■使用俄歇发射器(AE)的靶向放射性核素治疗(TRT)是一种允许使用放射性核素靶向肿瘤细胞上的特定部位的技术。AE的毒性主要取决于其与DNA的接近度。这项研究的目的是使用MonteCarlo径迹结构模拟来量化掺入哺乳动物细胞DNA中的有前途的AE放射性核素铜64(64Cu)的DNA损伤和放射治疗潜力。
■使用TOPAS-nBio中可用的直径为9.3μm的哺乳动物细胞核模型。细胞核由直径为2.3nm的双螺旋DNA几何模型组成,被厚度为0.16nm的水合壳包围,组织在46条染色体中,总共产生6.08千兆碱基对(DNA密度为14.4Mbp/μm3)。细胞核被单能电子和包括111In在内的几种放射性核素的辐射辐射辐照,125I,123I,和99mTc除64Cu。对于单能电子,对原子核内随机分布的各向同性点源进行了建模。放射性核素在双螺旋DNA模型的中心轴附近的两个位置(1)离中心轴0.25nm和(2)在DNA的外围(离中心轴1.15nm)处掺入随机选择的DNA碱基对中。对于除99mTc以外的所有放射性核素,明确模拟了完整的物理衰减过程。对于99mTc,仅使用来自公开数据的总电子光谱。定量来自直接和间接作用的每次衰变的DNA双链断裂(DSB)产量。单能电子和放射性核素111In的结果,125I,123I,和99mTc与文献中的测量和计算数据进行比较,以进行验证。这项工作首次报道了64Cu在DNA中掺入的每次衰变的DSB产量。64Cu的治疗效果(在两次细胞分裂后导致37%细胞存活的活性)是根据掺入细胞核中的原子数确定的,所述原子数将导致100个125I衰变的相同DSB。进行模拟,直到达到2%的统计不确定度(1个标准偏差)。
■DSB作为单能电子能量函数的行为与已发表的数据一致,DSB随着能量的增加而增加,直到达到500eV附近的最大值,然后连续递减。对于64Cu,当在评估的位置(1)和(2)处掺入基因组中时,DSB为0.171±0.003和0.190±0.003DSB/衰减,分别。将引起治疗效果的64Cu掺入基因组(每个细胞)中的初始原子数估计为3,107±28,对应于47.1±0.4×10-3Bq的初始活性。
■我们的结果表明,具有64Cu的TRT在细胞中具有与目前在临床实践中使用的放射性核素的TRT相当的治疗效果。
UNASSIGNED: Targeted Radionuclide Therapy (TRT) with Auger Emitters (AE) is a technique that allows targeting specific sites on tumor cells using radionuclides. The toxicity of AE is critically dependent on its proximity to the DNA. The aim of this study is to quantify the DNA damage and radiotherapeutic potential of the promising AE radionuclide copper-64 (64Cu) incorporated into the DNA of mammalian cells using Monte Carlo track-structure simulations.
UNASSIGNED: A mammalian cell nucleus model with a diameter of 9.3 μm available in TOPAS-nBio was used. The cellular nucleus consisted of double-helix DNA geometrical model of 2.3 nm diameter surrounded by a hydration shell with a thickness of 0.16 nm, organized in 46 chromosomes giving a total of 6.08 giga base-pairs (DNA density of 14.4 Mbp/μm3). The cellular nucleus was irradiated with monoenergetic electrons and radiation emissions from several radionuclides including 111In, 125I, 123I, and 99mTc in addition to 64Cu. For monoenergetic electrons, isotropic point sources randomly distributed within the nucleus were modeled. The radionuclides were incorporated in randomly chosen DNA base pairs at two positions near to the central axis of the double-helix DNA model at (1) 0.25 nm off the central axis and (2) at the periphery of the DNA (1.15 nm off the central axis). For all the radionuclides except for 99mTc, the complete physical decay process was explicitly simulated. For 99mTc only total electron spectrum from published data was used. The DNA Double Strand Breaks (DSB) yield per decay from direct and indirect actions were quantified. Results obtained for monoenergetic electrons and radionuclides 111In, 125I, 123I, and 99mTc were compared with measured and calculated data from the literature for verification purposes. The DSB yields per decay incorporated in DNA for 64Cu are first reported in this work. The therapeutic effect of 64Cu (activity that led 37% cell survival after two cell divisions) was determined in terms of the number of atoms incorporated into the nucleus that would lead to the same DSBs that 100 decays of 125I. Simulations were run until a 2% statistical uncertainty (1 standard deviation) was achieved.
UNASSIGNED: The behavior of DSBs as a function of the energy for monoenergetic electrons was consistent with published data, the DSBs increased with the energy until it reached a maximum value near 500 eV followed by a continuous decrement. For 64Cu, when incorporated in the genome at evaluated positions (1) and (2), the DSB were 0.171 ± 0.003 and 0.190 ± 0.003 DSB/decay, respectively. The number of initial atoms incorporated into the genome (per cell) for 64Cu that would cause a therapeutic effect was estimated as 3,107 ± 28, that corresponds to an initial activity of 47.1 ± 0.4 × 10-3 Bq.
UNASSIGNED: Our results showed that TRT with 64Cu has comparable therapeutic effects in cells as that of TRT with radionuclides currently used in clinical practice.