Radiopharmaceutical and Eu 3+ doped gadolinium oxide nanoparticles mediated triple-excited fluorescence imaging and image-guided surgery

Cerenkov luminescence imaging (CLI) is a novel optical imaging technique that has been applied in clinic using various radionuclides and radiopharmaceuticals. However, clinical application of CLI has been limited by weak optical signal and restricted tissue penetration depth. Various fluorescent probes have been combined with radiopharmaceuticals for improved imaging performances. However, as most of these probes only interact with Cerenkov luminescence (CL), the low photon fluence of CL greatly restricted it's interaction with fluorescent probes for in vivo imaging. Therefore, it is important to develop probes that can effectively convert energy beyond CL such as β and γ to the low energy optical signals. In this study, a Eu doped gadolinium oxide (Gd O :Eu) was synthesized and combined with radiopharmaceuticals to achieve a red-shifted optical spectrum with less tissue scattering and enhanced optical signal intensity in this study. The interaction between Gd O :Eu and radiopharmaceutical were investigated using F-fluorodeoxyglucose ( F-FDG). The ex vivo optical signal intensity of the mixture of Gd O :Eu and F-FDG reached 369 times as high as that of CLI using F-FDG alone. To achieve improved biocompatibility, the Gd O :Eu nanoparticles were then modified with polyvinyl alcohol (PVA), and the resulted nanoprobe PVA modified Gd O :Eu (Gd O :Eu@PVA) was applied in intraoperative tumor imaging. Compared with F-FDG alone, intraoperative administration of Gd O :Eu@PVA and F-FDG combination achieved a much higher tumor-to-normal tissue ratio (TNR, 10.24 ± 2.24 vs. 1.87 ± 0.73, P = 0.0030). The use of Gd O :Eu@PVA and F-FDG also assisted intraoperative detection of tumors that were omitted by preoperative positron emission tomography (PET) imaging. Further experiment of image-guided surgery demonstrated feasibility of image-guided tumor resection using Gd O :Eu@PVA and F-FDG. In summary, Gd O :Eu can achieve significantly optimized imaging property when combined with F-FDG in intraoperative tumor imaging and image-guided tumor resection surgery. It is expected that the development of the Gd O :Eu nanoparticle will promote investigation and application of novel nanoparticles that can interact with radiopharmaceuticals for improved imaging properties. This work highlighted the impact of the nanoprobe that can be excited by radiopharmaceuticals emitting CL, β, and γ radiation for precisely imaging of tumor and intraoperatively guide tumor resection.