RADIOBIOLOGICAL AND COMPUTATIONAL EVALUATION OF THE AUGER ELECTRON EMITTERS, 67GA AND 111IN, FOR MOLECULAR RADIONUCLIDE THERAPY

Lefteris Livieratos博士是KCL的高级讲师，Guy's & St托马斯' Hospitals的核医学临床科学家（医学物理学家），并成功指导了两名博士生（其中一名在第一年后加入为导师）。他的研究重点是新放射性药物临床转化的图像量化方法。他在PET/CT、SPECT/CT和靶向放射性核素治疗方面拥有超过15年的经验，包括新疗法的临床实施（最近，90 Y和177 Lu-DOTATATE用于神经内分泌肿瘤，223 Ra用于骨转移前列腺癌）。他目前拥有为期五年的NIHR/HEFCE高级临床讲师（2013-2018），专注于放射性核素治疗。Livieratos博士将领导剂量测定并提供医学物理专家支持。Terry博士是KCL放射生物学讲师，是研究治疗性放射性核素（主要是俄歇电子发射器和外部束）在细胞和组织中的生物效应的专家，并在肽和抗体的分子放射性核素成像方面拥有丰富的经验。她还具有通过放射治疗后成像监测治疗反应的专业知识。她将监督生物学研究，这将为计算建模和模型验证提供输入。先前博士项目（2015年完成）的一些初步工作（Livieratos）利用来自I-131和Re-188显微放射自显影的小规模放射性药物分布来开发甲状腺内剂量分布的计算模型，以评估甲状腺滤泡细胞和甲状腺胶体中的吸收剂量。这些数据，以及小动物体内SPECT和PET数据，有助于Re-188作为治疗甲状腺疾病的潜在临床药物的微观和宏观剂量学特征。这项工作是基于MCNPx平台的Monte Carlo模拟发射能量高于10 keV。Jordan Cheng与Verger博士（博士后，Terry Group）合作的早期工作也为67 Ga的治疗潜力提供了有用的见解。总的来说，发现67 GaCl 3比111 InCl 3诱导更大的质粒损伤，提供了进一步的证据表明67 Ga释放的俄歇电子具有更高的能量，并且比111 In具有更高的细胞毒性。外照射放射治疗（EBRT）造成的质粒损伤也为质粒DNA损伤动力学提供了有趣的见解，我们的合作者（弗朗西斯克里克研究所的丹尼尔伯纳姆博士）的数据使数学建模成为可能。尽管缺乏任何修复酶，但较高的质粒浓度（1.25 ng/L vs. 5 ng/L）令人惊讶地提供了DNA免受EBRT处理的保护，并导致质粒构象转换率降低。

Dr Lefteris Livieratos is a Senior Lecturer at KCL, a Clinical Scientist (Medical Physicist) in Nuclear Medicine at Guy's & St Thomas' Hospitals and has successfully supervised two PhD students (for one of which joining as supervisor after year 1). His research focuses on image quantification methodology for clinical translation of new radiopharmaceuticals. He has over 15 years' experience in PET/CT, SPECT/CT and targeted radionuclide therapies, including clinical implementation of novel therapies (recently, 90Y- and 177Lu-DOTATATE for neuroendocrine tumours and 223Ra for bone-metastasised prostate cancer). He currently holds a five-year NIHR/HEFCE Senior Clinical Lectureship (2013-2018) focusing on radionuclide therapy. Dr Livieratos will lead on dosimetry and provide Medical Physics Expert support. Dr Terry is a Lecturer in Radiobiology at KCL and is an expert in studying biological effects of therapeutic radionuclides (mainly Auger electron emitters and external beam) in cells and tissues and has extensive experience in molecular radionuclide imaging with peptides and antibodies. She also has expertise in monitoring therapy response by imaging after radiotherapy. She will oversee the biological studies which will provide input to computational modelling and model verification. Some preliminary work (Livieratos) from a previous PhD project (completed 2015) utilised small-scale radiopharmaceutical distributions from micro-autoradiography with I-131 and Re-188 to develop a computational model for dose distributions within the thyroid in order to assess absorbed doses in thyroid follicular cells and in thyroid colloids. Such data, together with small animal in vivo data with SPECT and PET have contributed to the microscopic and macroscopic dosimetric profile of Re-188 as a potential clinical agent for the treatment of thyroid disease. This work was based on the MCNPx platform for Monte Carlo simulations of emission with energies higher than 10 keV. Earlier work by Jordan Cheng, in conjunction with Dr. Verger (postdoc, Terry Group), has also provided useful insights into the therapeutic potential of 67Ga with a cell-free plasmid assay. Overall, it was found that 67GaCl3 induced greater plasmid damage than 111InCl3, providing further evidence suggesting higher energy possessed by the released Auger electrons of 67Ga and potentially higher cytotoxicity than 111In. Plasmid damage by external beam radiotherapy (EBRT) also provided interesting insights into plasmid DNA damage kinetics, with the data enabling mathematical modelling by our collaborator (Dr. Daniel Burnham, Francis Crick Institute). Higher plasmid concentrations (1.25 ng/L vs. 5 ng/L) surprisingly offered protection of DNA from EBRT treatment, despite the lack of any repair enzymes, and resulted in reduced plasmid conformational switch rates.