Hydration Structure of 102No2+: A Density Functional Theory-Molecular Dynamics Study.

The hydration structure of No2+, the divalent cation of nobelium in water, was investigated by ab initio molecular dynamics (MD) simulations. First, a series of benchmark calculations were performed to validate the density functional theory (DFT) calculation methods for a molecule containing a No atom. The DFT-MD simulation of the hydration structure of No2+ was conducted after the MD method was validated by simulating the hydration structures of Ca2+ and Sr2+, whose behavior was previously reported to be similar to that of No2+. The model cluster containing M2+ (M = Ca, Sr, or No) and 32 water molecules was used for DFT-MD simulation. The results showed that the hydration distance of No2+ was intermediate between those of Ca2+ and Sr2+. This trend in the hydration distance is in good agreement with the elution position trend obtained in a previous radiochemical experiment. The calculated No-O bond lengths in the optimized structure of [No(H2O)8]2+ was 2.59 Å, while the average No-O bond length of [No(H2O)8]2+ in water by DFT-MD was 2.55 Å. This difference implies the importance of dynamic solvent effects, considering the second (and further) coordination sphere in the theoretical calculation of solution chemistry for superheavy elements.

Astatine-211-Labeled Gold Nanoparticles for Targeted Alpha-Particle Therapy via Intravenous Injection.

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.

Tuning the Ground- and Excited-State Redox Potentials of Octahedral Hexanuclear Rhenium(III) Complexes by the Combination of Terminal Halide and N-Heteroaromatic Ligands.

The present study reports that the ground- and excited-state Re6(23e)/Re6(24e) redox potentials of an octahedral hexanuclear rhenium(III) complex can be controlled by systematically changing the number and type of the N-heteroaromatic ligand (L) and the number of chloride ions at the six terminal positions. Photoirradiation of [Re6(µ3-S)8Cl6]4- with an excess amount of L afforded a mono-L-substituted hexanuclear rhenium(III) complex, [Re6(µ3-S)8Cl5(L)]3- (L = 4-dimethylaminopyridine (dmap), 3,5-lutidine (lut), 4-methylpyridine (mpy), pyridine (py), 4,4'-bipyridine (bpy), 4-cyanopyridine (cpy), and pyrazine (pz)). The bis- and tris-lut-substituted complexes, trans- and cis-[Re6(µ3-S)8Cl4(lut)2]2- and mer-[Re6(µ3-S)8Cl3(lut)3]-, were synthesized by the reaction of [Re6(µ3-S)8Cl6]3- with an excess amount of lut in refluxed N,N-dimethylformamide. The mono-L-substituted complexes showed one-electron redox processes assignable to E 1/2[Re6(23e)/Re6(24e)] = 0.49-0.58 V versus Ag/AgCl. The ground-state oxidation potentials were linearly correlated with the pK a of the N-heteroaromatic ligand [pK a(L)], the 1H NMR chemical shift of the ortho proton on the coordinating ligand, and the Hammett constant (σ) of the pyridyl-ligand substituent. The series of [Re6(µ3-S)8X6-n (L) n ] n-4 complexes (n = 0, X = Cl, Br, I, or NCS; n = 1-3, X = Cl) showed a linear correlation with the sum of the Lever electrochemical parameters at the six terminal ligands (ΣE L). The cyclic voltammograms of the mono-L-substituted complexes (L = bpy, cpy, and pz) showed one-electron redox waves assignable to E 1/2(L0/L-) = -1.28 to -1.48 V versus Ag/AgCl. Two types of photoluminescences were observed for the complexes, originating from the cluster core-centered excited triplet state (3CC) for L = dmap, lut, mpy, and py and from the metal-to-ligand charge-transfer excited triplet state (3MLCT) for L = bpy, cpy, and pz. The complexes with the 3CC character exhibited emission features and photophysical properties similar to those of ordinary hexanuclear rhenium complexes. The emission maximum wavelength of the complexes with 3MLCT shifted to the longer wavelength in the order L = 4-phenylpyridine (ppy), bpy, pz, and cpy, which agreed with the difference between E 1/2[Re6(23e)/Re6(24e)] and E 1/2(L0/L-). The calculated oxidation potential of the excited hexanuclear rhenium complex with the 3CC character was linearly correlated with pK a(L), σ, and ΣE L. The ground- and excited-state oxidation potentials were finely tuned by the combination of halide and L ligands at the terminal positions.

