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An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy. | LitMetric
The 18-membered macrocycle H macropa was investigated for Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all Ac (26 kBq) in 5 min at RT. [ Ac(macropa)] remained intact over 7 to 8 days when challenged with either excess La ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa-NCS, was conjugated to trastuzumab as well as to the prostate-specific membrane antigen-targeting compound RPS-070. Both constructs rapidly radiolabeled Ac in just minutes at RT, and macropa-Tmab retained >99 % of its Ac in human serum after 7 days. In LNCaP xenograft mice, Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free Ac over 96 h. These findings establish macropa to be a highly promising ligand for Ac chelation that will facilitate the clinical development of Ac TAT for the treatment of soft-tissue metastases.
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