Pre-clinical individualized dosimetry of iron-oxide nanoparticle based 177Lu-labelled folate conjugates targeted SPECT/CT imaging

Objectives: Folic acid conjugate of therapeutic radioisotope especially Lu-177 has been a valuable tool to implement novel and effective anticancer therapies. However, the high kidney absorbed dose due to the presence of folate receptors in proximal tubule cells remained a hurdle during targeted radionuclide (TRT) therapy of folate receptor positive cancers. In TRT, the toxicity and efficacy are of great concern and there is much less tolerance for inaccuracies in dosimetry. Recently, the GATE Monte Carlo (MC) simulation has gained attention in preclinical voxel-based dosimetry application. In this study, iron-oxide nanoparticle based radiolabeled folate (177Lu-NOTA-IONP-Folate) was prepared to overcome the previous challenges. We estimated the voxel-based absorbed doses using GATE MC from the SPECT/CT images of normal mice performed with177Lu-NOTA-IONP-Folate, 177Lu-NOTA-IONP and 177Lu-NOTA-Folate to evaluate the feasibility of 177Lu-NOTA-IONP-Folate for TRT.

Methods: The SPECT/CT images of normal male balb/c nude mice (8-10 weeks, n=5,) were acquired using 177Lu-NOTA-Folate (11.99±1.57 MBq), 177Lu-NOTA-IONP (9.16±1.21 MBq) and 177Lu-NOTA-IONP-Folate (5.50±0.10 MBq). All the mice were kept on folate-free diet for three weeks before the imaging studies. NanoSPECT/CT (Bioscan Inc.,) was used to acquire six sequential SPECT images immediately after IV injection of 177Lu-lableled conjugates followed by a CT. SPECT/CT Images were further acquired at 6, 24, 48 and 72 hours post injection. Image-based activity biodistributions in the organs were estimated to plot time-activity graphs for all three radiotracers. GATE MC toolkit was applied to estimate voxel-based absorbed dose in major organs (brain, heart, liver and kidneys). The real CT and SPECT images were used as voxelized phantom and source respectively as input for simulation. Absorbed doses were calculated from energy deposition maps obtained as output of simulation using 3D VOIs drawn over the organs on CT images. Voxel-based absorbed doses in the organs estimated from all three radiotracers using GATE MC were compared.

Results: The image-based biodistribution showed the uptake of all three 177Lu-labeled conjugates were highest in the liver followed by kidneys. The maximum uptakes of 177Lu-NOTA-Folate, 177Lu-NOTA-IONP and 177Lu-NOTA-IONP-Folate were 14%, 20% and 17%, respectively in the liver, 5%, 2.5% and 3.2%, respectively in left kidney and 6%, 2.8% and 4%, respectively in the right kidney. The uptakes of all three tracers in other organs were less than 1.5%. The voxel-based absorbed dose estimated in the kidneys was highest due 177Lu-NOTA-Folate (2.21±0.39 Gy/MBq) compared to 177Lu-NOTA-IONP-Folate (0.89±0.26 Gy/MBq) and 177Lu-NOTA-IONP (0.32±0.03 Gy/MBq). However, the liver absorbed dose was lowest for 177Lu-NOTA-Folate (0.79±0.08 Gy/MBq) than 177Lu-NOTA-IONP (0.91±0.23 Gy/MBq) and 177Lu-NOTA-IONP-Folate (1.07±0.06 Gy/MBq). The absorbed dose for other organs were less than 0.2 mGy/MBq with all three radiotracers. We found that 177Lu-NOTA-IONP-Folate reduced the absorbed dose to kidneys by nearly 56% when compared with 177Lu-NOTA-Folate (without IONP). Conclusion: The absorbed dose to the kidney was decreased significantly when Iron-oxide nanoparticle based 177Lu-lableled folate conjugate (177Lu-NOTA-IONP-Folate) was used in the study. Hence, it will be useful for targeted radionuclide therapy of folate receptor positive cancers.