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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.

项目总结/文摘

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