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

项目概要/摘要 使用α粒子的放射性药物治疗代表了治疗某些肿瘤的有前景的方法， 转移这种方式利用了α粒子的短距离（高达数十微米）来提供辐射 只针对癌细胞而不伤害周围的健康组织。要做到这一点，一个α放射性核素 涉及用于靶向肿瘤细胞中表达的生物分子的亲和配体。目前，有几个 临床应用已获批准，如用于治疗骨转移的223 Ra，或正在研究中。 特别是α-RPT可用于高危儿童神经母细胞瘤的治疗，其预后良好， 扶贫因为放射性药物治疗背后的基本原理是利用不同的辐射量 当肿瘤和健康组织受到辐射时，需要严格确定辐射剂量和效应。 将这项技术发挥到极致从一般的α粒子研究开始，这项研究将是 使用放射性药物[211 At] MM 4治疗小儿神经母细胞瘤，其靶向 PARP-1蛋白在这些肿瘤中的过度表达。一般来说，吸收剂量通常预测 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，存款他们的能量在一个更密集的方式，并能够产生更集中的损害 生物结构的DNA，这往往会损害细胞的修复机制。微剂量学是 在微观水平上研究这些相互作用的模式，并允许更好地确定效果 α粒子的吸收剂量。首席研究员以前曾研究过计算方法， α粒子的微剂量学量。因此，本项目的结构如下。首先，那些 微剂量学计算将与使用蒙特卡罗工具包对DNA的实际损伤联系起来 TOPAS及其亚细胞结构的扩展，TOPAS-nBio。第二，神经母细胞瘤细胞的初始损伤 将在这些细胞系中使用[211 At] MM 4对PARP-1的亲和力来研究细胞系，以创建真实的亚细胞 α粒子辐照模型永久性损伤发生后的修复机制也将 该模型通过由大学Makvandi博士的小组发表的实验数据进行评估。 宾夕法尼亚最后，研究了放射性药物在动物模型中跨器官和血液的生物分布， 将评估幻影并用于预测治疗结果。主要研究者将使用 他的指导团队（Harald Paganetti博士和Jan Schuemann博士）的经验和专业知识， 以及完成研究所需的能力。他还将参加研讨会，课程， 关于放射生物学，蒙特卡罗模拟和赠款写作和领导技能的会议，这将确保 为在这个项目之后运行一个独立的实验室奠定了坚实的基础。

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.