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

• 批准号: 10539325
• 负责人: Alejandro Bertolet Reina
• 金额: $ 9.38万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-10 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10539325
• 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

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.

项目摘要/摘要 用α粒子治疗放射药物是一种治疗某些肿瘤和的有前途的方法 转移。这种方式利用了多达数十微米的α粒子的短范围来提供辐射 仅在保留周围健康组织的同时仅用于癌细胞。为此，α发射放射线有限 用于靶向在肿瘤细胞中表达的生物分子的亲密配体。目前，这里有几个 临床应用要么被批准，例如223RA用于治疗奖励转移或正在调查中。 特别是，α-RPT可用于治疗高风险的小儿神经母细胞瘤，其预后保持 贫穷的。作为放射药物治疗背后的基本原理是利用降低辐射量 赋予肿瘤和健康组织，要求对辐射剂量测定和效果进行严格的测定 完全开发这种技术。从一般来说，从研究α粒子开始，这项研究将是 使用放射性药物[211AT] MM4定向治疗小儿神经母细胞瘤 PARP-1蛋白在这些肿瘤中的过表达。通常，吸收剂量通常可以预测 X射线，γ或β辐射的生物学或临床效应。但是，基于重粒子的辐射，例如α- 颗粒，以更密集的方式沉积能量，并能够产生更多的浓缩伤害 将生物结构作为DNA，倾向于损害细胞的修复机制。微测定法是 研究这些在微观水平上的相互作用模式，并可以更好地确定效果 α粒子的剂量比吸收剂量。首席研究者先前已经研究了计算的方法 α粒子的微量测量量。因此，该项目的结构如下。首先，那些 微观计算将与Monte Carlo Toolkit与DNA的实际损害连接 TOPA及其用于亚细胞结构的扩展，TOPAS-NBIO。第二，对神经母细胞瘤细胞的初始损害 线条将使用[211AT] MM4对PARP-1的亲和力进行研究，以创建逼真的亚细胞 α粒子照射的模型。发生修复机制后的永久损坏也将是 通过Makvandi博士小组发表的实验数据进行了建模 宾夕法尼亚州。最后，在动物模型中跨器官和血液的放射性药物生物分布，以及 幻影将被评估并用于预测治疗结果。主要调查员将使用 他的心理团队的经验和专业知识（Harald Paganetti博士和Jan Schuemann博士）学习技能 和完成拟议的研究所需的能力。他还将参加半手，课程和 关于放射生物学，蒙特卡洛模拟以及赠款写作和领导技能的会议，这将确保 在此项目之后，经营独立实验室的坚实基础。