Radiation dosimetry for alpha-particle radiopharmaceutical therapy and application to pediatric neuroblastoma

α粒子放射性药物治疗的放射剂量测定及其在小儿神经母细胞瘤中的应用

基本信息

批准号：
10894477
负责人：
Alejandro Bertolet Reina
金额：
$ 34.64万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-10 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10894477
关键词：
Affinity Alpha Particles Animal Model Antineoplastic Agents Beta Particle Binding Biodistribution Biological Blood Blood flow Cell Line Cell model Cells Chemicals Childhood Collaborations Complex DNA DNA Damage DNA Double Strand Break DNA Repair Data Deposition Disease Dose Dose Limiting Electrons Energy Transfer Ensure Event Foundations Gamma Rays Grant Human Hypoxia Impairment In Vitro Investigation Knowledge Laboratories Leadership Learning Skill Length Ligands Liquid substance Location Lymphocyte Malignant Neoplasms Mentors Metastatic Neoplasm to the Bone Methods Microscopic Modality Modeling Monte Carlo Method Neoplasm Metastasis Neuroblastoma Normal tissue morphology Organ Organism Pattern Pennsylvania Phase Poly(ADP-ribose) Polymerase Inhibitor Poly(ADP-ribose) Polymerases Positioning Attribute Prediction of Response to Therapy Principal Investigator Prognosis Proteins Publishing Radiation Radiation Dose Unit Radiation Interaction Radiation Tolerance Radiation therapy Radiobiology Radioisotopes Radiometry Radiopharmaceuticals Relative Biological Effectiveness Research Roentgen Rays Running Site Solid Neoplasm Structure Subcellular structure Techniques Tissues Toxic effect Treatment outcome Universities Variant Water Writing Xenograft Model absorption analytical method cancer cell cancer type clinical application clinical effect dosimetry enhancing factor experience high risk in vivo interest irradiation method development neoplastic cell neuroblastoma cell overexpression particle radiation absorbed dose radiation effect repaired response side effect simulation skills symposium theories tool tumor uptake

项目摘要

Project Summary/Abstract Radiopharmaceutical treatments with α-particles represent a promising approach to treat some tumors and metastases. This modality leverages the short range of α-particles, up to tens of microns, to deliver radiation only to cancer cells while sparing the surrounding healthy tissue. To do so, an α-emitting radionuclide is bounded to an affinitive ligand which is used to target biomolecules expressed in tumoral cells. Currently, here are several clinical applications either approved, such as 223Ra for the treatment of bony metastases, or under investigation. Particularly, α-RPT could be used for the treatment of high-risk pediatric neuroblastoma, whose prognosis keeps poor. As the rationale behind radiopharmaceutical treatments is to exploit the differential amount of radiation imparted to tumors and healthy tissue, a rigorous determination of radiation dosimetry and effects is requested to develop this technique to their full extent. Starting with the study of α-particles in general, this research will be oriented to the treatment of pediatric neuroblastoma using the radiopharmaceutical [211At]MM4, which targets the overexpression of PARP-1 proteins in these tumors. In general, the absorbed dose generally predicts the biological or clinical effect of X-rays, γ or β radiation. However, heavy-particle-based radiations, such as α- particles, deposit their energy in a much denser fashion and are capable to produce more concentrated damage to biological structures as the DNA, which tends to impair the repair mechanisms of a cell. Microdosimetry is the study of these patterns of interaction at the microscopic level and allows for a better determination of the effect of α-particles than absorbed dose. The principal investigator has previously investigated methods to calculate microdosimetric quantities for α-particles. Therefore, this project is structured as follows. First, those microdosimetric calculations will be connected with actual damage to the DNA using the Monte Carlo toolkit TOPAS and its extension for subcellular structures, TOPAS-nBio. Second, initial damage to neuroblastoma cell lines will be studied using the affinity of [211At]MM4 for PARP-1 in these cell lines to create realistic sub-cellular models of α-particle irradiation. Permanent damage after the occurrence of repair mechanisms will be also modelled assessed through experimental data published by Dr. Makvandi’s group from the University of Pennsylvania. Finally, biodistribution of radiopharmaceutical across organs and blood in animal models and phantoms will be assessed and used to predict treatment outcomes. The principal investigator will use the experience and expertise of his mentoring team (Dr. Harald Paganetti and Dr. Jan Schuemann) to learn the skills and abilities necessary to accomplish the proposed research. He will also attend seminars, coursework and conferences on radiobiology, Monte Carlo simulations and grant writing and leadership skills, which will ensure a strong foundation for running an independent laboratory after this project.

项目概要/摘要使用 α 粒子进行放射性药物治疗是治疗某些肿瘤和癌症的一种有前途的方法。这种方式利用短程 α 粒子（长达数十微米）来传递辐射。只针对癌细胞，同时不伤害周围的健康组织。为此，α发射放射性核素受到限制。目前，有几种用于靶向肿瘤细胞中表达的生物分子的亲和配体。临床应用要么已获批准，例如用于治疗骨转移的 223Ra，要么正在研究中。特别是，α-RPT可用于治疗高危儿童神经母细胞瘤，其预后保持良好由于放射性药物治疗的基本原理是利用不同的辐射量。给予肿瘤和健康组织时，需要严格测定辐射剂量和效应为了充分发展这项技术，这项研究将从 α 粒子的一般研究开始。旨在使用放射性药物 [211At]MM4 治疗小儿神经母细胞瘤，其目标是一般来说，吸收剂量通常可以预测这些肿瘤中 PARP-1 蛋白的过度表达。 X 射线、γ 或 β 辐射的生物或临床效应然而，基于重粒子的辐射，例如 α-辐射。粒子，以更密集的方式沉积能量，并且能够产生更集中的伤害 DNA 等生物结构往往会损害细胞的修复机制。在微观水平上研究这些相互作用模式，并可以更好地确定效果主要研究人员之前研究过计算α粒子的剂量的方法。因此，该项目的结构如下。使用蒙特卡罗工具包将微剂量计算与 DNA 的实际损伤联系起来 TOPAS 及其对亚细胞结构的扩展，TOPAS-nBio 其次，对神经母细胞瘤细胞的初始损伤。将使用[211At]MM4对这些细胞系中的PARP-1的亲和力来研究这些细胞系，以创建真实的亚细胞 α粒子辐照后发生永久性损伤的模型也将出现修复机制。模型通过马科万迪博士团队发表的实验数据进行评估最后，放射性药物在动物模型和血液中的生物分布。模型将被评估并用于预测治疗结果。他的导师团队（Harald Paganetti 博士和 Jan Schuemann 博士）的经验和专业知识来学习技能他还将参加研讨会、课程和完成拟议研究所需的能力。关于放射生物学、蒙特卡罗模拟以及拨款写作和领导技能的会议，这将确保为该项目后运行独立实验室奠定了坚实的基础。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Gadolinium-Based Nanoparticles Sensitize Ovarian Peritoneal Carcinomatosis to Targeted Radionuclide Therapy.

钆基纳米颗粒使卵巢腹膜癌对靶向放射性核素治疗敏感。

DOI：
发表时间：
2023-12-01
期刊：
影响因子：
0
作者：
Garcia;Carmes, Léna;Atis, Salima;Parach, Ali;Bertolet, Alejandro;Jarlier, Marta;Poty, Sophie;Garcia, Daniel Suarez;Shin, Wook;Du Manoir, Stanislas;Schuemann, Jan;Tillement, Olivier;Lux, François;Constanzo, Julie;Pouget
通讯作者：
Pouget