Cancer radiotheranostics targeting carbonic anhydrase-IX with ¹¹¹In- and ⁹⁰Y-labeled ureidosulfonamide scaffold for SPECT imaging and radionuclide-based therapy

Abstract

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 111In and 90Y complexes with a bivalent ureidosulfonamide scaffold as the CA-IX-binding moiety ([111In/90Y]US2).Methods: The targeting ability of [111In]US2 was evaluated by in vivo biodistribution study in CA-IX high-expressing (HT-29) tumor-bearing mice. In vivo imaging of HT-29 tumors was carried out using single photon emission computed tomography (SPECT). [90Y]US2 was administered to HT-29 tumor-bearing mice to evaluate cancer therapeutic effects.Results: [111In]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 [90Y]US2 significantly delayed HT-29 tumor growth compared with that of untreated mice (P = 0.02 on day 28, Student's t-test), without any critical hematological toxicity due to its rapid pharmacokinetics.Conclusion: These results indicate that cancer radiotheranostics with [111In/90Y]US2 provides a novel strategy of theranostics for cancer hypoxia.

The role of carbonic anhydrase IX in cancer development: links to hypoxia, acidosis, and beyond

“…Careful selection of the antibodies for detection and/or targeting is therefore of key importance for better understanding and clinical exploitation of CA IX. Promising clinical uses of CA IX include molecular imaging in vivo , which currently attracts a lot of attention and includes approaches using diverse imaging agents based on monoclonal antibodies, inhibitors, and other compounds labeled by various radionuclides [99–102].…”

Clinical and Pre-Clinical Evidence of Carbonic Anhydrase IX in Pancreatic Cancer and Its High Expression in Pre-Cancerous Lesions

“…Indeed, an 131 I-cG250 conjugated antibody-recognizing CAIX protein was successfully used in clinics to detect CAIX-positive primary tumor and disseminated metastasis [ 151 ]. Animal models show that CAIX can be a useful target for molecular imaging based on monoclonal antibodies or inhibitors tagged with various radionuclides [ 215 , 216 , 217 ].…”

Carbonic Anhydrase Inhibitors Targeting Metabolism and Tumor Microenvironment

“…It is worth noting that the molecular docking analysis disclosed that thiazolo[3,2- a ]benzimidazole moiety is a good bioisoster for the SLC-0111 phenyl tail due to its ability to establish many hydrophobic interactions within the hCA IX and XII active sites, as well as involving the sp 2 nitrogen of the tricyclic ring in hydrogen bonding. The fluorine atom from SLC-0111 was also replaced by metal-complexing polycyclic amines, which coordinate positron-emitting (PET) metal ions (e.g., 111 In and 90 Y) for PET imaging [ 156 ].…”