Large-scale in vitro microdosimetry via live cell microscopy imaging: implications for radiosensitivity and RBE evaluations in alpha-emitter radiopharmaceutical therapy.
Large-scale in vitro microdosimetry via live cell microscopy imaging: implications for radiosensitivity and RBE evaluations in alpha-emitter radiopharmaceutical therapy.
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通过活细胞显微镜成像进行大规模体外微剂量测定：对α发射体放射性药物治疗中放射敏感性和相对生物学效应（RBE）评估的意义
DOI：
10.1186/s12967-023-03991-1
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发表时间：
2023-02-24
影响因子：
7.4
通讯作者：
Sgouros, George
中科院分区：
文献类型：
--
作者：
Bastiaannet, Remco;Liatsou, Ioanna;Hobbs, Robert;Sgouros, George
关键词：
Alpha-emitter radiopharmaceutical therapy (αRPT) has shown promising outcomes in metastatic disease. However, the short range of the alpha particles necessitates dosimetry on a near-cellular spatial scale. Current knowledge on cellular dosimetry is primarily based on in vitro experiments using cell monolayers. The goal of such experiments is to establish cell sensitivity to absorbed dose (AD). However, AD cannot be measured directly and needs to be modeled. Current models, often idealize cells as spheroids in a regular grid (geometric model), simplify binding kinetics and ignore the stochastic nature of radioactive decay. It is unclear what the impact of such simplifications is, but oversimplification results in inaccurate and non-generalizable results, which hampers the rigorous study of the underlying radiobiology. We systematically mapped out 3D cell geometries, clustering behavior, agent binding, internalization, and subcellular trafficking kinetics for a large cohort of live cells under representative experimental conditions using confocal microscopy. This allowed for realistic Monte Carlo-based (micro)dosimetry. Experimentally established surviving fractions of the HER2 + breast cancer cell line treated with a 212Pb-labelled anti-HER2 conjugate or external beam radiotherapy, anchored a rigorous statistical approach to cell sensitivity and relative biological effectiveness (RBE) estimation. All outcomes were compared to a reference geometric model, which allowed us to determine which aspects are crucial model components for the proper study of the underlying radiobiology. In total, 567 cells were measured up to 26 h post-incubation. Realistic cell clustering had a large (2x), and cell geometry a small (16.4% difference) impact on AD, compared to the geometric model. Microdosimetry revealed that more than half of the cells do not receive any dose for most of the tested conditions, greatly impacting cell sensitivity estimates. Including these stochastic effects in the model, resulted in significantly more accurate predictions of surviving fraction and RBE (permutation test; p < .01). This comprehensive integration of the biological and physical aspects resulted in a more accurate method of cell survival modelling in αRPT experiments. Specifically, including realistic stochastic radiation effects and cell clustering behavior is crucial to obtaining generalizable radiobiological parameters. The online version contains supplementary material available at 10.1186/s12967-023-03991-1.
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影响因子：
3.9
作者：
Pouget JP;Constanzo J
通讯作者：
Constanzo J
影响因子：
2.6
作者：
通讯作者：
--
DOI：
10.1186/s13046-017-0667-1
发表时间：
2018-02-06
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Chalouni C;Doll S
通讯作者：
Doll S
影响因子：
51.1
作者：
Arnold, Melina;Rutherford, Mark J.;Bray, Freddie
通讯作者：
Bray, Freddie
影响因子：
2.3
作者：
Chouin, Nicolas;Bardies, Manuel
通讯作者：
Bardies, Manuel