Tumor dosimetry using [124I]m-iodobenzylguanidine microPET/CT for [131I]m-iodobenzylguanidine treatment of neuroblastoma in a murine xenograft model

Abstract

Purpose: [(124)I]m-iodobenzylguanidine ((124)I-mIBG) provides a quantitative tool for pretherapy tumor imaging and dosimetry when performed before [(131)I]m-iodobenzylguanidine ((131)I-mIBG) targeted radionuclide therapy of neuroblastoma. (124)I (T (1/2) = 4.2 days) has a comparable half-life to that of (131)I (T (1/2) = 8.02 days) and can be imaged by positron emission tomography (PET) for accurate quantification of the radiotracer distribution. We estimated expected radiation dose in tumors from (131)I-mIBG therapy using (124)I-mIBG microPET/CT imaging data in a murine xenograft model of neuroblastoma transduced to express high levels of the human norepinephrine transporter (hNET).

Procedures: In order to enhance mIBG uptake for in vivo imaging and therapy, NB 1691-luciferase (NB1691) human neuroblastoma cells were engineered to express high levels of hNET protein by lentiviral transduction (NB1691-hNET). Both NB1691 and NB1691-hNET cells were implanted subcutaneously and into renal capsules in athymic mice. (124)I-mIBG (4.2-6.5 MBq) was administered intravenously for microPET/CT imaging at 5 time points over 95 h (0.5, 3-5, 24, 48, and 93-95 h median time points). In vivo biodistribution data in normal organs, tumors, and whole-body were collected from reconstructed PET images corrected for photon attenuation using the CT-based attenuation map. Organ and tumor dosimetry were determined for (124)I-mIBG. Dose estimates for (131)I-mIBG were made, assuming the same in vivo biodistribution as (124)I-mIBG.

Results: All NB1691-hNET tumors had significant uptake and retention of (124)I-mIBG, whereas unmodified NB1691 tumors did not demonstrate quantifiable mIBG uptake in vivo, despite in vitro uptake. (124)I-mIBG with microPET/CT provided an accurate three-dimensional tool for estimating the radiation dose that would be delivered with (131)I-mIBG therapy. For example, in our model system, we estimated that the administration of (131)I-mIBG in the range of 52.8-206 MBq would deliver 20 Gy to tumors.

Conclusions: The overexpression of hNET was found to be critical for (124)I-mIBG uptake and retention in vivo. The quantitative (124)I-mIBG PET/CT is a promising new tool to predict tumor radiation doses with (131)I-mIBG therapy of neuroblastoma. This methodology may be applied to tumor dosimetry of (131)I-mIBG therapy in human subjects using (124)I-mIBG pretherapy PET/CT data.

Fig. 1

¹²⁴I-mIBG in vitro studies of cell association (binding or uptake) using unmodified NB1691, hNET-overexpressing NB1691 (NB1691-hNET), NIH 3T3, and HEK 293T cell lines as well as their corresponding cells blocked by imipramine, showing that ¹²⁴I-mIBG uptake is significantly higher in NB1691-hNET cells than in unmodified NB1691, NIH 3T3, and HEK 293T cells or in cells with blocked uptake. Western blot data (right) also show the enhanced hNET expression in the transduced NB1691 cells. The endogenous hNET is not evident in the western blot, which is only showing exogenously expressed, V5 tagged hNET. On the western blot data, amplification of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is used as a loading control and normalization.

Fig. 2

Six animals with subcutaneous (SubQ) NB1691 tumors on both shoulders presented as three-dimensional volume renderings of PET (orange color) overlaid on CT (gray-scale) images at 93–95 h after administration of ¹²⁴I-mIBG. The NB1691-hNET tumors (right shoulders) show significant uptake of mIBG, whereas unmodified NB1691 tumors (left shoulders) do not show any quantifiable ¹²⁴I-mIBG uptake. There is weak uptake (arrows) of ¹²⁴I-mIBG visualized in left kidneys of the first four animals (#1 – #4) where NB1691 cells were also injected. The first two (#1 and #2) were injected with hNET-overexpressing NB1691 cells, and the other two (#3 and #4) were injected with unmodified NB1691 cells.

Fig. 3

Three animals with hNET-transduced NB1691 tumors in the left renal capsules (RC) presented as three-dimensional volume renderings of PET (orange color) overlaid on CT (gray-scale) images at 93–95 h after administration of ¹²⁴I-mIBG. The hNET-overexpressing NB1691 tumors show significant uptake of mIBG. A photograph of tumors formed in the renal capsule and the corresponding tumor locations in PET/CT images (arrows) are shown in this animal model.

Fig. 4

Biokinetic data of ¹²⁴I-mIBG uptake in heart, thyroid, bladder, kidney, liver, lung, and tumors (as shown in Figs. 2 and 3). Mean percent injected activity values and standard errors for the organs (%IA/organ) are shown as those extrapolated to the adult human-equivalent values. Percent injected activity values are shown for tumors (%IA/tumor) are shown without the extrapolation.

Fig. 5

Representative PET/CT three-dimensional volume renderings at 0.5 (a), 4 (b), 24 (c), 48 (d), and 95 (e) hours after ¹²⁴I-mIBG administration. Temporal changes of mIBG uptake in whole-body are shown in the animal that has NB1691-hNET renal capsule tumor (#8 in Fig. 3).