| Title |
Radiobiological investigations of a [212Pb]Pb-carbonic anhydrase IX-targeting small-molecule ligand in renal cell carcinoma and colorectal cancer models |
| Authors |
Kristiansen, Sandra K ; Shubin, Kirill ; Zubrienė, Asta ; Matulis, Daumantas ; Dernjani, Nurtene ; Juzenas, Petras ; Bruland, Øyvind S ; Juzeniene, Asta |
| DOI |
10.1080/09553002.2025.2595630 |
| Full Text |
|
| Is Part of |
International journal of radiation biology.. Abingdon : Taylor and Francis Ltd.. 2026, vol. 102, iss. 2, p. 127-137.. ISSN 0955-3002. eISSN 1362-3095 |
| Keywords [eng] |
Carbonic anhydrase IX ; hypoxia ; lead-212 ; radiobiology ; targeted alpha-therapy |
| Abstract [eng] |
Purpose: Carbonic anhydrase IX (CAIX), overexpressed in multiple cancers but limited in normal tissue, is a promising target for radionuclide therapy. This study evaluates [212Pb]Pb-MKV-509, a novel DOTA-conjugated small-molecule ligand, for CAIX-targeted alpha therapy in preclinical renal carcinoma (SK-RC-52) and colorectal (HT-29) cancer models. Materials and methods: [212Pb]Pb-MKV-509 was assessed for radiochemical purity and stability. Binding assays determined receptor density and dissociation constants. Clonogenic survival, flow cytometry (viability, DNA damage, cell cycle), and spheroid assays (cross-sectional area, doubling time) evaluated biological responses. An in vivo biodistribution study was performed in SK-RC-52 xenograft-bearing mice, with and without carbonic anhydrase pre-blocking using acetazolamide. Results: [212Pb]Pb-MKV-509 exhibited high radiochemical purity (>96%) and stability for up to 48 h. Specific binding was higher in SK-RC-52 than in HT-29 cells. Treatment induced activity-dependent clonogenic inhibition, G2/M arrest, and DNA damage, with greater sensitivity observed in SK-RC-52 cells. Clonogenic survival was reduced by 50% at 3.4 kBq/mL (SK-RC-52) and 7.1 kBq/mL (HT-29). In spheroid models, 2.5–5.0 kBq/mL delayed growth and prolonged doubling time, indicating cross-fire effects. The biodistribution study revealed significant tumor uptake (4.7%IA/g at 2 h), along with high gastrointestinal accumulation. Pretreatment with acetazolamide partially reduced uptake in the stomach and intestines as well as in the tumor. Conclusions: These findings highlight the potential of CAIX-targeted alpha therapy. CAIX expression and receptor density impact binding affinity and therapeutic response. The study demonstrates the importance of 3D tumor models in evaluating alpha-particle cross-fire effects. Further ligand optimization is warranted to enhance tumor specificity and minimize off-target uptake. |
| Published |
Abingdon : Taylor and Francis Ltd |
| Type |
Journal article |
| Language |
English |
| Publication date |
2026 |
| CC license |
|
