Several radiolabeled folic acid conjugates have been developed for targeted imaging and therapy. However, the therapeutic concept with radiolabeled folate conjugates has not yet been applied to clinical applications owing to the high renal absorbed dose. The effectiveness of targeted radionuclide therapy (TRT) depends primarily on the absorbed dose rate and on the total absorbed dose delivered to the tumor and to normal tissue. Owing to various limitations associated with organ level dosimetry, voxel-based dosimetry has become essential for the assessment of a more accurate absorbed dose during TRT. In this study, we synthesized iron oxide nanoparticle (IONP)-conjugated radiolabeled folate (¹⁷⁷Lu-IONP-Folate) and performed voxel-based dosimetry using SPECT/CT images of normal mice through direct Geant4 application for emission tomography (GATE) Monte Carlo (MC) simulation. We also prepared ¹⁷⁷Lu-Folate and ¹⁷⁷Lu-IONPs for the comparison of absorbed doses with that of ¹⁷⁷Lu-IONP-Folate. In addition, we calculated the mean absorbed dose at the organ-level using the medical internal radiation dose (MIRD) schema. The radioactivities of all three radiotracers were mainly accumulated in the liver and kidneys immediately after injection. For the kidneys, the voxel-based absorbed doses obtained with ¹⁷⁷Lu-IONP-Folate, ¹⁷⁷Lu-Folate, and ¹⁷⁷Lu-IONPs were 1.01 ± 0.17, 2.46 ± 0.50, and 0.52 ± 0.08 Gy/MBq, respectively. The renal absorbed dose decreased significantly (∼half) when ¹⁷⁷Lu-IONP-Folate was used compared with when the ¹⁷⁷Lu-Folate only was used. The mean absorbed dose values obtained at organ-level using the MIRD schema were comparable to voxel-based absorbed doses estimated with GATE MC. The voxel-based absorbed dose values obtained in this study of individualized activity show that the renal absorbed dose could be reduced to almost half with ¹⁷⁷Lu-IONP-Folate. Therefore, ¹⁷⁷Lu-IONP-Folate could be clinically applicable in the TRT of folate receptor-positive cancers in a personalized manner when using the voxel-based dosimetry method.

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