Comparison of the Therapeutic Effects of [211At]NaAt and [131I]NaI in an NIS-Expressing Thyroid Cancer Mouse Model.

Astatine (211At) is an alpha-emitter with a better treatment efficacy against differentiated thyroid cancer compared with iodine (131I), a conventional beta-emitter. However, its therapeutic comparison has not been fully evaluated. In this study, we compared the therapeutic effect between [211At]NaAt and [131I]NaI. In vitro analysis of a double-stranded DNA break (DSB) and colony formation assay were performed using K1-NIS cells. The therapeutic effect was compared using K1-NIS xenograft mice administered with [211At]NaAt (0.4 MBq (n = 7), 0.8 MBq (n = 9), and 1.2 MBq (n = 4)), and [131I]NaI (1 MBq (n = 4), 3 MBq (n = 4), and 8 MBq (n = 4)). The [211At]NaAt induced higher numbers of DSBs and had a more reduced colony formation than [131I]NaI. In K1-NIS mice, dose-dependent therapeutic effects were observed in both [211At]NaAt and [131I]NaI. In [211At]NaAt, a stronger tumour-growth suppression was observed, while tumour regrowth was not observed until 18, 25, and 46 days after injection of 0.4, 0.8, and 1.2 MBq of [211At]NaAt, respectively. While in [131I]NaI, this was observed within 12 days after injection (1, 3, and 8 MBq). The superior therapeutic effect of [211At]NaAt suggests the promising clinical applicability of targeted alpha therapy using [211At]NaAt in patients with differentiated thyroid cancer refractory to standard [131I]NaI treatment.

Non-destructive 3D imaging method using muonic X-rays and a CdTe double-sided strip detector.

Elemental analysis based on muonic X-rays resulting from muon irradiation provides information about bulk material composition without causing damage, which is essential in the case of precious or otherwise unreachable samples, such as in archeology and planetary science. We developed a three-dimensional (3D) elemental analysis technique by combining the elemental analysis method based on negative muons with an imaging cadmium telluride double-sided strip detector (CdTe-DSD) designed for the hard X-ray and soft [Formula: see text]-ray observation. A muon irradiation experiment using spherical plastic samples was conducted at the Japan Proton Accelerator Research Complex (J-PARC); a set of projection images was taken by the CdTe-DSD, equipped with a pinhole collimator, for different sample rotation angles. The projection images measured by the CdTe-DSD were utilized to obtain a 3D volumetric phantom by using the maximum likelihood expectation maximization algorithm. The reconstructed phantom successfully revealed the 3D distribution of carbon in the bulk samples and the stopping depth of the muons. This result demonstrated the feasibility of the proposed non-destructive 3D elemental analysis method for bulk material analysis based on muonic X-rays.

Coprecipitation with samarium hydroxide using multitracer produced through neutron-induced fission of 235U toward chemical study of heavy elements.

For new chemical studies on heavy elements, we previously investigated the coprecipitation behaviors with samarium hydroxide for various elements. Herein, we report the coprecipitation experiment using multitracer produced by neutron-induced fission of 235U. The coprecipitation behaviors of 10 elements were investigated: new data were obtained for Sr, Ru, I, Pm, and Np. The present results support the previously obtained conclusion that the hydroxide precipitation properties of various elements can be qualitatively investigated through their coprecipitation behaviors.

Fibroblast activation protein targeted therapy using [177Lu]FAPI-46 compared with [225Ac]FAPI-46 in a pancreatic cancer model.

