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Purpose: The surgery of glioblastoma (GBM) requires a maximal resection of the tumor when it is safe and feasible. The infiltrating growth property of the GBM makes it a challenge for neurosurgeons to identify the tumor tissue even with the assistance of the surgical microscope. This highlights the urgent requirement for imaging techniques that can differentiate tumor tissues during surgery in real time. Fluorescence image-guided surgery of GBM has been investigated using several non-specific fluorescent probes that emit light in the visible and the first near-infrared window (NIR-I, 700–900 nm), which limit the detection accuracy because of the non-specific targeting mechanism and spectral characteristics. Targeted NIR-II (1000–1700 nm) fluorescent probes for GBM are thus highly desired. The folate receptor (FR) has been reported to be upregulated in GBM, which renders it to be a promising target for specific tumor imaging. Methods: In this study, the folic acid (FA) that can target the FR was conjugated with the clinically approved indocyanine green (ICG) dye and DOTA chelator for radiolabeling with 64Cu to achieve targeted positron emission tomography (PET) and fluorescence imaging of GBM. Results: Surprisingly it was found that the resulted bioconjugate, DOTA-FA-ICG and non-radioactive natCu-DOTA-FA-ICG, were both self-assembled into nanoparticles with NIR-II emission signal. The radiolabeled DOTA-FA-ICG, 64Cu-DOTA-FA-ICG, was found to specifically accumulate in the orthotopic GBM models using in vivo PET, NIR-II, and NIR-I fluorescence imaging. The best time window of fluorescence imaging was demonstrated to be 24 h after DOTA-FA-ICG injection. NIR-II fluorescence image-guided surgery was successfully conducted in the orthotopic GBM models using DOTA-FA-ICG. All the fluorescent tissue was removed and proved to be GBM by the H&E examination. Conclusion: Overall, our study demonstrates that the probes, 64Cu-DOTA-FA-ICG and DOTA-FA-ICG, hold promise for preoperative PET examination and intraoperative NIR-II fluorescence image-guided surgery of GBM, respectively. [ABSTRACT FROM AUTHOR]

Objective: This translational study aims to investigate the clinical benefits of indocyanine green (ICG) based near-infrared window II (NIR-II) fluorescence image-guided surgery (FGS) on high-grade glioma (HGG) patients. Methods: Patients were randomly assigned to receive FGS or traditional white light image-guided surgery (WLS). The detection rate of NIR-II fluorescence was observed. Complete resection rate, progression-free survival (PFS), overall survival (OS), and neurological status were compared. Tissue samples were obtained from the FGS group, with the diagnosis based on the surgeons and the fluorescence recorded for comparison of diagnostic capability. Patients with WHO grade III gliomas or glioblastomas (GBM) were analyzed separately. Results: 15 GBM and 4 WHO grade III glioma patients in the FGS group and 18 GBM and 4 WHO grade III glioma patients in the WLS group were enrolled. The detection rate of NIR-II fluorescence was 100% for GBM. The complete resection rate was significantly increased by the FGS for GBM (FGS, 100% [95% CI 73.41-100] vs. WLS, 50% [95% CI 29.03-70.97], P = 0.0036). The PFS and OS of the FGS group were also significantly prolonged (Median PFS: FGS, 9.0 months vs. WLS, 7.0 months, P < 0.0001; Median OS: FGS, 19.0 months vs. WLS, 15.5 months, P = 0.0002). No recurrence was observed in WHO grade III glioma patients. Conclusions: NIR-II FGS achieves a much better complete resection rate of GBM than conventional WLS, leading to greatly improved survival of GBM patients. Significance: NIR-II FGS is a highly promising technique worthy of exploring more clinical applications. [ABSTRACT FROM AUTHOR]

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 Eu3+ doped gadolinium oxide (Gd2O3: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 Gd2O3:Eu and radiopharmaceutical were investigated using 18F-fluorodeoxyglucose (18F-FDG). The ex vivo optical signal intensity of the mixture of Gd2O3:Eu and 18F-FDG reached 369 times as high as that of CLI using 18F-FDG alone. To achieve improved biocompatibility, the Gd2O3:Eu nanoparticles were then modified with polyvinyl alcohol (PVA), and the resulted nanoprobe PVA modified Gd2O3:Eu (Gd2O3:Eu@PVA) was applied in intraoperative tumor imaging. Compared with 18F-FDG alone, intraoperative administration of Gd2O3:Eu@PVA and 18F-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 Gd2O3:Eu@PVA and 18F-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 Gd2O3:Eu@PVA and 18F-FDG. In summary, Gd2O3:Eu can achieve significantly optimized imaging property when combined with 18F-FDG in intraoperative tumor imaging and image-guided tumor resection surgery. It is expected that the development of the Gd2O3: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. [ABSTRACT FROM AUTHOR]

Radical resection is the most effective method for malignant tumor treatments. However, conventional imaging cannot fully satisfy the clinical needs of surgical navigation. This study presents a novel triple‐modality positron emission tomography (PET)–Cerenkov radiation energy transfer (CRET)–confocal laser endomicroscopy (CLE) imaging strategy for intraoperative tumor imaging and surgical navigation. Using clinical radiopharmaceuticals and fluorescein sodium (FS), this strategy can accurately detect the tumor and guide the tumor surgery. The FS emission property under Cerenkov radiation excitation is investigated using 2‐deoxy‐2‐18F‐fluoroglucose and 11C‐choline. Performances of the PET–CRET–CLE imaging and the CRET–CLE image‐guided surgery are evaluated on mouse models. The CRET signal at 8 mm depth is stronger than the Cerenkov luminescence at 1 mm depth in phantoms. In vivo experiments indicate that 0.5 mL kg−1 of 10% FS generates the strongest CRET signal, which can be observed immediately after FS injection. A surgical navigation study shows that the tumors are precisely detected and resected using intraoperative CRET–CLE. In summary, a PET–CRET–CLE triple‐modality imaging strategy is developed. This strategy can detect the tumors and precisely guide the tumor resection using clinical pharmaceuticals. This triple‐modality imaging shows high potential in surgical navigation research and clinical translation. [ABSTRACT FROM AUTHOR]