Voxel-Based Dosimetry of Iron Oxide Nanoparticle-Conjugated ¹⁷⁷Lu-Labeled Folic Acid Using SPECT/CT Imaging of Mice

Abstract

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, voxelbased 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 ( 177 Lu-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 177 Lu-Folate and 177 Lu-IONPs for the comparison of absorbed doses with that of 177 Lu-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 177 Lu-IONP-Folate, 177 Lu-Folate, and 177 Lu-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 177 Lu-IONP-Folate was used compared with when the 177 Lu-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 177 Lu-IONP-Folate. Therefore, 177 Lu-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.

Phase I Clinical Trial of Prostate-Specific Membrane Antigen-Targeting 68Ga-NGUL PET/CT in Healthy Volunteers and Patients with Prostate Cancer

“…However, this assumption is difficult to apply in actual clinical practice. Voxel-based dosimetry may overcome these limitations and a more accurate dose profile can be obtained [ 22 ].…”

Comparison of voxel S‐value methods for personalized voxel‐based dosimetry of 177Lu‐DOTATATE

“…To reduce the computation time, simulations were conducted only for 1% of the timeintegrated activity, as in previous studies. 10,27,28 The statistical uncertainty of the dose estimation using 1% data was less than 3% at the voxel level. All simulations were performed with an in-house computing cluster with 60 CPU cores and 128 GB RAM.…”

“…The energy cut‐off for radiation transport simulation was set to 0.1 keV for electrons and photons. To reduce the computation time, simulations were conducted only for 1% of the time‐integrated activity, as in previous studies 10,27,28 . The statistical uncertainty of the dose estimation using 1% data was less than 3% at the voxel level.…”

Preclinical Evaluation of a Companion Diagnostic Radiopharmaceutical, [18F]PSMA-1007, in a Subcutaneous Prostate Cancer Xenograft Mouse Model

“…The absorbed doses in the tumor and salivary glands were 0.079 ± 0.010 Gy/MBq and 0.036 ± 0.006 Gy/MBq, respectively. The variance of the net influx (K i ) of [ 18 F]PSMA-1007 to the tumor was minimal between scans performed in the same animals (within-subject coefficient of variation = 7.57%).…”

“…[ 18 F]PSMA-1007 uptake in the tumor was specifically decreased by 32% in K i after treatment with a PSMA inhibitor 2-(phosphonomethyl)-pentanedioic acid (2-PMPA). In the present study, we investigated the in vivo preclinical characteristics of [ 18 F]PSMA-1007.…”