Antimony-119 for Targeted Radionuclide Therapy

项目总结/摘要 2017年，癌症是美国第二大死亡原因[1]，这说明迫切需要创新，有效的治疗方法。 治疗我们建议测试Meitner-Auger电子（MAE）发射放射性核素锑-119（119 Sb）的癌症 靶向放射性核素治疗（TRT），通过测量细胞杀伤效率，与临床标准进行比较，并定量 通过体内和离体实验的生物分布和致死剂量递送。TRT使用生物靶向载体（信号 分子、抗体）调谐到细胞疾病标志物（受体、过表达的蛋白质），以递送 在病变细胞内释放出短距离的，高度破坏性的放射性物质。TRT具有治疗潜力，包括转移性 疾病，并且可以减轻当前放射治疗的副作用。B-（高能电子）放射性核素，a 粒子（氦核）发射和低能MAE发射已被提出用于TRT应用[2]。MAE- 发射放射性核素提供高辐射剂量递送（优于临床标准B-发射体[3]）， 稳定的同位素，提供简单的剂量跟踪（优于a-发射体），并可在小型回旋加速器上生产 在全世界联网（这是一个优于a-发射器的优势，因为a-发射器的生产非常具有挑战性[4]）。许多计算机模拟 对MAE TRT的研究促进了119 Sb作为理想的TRT候选物[5-7]，这是由于其23- 24低能量MAE [8]，低X射线发射提供清洁剂量分布，以及高回旋加速器生产产量。然而，在这方面， 缺乏开发的生产技术和双功能螯合剂支架阻碍了119 Sb的应用。我 我花了前三年的博士前培训开发医疗质量119 Sb的生产，我们已经报告 第一个稳定的络合放射性锑与双功能螯合剂-我现在唯一的定位，以探索其 生物应用我们假设119 Sb TRT药物将比目前的临床治疗更有效地杀死癌细胞。 TRT标准。我们建议将我们的双功能螯合剂与结合前列腺的谷氨酸-尿素-赖氨酸部分缀合 特异性膜抗原（PSMA），一种公认的前列腺癌疾病标志物，并表征119 Sb-三巯基- PSMA放射性药物与HPLC、血清稳定性、亲脂性和表观摩尔活性（AMA）测量。到 证明PSMA载体的靶向、结合亲和力、内化动力学和外排动力学测定的保留将是 进行。ATP细胞活力测定将测量细胞杀伤效力，克隆形成测定将监测遗传效应。 177 Lu-PSMA-617的类似研究将比较我们的TRT试剂与临床标准。我们还将调查 使用g-H2 AX用荧光显微镜定量双链DNA断裂的损伤机制。我们将 使用感兴趣区域分析测量放射性同位素成像类似物117 Sb-三硫醇-PSMA的体内药代动力学 单光子发射计算机断层扫描（SPECT）图像，并通过伽马计数活动测量将 确定异种移植癌症肿瘤小鼠模型中的离体生物分布，提供关于 放射性药物靶向、递送、代谢和体内复合物稳定性。OLINDA计算公式将 从体内数据估计我们的119 Sb-三硫醇-PSMA的全身、肿瘤和器官特异性剂量测定。这项工作将 彻底探测119 Sb的TRT能力，并为我提供了良好的博士前培训。

Project Summary/Abstract In 2017, cancer was the second leading cause of death in the USA [1], illustrating the dire need for innovative, effective therapies. We propose to test the Meitner-Auger electron (MAE)-emitting radionuclide antimony-119 (119Sb) for cancer targeted radionuclide therapy (TRT) by measuring cell killing efficacy, comparing against clinical standard, and quantifying biodistriubtion and lethal dose delivery via in vivo and ex vivo experiments. TRT uses biological targeting vectors (signal molecules, antibodies) tuned to cellular disease markers (receptors, overexpressed proteins) to deliver radionuclides that emit short range, highly damaging radioactivity inside diseased cells. TRT holds curative potential, including metastatic disease, and can mitigate current radiation therapy side effects. Radionuclides with b- (high energy electron) emissions, a particle (helium nucleus) emissions, and low energy MAE emissions have been proposed for TRT application [2]. MAE- emitting radionuclides provide high radiation dose delivery (an advantage over clinical standard b--emitters [3]), decay to stable isotopes providing simple dose tracking (an advantage over a-emitters), and can be produced on small cyclotrons networked across the world (an advantage over a-emitters which are very challenging to produce [4]). Many in silico studies on MAE TRT promote 119Sb as an ideal TRT candidate [5–7] due to the highly localized energy deposition of its 23- 24 low energy MAEs [8], low x-ray emissions providing clean dose profile, and high cyclotron production yields. However, the lack of developed production technology and bifunctional chelator scaffolds have prevented application of 119Sb. I spent the first three years of my predoctoral training developing production of medical quality 119Sb, and we have reported the first stable complexation of radioantimony with a bifunctional chelator – I am now uniquely positioned to explore its biological application. We hypothesize that 119Sb TRT agents will kill cancer cells more effectively than the current clinical TRT standard. We propose to conjugate our bifunctional chelator to a glutamate-urea-lysine moiety which binds prostate specific membrane antigen (PSMA), a well-recognized prostate cancer disease marker, and characterize the 119Sb-trithiol- PSMA radiopharmaceutical with HPLC, serum stability, lipophilicity, and apparent molar activity (AMA) measurements. To prove retention of the PSMA vector’s targeting, binding affinity, internalization kinetics, and efflux kinetics assays will be conducted. ATP cell viability assays will measure cell killing efficacy and a clonogenic assay will monitor hereditary effects. Similar studies of 177Lu-PSMA-617 will compare our TRT agent with the clinical standard. We will also investigate the mechanism of damage with fluorescence microscopy using g-H2AX to quantify double stranded DNA breaks. We will measure the radioisotope imaging analogue 117Sb-trithiol-PSMA in vivo pharmacokinetics using region-of-interest analysis of single photon emission computed tomography (SPECT) images, and activity measurements via gamma counting will determine ex vivo biodistribution in xenografted cancer tumor mouse models, providing information about radiopharmaceutical targeting, delivery, metabolism, and in vivo complex stability. The OLINDA calculation formulism will estimate whole-body, tumor, and organ specific dosimetry of our 119Sb-trithiol-PSMA from in vivo data. This work will thoroughly probe 119Sb’s TRT capability and afford me access to excellent predoctoral training.