Background: Boron neutron capture therapy (BNCT) is a molecular radiation treatment based on the ¹⁰B (n, α) ⁷Li nuclear reaction in cancer cells, in which delivery of ¹⁰B by 4-borono-phenylalanine conjugated with fructose (BPA-fr) to the cancer cells is of critical importance. The PET tracer 4-borono-2-¹⁸ F-fluoro-phenylalanine (FBPA) has been used to predict the accumulation of BPA-fr before BNCT. However, because of the difference in chemical structure between BPA-fr and FBPA and the difference in the dose administered between BPA-fr (therapeutic dose) and FBPA (tracer dose), the predictive value of FBPA PET for BPA-fr accumulation in the tumor and normal tissues is not yet clearly proven. We conducted this study to validate FBPA PET as a useful test to predict the accumulation of BPA-fr in the tumor and normal tissues before BNCT. Methods: RGC-6 rat glioma cells (1.9 × 10⁷) were implanted subcutaneously in seven male F344 rats. On day 20 after the tumor implantation, dynamic PET scan was performed on four rats after injection of FBPA for 1 h. Whole-body PET/CT was performed 1 h after intravenous injection of the FBPA solution (30.5 ± 0.7 MBq, 1.69 ± 1.21 mg/kg). PET accumulation of FBPA in the tumor tissue and various normal tissues was estimated as a percentage of the injected dose per gram (%ID/g). One hour after the PET/CT scan, BPA-fructose (167.32 ± 18.65 mg/kg) was injected intravenously, and the rats were dissected 1 h after the BPA-fr injection. The absolute concentration of ¹⁰B in the autopsied tissues and blood was measured by inductively coupled plasma optical emission spectrometry (ICP-OES). Results: The highest absolute concentration of ¹⁰B determined by ICP-OES was found in the kidney (4.34 ± 0.84 %ID/g), followed by the pancreas (2.73 ± 0.63 %ID/g), and the tumor (1.44 ± 0.44 %ID/g). A significant positive correlation was found between the accumulation levels of BPA-fr and FBPA (r = 0.91, p < 0.05). Conclusions: FBPA PET can reliably predict accumulation of BPA-fr in the tumor as well as normal tissues.

Background: ²¹¹At is a high-energy α-ray emitter with a relatively short half-life and a high cytotoxicity for cancer cells. Its dispersion can be imaged using clinical scanners, and it can be produced in cyclotrons without the use of nuclear fuel material. This study investigated the biodistribution and the antitumor effect of ²¹¹At-labeled gold nanoparticles (²¹¹At-AuNP) administered intratumorally. Results: AuNP with a diameter of 5, 13, 30, or 120 nm that had been modified with poly (ethylene glycol) methyl ether (mPEG) thiol and labeled with ²¹¹At (²¹¹At-AuNP-S-mPEG) were incubated with tumor cells, or intratumorally administered to C6 glioma or PANC-1 pancreatic cancers subcutaneously transplanted into rodent models. Systemic and intratumoral distributions of the particles in the rodents were then evaluated using scintigraphy and autoradiography, and the changes in tumor volumes were followed for about 40 days. ²¹¹At-AuNP-S-mPEG was cytotoxic when it was internalized by the tumor cells. After intratumoral administration, ²¹¹At-AuNP-S-mPEG became localized in the tumor and did not spread to systemic organs during a time period equivalent to 6 half-lives of ²¹¹At. Tumor growth was strongly suppressed for both C6 and PANC-1 by ²¹¹At-AuNP-S-mPEG. In the C6 glioma model, the strongest antitumor effect was observed in the group treated with ²¹¹At-AuNP-S-mPEG with a diameter of 5 nm. Conclusions: The intratumoral single administration of a simple nanoparticle, ²¹¹At-AuNP-S-mPEG, was shown to suppress the growth of tumor tissue strongly in a particle size-dependent manner without radiation exposure to other organs caused by systemic spread of the radionuclide. Graphic

The accuracy of fluorine-18-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) can be influenced by the increased glycolytic activity of inflammatory lesions. Here, using clinical data obtained from gynecological cancer patients, tumor samples and animal models, we investigate the impact of pretreatment tumor-related leukocytosis (TRL) on the diagnostic performance of 18F-FDG-PET/CT in detecting pelvic and paraaortic lymph node metastasis. We demonstrate that pretreatment TRL misleads 18F-FDG-PET/CT during lymph node staging in gynecological malignancies. In the mechanistic investigations, we show that the false-positive 18F-FDG-PET/CT result for detecting nodal metastasis can be reproduced in animal models of TRL-positive cancer bearing G-CSF expressing cervical cancer cells. We also show that increased 18F-FDG uptake in non-metastatic nodes can be explained by the MDSC-mediated premetastatic niche formation in which proinflammatory factors, such as S100A8 or S100A9, are abundantly expressed. Together, our results suggest that the MDSC-mediated premetastatic niche created in the lymph node of TRL-positive patients misleads 18F-FDG-PET/CT for detecting nodal metastasis.

