Cancer Radiotheranostics Targeting Carbonic Anhydrase-IX with In- and Y-labeled Ureidosulfonamide Scaffold for SPECT Imaging and Radionuclide-based Therapy

Hypoxic cells dynamically translocate during tumor growth and after radiotherapy. The most desirable direction for therapy targeting hypoxic cells is combining imaging and therapy (theranostics), which may help realize personalized medicine. Here, we conducted cancer radiotheranostics targeting carbonic anhydrase-IX (CA-IX), which is overexpressed in many kinds of hypoxic cancer cells, using low-molecular-weight In and Y complexes with a bivalent ureidosulfonamide scaffold as the CA-IX-binding moiety ([In/Y]US2). The targeting ability of [In]US2 was evaluated by biodistribution study in CA-IX high-expressing (HT-29) tumor-bearing mice. imaging of HT-29 tumors was carried out using single photon emission computed tomography (SPECT). [Y]US2 was administered to HT-29 tumor-bearing mice to evaluate cancer therapeutic effects. [In]US2 highly and selectively accumulated within HT-29 tumors (4.57% injected dose/g tumor at 1 h postinjection), was rapidly cleared from the blood pool and muscle after 4 h based on a biodistribution study, and visualized HT-29 tumor xenografts in mice at 4 h postinjection with SPECT. Radionuclide-based therapy with [Y]US2 significantly delayed HT-29 tumor growth compared with that of untreated mice ( = 0.02 on day 28, Student's -test), without any critical hematological toxicity due to its rapid pharmacokinetics. These results indicate that cancer radiotheranostics with [In/Y]US2 provides a novel strategy of theranostics for cancer hypoxia.