In vitro and in vivo characterization of [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 Cu(II)-elesclomol ([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 [Cu]CuCl and [diacetyl-bis(N4-methylthiosemicarbazone) [Cu][Cu(ATSM)].

Methods: Cu-64 was produced using a biomedical cyclotron at 12 MeV with the reaction Ni(p,n)Cu, followed by synthesis of [Cu]CuCl, [Cu][Cu(ATSM)], and [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 [Cu][Cu(ES)] reduced cell survival and inhibited tumor growth more effectively than [Cu][Cu(ATSM)] and [Cu]CuCl. Hypoxia increased the cellular uptake and internalization of [Cu][Cu(ES)] and [Cu][Cu(ATSM)]. [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 [Cu]CuCl to [Cu][Cu(ES)]. We demonstrated superior therapeutic effects of [Cu][Cu(ES)] compared to [Cu][Cu(ATSM)] and [Cu]CuCl and that [Cu][Cu(ES)]-PET is feasible. [Cu][Cu(ES)] is a promising theranostic agent for hypoxic solid tumors.