Multimodal imaging of two-cycle PRRT with ¹⁷⁷Lu-DOTA-JR11 and ¹⁷⁷Lu-DOTATOC in an orthotopic neuroendocrine xenograft tumor mouse model

Abstract

Background: Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin receptor (SSTR) analogs is a common therapy approach in advanced neuroendocrine neoplasms (NEN). Recently, SSTR antagonists have shown promising results for imaging and therapy due to a higher number of binding sites compared with commonly used agonists. We evaluated PRRT with SSTR agonist ¹⁷⁷Lu-DOTATOC and antagonist ¹⁷⁷Lu-DOTA-JR11 longitudinally in an orthotopic murine pancreatic NEN model expressing human SSTR2. Morphologic and metabolic changes during treatment were assessed using multimodal imaging, including hybrid PET/MRI and SPECT/CT. Methods: In vitro radioligand binding and internalization assays and cell cycle analysis have been performed. SSTR2-transfected BON cells (BON-SSTR2) were used for in vivo experiments. Tumor-bearing mice received two intravenous injections of either 100 µl saline, 30 MBq ¹⁷⁷Lu-DOTATOC or 20 MBq ¹⁷⁷Lu-DOTA-JR11 with an interval of three weeks. Weekly T2w MRI was performed for tumor monitoring. Viability of the tumor tissue was assessed by FDG-PET/MRI once after PRRT. Tumor as well as kidney uptake of the respective radiopharmaceuticals were measured 24 h after injection by SPECT/CT. Results: ¹⁷⁷Lu-DOTA-JR11 treatment resulted in increased accumulation of cells in G2/M phase compared to ¹⁷⁷Lu-DOTATOC was observed. Animals treated with the SSTR antagonist showed a significant reduction in tumor size (P < 0.001) and longer median survival (207 d (IQR = 132–228)) compared to ¹⁷⁷Lu-DOTATOC (126 d (IQR = 118–129). SPECT/CT revealed a 4-fold higher median tumor uptake for the antagonist and a 3-fold higher tumor-to-kidney ratio in the first treatment cycle. During the second therapy cycle, tumor uptake of ¹⁷⁷Lu-DOTATOC was significantly lower (P = 0.01) while ¹⁷⁷Lu-DOTA-JR11 uptake remained stable. Imaging of tumor morphology indicated comparatively larger necrotic fractions for ¹⁷⁷Lu-DOTA-JR11 despite further tumor growth. These results were confirmed by FDG-PET, revealing the least amount of viable tumor tissue in ¹⁷⁷Lu-DOTA-JR11 treated animals with 6.2% (IQR = 2–23%). Conclusion: ¹⁷⁷Lu-DOTA-JR11 showed a higher tumor-to-kidney ratio as well as a more pronounced cytotoxic effect in comparison to ¹⁷⁷Lu-DOTATOC. Additionally, tumor uptake was more stable over the course of two treatment cycles.