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Abstract：
BACKGROUND: Recently, a new family of 99mTc(I)-tricarbonyl complexes bearing an acridine orange (AO) DNA targeting unit and different linkers between the Auger emitter (99mTc) and the AO moiety was evaluated for Auger therapy. Among them, 99mTc-C3 places the corresponding radionuclide at a shortest distance to DNA and produces important double strand breaks (DSB) yields in plasmid DNA providing the first evidence that 99mTc can efficiently induce DNA damage when well positioned to the double helix. Here in, we have extended the studies to human prostate cancer PC3 cells using the 99mTc-C3 and 99mTc-C5 complexes, aiming to assess how the distance to DNA influences the radiation-induced biological effects in this tumoral cell line, namely, in which concerns early and late damage effects.
RESULTS: Our results highlight the limited biological effectiveness of Auger electrons, as short path length radiation, with increasing distances to DNA. The evaluation of the radiation-induced biological effects was complemented with a comparative microdosimetric study based on intracellular dose values. The comparative study, between MIRD and Monte Carlo (MC) methods used to assess the cellular doses, revealed that efforts should be made in order to standardize the bioeffects modeling for DNA-incorporated Auger electron emitters.
CONCLUSIONS: 99mTc might not be the ideal radionuclide for Auger therapy but can be useful to validate the design of new classes of Auger-electron emitting radioconjugates. In this context, our results highlight the crucial importance of the distance of Auger electron emitters to the target DNA and encourage the development of strategies for the fine tuning of the distance to DNA for other medical radionuclides (e.g., 111In or 161Tb) in order to enhance their radiotherapeutic effects within the Auger therapy of cancer.
RESULTS: Our results highlight the limited biological effectiveness of Auger electrons, as short path length radiation, with increasing distances to DNA. The evaluation of the radiation-induced biological effects was complemented with a comparative microdosimetric study based on intracellular dose values. The comparative study, between MIRD and Monte Carlo (MC) methods used to assess the cellular doses, revealed that efforts should be made in order to standardize the bioeffects modeling for DNA-incorporated Auger electron emitters.
CONCLUSIONS: 99mTc might not be the ideal radionuclide for Auger therapy but can be useful to validate the design of new classes of Auger-electron emitting radioconjugates. In this context, our results highlight the crucial importance of the distance of Auger electron emitters to the target DNA and encourage the development of strategies for the fine tuning of the distance to DNA for other medical radionuclides (e.g., 111In or 161Tb) in order to enhance their radiotherapeutic effects within the Auger therapy of cancer.
摘要：
背景：最近，一个新的99mTc（I）-三羰基复合物家族，该复合物带有吖啶橙（AO）DNA靶向单元以及俄歇发射体（99mTc）和AO部分之间的不同连接体，用于俄歇治疗。其中,99mTc-C3将相应的放射性核素放置在距DNA最短距离的位置，并在质粒DNA中产生重要的双链断裂（DSB）产量，这提供了第一个证据，表明99mTc在双螺旋上定位良好时可以有效诱导DNA损伤。在这里，我们已经使用99mTc-C3和99mTc-C5复合物将研究扩展到人类前列腺癌PC3细胞，旨在评估与DNA的距离如何影响该肿瘤细胞系中辐射诱导的生物学效应，即,其中涉及早期和晚期损害效应。
结果：我们的结果突出了俄歇电子的有限生物学功效，作为短路径长度辐射，与DNA的距离越来越远。辐射诱导的生物效应的评估得到了基于细胞内剂量值的比较微剂量研究的补充。比较研究，在用于评估细胞剂量的MIRD和蒙特卡罗(MC)方法之间，透露，应努力使掺入DNA的俄歇电子发射器的生物效应建模标准化。
结论：99mTc可能不是俄歇治疗的理想放射性核素，但可用于验证新型俄歇电子发射放射缀合物的设计。在这种情况下，我们的结果强调了俄歇电子发射器到目标DNA的距离至关重要，并鼓励开发用于微调其他医学放射性核素到DNA的距离的策略（例如，111In或161Tb），以增强它们在癌症的俄歇疗法中的放射治疗效果。
结果：我们的结果突出了俄歇电子的有限生物学功效，作为短路径长度辐射，与DNA的距离越来越远。辐射诱导的生物效应的评估得到了基于细胞内剂量值的比较微剂量研究的补充。比较研究，在用于评估细胞剂量的MIRD和蒙特卡罗(MC)方法之间，透露，应努力使掺入DNA的俄歇电子发射器的生物效应建模标准化。
结论：99mTc可能不是俄歇治疗的理想放射性核素，但可用于验证新型俄歇电子发射放射缀合物的设计。在这种情况下，我们的结果强调了俄歇电子发射器到目标DNA的距离至关重要，并鼓励开发用于微调其他医学放射性核素到DNA的距离的策略（例如，111In或161Tb），以增强它们在癌症的俄歇疗法中的放射治疗效果。
