Evaluation of Novel 64Cu-Labeled Theranostic Gadolinium-Based Nanoprobes in HepG2 Tumor-Bearing Nude Mice

Abstract

Radiation therapy of liver cancer is limited by low tolerance of the liver to radiation. Radiosensitizers can effectively reduce the required radiation dose. AGuIX nanoparticles are small, multifunctional gadolinium-based nanoparticles that can carry radioisotopes or fluorescent markers for single-photon emission computed tomography (SPECT), positron emission tomography (PET), fluorescence imaging, and even multimodality imaging. In addition, due to the high atomic number of gadolinium, it can also serve as a tumor radiation sensitizer. It is critical to define the biodistribution and pharmacokinetics of these gadolinium-based nanoparticles to quantitate the magnitude and duration of their retention within the tumor microenvironment during radiotherapy. Therefore, in this study, we successfully labeled AGuIX with 64Cu through the convenient built-in chelator. The biodistribution studies indicated that the radiotracer 64Cu-AGuIX accumulates to high levels in the HepG2 xenograft of nude mice, suggesting that it would be a potential theranostic nanoprobe for image-guided radiotherapy in HCC. We also used a transmission electron microscope to confirm AGuIX uptake in the HepG2 cells. In radiation therapy studies, a decrease in 18F-FDG uptake was observed in the xenografts of the nude mice irradiated with AGuIX, which was injected 1 h before. These results provide proof-of-concept that AGuIX can be used as a theranostic radiosensitizer for PET imaging to guide radiotherapy for liver cancer.

AGuIX® from bench to bedside—Transfer of an ultrasmall theranostic gadolinium-based nanoparticle to clinical medicine

“…Another potentially interesting local administration is intraperitoneal (i.p.) delivery as recently shown by an independent study of Hu et al in a hepatocellular carcinoma model 51 ( Figure 5B ). The biodistribution of the AGuIX NPs has been assessed after radiolabelling by 64 Cu and animals sacrificing 9, 21 and 40 h after i.p.…”

“…AGuIX NPs have already shown their efficiency as a radiosensitizer for different in vivo preclinical models of cancer (glioblastoma, 29 , 33,40 brain metastases, 16 melanoma, 1 pancreatic cancer, 46 , 66 liver cancer, 51 chondrosarcoma, head and neck cancer 50 and lung cancer 49 ) ( Figure 10 ). A particular attention has been paid to tumours of the CNS with studies on 9L gliosarcoma bearing rats and B16F10 melanoma brain metastases bearing mice.…”

Gadolinium-Based Nanoparticles for Theranostic MRI-Guided Radiosensitization in Hepatocellular Carcinoma

“…In order to study the radiosensitization effect of AGuIX on HCC RT, we next irradiated HepG2 cells. Our previous research showed that AGuIX can be taken up into the HepG2 cytoplasm and has a good dispersion shape in HepG2 cells, indicating that AGuIX was stable in the cells (Hu et al, 2017). The obtained of radiation dose enhancement studies in HepG2 cells (Figure 1) are similar to that by Porcel et al in pancreatic cancer cells (Detappe et al, 2015).…”

“…Our previous research confirmed AGuIX uptake in the HepG2 cells and defined their biodistribution and pharmacokinetics in HepG2 tumor-bearing nude mice. This also indicated that the AGuIX accumulates in the HepG2 xenografts (Hu et al, 2017). Here, we evaluated the radiosensitization effect of AGuIX on HepG2 cells in vitro and performed MRI-guided RT using AGuIX radiosensitizer.…”

Emerging Strategies of Nanomaterial‐Mediated Tumor Radiosensitization

“…Several phases I clinical trials are ongoing in patients with brain metastases (NCT02820454) to enhance the sensitization of brain metastatic tumor cells to radiation . Also, AGuIX nanoparticles also have the potential to treat cervical and liver cancer . The safety, tolerability of doses of AGuIX in combination with radiation and CDDP‐based chemotherapy in patients with locally advanced cervical cancer are being evaluated in phase 1 clinical trials (NCT03308604).…”