In vitro and in vivo characterization of [(64)Cu][Cu(elesclomol)] as a novel theranostic agent for hypoxic solid tumors

PURPOSE: Hypoxic tumors are associated with therapy resistance and poor cancer prognosis, but methods to detect and counter tumor hypoxia remain insufficient. Our purpose was to investigate (64)Cu(II)-elesclomol ([(64)Cu][Cu(ES)]) as a novel theranostic agent for hypoxic tumors, by implementing an improved production method and assessing its therapeutic and diagnostic potential compared to the established Cu-64 radiopharmaceuticals [(64)Cu]CuCl(2) and [diacetyl-bis(N4-methylthiosemicarbazone) [(64)Cu][Cu(ATSM)]. METHODS: Cu-64 was produced using a biomedical cyclotron at 12 MeV with the reaction (64)Ni(p,n)(64)Cu, followed by synthesis of [(64)Cu]CuCl(2), [(64)Cu][Cu(ATSM)], and [(64)Cu][Cu(ES)]. In vitro therapeutic effects were assessed in both normoxic and hypoxic cells (22Rv1 and PC3 prostate cancer cells, and U-87MG glioblastoma cells) using the clonogenic assay and analyzing cellular uptake and internalization. In vivo therapeutic effects were assessed in 22Rv1 xenografts in BALB/cAnN-Foxn1nu/nu/Rj mice receiving a single or multiple doses of radiopharmaceutical, before their feasibility to detect tumor hypoxia was assessed by positron emission tomography (PET) in 22Rv1 and U-87MG xenografts. RESULTS: In vitro and in vivo studies demonstrated that [(64)Cu][Cu(ES)] reduced cell survival and inhibited tumor growth more effectively than [(64)Cu][Cu(ATSM)] and [(64)Cu]CuCl(2). Hypoxia increased the cellular uptake and internalization of [(64)Cu][Cu(ES)] and [(64)Cu][Cu(ATSM)]. [(64)Cu][Cu(ES)]-PET tumor hypoxia detection was feasible and also revealed an unexpected finding of uptake in the brain. CONCLUSION: To the best of our knowledge, this is the first time that ES is radiolabeled with [(64)Cu]CuCl(2) to [(64)Cu][Cu(ES)]. We demonstrated superior therapeutic effects of [(64)Cu][Cu(ES)] compared to [(64)Cu][Cu(ATSM)] and [(64)Cu]CuCl(2) and that [(64)Cu][Cu(ES)]-PET is feasible. [(64)Cu][Cu(ES)] is a promising theranostic agent for hypoxic solid tumors. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-023-06310-4.