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Expanding the Therapeutic Potential of the Alpha Emitter Radium-223

扩大 Alpha 发射体 Radium-223 的治疗潜力

基本信息

批准号：
10242812
负责人：
Justin J Wilson
金额：
$ 19.83万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-16 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242812
关键词：
90Y Actinium Affinity Alpha Particle Emitter Alpha Particles Amines Antibodies Beta Particle Biodistribution Biological Calcium Cancer Patient Chelating Agents Chemicals Chemistry Clinical Complex Cone DNA Damage Data Dental crowns Deposition Development Dose Event FDA approved Formulation Goals Human I131 isotope In Vitro Intravenous Ions Isothiocyanates Kinetics Label Lesion Ligands Linear Energy Transfer Literature Malignant Neoplasms Malignant neoplasm of prostate Measures Medicine Metals Metastatic Neoplasm to the Bone Molecular Motivation Mus Myeloid Leukemia Nature Neoplasm Metastasis Patients Penetration Peptides Property Radiation Radioactive Radiochemistry Radioisotopes Radiolabeled Radionuclide therapy Radiopharmaceuticals Radium Research Savings Serum Sodium Chloride Soft Tissue Neoplasms Structure System Technology Testing Therapeutic Therapeutic Uses Tissues Treatment Efficacy Work Y 90 Ibritumomab Tiuxetan antibody conjugate base cancer cell cancer type castration resistant prostate cancer chelation clinically significant cytotoxic functional group improved in vivo iodine-131-tositumomab millimeter mimetics neoplastic cell novel prostate cancer metastasis scaffold soft tissue tumor tumor xenograft vector

项目摘要

PROJECT SUMMARY Radium-223 is the only FDA-approved alpha-emitting radionuclide. It is employed for the treatment of bone metastases in patients with castration-resistant prostate cancer. It is administered in the chemical form of the simple radium dichloride salt, which enables the unchelated calcium-mimetic radium(II) ion to localize to rapidly dividing bone metastases. Despite the significant therapeutic potential of this radionuclide, its current FDA-approved formulation cannot be applied for the treatment of soft-tissue metastases. The goal of this proposal is to expand the therapeutic potential of this nuclide to soft-tissue metastases by developing bifunctional chelating agents that can stably retain and deliver radium-223 in vivo. In Aim 1, we will synthesize novel diaza- 18-crown-6 macrocycles and calix[4]arene-based ligands as potential candidates for radium chelation. Our motivation for exploring these classes of ligands is dictated by literature precedence, which shows that these ligands are uniquely selective for large ions like radium(II). In Aim 2, we will collaborate with Prof. Babich at Weill Cornell Medicine to evaluate the radiochemistry of our best ligand candidates with radium-223. The radiolabeling kinetics and the stabilities of the resulting complexes will be measured. An ideal candidate for radium-223 chelation will rapidly and quantitatively form a complex with the radium(II) ion that is stable in serum over a period of at least 10 days. Based on these data, we will pursue the synthesis of bifunctional chelating agents in Aim 3. Using our most effective radium-223 chelating agent, we will synthetically install an amine-reactive isothiocyanate functional group onto the ligand to allow for its conjugation to soft-tissue tumor-targeting antibodies. This ligand-antibody conjugate will be radiolabeled with radium-223, and its in vivo biodistribution will be evaluated in tumor-bearing mice to test the long-term stability of our radiometal construct. Collectively, the successful execution of these three aims will lead to the discovery of new, bifunctional chelating agents for radium-223, which will expand the therapeutic use of this radionuclide to patients with soft-tissue metastases. Thus, this technology has the potential to significantly prolong and improve the lives of cancer patients by rendering access to the highly promising radium-223 radionuclide.

项目总结