Abstract
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Objectives: Actinium-225 is a promising isotope for targeted alpha therapy (TAT) because of its favorable half-life (9.9 days) and high cytotoxicity with the four alpha particle emissions. Currently, chelation strategies for actinium are limited, hindering its clinical application. The goal is to develop a new chelator for actinium that can coordinate under mild conditions and produce a stable complex in vivo.
Methods: A new ligand named Crown was designed and synthesized. Crown is a macrocycle capable of accommodating large metal ions while retaining the structural simplicity and hydrophilicity. The labeling conditions at various concentrations, buffers and pH were tested. The chemical stability of Ac-225-Crown was assessed. The ligand was attached to octreotate (TATE) and the peptide conjugate was labeled with Ac-225. The serum stability and biodistribution of Ac-225-Crown-TATE in AR42J tumor-bearing-mice was studied.
Results: Crown can form a stable complex with Ac-225 at room temperature and neutral pH quantitatively. Ac-225-Crown-TATE was stable in mice and human serum. Biodistribution in AR42J tumor bearing mice at 1h and 4h showed low liver accumulation (2.41±1.15 %ID/g at 1h and 2.44±1.15 %ID/g at 4h) indicating in vivo stability. The activity was primarily accumulated in kidneys, bladder and tumor (8.10±2.36 %ID/g at 1h and 6.55±0.88 %ID/g at 4h).
Conclusions: Crown is a suitable ligand for actinium, and Ac-225-Crown-TATE is a promising candidate for further therapeutic studies.