PURPOSE: Fibroblast activation protein (FAP), which has high expression in cancer-associated fibroblasts of epithelial cancers, can be used as a theranostic target. Our previous study used 64Cu and 225Ac-labelled FAP inhibitors (FAPI-04) for a FAP-expressing pancreatic cancer xenograft imaging and therapy. However, the optimal therapeutic radionuclide for FAPI needs to be investigated further. In this study, we evaluated the therapeutic effects of beta-emitter (177Lu)-labelled FAPI-46 and alpha-emitter (225Ac)-labelled FAPI-46 in pancreatic cancer models. METHODS: PET scans (1 h post injection) were acquired in PANC-1 xenograft mice (n = 9) after the administration of [18F]FAPI-74 (12.4 ± 1.7 MBq) for the companion imaging. The biodistribution of [177Lu]FAPI-46 and [225Ac]FAPI-46 were evaluated in the xenograft model (total n = 12). For the determination of treatment effects, [177Lu]FAPI-46 and [225Ac]FAPI-46 were injected into PANC-1 xenograft mice at different doses: 3 MBq (n = 6), 10 MBq (n = 6), 30 MBq (n = 6), control (n = 4) for [177Lu]FAPI-46, and 3 kBq (n = 3), 10 kBq (n = 2), 30 kBq (n = 6), control (n = 7) for [225Ac]FAPI-46. Tumour sizes and body weights were followed. RESULTS: [18F]FAPI-74 showed rapid clearance by the kidneys and high accumulation in the tumour and intestine 1 h after administration. [177Lu]FAPI-46 and [225Ac]FAPI-46 also showed rapid clearance by the kidneys and relatively high accumulation in the tumour at 3 h. Both [177Lu]FAPI-46 and [225Ac]FAPI-46 showed tumour-suppressive effects, with a mild decrease in body weight. The treatment effects of [177Lu]FAPI-46 were relatively slow but lasted longer than those of [225Ac]FAPI-46. CONCLUSION: This study suggested the possible application of FAPI radioligand therapy in FAP-expressing pancreatic cancer. Further evaluation is necessary to find the best radionuclide with shorter half-life, as well as the combination with therapies targeting tumour cells directly.

Intratumoral administration of astatine-211-labeled gold nanoparticle for alpha therapy.

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.

Synthesis of [211At]4-astato-L-phenylalanine by dihydroxyboryl-astatine substitution reaction in aqueous solution.

Astatine-211 (211At)-labeled phenylalanine is expected to be a promising agent for targeted alpha-particle therapy for the treatment of patients with glioma. The existing reactions to prepare the labeled compound usually require organic solvents and metals that are toxic and hazardous to the environment. In this study, we developed a novel method wherein astatination was realized via the substitution of 211At for a dihydroxyboryl group coupled to phenylalanine. [211At]4-astato-L-phenylalanine was obtained as the carrier-free product in aqueous medium in high radiochemical yields (98.1 ± 1.9%, n = 5). The crude reaction mixture was purified by solid-phase extraction, and the radiochemical purity of the product was 99.3 ± 0.7% (n = 5). The high yield and purity were attributed to the formation of [211At]AtI and AtI2- as the reactive intermediates in the astatination reaction. The reaction did not require any organic solvents or toxic reagents, suggesting that this method is suitable for clinical applications.

Extended single-dose toxicity study of [211At]NaAt in mice for the first-in-human clinical trial of targeted alpha therapy for differentiated thyroid cancer.

