[177Lu]Lu-XYIMSR-01: A Novel CAIX-Targeted Radiotherapeutic for Enhanced Treatment of Malignant Glioma

Malignant glioma highly expresses carbonic anhydrase IX (CAIX). This study aimed to develop [177Lu]Lu-XYIMSR-01, a small-molecule therapeutic agent CAIX, to assess its potential for treating malignant glioma. [177Lu]Lu-XYIMSR-01 was synthesized by radiolabeling DOTA-XYIMSR-01 with 177Lu. In vitro assays were conducted to evaluate the affinity for U87MG tumor cells. The probe was injected via the tail vein into subcutaneous and orthotopic U87MG models for micro-SPECT/CT imaging. The survival rates of tumor-bearing mice were assessed after [177Lu]Lu-XYIMSR-01 injection by intratumoral in orthotopic models, including untreated controls and those treated with Temozolomide or combination therapy. After purification, the radiochemical yield of [177Lu]Lu-XYIMSR-01 was 86.47 ± 2.42%, with a radiochemical purity (RCP) of 99%. Its cell uptake in U87MG cells was 3.70 ± 0.57 ‰ AD/105 cells, significantly higher than that in HCT116 cells (0.68 ± 0.16 ‰ AD/105 cells, P = 0.001). In the biodistribution study, [177Lu]Lu-XYIMSR-01 uptake in U87MG tumors was 6.19 ± 1.37%ID/g, with a tumor/muscle ratio of 20.14 ± 3.24. In the orthotopic glioma model, local injection combined with Temozolomide significantly improved survival and inhibited tumor growth. The results indicate that [177Lu]Lu-XYIMSR-01 is a promising therapeutic molecular probe for targeting CAIX, and its combination with Temozolomide significantly enhances treatment outcomes for malignant glioma.