Radionuclide-embedded gold nanoparticles (RIe-AuNPs) were developed as a highly sensitive and stable nuclear and optical imaging agent for efficient dendritic cell (DC)-based immunotherapy and sensitive tracking of DC-migration to lymph nodes. The RIe-AuNPs were synthesized via simple and straightforward DNA-based radiolabeling chemistry and additional Au shell formation strategies, leading to high radiosensitivity and excellent in vivo stability. The RIe-AuNPs exert no adverse effects on the biological functions of DCs, and labeled DCs show strong antitumor immunity for lung cancer. Furthermore, the high radiosensitivity of the RIe-AuNPs allows for sensitive and long-term monitoring of DC migration to draining lymph nodes. The developed Cerenkov radiation-based optical imaging approach provides quantitative and sensitive results comparable with that of positron emission tomography imaging. These results highlight the strong potential of the RIe-AuNPs as a highly sensitive and stable nuclear and optical imaging platform for future bioimaging application such as cell tracking and tumor imaging.

Anaplastic thyroid cancer (ATC), a rare thyroid cancer with poor prognosis, is associated with insufficient function of the sodium iodide symporter (NIS). Estrogen-related receptor gamma (ERRγ) is a member of the orphan nuclear receptors, with important functions in cell development and homeostasis. However, there are no reports that demonstrate whether ERRγ is related with NIS function. Here, we evaluated the role of ERRγ on the regulation of NIS function in ATC cells by using GSK5182, an inverse agonist of ERRγ. Methods: Two ATC cell lines, BHT-101 and CAL62, were incubated with the GSK5182 at various time points and dosages. Serial assessment of the NIS function was performed in the ATC cells by their uptake of radioiodine. The effects of GSK5182 on ERRγ and the mitogen-activated protein (MAP) kinase pathway as well as on NIS protein were evaluated by immunoblot assay. To examine whether the GSK5182-induced NIS functional activity can be affected by inhibition of the MAP kinase pathway, the MAP kinase activity and levels of radioiodine uptake were determined following treatment of an MEK inhibitor to GSK5182-treated cells. Finally, the cytotoxic effect of ¹³¹I was determined by clonogenic assay. Results: Treatment with GSK5182 resulted in dose- and time-dependent increases in iodide uptake in ATC cells, which were accompanied by both the down-regulation of ERRγ protein and the activation of extracellular signal-regulated kinase (ERK)-1/2. Both the increased radioiodine uptake and ERK-1/2 activation of ATC cells were completely inhibited by the specific MEK inhibitor. GSK5182 treatment enhanced the membrane localization of NIS in both ATC cells. Accordingly, pre-exposure to GSK5182 resulted in enhanced cytotoxic effects of ¹³¹I treatment in ATC cells. Conclusion: These findings suggest that the inverse agonist of ERRγ enhances the responsiveness of radioiodine therapy by modulating NIS function in ATC cells via the regulation of ERRγ and the MAP kinase signaling pathway.

We sought to evaluate the feasibility of molecular imaging using the human sodium iodide symporter (hNIS) gene as a reporter, in addition to the enhanced firefly luciferase (effluc) gene, for tracking dendritic cell (DCs) migration in living mice. A murine dendritic cell line (DC2.4) co-expressing hNIS and effluc genes (DC/NF) was established. For the DC-tracking study, mice received either parental DCs or DC/NF cells in the left or right footpad, respectively and combined I-124 PET/CT and bioluminescence imaging (BLI) were performed. In vivo PET/CT imaging with I-124 revealed higher activity of the radiotracer in the draining popliteal lymph nodes (DPLN) of the DC/NF injection site at day 1 than DC injection site (p < 0.05). The uptake value further increased at day 4 (p < 0.005). BLI also demonstrated migration of DC/NF cells to the DPLNs at day 1 post-injection and signals at the DPLNs were much higher at day 4. These data support the feasibility of hNIS reporter gene imaging in the tracking of DC migration to lymphoid organs in living mice. DCs expressing the NIS reporter gene could be a useful tool to optimize various strategies of cell-based immunotherapy.

Plasmonic nanostructure-mediated photothermal therapy (PTT) has proven to be a promising approach for cancer treatment, and new approaches for its effective delivery to tumor lesions are currently being developed. This study aimed to assess macrophage-mediated delivery of PTT using radioiodine-124-labeled gold nanoparticles with crushed gold shells (¹²⁴I-Au@AuCBs) as a theranostic nanoplatform. ¹²⁴I-Au@AuCBs exhibited effective photothermal conversion effects both in vitro and in vivo and were efficiently taken up by macrophages without cytotoxicity. After the administration of ¹²⁴I-Au@AuCB-labeled macrophages to colon tumors, intensive signals were observed at tumor lesions, and subsequent in vivo PTT with laser irradiation yielded potent antitumor effects. The results indicate the considerable potential of ¹²⁴I-Au@AuCBs as novel theranostic nanomaterials and the prominent advantages of macrophage-mediated cellular therapies in treating cancer and other diseases.