New Ligands for Radioimmunotherapy and MRI of Cancer

用于癌症放射免疫治疗和 MRI 的新配体

• 批准号: 7122036
• 负责人: HYUN-SOON CHONG
• 金额: $ 15.18万
• 依托单位: ILLINOIS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-23 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7122036
• 关键词: chemical binding; chemical synthesis; contrast media; drug design /synthesis /production; drug vehicle; human tissue; intracellular transport; laboratory mouse; ligands; magnetic resonance imaging; metal complex; neoplasm /cancer diagnosis; neoplasm /cancer radioimmunotherapy; neoplasm /cancer radionuclide therapy; pharmacokinetics; steroids; transfection /expression vector

DESCRIPTION (provided by applicant): The development of the adequate ligands to effectively hold metals is a critical step for enhancing the efficacy of radioimmunotherapy (RIT) and magnetic resonance imaging (MRI). The long-term objective of the proposed research is to develop clinically viable ligands that have direct applications in two cancer research fields, RIT and MRI. In the current proposal we will focus our effort on two specific aims regarding the design of macrocyclic ligands that may address the pressing needs for active clinical exploration of RIT and MRI. The first specific aim is to explore a bimodal binding approach to generate better bifunctional ligands to efficiently bind promising radionuclides for use in RIT. This aim is based on the hypothesis that the cooperative binding using both a macrocyclic cavity and an acyclic pendant binding group may provide enhanced kinetics in metal complexation while maintaining a high level of complex stability. Our preliminary data indicate that one of the new ligands, NOETA binds Y-86, an important radioactive metal for RIT for the first time, with excellent kinetics and in vivo stability. We will further test the bimodal binding approach by preparing bifunctional ligands for RIT applications, and by evaluating complexation kinetics and thermodynamics of the bifunctional ligands with a variety of radioactive metals for RIT such as Y-90, Bi-213 and Ac-225. The second specific aim is to investigate how incorporation of naturally occurring steroid(s) into the conventional contrast agent affects criteria of tumor-specific MR contrast agents, i.e., high and extended signal intensity, in vivo stability, good cell permeation, complete clearance, and high target specificity. This aim is based on the hypothesis that a steroid moiety incorporated into the conventional MR contrast agent promotes non-covalent interactions between the steroid transporters and the conjugated contrast construct. The new ligand NOETA also has shown MR signal intensity, and in vivo stability comparable to the clinically approved non-specific MRI agents. Using this ligand as a scaffold, we will investigate the potential of the attached steroid as a tumor targeting vector of tumor-specific MR contrast agents. The results of the proposed research will contribute to the development of better drugs for both MRI and RIT, which will greatly enhance clinical exploration of both modalities, and directly benefit cancer patients.

描述（由申请人提供）：开发有效固定金属的适当配体是增强放射免疫疗法（RIT）和磁共振成像（MRI）功效的关键步骤。 拟议研究的长期目标是开发临床上可行的配体，这些配体可直接应用于 RIT 和 MRI 这两个癌症研究领域。 在当前的提案中，我们将集中精力致力于大环配体设计的两个具体目标，这可能会满足 RIT 和 MRI 积极临床探索的迫切需求。 第一个具体目标是探索双模式结合方法，以产生更好的双功能配体，以有效结合有希望用于 RIT 的放射性核素。 该目标基于这样的假设：使用大环空腔和无环侧链结合基团的协同结合可以增强金属络合的动力学，同时保持高水平的络合物稳定性。 我们的初步数据表明，新配体之一NOETA首次与RIT的重要放射性金属Y-86结合，具有优异的动力学和体内稳定性。 我们将进一步测试双峰结合方法，制备用于 RIT 应用的双功能配体，并评估双功能配体与各种 RIT 放射性金属（如 Y-90、Bi-213 和 Ac-225）的络合动力学和热力学。 第二个具体目标是研究将天然存在的类固醇掺入常规造影剂中如何影响肿瘤特异性 MR 造影剂的标准，即高且扩展的信号强度、体内稳定性、良好的细胞渗透性、完全清除和高目标特异性。 这一目标基于这样的假设：常规 MR 造影剂中掺入的类固醇部分促进类固醇转运蛋白和缀合造影剂构建体之间的非共价相互作用。 新配体NOETA还显示出与临床批准的非特异性MRI药物相当的MR信号强度和体内稳定性。 使用该配体作为支架，我们将研究所连接的类固醇作为肿瘤特异性 MR 造影剂的肿瘤靶向载体的潜力。 拟议研究的结果将有助于开发更好的 MRI 和 RIT 药物，这将大大加强这两种模式的临床探索，并直接造福癌症患者。

项目成果

A novel cholic acid-based contrast enhancement agent for targeted MRI.

• DOI: 10.1016/j.bmcl.2008.01.044
• 发表时间: 2008-04
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Hyun-Soon Chong;Hyun A. Song;Sooyoun Lim;Keith W Macrenaris;Xiang Ma;Haisung Lee;P. Bui;T. Meade

Synthesis and evaluation of a bifunctional chelate for development of Bi(III)-labeled radioimmunoconjugates.

• DOI: 10.1016/j.bmcl.2011.06.107
• 发表时间: 2011-12-15
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
• 影响因子: 2.7
• 作者: Dadwal, Mamta;Kang, Chi Soo;Song, Hyun A.;Sun, Xiang;Dai, Anzhi;Baidoo, Kwamena E.;Brechbiel, Martin W.;Chong, Hyun-Soon
• 通讯作者: Chong, Hyun-Soon