Expanding the Therapeutic Potential of the Alpha Emitter Radium-223

项目摘要 镭-223是FDA批准的唯一α放射性核素。它被用于治疗 去势抵抗性前列腺癌患者的骨转移。它以化学形式给药， 简单的二氯化镭盐，它使未螯合的拟钙镭（II）离子定位于 快速分裂的骨转移瘤尽管这种放射性核素具有显著的治疗潜力，但其目前 FDA批准的制剂不能用于治疗软组织转移。这个目标 一项建议是通过开发双功能放射性核素， 螯合剂，可以稳定地保留和输送镭-223在体内。在目标1中，我们将合成新的二氮杂- 18-冠-6大环化合物和杯[4]芳烃配体作为镭螯合的潜在候选物。我们 探索这些配体类别的动机是由文献优先权决定的，这表明这些配体 配体对大离子如镭（II）具有独特的选择性。在目标2中，我们将与威尔的Babich教授合作 康奈尔大学医学评估放射化学我们最好的配体候选人与镭-223。放射性标记 将测量所得络合物的动力学和稳定性。镭-223的理想候选者 螯合作用将快速和定量地与镭（II）离子形成络合物，该络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中继续合成双官能螯合剂。 使用我们最有效的镭-223螯合剂，我们将合成安装胺反应 将异硫氰酸酯官能团连接到配体上，以允许其缀合到软组织肿瘤靶向 抗体的该配体-抗体缀合物将用镭-223放射性标记，并且其体内生物分布将与放射性标记的配体-抗体缀合物结合。 在荷瘤小鼠中进行评估，以测试我们的放射性金属构建体的长期稳定性。统称 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，这项技术有可能通过以下方式显著延长和改善癌症患者的生命： 从而能够获得非常有希望的镭-223放射性核素。

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.