性风险评估，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有关，并且与 发射阿尔法粒子MIRD方案指出，可以计算目标区域的吸收剂量 作为源区中时间积分活动的产物（即，放射性核素衰变总数）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将源和目标区域定义为整个器官（肝脏或肾脏）或可能的器官子区域（例如， 肝叶或肾皮质）。然而，给定α粒子的范围，源和目标区域理想地 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综合图书馆， 将支持以下器官中的CIRRPT的微尺度S值：骨髓、肾、肝、肺、唾液 腺体、泪腺和小肠。Aim 1将开发这些组织的几何模型， 人和小鼠;我们以前已经发表了骨髓和肾脏的这种模型。在Aim中 2，我们将开发新一代3D组织模型，用于基于 这些相同组织的高质量系列组织学图像的广泛库。这些模型（小鼠和 人）将在多个ROI（量化器官内变异性）和多个个体之间构建 （量化患者间变异性）。先前的研究表明，实验室小鼠不是一个强大的前- 临床模型的研究。因此，在目标3中，研究将重点关注微尺度骨 小型猪的高种属模型中的骨髓S值。此外，猪肾的微型模型将 以便进行物种间推断。目标4研究将重点验证我们的目标2和3 关于组织体积变化和组织毛细血管中血液的潜在损失的模型。理解 这些变化将允许对它们的体内状态进行更精确的建模。

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.