OBJECTIVE: Astatine (211At) is a promising alpha emitter as an alternative to iodine (131I). We are preparing the first-in-human (FIH) clinical trial of targeted alpha therapy for differentiated thyroid cancer in consultation with Pharmaceuticals and Medical Devices Agency. Here, we performed an extended single-dose toxicity examination under a reliability standard, as a preclinical safety assessment of [211At]NaAt to determine the FIH dose. METHODS: [211At]NaAt solution was injected into normal 6-week-old mice (male (n = 50) and female (n = 50), body weight: male 33.2 ± 1.7 g, female 27.3 ± 1.5 g), which were then divided into four groups: 5 MBq/kg (n = 20), 20 MBq/kg (n = 20), 50 MBq/kg (n = 30), saline control (n = 30). The mice were followed up for 5 days (primary evaluation point for acute toxicity: n = 80) or 14 days (n = 20: evaluation point for recovery) to monitor general condition and body weight change. At the end of the observation period, necropsy, blood test, organ weight measurement, and histopathological examination were performed. For body weight, blood test, and organ weight, statistical analyses were performed to compare data between the control and injected groups. RESULTS: No abnormal findings were observed in the general condition of mice. In the 50 MBq/kg group, males (days 3 and 5) showed a significant decrease in body weight compared with the control. However, necropsy did not differ significantly beyond the range of spontaneous lesions. In the blood test, males (50 MBq/kg) and females (50 MBq/kg) showed a decrease in white blood cell and platelet counts on day 5, and recovery on day 14. In the testis, a considerable weight decrease was observed on day 14 (50 MBq/kg), and multinucleated giant cells were observed in all mice, indicating a significant change related to the administration of [211At]NaAt. CONCLUSIONS: In the extended single-dose toxicity study of [211At]NaAt, administration of high doses resulted in weight loss, transient bone marrow suppression, and pathological changes in the testis, which require consideration in the FIH clinical trial.

Co-precipitation behaviour of single atoms of rutherfordium in basic solutions.

All superheavy elements (SHEs), with atomic numbers (Z) ≥104, have been artificially synthesized one atom at a time and their chemical properties are largely unknown. Because these heavy nuclei have short lifetimes as well as extremely low production rates, chemical experiments need to be carried out on single atoms and have mostly been limited to adsorption and extraction. We have now investigated the precipitation properties of the SHE Rf (Z = 104). A co-precipitation method with samarium hydroxide had previously established that the co-precipitation behaviour of a range of elements reflected these elements' tendency to form hydroxide precipitates and/or ammine complex ions. Here we investigated co-precipitation of Rf in basic solutions containing NH3 or NaOH. Comparisons between the behaviour of Rf with that of Zr and Hf (lighter homologues of Rf) and actinide Th (a pseudo-homologue of Rf) showed that Rf does not coordinate strongly with NH3, but forms a hydroxide (co)precipitate that is expected to be Rf(OH)4.

α-Emitting cancer therapy using 211 At-AAMT targeting LAT1.

α-Methyl-l-tyrosine (AMT) has a high affinity for the cancer-specific l-type amino acid transporter 1 (LAT1). Therefore, we established an anti-cancer therapy, with 211 At-labeled α-methyl-l-tyrosine (211 At-AAMT) as a carrier of 211 At into tumors. 211 At-AAMT had high affinity for LAT1, inhibited tumor cell growth, and induced DNA double-stranded breaks in vitro. We evaluated the accumulation of 211 At-AAMT in vivo and the role of LAT1. Treatment with 0.4 MBq/mouse 211 At-AAMT inhibited tumor growth in the PANC-1 tumor model and 1 MBq/mouse 211 At-AAMT inhibited metastasis in the lung of the B16F10 metastasis model. Our results suggested that 211 At would be useful for anti-cancer therapy and that LAT1 is suitable as a target for radionuclide therapy.

Structural and compositional characteristics of Fukushima release particulate material from Units 1 and 3 elucidates release mechanisms, accident chronology and future decommissioning strategy.

The structural form and elemental distribution of material originating from different Fukushima Daiichi Nuclear Power Plant reactors (Units 1 and 3) is hereby examined to elucidate their contrasting release dynamics and the current in-reactor conditions to influence future decommissioning challenges. Complimentary computed X-ray absorption tomography and X-ray fluorescence data show that the two suites of Si-based material sourced from the different reactor Units have contrasting internal structure and compositional distribution. The known event and condition chronology correlate with the observed internal and external structures of the particulates examined, which suggest that Unit 1 ejecta material sustained a greater degree of melting than that likely derived from reactor Unit 3. In particular, we attribute the near-spherical shape of Unit 1 ejecta and their internal voids to there being sufficient time for surface tension to round these objects before the hot (and so relatively low viscosity) silicate melt cooled to form glass. In contrast, a more complex internal form associated with the sub-mm particulates invoked to originate from Unit 3 suggest a lower peak temperature, over a longer duration. Using volcanic analogues, we consider the structural form of this material and how it relates to its environmental particulate stability and the bulk removal of residual materials from the damaged reactors. We conclude that the brittle and angular Unit 3 particulate are more susceptible to further fragmentation and particulate generation hazard than the round, higher-strength, more homogenous Unit 1 material.

