New Ligands for Radioimmunotherapy and MRI of Cancer

描述（由申请人提供）： 开发适当的配体以有效地保持金属是提高放射免疫治疗（RIT）和磁共振成像（MRI）疗效的关键步骤。 这项研究的长期目标是开发临床上可行的配体，这些配体在两个癌症研究领域（RIT和MRI）中具有直接应用。 在目前的提案中，我们将集中精力在两个具体的目标，关于大环配体的设计，可以解决迫切需要积极的临床探索RIT和MRI。 第一个具体的目标是探索一种双峰结合方法，以产生更好的双功能配体，有效地结合有前途的放射性核素用于RIT。 这一目标是基于这样的假设，即使用大环空腔和无环侧基结合基团的合作结合可以提供增强的金属络合动力学，同时保持高水平的络合物稳定性。 我们的初步数据表明，一个新的配体，NOETA结合Y-86，一个重要的放射性金属RIT的第一次，具有良好的动力学和体内稳定性。 我们将进一步测试双峰结合的方法，通过制备双功能配体的RIT应用，并通过评估络合动力学和热力学的双功能配体与各种放射性金属的RIT，如Y-90，Bi-213和Ac-225。 第二个具体目的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，高和扩展的信号强度、体内稳定性、良好的细胞渗透、完全清除和高靶向特异性。 该目的是基于以下假设：掺入常规MR造影剂中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。 新的配体NOETA也显示出MR信号强度，以及与临床批准的非特异性MRI试剂相当的体内稳定性。 使用这种配体作为支架，我们将调查的潜力，附加类固醇作为肿瘤靶向载体的肿瘤特异性MR造影剂。 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，并直接使癌症患者受益。

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.