Microscale Radionuclide S-values for αRPT

αRPT 的微量放射性核素 S 值

基本信息

批准号：
10713711
负责人：
WESLEY E BOLCH
金额：
$ 47.7万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10713711
关键词：
3-Dimensional Address Alpha Particle Emitter Alpha Particles Anatomic Models Anatomy Beta Particle Blood Blood capillaries Bone Marrow Cells Chemoresistance Clinical Clinical Trials Development Disease Disseminated Malignant Neoplasm Dose Family suidae Freezing Future Generations Geometry Goals Harvest Hemorrhage Histology Human Image Individual Kidney Kupffer Cells Label Laboratory mice Lacrimal gland structure Libraries Linear Energy Transfer Liver Lobe Lobule Lung Marrow Methodology Methods Microanatomy Miniature Swine Modeling Mus Nephrons Normal tissue morphology Organ Organ Model Pathology Patients Photons Population Pre-Clinical Model Predisposition Publishing Radiation Dose Unit Radiobiology Radioisotopes Radiopharmaceuticals Risk Risk Assessment Salivary Glands Series Sinus Site Small Intestines Source Specimen Structure Systemic Therapy Testing Time Tissue Model Tissues Toxic effect Uncertainty Work absorption cancer radiation therapy cancer therapy digital imaging dosimetry effective therapy human imaging in vivo individual patient individualized medicine interest interpatient variability kidney cortex microCT neoplastic cell novel particle porcine model preservation programs radiation resistance skeletal soft tissue targeted treatment three-dimensional modeling tissue preparation tool treatment planning tumor validation studies

项目摘要

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.

摘要/总结 – 项目 2 用α粒子发射体（RPT）标记的放射性药物独特地满足了各种治疗条件晚期癌症的α粒子具有高线性能量转移（~100 keV/μm），因此时间短。因此，它们只需 1-3 次粒子遍历即可杀死肿瘤细胞。与数千次 β 粒子遍历的要求相反，它们不易受到影响。化学耐药性，并且对放射耐药性的敏感性最小。 RPT 治疗计划的主要目标之一是确保正常组织和器官接近但仍低于器官α粒子剂量测定的阈值。潜在毒性风险可以通过 MIRD 模式进行，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有关，并且与 MIRD 模式指出，可以计算目标区域的吸收剂量。作为源区域时间积分活动的乘积（即放射性核素衰变的总数）和放射性核素 S 值（源区域每次衰变目标区域的吸收剂量）。 MIRD 将源区域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，然而，考虑到α粒子的范围，源区域和目标区域将是理想的。因此，项目 2 的主要目标是开发一个综合库。微尺度 S 值将支持以下器官中的 RPT：骨髓、肾脏、肝脏、肺、唾液目标 1 将开发这两种组织的几何模型。人类和小鼠；我们之前已经发表过此类骨髓和肾脏模型。 2、我们将开发新一代3D组织模型，用于基于微尺度S值计算这些相同组织的高质量连续组织学图像的广泛库。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）。 Aim 3 研究中测试的 RPT 诱导的骨髓毒性临床模型将侧重于微型骨。小型猪的高等物种模型中的骨髓 S 值此外，猪肾脏的微型模型也会出现这种情况。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潜在的血液损失的模型。这些变化将允许对其体内状态进行更准确的建模。