Bordes Julien, Incerti Sébastien, Mora-Ramirez Erick, Tranel Jonathan, Rossi Cédric, Bezombes Christine, Bordenave Julie, Bardiès Manuel, Brown Richard, Bordage Marie-Claude
CRCT, UMR 1037 INSERM, Université Paul Sabatier, Toulouse, F-31037, France.
UMR 1037, CRCT, Université Toulouse III-Paul Sabatier, Toulouse, F-31037, France.
Med Phys. 2020 Oct;47(10):5222-5234. doi: 10.1002/mp.14370. Epub 2020 Aug 18.
Small-scale dosimetry studies generally consider an artificial environment where the tumors are spherical and the radionuclides are homogeneously biodistributed. However, tumor shapes are irregular and radiopharmaceutical biodistributions are heterogeneous, impacting the energy deposition in targeted radionuclide therapy. To bring realism, we developed a dosimetric methodology based on a three-dimensional in vitro model of follicular lymphoma incubated with rituximab, an anti-CD20 monoclonal antibody used in the treatment of non-Hodgkin lymphomas, which might be combined with a radionuclide. The effects of the realistic geometry and biodistribution on the absorbed dose were highlighted by comparison with literature data. Additionally, to illustrate the possibilities of this methodology, the effect of different radionuclides on the absorbed dose distribution delivered to the in vitro tumor were compared.
The starting point was a model named multicellular aggregates of lymphoma cells (MALC). Three MALCs of different dimensions and their rituximab biodistribution were considered. Geometry, antibody location and concentration were extracted from selective plane illumination microscopy. Assuming antibody radiolabeling with Auger electron ( I and In) and β particle emitters ( Lu, I and Y), we simulated energy deposition in MALCs using two Monte Carlo codes: Geant4-DNA with "CPA100" physics models for Auger electron emitters and Geant4 with "Livermore" physics models for β particle emitters.
MALCs had ellipsoid-like shapes with major radii, r, of ~0.25, ~0.5 and ~1.3 mm. Rituximab was concentrated in the periphery of the MALCs. The absorbed doses delivered by Lu, I and Y in MALCs were compared with literature data for spheres with two types of homogeneous biodistributions (on the surface or throughout the volume). Compared to the MALCs, the mean absorbed doses delivered in spheres with surface biodistributions were between 18% and 38% lower, while with volume biodistribution they were between 15% and 29% higher. Regarding the radionuclides comparison, the relationship between MALC dimensions, rituximab biodistribution and energy released per decay impacted the absorbed doses. Despite releasing less energy, I delivered a greater absorbed dose per decay than In in the r ~ 0.25 mm MALC (6.78·10 vs 6.26·10 µGy·Bq ·s ). Similarly, the absorbed doses per decay in the r ~ 0.5 mm MALC for Lu (2.41·10 µGy·Bq ·s ) and I (2.46·10 µGy·Bq ·s ) are higher than for Y (1.98·10 µGy·Bq ·s ). Furthermore, radionuclides releasing more energy per decay delivered absorbed dose more uniformly through the MALCs. Finally, when considering the radiopharmaceutical effective half-life, due to the biological half-life of rituximab being best matched by the physical half-life of Lu and I compared to Y, the first two radionuclides delivered higher absorbed doses.
In the simulated configurations, β emitters delivered higher and more uniform absorbed dose than Auger electron emitters. When considering radiopharmaceutical half-lives, Lu and I delivered absorbed doses higher than Y. In view of real irradiation of MALCs, such a work may be useful to select suited radionuclides and to help explain the biological effects.
小规模剂量学研究通常考虑一种人工环境，其中肿瘤为球形且放射性核素均匀地生物分布。然而，肿瘤形状不规则且放射性药物的生物分布是异质性的，这会影响靶向放射性核素治疗中的能量沉积。为了更贴近实际情况，我们基于滤泡性淋巴瘤的三维体外模型开发了一种剂量学方法，该模型与利妥昔单抗一起孵育，利妥昔单抗是一种用于治疗非霍奇金淋巴瘤的抗CD20单克隆抗体，可与放射性核素联合使用。通过与文献数据比较，突出了实际几何形状和生物分布对吸收剂量的影响。此外，为了说明这种方法的可能性，比较了不同放射性核素对体外肿瘤吸收剂量分布的影响。
起始模型是一个名为淋巴瘤细胞多细胞聚集体（MALC）的模型。考虑了三个不同尺寸的MALC及其利妥昔单抗的生物分布。从选择性平面照明显微镜中提取几何形状、抗体位置和浓度。假设抗体用俄歇电子发射体（¹²⁵I和¹¹¹In）和β粒子发射体（¹⁷⁷Lu、¹²⁵I和⁹⁰Y）进行放射性标记，我们使用两个蒙特卡罗代码模拟MALC中的能量沉积：用于俄歇电子发射体的具有“CPA100”物理模型的Geant4-DNA和用于β粒子发射体的具有“Livermore”物理模型的Geant4。
MALC呈椭球状，主半径r约为0.25、0.5和1.3毫米。利妥昔单抗集中在MALC的周边。将¹⁷⁷Lu、¹²⁵I和⁹⁰Y在MALC中产生的吸收剂量与具有两种均匀生物分布类型（表面或整个体积）的球体的文献数据进行了比较。与MALC相比，表面生物分布的球体中产生的平均吸收剂量低18%至38%，而体积生物分布的球体中则高15%至29%。关于放射性核素的比较，MALC尺寸、利妥昔单抗生物分布与每次衰变释放能量之间的关系影响了吸收剂量。尽管¹²⁵I释放的能量较少，但在半径约为0.25毫米的MALC中，¹²⁵I每次衰变产生的吸收剂量比¹¹¹In更高（6.78·10⁻⁶对6.26·10⁻⁶微戈瑞·贝克勒尔⁻¹·秒⁻¹）。同样，在半径约为0.5毫米的MALC中，¹⁷⁷Lu（2.41·10⁻⁶微戈瑞·贝克勒尔⁻¹·秒⁻¹）和¹²⁵I（2.46·10⁻⁶微戈瑞·贝克勒尔⁻¹·秒⁻¹）每次衰变的吸收剂量高于⁹⁰Y（1.98·10⁻⁶微戈瑞·贝克勒尔⁻¹·秒⁻¹）。此外，每次衰变释放更多能量的放射性核素在MALC中产生的吸收剂量分布更均匀。最后，考虑到放射性药物的有效半衰期，由于利妥昔单抗的生物半衰期与¹⁷⁷Lu和¹²⁵I的物理半衰期比与⁹⁰Y的更匹配，前两种放射性核素产生的吸收剂量更高。
在模拟配置中，β发射体产生的吸收剂量比俄歇电子发射体更高且更均匀。考虑放射性药物半衰期时，¹⁷⁷Lu和¹²⁵I产生的吸收剂量高于⁹⁰Y。鉴于对MALC的实际照射，这样的工作可能有助于选择合适的放射性核素并有助于解释生物学效应。