Development of high-resolution YAP(Ce) x-ray camera for the imaging of astatine-211(At-211) in small animals.

PURPOSE: Astatine-211 (At-211) is a promising alpha emitter for radionuclide therapy. High-resolution in vivo imaging of At-211 in small animals is needed for the development of At-211 radiopharmaceuticals. For this purpose, we developed a low-energy x-ray camera using a thin YAlO3 :Ce (YAP(Ce)) plate to image the low-energy x rays (73-87 keV) from the daughter radionuclide of At-211 (Po-211). METHOD: We optically coupled a 38 × 38 × 1-mm YAP (Ce) plate to a position-sensitive photomultiplier (PSPMT) to develop an imaging detector. A pinhole or a parallel hole collimator was attached to the imaging detector, and the performance was measured for 60-keV gamma photons. With the developed x-ray camera, we carried out imaging of a mouse that had been administered At-211-NaAt. RESULTS: The intrinsic spatial resolution of the YAP (Ce) x-ray camera was approximately 1.2 mm FWHM, and the energy resolution was 22% FWHM. With a 5-mm-thick parallel hole collimator, the spatial resolution was 3.8 mm FWHM with a sensitivity of 8 × 10-4 at 10 mm, which is a typical distance from the surface of the collimator to a subject in mouse imaging. Using a 1-mm diameter pinhole collimator, the spatial resolution was 1.8 mm FWHM with a sensitivity of 3.5 × 10-4 at 10 mm from the collimator. In the mouse images measured by the developed x-ray camera, we could clearly observe that the At-211 accumulated in the thyroid gland and the stomach of the mouse. CONCLUSION: We concluded that the YAP (Ce) x-ray camera is useful for in vivo imaging of At-211.

Targeted alpha therapy using astatine (211At)-labeled phenylalanine: A preclinical study in glioma bearing mice.

Phenylalanine derivatives, which target tumors especially through L-type amino acid transporter-1 (LAT1), have elicited considerable attention. In this study, we evaluated the treatment effect of phenylalanine labeled with the alpha emitter astatine (211At-PA) in tumor bearing mice. The C6 glioma, U-87MG, and GL261 cell lines were subjected to a cellular 211At-PA uptake analysis that included an evaluation of the uptake inhibition by the system L amino acid transporter inhibitor 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH). BCH significantly inhibited para-211At-PA uptake in C6 glioma (12.2 ± 0.8%), U-87MG (27.6 ± 1.1%), and GL261 (12.6 ± 2.0%) cells compared to baseline, suggesting an uptake contribution by system L amino acid transporters. Subsequently, xenograft and allograft models were prepared by subcutaneously injecting C6 glioma (n = 12) or GL-261 cells (n = 12), respectively. C6 glioma mice received three 211At-PA doses (0.1, 0.5, or 1 MBq, n = 3/dose), while GL261 mice received one high dose (1 MBq, n = 7). 211At-PA exhibited a tumor growth suppression effect in C6 glioma models in a dose-dependent manner as well as in GL-261 models. This phenylalanine derivative labeled with astatine may be applicable as an alpha therapy that specifically targets system L amino acid transporters.

Preclinical Evaluation of Radiation-Induced Toxicity in Targeted Alpha Therapy Using [211At] NaAt in Mice: A Revisit.

