Expanding the Therapeutic Potential of the Alpha Emitter Radium-223

项目总结 镭-223是FDA批准的唯一一种阿尔法发射放射性核素。它被用来治疗 抗去势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，它使未与钙离子结合的类钙离子(II)能够定位到 迅速分化的骨转移瘤。尽管这种放射性核素具有巨大的治疗潜力，但它目前的 FDA批准的配方不能用于软组织转移的治疗。这样做的目的是 建议通过开发双功能来扩大这种核素对软组织转移的治疗潜力 能够在体内稳定地保留和输送Re-223的螯合剂。在目标1中，我们将合成新型的二氮杂- 18-冠-6大环和杯[4]芳烃配体作为潜在的镭螯合候选者。我们的 探索这类配体的动机取决于文献的优先顺序，这表明这些 配体对大离子如镭(II)具有独特的选择性。在Aim 2中，我们将与Weill的Babich教授合作 康奈尔医学评估我们最好的候选配体的放射化学与镭-223。放射性标记 将测量生成的络合物的动力学和稳定性。Re-223的理想候选者 螯合作用会迅速和定量地与在血清中稳定存在一段时间的镭(II)离子形成络合物。 至少10天。在这些数据的基础上，我们将在目标3中进行双功能螯合剂的合成。 使用我们最有效的Re-223螯合剂，我们将合成一种胺反应 将异硫氰酸酯官能团连接到配体上，以允许其与软组织肿瘤靶向的结合 抗体。这种配体-抗体结合物将被放射性标记为镭-223，其在体内的生物分布将 在荷瘤小鼠身上进行评估，以测试我们放射性金属结构的长期稳定性。总体而言， 这三个目标的成功实现将导致发现新的双功能螯合剂 这将把这种放射性核素的治疗用途扩大到软组织转移患者。 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 使得我们能够接触到极有希望的镭-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.