Alpha-particle radiotherapy has gained considerable attention owing to its potent anti-cancer effect. ²¹¹At, with a relatively short half-life of 7.2 h, emits an alpha particle within a few cell diameters with high kinetic energy, which damages cancer cells with high biological effectiveness. In this study, we investigated the intravenous injection of ²¹¹At-labeled gold nanoparticles (AuNPs) for targeted alpha-particle therapy (TAT). Different kinds of surface-modified gold nanoparticles can be labeled with ²¹¹At in high radiochemical yield in 5 min, and no purification is necessary. The in vivo biodistribution results showed the accumulation of 5 nm ²¹¹At-AuNPs@mPEG at 2.25% injection dose per gram (% ID/g) in tumors within 3 h via the enhanced permeability and retention (EPR) effect. Additionally, we observed a long retention time in tumor tissues within 24 h. This is the first study to demonstrate the anti-tumor efficacy of 5 nm ²¹¹At-AuNPs@mPEG that can significantly suppress tumor growth in a pancreatic cancer model via intravenous administration. AuNPs are satisfactory carriers for ²¹¹At delivery, due to simple and efficient synthesis processes and high stability. The intravenous administration of 5 nm ²¹¹At-AuNPs@mPEG has a significant anti-tumor effect. This study provides a new framework for designing nanoparticles suitable for targeted alpha-particle therapy via intravenous injection.

Background: Fibroblast activation protein (FAP) is overexpressed in the stroma of many types of cancer. [¹⁸F]AlF-FAPI-74 is a positron emission tomography tracer with high selectivity for FAP, which has already shown high accumulation within human tumors in clinical studies. However, [¹⁸F]AlF-FAPI-74 radiosynthesis has not been optimized using an automated synthesizer. Herein, we report a one-pot and one-step automated radiosynthesis method using a multi purpose synthesizer. Results: Radiosynthesis of [¹⁸F]AlF-FAPI-74 was performed using a cassette-type multi purpose synthesizer CFN-MPS200. After the recovery rate of trapped [¹⁸F]fluoride onto the anion-exchange cartridge using a small amount of eluent was investigated manually, a dedicated [¹⁸F]AlF-FAPI-74 synthesis cassette and synthesis program for one-pot and one-step fluorination was developed. The solutions for the formulation of [¹⁸F]AlF-FAPI-74 synthesized using this were evaluated to obtain stable radiochemical purity. The recovery rate of [¹⁸F]fluoride with only 300 µL of eluent ranged 90 ± 9% by introduction from the male side and elution from the female side of the cartridge. In automated synthesis, the eluted [¹⁸F]fluoride and precursor solution containing aluminum chloride were mixed; then, fluorination was performed in a one-pot and one-step process at room temperature for 5 min, followed by 15 min at 95 °C. As a result, the radioactivity of [¹⁸F]AlF-FAPI-74 was 11.3 ± 1.1 GBq at the end of synthesis from 32 to 40 GBq of [¹⁸F]fluoride, and its radiochemical yield was 37 ± 4% (n = 10). The radiochemical purity at the end of the synthesis was ≥ 97% for all formulation solutions. When the diluent was saline, the radiochemical purity markedly decreased after 4 h of synthesis. In contrast, with phosphate-buffered saline (pH 7.4) or 10 mM phosphate-buffered saline (pH 6.7) containing 100 mg of sodium ascorbate, the radiochemical purity was stable at 97%. Non-radioactive AlF-FAPI-74 and total impurities, including non-radioactive AlF-FAPI-74, were 0.3 ± 0.1 µg/mL and 2.8 ± 0.6 µg/mL. Ethanol concentration and residual DMSO were 5.5 ± 0.2% and 21 ± 6 ppm, respectively. Conclusions: We established a one-pot one-step automated synthesis method using a CFN-MPS200 synthesizer that provided high radioactivity and stable radiochemical purity for possible clinical applications.