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.

Chisocheton plants from the family Meliaceae have traditionally been used to treat several diseases; however, scientific evidence is limited. The most abundant chemical constituents of this plant are the limonoids, which are known for their various biological activities, including anti-inflammatory effects. However, the anti-inflammatory effects and underlying mechanisms of action of the constituents of Chisocheton plants have not been fully explored. In this report, we evaluated the anti-inflammatory activity of 17 limonoid compounds from Chisocheton plant primarily by measuring their inhibitory effects on the production of pro-inflammatory cytokines, including TNF-α, IL-6, IL-1β, and MCP-1, in LPS-stimulated THP-1 cells using an ELISA assay. Compounds 3, 5, 9, and 14–17 exhibited significant activity in inhibiting the evaluated pro-inflammatory markers, with IC₅₀ values less than 20 µM and a high selectivity index (SI) range. Compounds 3, 5, 9, and 15 significantly suppressed the expression of phosphorylated p38 MAPK in THP-1 cells stimulated with LPS. These findings support the use of limonoids from Chisocheton plants as promising candidates for anti-inflammatory therapy.

Targeted alpha therapy is generally evaluated by absorbed dose and direct tumor-cell killing, but whether alpha-particle–injured tumor cells can induce systemic antitumor immunity remains poorly defined. We investigated the immunogenic consequences of astatine-211 (²¹¹At) injury in a prophylactic melanoma vaccination–challenge model. B16F10 cells were exposed ex vivo to ²¹¹At, etoposide, or ultraviolet irradiation under conditions that reduced viable-cell counts at 24 hours to approximately 40% of untreated controls. Injured cells were administered subcutaneously to syngeneic C57BL/6J mice before intravenous challenge with viable B16F10 cells. Vaccination with cells exposed to 1 MBq/mL ²¹¹At suppressed pulmonary metastasis, reduced regulatory T-cell proportions, and elicited tumor-reactive interferon-γ responses and antibodies. Transcriptomic profiling revealed enrichment of type I interferon, inflammatory, and chemokine-related signatures, together with suppression of cell-cycle, translation, and metabolic programs. At the cellular level, ²¹¹At injury was accompanied by γH2AX accumulation, G2/M arrest, increased reactive oxygen species and cytosolic double-stranded DNA, and senescence-like changes. These features arose without consistent increases in classical damage-associated molecular patterns or prominent induction of senescence-associated secretory phenotype factors at 1 MBq/mL. In vivo pharmacologic inhibition of stimulator of interferon genes (STING) signaling attenuated the antimetastatic effect of vaccination. Together, these findings demonstrate that ²¹¹At injury can generate an immunostimulatory tumor-cell state characterized by DNA damage and altered inflammatory signaling. STING contributes to the resulting immune protection, highlighting immunogenic tumor-cell conversion as a consideration in the design of targeted alpha therapies.

N-(4-hydroxyphenyl)-retinamide (4-HPR) inhibits the dihydroceramide Δ4-desaturase 1 (DEGS1) enzymatic activity. We previously reported that 4-HPR suppresses the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) spike protein-mediated membrane fusion through a decrease in membrane fluidity in a DEGS1-independent manner. However, the precise mechanism underlying the inhibition of viral entry by 4-HPR remains unclear. In this study, we examined the role of reactive oxygen species (ROS) in the inhibition of membrane fusion by 4-HPR, since 4-HPR is a well-known ROS-inducing agent. Intracellular ROS generation was found to be increased in the target cells in a cell–cell fusion assay following 4-HPR treatment, which was attenuated by the addition of the antioxidant, α-tocopherol (TCP). The reduction in membrane fusion susceptibility by 4-HPR treatment in the cell–cell fusion assay was alleviated by TCP addition. Furthermore, fluorescence recovery after photobleaching analysis showed that the lateral diffusion of glycosylphosphatidylinositol-anchored protein and SARS CoV-2 receptor was reduced by 4-HPR treatment and restored by TCP addition. These results indicate that the decrease in SARS-CoV-2 spike protein-mediated membrane fusion and membrane fluidity by 4-HPR was due to ROS generation. Taken together, these results demonstrate that ROS production is associated with the 4-HPR inhibitory effect on SARS-CoV-2 entry.