We recently reported the dose-dependent therapeutic effect of 211At-NaAt in differentiated thyroid cancer xenograft models. In the present study, we evaluated the radiation-induced toxicity of 211At-NaAt using detailed hematological, biochemical, and histological analyses. Biodistribution of 211At-NaAt was measured in normal ICR mice (n = 12), absorbed doses in the major organs were calculated. Groups of ICR mice (n = 60) were injected with 0.1 MBq or 1 MBq of 211At-NaAt, using saline as the control group (n = 30). Body weight and food intake were followed up for 60 days. Blood cell counts and serum level of biochemical parameters were measured 3, 7, 15, 29, 60 days after injection. Histological analyses of the major organs with hematoxylin and eosin staining were performed. Biodistribution study revealed a high-absorbed dose in the thyroid gland, stomach, bladder, heart, lungs, spleen, kidneys, and testis. The 0.1 MBq group showed no abnormalities. The 1 MBq group showed decreased body weight and food intake. Histological analysis showed atrophy and fibrosis in the thyroid gland, a transient hypospermatogenesis in the testis on day 29 was found in one mouse. Hematological toxicity was mild and transient. The total cholesterol, albumin, and total protein increased with no signs of recovery, which was considered to be caused by hypothyroidism. High-dose administration of 211At-NaAt showed transient toxicity in the white blood cells and testis without severe hematological or renal toxicity, suggesting its tolerable safety as targeted alpha-therapy for differentiated thyroid cancer in the 1 MBq group.

Effect of short-term betamethasone administration on the regeneration process of tissue-engineered bone.

Local inflammation at the transplanted site of tissue-engineered bone may cause apoptosis of the transplanted cells, thus negatively affecting bone regeneration. To maximize the efficacy of bone tissue engineering, the local effect of short-term corticosteroid administration at the transplanted site of tissue-engineered bone was studied with respect to the expression of inflammatory cytokines. Compact bone-derived cells from mouse leg bones were isolated, cultured and seeded onto ß-tricalcium phosphate granules. The constructs were transplanted to the back of syngeneic mice. Betamethasone sodium phosphate was administered intraperitoneally to an experimental (betamethasone) group, whereas the same amount of saline was administered to a control group. When betamethasone was administered three times (immediately after operation and 12 hours and 24 hours after transplantation), the number of SP7/osterix-positive osteoblasts was larger in the betamethasone group. Three times of betamethasone administration (immediately after operation and 12 hours and 24 hours after transplantation) did not change the number of apoptotic cells and osteoclasts, but showed a slight upregulation of IL-4 and a downregulation of IL-6. However, 7 doses of betamethasone administration (over 7 consecutive days) increased the number of apoptotic cells and osteoclasts, which was correlated with a downregulation of IL-4 and an upregulation of IL-6. TNF-α expression levels showed no significant differences between the two groups. The results showed beneficial effects of 3 betamethasone administrations for bone regeneration therapy but contrary effects when betamethasone was administered 7 times due to the downregulation of anti-inflammatory cytokines (IL-4) and the upregulation of inflammatory cytokines (IL-6). As a conclusion, our results suggested the importance of the cautious usage of corticosteroids to control local inflammation at transplanted sites in bone tissue engineering.

Theranostics Targeting Fibroblast Activation Protein in the Tumor Stroma: 64Cu- and 225Ac-Labeled FAPI-04 in Pancreatic Cancer Xenograft Mouse Models.

Fibroblast activation protein (FAP), which promotes tumor growth and progression, is overexpressed in cancer-associated fibroblasts of many human epithelial cancers. Because of its low expression in normal organs, FAP is an excellent target for theranostics. In this study, we used radionuclides with relatively long half-lives, 64Cu (half-life, 12.7 h) and 225Ac (half-life, 10 d), to label FAP inhibitors (FAPIs) in mice with human pancreatic cancer xenografts. Methods: Male nude mice (body weight, 22.5 ± 1.2 g) were subcutaneously injected with human pancreatic cancer cells (PANC-1, n = 12; MIA PaCa-2, n = 8). Tumor xenograft mice were investigated after the intravenous injection of 64Cu-FAPI-04 (7.21 ± 0.46 MBq) by dynamic and delayed PET scans (2.5 h after injection). Static scans 1 h after the injection of 68Ga-FAPI-04 (3.6 ± 1.4 MBq) were also acquired for comparisons using the same cohort of mice (n = 8). Immunohistochemical staining was performed to confirm FAP expression in tumor xenografts using an FAP-α-antibody. For radioligand therapy, 225Ac-FAPI-04 (34 kBq) was injected into PANC-1 xenograft mice (n = 6). Tumor size was monitored and compared with that of control mice (n = 6). Results: Dynamic imaging of 64Cu-FAPI-04 showed rapid clearance through the kidneys and slow washout from tumors. Delayed PET imaging of 64Cu-FAPI-04 showed mild uptake in tumors and relatively high uptake in the liver and intestine. Accumulation levels in the tumor or normal organs were significantly higher for 64Cu-FAPI-04 than for 68Ga-FAPI-04, except in the heart, and excretion in the urine was higher for 68Ga-FAPI-04 than for 64Cu-FAPI-04. Immunohistochemical staining revealed abundant FAP expression in the stroma of xenografts. 225Ac-FAPI-04 injection showed significant tumor growth suppression in the PANC-1 xenograft mice, compared with the control mice, without a significant change in body weight. Conclusion: This proof-of-concept study showed that 64Cu-FAPI-04 and 225Ac-FAPI-04 could be used in theranostics for the treatment of FAP-expressing pancreatic cancer. α-therapy targeting FAP in the cancer stroma is effective and will contribute to the development of a new treatment strategy.

