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: 10359916
• 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/10359916
• 关键词: Affinity; Alpha Particle Emitter; Alpha Particles; Animal Model; Antineoplastic Agents; Biodistribution; Biological; Blood; Blood flow; Bos taurus PARP protein; Cell Line; Cell model; Cells; Chemicals; Childhood; Complex; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; Data; Deposition; Disease; Dose; Dose-Limiting; Electrons; Energy Transfer; Ensure; Event; Foundations; 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; Positioning Attribute; 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; analytical method; base; cancer cell; cancer type; clinical application; clinical effect; enhancing factor; experience; high risk; in vivo; inhibitor; 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 使用α颗粒进行放射药物治疗是治疗某些肿瘤和 转移瘤。这种方式利用短距离的α粒子，最大可达数十微米，以发射辐射 只对癌细胞起作用，而不影响周围的健康组织。要做到这一点，发射α的放射性核素是有界的 一种亲和配体，用于靶向在肿瘤细胞中表达的生物分子。目前，以下是几个 临床应用已获批准，如223Ra用于治疗骨转移，或正在研究中。 尤其是α-RPT可用于治疗预后稳定的高危儿童神经母细胞瘤。 可怜。因为放射性药物治疗背后的原理是利用不同的辐射量 对于肿瘤和健康组织，要求严格测定辐射剂量和效应。 以最大限度地发展这项技术。从α粒子的一般研究开始，这项研究将是 靶向放射性药物[211At]MM4治疗儿童神经母细胞瘤 PARP-1蛋白在这些肿瘤中的过度表达。一般说来，吸收剂量通常可以预测 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，如α- 粒子，以更密集的方式储存能量，并能够产生更集中的损害 对生物结构，如DNA，这往往会损害细胞的修复机制。微剂量学是 在微观层面上研究这些相互作用的模式，并允许更好地确定影响 α-粒子的剂量大于吸收剂量。首席调查员此前曾研究过计算方法 α粒子的微剂量量。因此，这个项目的结构如下。首先，那些 微剂量学计算将与使用蒙特卡罗工具包的DNA实际损伤联系起来 Topas及其对亚细胞结构的扩展Topas-nBio。第二，神经母细胞瘤细胞的初始损伤 将利用[211At]MM4对这些细胞系中PARP-1的亲和力来研究这些细胞系，以创建真实的亚细胞 α粒子辐照模型。永久性损坏发生后，修复机制也会出现 由芝加哥大学Makvandi博士的研究小组发布的实验数据进行建模评估 宾夕法尼亚州。最后，放射性药物在动物模型和血液中的生物分布 将对幻影进行评估并用于预测治疗结果。首席调查员将使用 他的指导团队(Harald Paganetti博士和Jan Schuemann博士)学习技能的经验和专业知识 以及完成拟议研究所需的能力。他还将参加研讨会、课程和 关于放射生物学、蒙特卡洛模拟和赠款撰写和领导技能的会议，这将确保 为在该项目后运营独立实验室奠定了坚实的基础。