Background: Gold nanoparticles (GNPs) are widely used in nanomedicine as drug carriers, including in targeted radionuclide therapy where therapeutic radionuclides are bound to GNPs. Quantitative assessment of their biodistribution is essential. X-ray fluorescence imaging (XFI) is well suited for detecting high-Z elements, but its quantitative accuracy is compromised by strong attenuation effects, particularly in L-shell XFI where low-energy fluorescence (~10 to 12 keV) is heavily absorbed in tissue. Methods: We developed a computed tomography (CT)-guided attenuation correction algorithm for L-shell XFI. The method generates energy-dependent attenuation maps from co-registered CT data and performs voxel-wise corrections along both excitation and emission paths. The approach was tested on an ex vivo murine tumor sample resected three hours after intratumoral injection of 34.7 μg PEG-modified GNPs. Results: Application of the CT-guided correction substantially improved the relative accuracy of L-shell XFI reconstructions compared to uncorrected data. The corrected distribution maps showed consistent mass recovery across different measurement geometries, demonstrating that the algorithm compensates for the theoretically expected attenuation due to heterogeneous biological tissue. Conclusions: This study provides a proof-of-principle that CT-based attenuation correction enables more reliable and quantitative L-shell XFI of GNPs in biological samples. The approach represents a promising step toward accurate nanoparticle biodistribution assessment in biomedical research, including preclinical studies in targeted radionuclide therapy.

Background/Objectives: Peritoneal dissemination of malignancies leads to poor prognoses, and no effective treatment currently exists. The difficulty of treating such malignancies is likely because systemically administered drugs cannot easily target malignant cells in the abdominal cavity. High intraperitoneal drug retention, non-toxicity towards normal tissues, and successful targeting of malignant cells are important for an effective therapy. The aim of this study was to evaluate an intraperitoneally administered astatine-labeled, integrin-targeted nanodrug, mPEG(Mn:350)-S-AuNP[²¹¹At]-c[RGDfK(C)] ([²¹¹At]AuNP@PEG/RGD), with respect to its kinetics, therapeutic efficacy, and safety. Methods: C6 rat glioma cells (10⁷), and BxPC3 (10⁷) and PANC-1 (10⁷) human pancreatic cancer cells were seeded intraperitoneally into nude mice, and [²¹¹At]AuNP@PEG/RGD (0.979 ± 0.194 MBq for C6 models (n = 3), 1.139 ± 0.035 MBq for BxPC3 models (n = 10), and 1.308 ± 0.039 MBq for PANC-1 models (n = 10) per mouse) or saline were intraperitoneally administered 4–7 days later. Cytotoxicity against malignant cells, pharmacokinetics after administration, therapeutic efficacy, and safety in abdominal organs were evaluated. Results: Intraperitoneally administered [²¹¹At]AuNP@PEG/RGD accumulated exclusively in the peritoneal cavity for a long period of time and showed minimal systemic diffusion through the blood. In the C6 model, the intraperitoneal tumor mass was significantly lower in the treated group compared with that of the controls (p = 0.05). For the BxPC3 (median survival time: control/treated = 41/65 days, p < 0.001) and PANC-1 (median survival time: control/treated = 19/35 days, p < 0.001) peritoneal dissemination models, survival analysis revealed that [²¹¹At]AuNP@PEG/RGD significantly prolonged overall survival. Although transient weight loss, leukopenia, and thrombocytopenia were observed at one week post-administration, a short recovery trend was evident thereafter. One month after administration, no abnormalities were found in hematological tests or histological analyses of intra-abdominal organs. Conclusions: The intraperitoneal administration of astatine-labeled integrin-targeted [²¹¹At]AuNP@PEG/RGD nanoparticles showed promising findings in terms of safety and efficacy for treating peritoneally disseminated malignant tumors.