Expanding the Therapeutic Potential of the Alpha Emitter Radium-223

扩大 Alpha 发射体 Radium-223 的治疗潜力

• 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
• 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

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.

项目概要 Radium-223 是 FDA 批准的唯一一种发射 α 的放射性核素。它用于治疗 去势抵抗性前列腺癌患者的骨转移。它以化学形式施用 简单的二氯化镭盐，使未螯合的钙模拟镭 (II) 离子定位于 快速分裂骨转移。尽管这种放射性核素具有显着的治疗潜力，但其目前 FDA批准的配方不能用于治疗软组织转移瘤。此举的目标 建议通过开发双功能扩大这种核素对软组织转移的治疗潜力 能够在体内稳定保留和递送镭223的螯合剂。在目标 1 中，我们将合成新型二氮杂- 18-冠-6 大环化合物和基于杯[4]芳烃的配体作为镭螯合的潜在候选物。我们的 探索这些配体类别的动机是由文献优先顺序决定的，这表明这些配体 配体对镭(II)等大离子具有独特的选择性。在目标 2 中，我们将与 Weill 的 Babich 教授合作 Cornell Medicine 评估我们最好的候选配体镭 223 的放射化学。放射性标记 将测量所得复合物的动力学和稳定性。镭 223 的理想候选者 螯合会快速定量地与镭（II）离子形成复合物，该复合物在血清中稳定一段时间 至少 10 天。基于这些数据，我们将在目标 3 中追求双功能螯合剂的合成。 使用我们最有效的镭 223 螯合剂，我们将合成胺反应性 将异硫氰酸酯官能团附着到配体上，使其能够与软组织肿瘤靶向结合 抗体。这种配体-抗体缀合物将用镭223进行放射性标记，其体内生物分布将 在荷瘤小鼠中进行评估，以测试我们的放射性金属结构的长期稳定性。总的来说， 这三个目标的成功实现将导致新的双功能螯合剂的发现 镭-223，这将扩大这种放射性核素对软组织转移患者的治疗用途。 因此，该技术有可能通过以下方式显着延长和改善癌症患者的生命： 获得极具前景的镭223放射性核素。