Onecha Victor V, Suarez-García D, Bosque Jesús J, Lee Hwan, Simpkins Fiona, Gitto Sarah B, Pryma Daniel A, Bertolet Alejandro
Department of Radiation Oncology, Massachusetts General Hospital, and Harvard Medical School, Massachusetts, USA.
Departamento de Física Nuclear, Atómica y Molecular, Universidad de Sevilla, Sevilla, Spain.
Int J Radiat Oncol Biol Phys. 2025 Jun 21. doi: 10.1016/j.ijrobp.2025.05.085.
Radiopharmaceutical Therapy (RPT) aims to irradiate tumors using antibodies or small molecules chelated with radioisotopes that target tumor cells. The biological response resulting from the complex interplay between radioisotope decay and cell binding processes is yet not fully understood. Since dose, including its spatiotemporal pattern, strongly correlates with ionizing radiation effects, detailed dosimetry is essential to predict biological responses. This study introduces TOPAS-RPT, a Monte Carlo platform for stochastic and spatiotemporal heterogeneous radiation exposures that models the interplay of radioisotope decay and radioligand-receptor binding.
We implemented new models within the TOPAS Monte Carlo platform to enable the dynamic simulation of RPT exposures. Simulations were discretized over time in a series of independent runs. Binding kinetics were implemented using a compartmental model with dynamic populations, updating the abundance and distribution of the isotopes at every time step. In this work, TOPAS-RPT was applied to replicate in vitro viability experiments on ovarian cancer cells (SKOV3 and PEO1) treated under different conditions with astatine-211-ParaThanatrace ([At]At-PTT), a radiolabeled poly (ADP-ribose) polymerase (PARP) inhibitor. We aimed to characterize the cell response in terms of viability and (micro)dosimetry and evaluate time and spatial heterogeneity as factors that can explain different dose-viability responses.
We used the proposed TOPAS-RPT to perform a dose-viability analysis. In PEO1 cells, we observed consistent dose-viability response when cells were exposed to [At]At-PTT for 1 or 72 hours, resulting in similar Median effective dose (ED50) (∼1Gy) and similar microdosimetric distributions. However, when SKOV3 cells were treated with targeted and free At, we observed distinct ED values of 21.2 Gy and 13.3 Gy, respectively, potentially due to substantial differences in the radiation quality of α-particles reaching the cell nuclei.
The characterized time- and space-structure of the absorbed dose need to be accounted for to explain variabilities in radiosensitivity to RPT exposures with diverse binding properties and radiation emissions.
放射性药物治疗（RPT）旨在利用与靶向肿瘤细胞的放射性同位素螯合的抗体或小分子对肿瘤进行照射。放射性同位素衰变与细胞结合过程之间复杂相互作用所产生的生物学反应尚未完全了解。由于剂量，包括其时空模式，与电离辐射效应密切相关，详细的剂量测定对于预测生物学反应至关重要。本研究介绍了TOPAS-RPT，这是一个用于随机和时空异质辐射暴露的蒙特卡罗平台，可模拟放射性同位素衰变与放射性配体-受体结合的相互作用。
我们在TOPAS蒙特卡罗平台内实现了新模型，以实现RPT暴露的动态模拟。模拟在一系列独立运行中随时间离散化。结合动力学使用具有动态群体的隔室模型实现，在每个时间步更新同位素的丰度和分布。在这项工作中，TOPAS-RPT被应用于复制用211砹-帕拉塔纳特拉丝（[At]At-PTT）（一种放射性标记的聚（ADP-核糖）聚合酶（PARP）抑制剂）在不同条件下处理的卵巢癌细胞（SKOV3和PEO1）的体外活力实验。我们旨在从活力和（微）剂量测定方面表征细胞反应，并评估时间和空间异质性作为可以解释不同剂量-活力反应的因素。
我们使用所提出的TOPAS-RPT进行剂量-活力分析。在PEO1细胞中，当细胞暴露于[At]At-PTT 1小时或72小时时，我们观察到一致的剂量-活力反应，导致相似的半数有效剂量（ED50）（约1Gy）和相似的微剂量分布。然而，当SKOV3细胞用靶向和游离的砹处理时，我们分别观察到明显的ED值为21.2 Gy和13.3 Gy，这可能是由于到达细胞核的α粒子的辐射质量存在实质性差异。
需要考虑吸收剂量的特征化时间和空间结构，以解释对具有不同结合特性和辐射发射的RPT暴露的放射敏感性差异。
