Radioimmunotherapy (RIT) employs tumor-targeting antibody for selective delivery of a cytotoxic radionuclide to tumor cells thereby minimizing exposure to healthy cells. The success of this therapy is critical in that numerous cancer patients in external radiation treatment suffer from significant radiotoxic side effects rather than receive cancer therapy. 90Y, 177Lu, 212Bi, 213Bi, 212Pb, and 225Ac are effective radionuclides for RIT. The development of the adequate ligands to effectively hold the radionuclides after being conjugated with mAbs is a critical step for enhancing the efficacy of RIT. The long-term objective of the proposed research is to develop clinically viable radioimmunoconjugates that have direct applications in RIT. In the current proposal we will focus on the design and evaluation of bifunctional ligands that may address the pressing needs for active clinical exploration of RIT. The proposed new ligands possess both a macrocyclic cavity and an acyclic pendant binding group. The hypothesis based on the design of the new ligands is that the cooperative binding using both a macrocyclic ring and an acyclic pendant arm may provide enhanced kinetics in metal complexation while maintaining a high level of complex stability. The objective of this proposal is the investigation of bimodal binding property of the new ligands and identification of the useful radioimmunoconjugates based on the new ligand labeled with 90-Y, 212-Bi, 213-Bi, 212-Pb, 177-Lu, and 225-Ac. Our preliminary data indicate that one of the structurally new ligands binds 86-Y for the first time, with excellent kinetics, and in vitro and in vivo stability. The new ligand also forms a very stable complex with 205/6-Bi, 203-Pb, and 177-Lu in human serum or mice. We will further investigate the proposed hypothesis by evaluating the new ligands for complexation kinetics and thermodynamics studies and x-ray crystallographic studies using the proposed metals. The radiolabeled antibody conjugates using the new bifunctional ligands will be prepared, and their complexation kinetics and stability in binding the radionuclides in serum will be investigated. The best radioimmunoconjugates screened from in vitro evaluations will be further evaluated for in vivo studies using athymic mice. The results of the of the proposed research may potentially contribute to the development of less toxic, safer, and more potent RIT drugs using practical and facile radiolabeling condition. ? ? ?
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