An antibody-targeted radiotherapy using lanthanides or actinides has shown great promise in the treatment of various cancers as demonstrated by numerous clinical and preclinical studies. Alpha-particle emitting radioisotopes have been proven to be effective in treatment of leukemia and lymphoma and micrometastatic cancers. 225Ac (t1/2 = 10 d) with high a energy (5-8 MeV) and a short range emission (50-80 mm) were proposed to selectively and effectively kill tumor cells with a minimum damage to normal cells.<br/>To minimize radiotoxicity and enhance potency of RIT, a bifunctional ligand that can effectively sequester the radionuclide must be employed. While Ac-225 is a potent radionuclide, less progress has been made on development of an effective bifunctional ligand for the alpha radiotherapy. A bifunctional ligand that can tightly hold 225Ac while being conjugated to a highly sensitive antibody without compromising its biological activity is a critical component for successful targeted alpha therapy of cancer.<br/>In this presentation, we report synthesis and evaluation of bifunctional ligands for potential applications of Ac-225 radionuclide therapy. We have designed and prepared the structurally unique chelators in the series of NETA and DEPA for better understanding of Ac(III)-coordination chemistry. The bifunctional chelators were evaluated for radiolabeling kinetics and complex stability with Ac-225 and conjugated to two model monoclonal antibodies, Herceptin and Panitumumab that are approved for use in cancer therapy.<br/>

Bifunctional ligands of Ac-225 for potential applications in antibody-targeted alpha radiotherapy of cancer

256th National Meeting (2018)

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