Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center, Houston, Texas, USA.
Med Phys. 2024 Sep;51(9):6276-6291. doi: 10.1002/mp.17275. Epub 2024 Jun 27.
Gold nanoparticles (GNPs) accumulated within tumor cells have been shown to sensitize tumors to radiotherapy. From a physics point of view, the observed GNP-mediated radiosensitization is due to various downstream effects of the secondary electron (SE) production from internalized GNPs such as GNP-mediated dose enhancement. Over the years, numerous computational investigations on GNP-mediated dose enhancement/radiosensitization have been conducted. However, such investigations have relied mostly on simple cellular geometry models and/or artificial GNP distributions. Thus, it is at least desirable, if not necessary, to conduct further investigations using cellular geometry models that properly reflect realistic cell morphology as well as internalized GNP distributions at the nanoscale.
The primary aim of this study was to develop a nanometer-resolution geometry model of a GNP-laden tumor cell for computational investigations of GNP-mediated dose enhancement/radiosensitization. The secondary aim was to demonstrate the utility of this model by quantifying GNP-induced SE tracks/dose distribution at sub-cellular levels for further validation of a nanoscopic dose point kernel (nDPK) method against full-fledged Geant4 Monte Carlo (MC) simulation.
A transmission electron microscopy (TEM) image of a single cell showing cytoplasm, cellular nucleus, and internalized GNPs in the cellular endosome was segmented into sub-cellular levels based on pixel value thresholding. A corresponding material density was allocated to each pixel, and, by adding a thickness, each pixel was transformed to a geometric voxel and imported as a Geant4-acceptable input geometry file. In Geant4-Penelope MC simulation, a clinical 6 MV photon beam was applied, vertically or horizontally to the cell surface, and energy deposition to the cellular nucleus and cytoplasm, due to SEs emitted by internalized GNPs, was scored. Next, nDPK calculations were performed by generating virtual electron tracks from each GNP voxel to all nucleus and cytoplasm voxels. Subsequently, another set of Geant4 simulation was performed with both Penelope and DNA physics models under the geometry closely mimicking in vitro cell irradiation with a clinical 6 MV photon beam, allowing for derivation of nDPK specific to this geometry and further comparison between Gean4 simulation and nDPK method.
The Geant4-calculated SE tracks and associated energy depositions showed significant dependence on photon incidence angle. For perpendicular incidence, nDPK results showed good agreement (average percentage pixel-to-pixel difference of 0.4% for cytoplasm and 0.5% for nucleus) with Geant4 results, while, for parallel incidence, the agreement became worse (-1.7%-0.7% for cytoplasm and -5.5%-0.8% for nucleus). Under the 6 MV cell irradiation geometry, nDPK results showed reasonable agreement (pixel-to-pixel Pearson's product moment correlation coefficient of 0.91 for cytoplasm and 0.98 for nucleus) with Geant4 results.
The currently developed TEM-based model of a GNP-laden cell offers unprecedented details of realistic intracellular GNP distributions for nanoscopic computational investigations of GNP-mediated dose enhancement/radiosensitization. A benchmarking study performed with this model showed reasonable agreement between Geant4- and nDPK-calculated intracellular dose deposition by SEs emitted from internalized GNPs, especially under perpendicular incidence - a popular cell irradiation geometry and when the Geant4-Penelope physics model was used.
已证实，肿瘤细胞内积累的金纳米颗粒（GNPs）可使肿瘤对放射疗法敏感。从物理角度来看，观察到的 GNP 介导的放射增敏作用是由于内部化的 GNPs 产生的次级电子（SE）的各种下游效应引起的，例如 GNP 介导的剂量增强。多年来，已经进行了许多关于 GNP 介导的剂量增强/放射增敏作用的计算研究。但是，这种研究主要依赖于简单的细胞几何模型和/或人工 GNP 分布。因此，至少有必要（如果不是必需的话）使用适当反映真实细胞形态以及纳米级内部化 GNP 分布的细胞几何模型进行进一步研究。
本研究的主要目的是开发载有 GNP 的肿瘤细胞的纳米分辨率几何模型，用于研究 GNP 介导的剂量增强/放射增敏作用。次要目的是通过在亚细胞水平上量化 GNP 诱导的 SE 轨迹/剂量分布，来证明该模型的实用性，以进一步验证纳米级剂量点核（nDPK）方法与全面的 Geant4 蒙特卡罗（MC）模拟的有效性。
根据像素值阈值将显示细胞质、细胞核和细胞内体中内部化 GNPs 的单个细胞的透射电子显微镜（TEM）图像分割成亚细胞水平。为每个像素分配相应的材料密度，并通过添加厚度将每个像素转换为几何体素，并作为 Geant4 可接受的输入几何文件导入。在 Geant4-Penelope MC 模拟中，将临床 6 MV 光子束垂直或水平施加到细胞表面，由于内部化的 GNPs 发出的 SE，对细胞核和细胞质中的能量沉积进行了评分。接下来，通过从每个 GNP 体素来生成虚拟电子轨迹，对所有核和细胞质体素来进行 nDPK 计算。随后，使用 Penelope 和 DNA 物理模型进行另一组 Geant4 模拟，该模拟的几何形状紧密模仿了临床 6 MV 光子束照射体外细胞的情况，从而得出了此几何形状特有的 nDPK，并进一步比较了 Gean4 模拟和 nDPK 方法。
Geant4 计算得出的 SE 轨迹和相关的能量沉积与光子入射角度有明显的关系。对于垂直入射，nDPK 结果与 Geant4 结果吻合较好（细胞质的平均像素到像素差异百分比为 0.4%，细胞核为 0.5%），而对于平行入射，吻合程度较差（细胞质为-1.7%至-0.7%，细胞核为-5.5%至-0.8%）。在 6 MV 细胞照射几何形状下，nDPK 结果与 Geant4 结果具有合理的一致性（细胞质为 0.91，细胞核为 0.98）。
目前开发的载有 GNP 的细胞的基于 TEM 的模型为 GNP 介导的剂量增强/放射增敏作用的纳米级计算研究提供了前所未有的真实细胞内 GNP 分布的详细信息。使用该模型进行的基准研究表明，Geant4 和 nDPK 计算的由内部化的 GNPs 发出的 SE 引起的细胞内剂量沉积之间具有合理的一致性，尤其是在垂直入射的情况下-这是一种流行的细胞照射几何形状，并且当使用 Geant4-Penelope 物理模型时。
