Antimony-119 for Targeted Radionuclide Therapy

用于靶向放射性核素治疗的 Antimony-119

基本信息

批准号：
10425275
负责人：
Aeli P Olson
金额：
$ 3.49万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10425275
关键词：
3D Print 90Y Actinium Address Affinity Alpha Particles Amines Antibodies Antimony Area Astatine Belief Binding Biodistribution Biological Biological Assay Cancer Patient Carboxylic Acids Cause of Death Cell Nucleus Cell Survival Cell surface Cells Cellular Assay Chelating Agents Chemicals Clinical Clinical Treatment Complex Coupling Cyclotrons DNA DNA Double Strand Break Data Deposition Diagnostic Diagnostic Imaging Disease Disease Management Disease Marker Disease model Dose Drug Kinetics Electrons External Beam Radiation Therapy FOLH1 gene Fluorescence Fluorescence Microscopy Glutamates Goals Half-Life Heavy Ions Helium High Pressure Liquid Chromatography Hour Human Image In Vitro Inherited Ions Isotopes Kinetics Left Length Linear Energy Transfer Lutetium Lysine Malignant Neoplasms Malignant neoplasm of prostate Measurement Measures Medical Metabolism Methodology Molecular Molecular Conformation Monitor Mus Organ Patients Photons Positioning Attribute Production Property Proteins Radiation Radiation Dose Unit Radiation therapy Radioactivity Radioisotopes Radiology Specialty Radionuclide therapy Radiopharmaceuticals Relative Biological Effectiveness Reporting Research Personnel Resolution Roentgen Rays Serum Signaling Molecule Staging Survival Rate Technology Testing Therapeutic Tin Tissues Training Urea Urine Work Xenograft procedure analog cancer cell cancer therapy cell injury cell killing chelation dosimetry effective therapy electron energy experimental study in silico in vivo innovation interest lipophilicity malignant breast neoplasm microscopic imaging mouse model overexpression particle pre-doctoral prevent receptor response scaffold side effect single photon emission computed tomography stable isotope standard measure success targeted delivery theranostics tumor uptake vector

项目摘要

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.

项目概要/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、有效的治疗方法我们建议测试发射迈特纳-俄歇电子 (MAE) 的放射性核素锑 119 (119Sb) 是否有助于治疗癌症。通过测量细胞杀伤功效、与临床标准进行比较并量化来进行靶向放射性核素治疗 (TRT) 通过体内和离体实验进行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）调整到细胞疾病标记物（受体、过表达的蛋白质）以传递放射性核素， TRT 在病变细胞内发射短程、高度破坏性的放射性，具有治疗潜力，包括转移性细胞。疾病，并可以减轻当前放射治疗的副作用，具有b-（高能电子）发射，a。粒子（氦核）发射和低能 MAE 发射已被提议用于 TRT 应用 [2]。发射放射性核素提供高辐射剂量输送（优于临床标准 b-发射体 [3]），衰变至稳定同位素提供简单的剂量跟踪（优于α发射器），并且可以在小型回旋加速器上产生遍布世界各地的网络（相对于 a 发射器来说是一个优势，a 发射器的生产非常具有挑战性 [4]）。 MAE TRT 的研究将 119Sb 推广为理想的 TRT 候选者 [5-7]，因为其 23- 的高度局部能量沉积 24 种低能量 MAE [8]、提供清洁剂量分布的低 X 射线发射以及高回旋加速器产量。缺乏成熟的生产技术和双功能螯合剂支架阻碍了 119Sb I 的应用。我博士前培训的前三年用于开发医用级 119Sb 的生产，我们已经报告了放射性锑与双功能螯合剂的第一个稳定络合——我现在处于独特的地位来探索它我们追求119Sb TRT制剂比目前临床上更有效地杀死癌细胞。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-赖氨酸部分结合。特异性膜抗原 (PSMA)，一种公认的前列腺癌疾病标记物，并表征了 119Sb-三硫醇- PSMA 放射性药物，具有 HPLC、血清稳定性、亲脂性和表观摩尔活度 (AMA) 测量。证明 PSMA 载体的靶向性、结合亲和力、内化动力学和流出动力学测定的保留 ATP 细胞活力测定将测量细胞杀伤功效，克隆形成测定将监测遗传效应。 177Lu-PSMA-617 的类似研究将我们的 TRT 药物与临床标准进行比较，我们还将调查其效果。我们将使用 g-H2AX 来量化双链 DNA 断裂的荧光显微镜的损伤机制。使用感兴趣区域分析测量放射性同位素成像类似物 117Sb-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) 图像以及通过伽马计数进行的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，提供有关 OLINDA 计算公式将放射性药物靶向、递送、代谢和体内复合物稳定性。这项工作将根据体内数据估计 119Sb-三硫醇-PSMA 的全身、肿瘤和器官特异性剂量测定。彻底探索 119Sb 的 TRT 能力，并为我提供优秀的博士前培训。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Third Generation Potentially Bifunctional Trithiol Chelate, Its nat,1XXSb(III) Complex, and Selective Chelation of Radioantimony (119Sb) from Its Sn Target.

第三代潜在双功能三硫醇螯合物、其 nat,1XXSb(III) 络合物以及其 Sn 靶标中放射性锑 (119Sb) 的选择性螯合。

DOI：
发表时间：
2021-10-18
期刊：
影响因子：
4.6
作者：
Olson, Aeli P;Ma, Li;Feng, Yutian;Najafi Khosroshahi, Firouzeh;Kelley, Steven P;Aluicio;Barnhart, Todd E;Hennkens, Heather M;Ellison, Paul A;Jurisson, Silvia S;Engle, Jonathan W
通讯作者：
Engle, Jonathan W

Radionuclide Tracing Based in situ Corrosion and Mass Transport Monitoring of 316L Stainless Steel in a Molten Salt Closed Loop.

基于放射性核素示踪的熔盐闭环中 316L 不锈钢的原位腐蚀和传质监测。