Background: Radiation therapy (RT) of hepatocellular carcinoma (HCC) is limited by low tolerance of the liver to radiation, whereas radiosensitizers are effective in reducing the required radiation dose. Multimodality gadolinium-based nanoparticles (AGuIX) are small and have enhanced permeability and retention effects; thus, they are very suitable for radiation sensitizer HCC RT. Here, we evaluated the potential value of AGuIX for theranostic MRI-radiosensitization in HCC.Methods: The radiosensitization effects of AGuIX were evaluated via in vitro and in vivo experiments. Tumor growth, apoptosis imaging, and immunohistochemistry were performed to verify the antitumor effects of RT with AGuIX.Results:
In vitro evaluation of the efficacy of radiosensitivity of the AGuIX demonstrated that the presence of AGuIX significantly decreased HepG2 cell survival when combined with an X-ray beam. In vivo MRI imaging showed the ratio of tumor/liver concentration of the AGuIX was the highest 1 h after intravenous injection. For antitumor effects, we found that the tumor size decreased by RT-only and RT with AGuIX. The antitumor effects were more effective with high-dose AGuIX-mediated RT. Apoptosis imaging and immunohistochemistry both demonstrated that the degree of the cell apoptosis was highest with a high dose of AGuIX-mediated RT.Conclusions: This study provides compelling data that AGuIX can facilitate theranostic MRI-radiosensitization in HCC.
Site-specific imaging agents play a key role in tumor targeting, but only a few agents are currently available for inflammation targeting. Since the P2X7 receptor (P2X7R) is a promising molecular target for inflammation, we evaluated the potential value of the 18 F-labeled tracer 18 F-PTTP (5-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-1-pyrimidin-2-yl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridin) for targeting P2X7Rs and thus differentiating inflammation from tumors. Methods: The radioligand 18 F-PTTP was achieved by a 1-step 18 Ftrifluoromethylation reaction. The binding affinity of the ligand for P2X7R and its stability were evaluated in vitro. Blood pharmacokinetics tests and biodistribution studies were performed in vivo. Dynamic 18 F-PTTP small-animal PET/CT imaging was performed for 60 min on A549 tumor-bearing mice and inflammation-model mice for targeting differentiation. Results: 18 F-PTTP was afforded with decay-corrected radiochemical yields of 2.5%-7.0%, specific activity of 296-370 MBq/μmol, and radiochemical purity over 95%. 18 F-PTTP showed excellent stability in 0.9% NaCl and 0.1% bovine serum albumin, good affinity to RAW264.7 cells, and rapid blood clearance in mice. In inflammation-model mice, uptake of 18 F-PTTP peaked at 5 min after injection and kept at an imageable level till 30 min, whereas no significant radioactivity uptake was found in tumor grafts till 1 h after injection. The specificity of 18 F-PTTP was verified by blocking studies and histologic analysis. Conclusion: The current study provides compelling data that 18 F-PTTP is a novel radioligand targeting P2X7R and has potential to screen new drugs, quantify peripheral inflammation, and distinguish inflammation from certain solid tumors.
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