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.

项目摘要/摘要 2017年，癌症是美国第二大死亡原因[1]，这说明了对创新，有效的迫切需求疗法。我们建议测试Meitner-Aiger Electron（MAE） - 发射放射性锑-119（119SB）的癌症通过测量细胞杀伤效率，与临床标准进行比较并进行量化，靶向放射线疗法（TRT）通过体内和体内实验的生物分布和致命剂量递送。 TRT使用生物学靶向向量（信号分子，抗体）调节细胞疾病标志物（受体，过表达蛋白质），以提供放射性的，这些放射线发射短范围，在解散的细胞内部发射高度破坏的放射性。 TRT具有治疗潜力，包括转移疾病，可以减轻当前的辐射疗法副作用。带有B-（高能电子）排放的放射线，A 已经提出了用于TRT应用的粒子（氦核）排放和低能MAE排放[2]。梅 - 发射放射线可提供高辐射剂量递送（比临床标准B-发射器[3]的优势），衰减至稳定的同位素可提供简单的剂量跟踪（比A-Emitter的优势），可以在小环体上产生在世界范围内建立网络（比A-Emitter的优势非常挑战[4]）。许多在硅中 MAE TRT的研究促进119SB作为理想的TRT候选者[5-7]，因为其23-- 24个低能量MAE [8]，低X射线排放，提供清洁剂量剖面和高回旋子产量的产量。然而，缺乏发达的生产技术和双功能螯合剂支架阻止了119SB的应用。我花在我的前三年培训的前三年开发医疗质量的生产119SB，我们报告了第一个稳定的放射障碍与双功能螯合剂的络合 - 我现在很独特地探索它生物应用。我们假设119SB TRT药物比当前的临床更有效地杀死癌细胞 TRT标准。我们建议将双功能螯合剂缀合到结合前列腺的谷氨酸 - 尿素 - 赖氨酸部分特定的膜抗原（PSMA），一种公认的前列腺癌疾病标志物，表征了119SB-三硫醇 PSMA放射性药物具有HPLC，血清稳定性，亲脂性和明显的摩尔活性（AMA）测量。到证明PSMA矢量的靶向，结合亲和力，内在化动力学和排出动力学测定将是实施。 ATP细胞活力测定将测量细胞杀伤的效率，而粘液性测定将监测遗传性效应。对177LU-PSMA-617的类似研究也会将我们的TRT药物与临床标准进行比较。我们还将调查使用G-H2AX使用荧光显微镜损伤的机理，以量化双链DNA断裂。我们将使用利率分析的放射性同位素成像模拟117SB-Trithiol-PSMA在体内药代动力学中单光子发射计算机断层扫描（SPECT）图像和通过伽马计数的活性测量确定异种移植的癌症肿瘤小鼠模型中的体内生物分布，提供有关放射药物靶向，递送，代谢和体内复杂稳定性。 Olinda计算公式化将从体内数据估算我们的119SB-Trithiol-PSMA的全身，肿瘤和器官特异性剂量法。这项工作将彻底探究了119SB的TRT功能，使我获得了出色的专用训练。

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）

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。

DOI：
10.21203/rs.3.rs-3415493/v1
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
Wang,Yafei;Olson,Aeli;Falconer,Cody;Kelleher,Brian;Mitchell,Ivan;Zhang,Hongliang;Sridharan,Kumar;Engle,Jonathan;Couet,Adrien
通讯作者：
Couet,Adrien