3 years ago

An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy

An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy
Anastasia Nikolopoulou, Victoria Brown, Clarence Williams, Shashikanth Ponnala, Samantha N. MacMillan, Nikki A. Thiele, James M. Kelly, Valery Radchenko, Caterina F. Ramogida, John W. Babich, Paul Schaffer, Justin J. Wilson, Cristina Rodríguez-Rodríguez, Andrew K. H. Robertson, Una Jermilova, Alejandro Amor-Coarasa
The 18-membered macrocycle H2macropa was investigated for 225Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all 225Ac (26 kBq) in 5 min at RT. [225Ac(macropa)]+ remained intact over 7 to 8 days when challenged with either excess La3+ 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 225Ac in just minutes at RT, and macropa-Tmab retained >99 % of its 225Ac in human serum after 7 days. In LNCaP xenograft mice, 225Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free 225Ac over 96 h. These findings establish macropa to be a highly promising ligand for 225Ac chelation that will facilitate the clinical development of 225Ac TAT for the treatment of soft-tissue metastases. Actinium in action! A macrocyclic ligand exhibits unprecedented radiolabeling efficiency for the large α-emitting radionuclide 225Ac3+. This ligand is extremely promising for the implementation of 225Ac in targeted alpha therapy for cancer. RCY=radiochemical yield.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/anie.201709532

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