Synthesis and Photoluminescence of Tetracyanidonitridorhenium(V) Complexes with Five-Membered N-Heteroaromatic Ligands and Photoluminescence-Intensity Change.

Novel tetracyanidonitridorhenium(V) complexes with five-membered N-heteroaromatic ligands, (PPh4)2[ReN(CN)4L] [L = imidazole (Him) (2), 1-methylimidazole (Mim) (3), and pyrazole (pyz) (4)] and (PPh4)2[ReN(CN)4L]·L [L = Him (5) and Mim (6)], were synthesized by the reactions of (PPh4)2[ReN(CN)4] (1) with Him, Mim, and pyz, and their structures were determined by single-crystal X-ray analysis. The complexes 2, 3, 4, and 6 showed intense photoluminescence, with the emission quantum yields (Φem) being 0.65-0.75 in the solid state at 296 K. In contrast, the Φem and τem values of 5 are significantly smaller and shorter, respectively, than the relevant values of 2. The interconversion reactions among 1, 2, and 5 accompanied by large photoluminescence-intensity changes were accomplished by solvent-free reactions and exposure of water. The mechanochemical reaction of 2 with 1 mol equiv of Him in the solid state gave 5. Complex 5 was also obtained by the mechanochemical reaction of 1 with 2 mol equivalents of Him in the solid state. By placing solid of 5 in water, the solid showed intense photoluminescence to give 2. Complex 1 was produced under vacuum at 185 °C from 2 or 5.

Synthesis, structures, redox properties, and theoretical calculations of thiohalide capped octahedral hexanuclear technetium(iii) clusters.

The first thiohalide µ3-capped octahedral hexanuclear technetium clusters with 24 valence electrons, [Tc6(µ3-S)8-n(µ3-Br)nBr6]n-4 [n = 1 ([Tc-S7Br]3-) and n = 2 ([Tc-S6Br2]2-)] and [Tc6(µ3-S)7(µ3-Cl)Cl6]3- ([Tc-S7Cl]3-), were synthesized and characterized. The structures of [Tc-S7Br]3-, [Tc-S6Br2]2-, and [Tc-S7Cl]3- were determined by single-crystal X-ray analysis. The Tc-Tc bond distances in [Tc-S7Br]3-, [Tc-S6Br2]2-, and [Tc-S7Cl]3- are 2.5842(6)-2.6029(6) Å (avg. 2.593(2) Å), 2.5835(10)-2.6049(10) Å (avg. 2.596(1) Å), and 2.5829(4)-2.5940(4) Å (avg. 2.587(3) Å), respectively. The capping halide and sulfide ligands in [Tc-S7Br]3-, [Tc-S6Br2]2-, and [Tc-S7Cl]3- were disordered in the crystals. The bond distances of Tc-S/Br as a function of the occupancies of the capping bromides for [Tc-S6Br2]2-, [Tc-S7Br]3-, and [Tc6(µ3-S)8Br6]4- ([Tc-S8]4-) showed a linear correlation. The one-electron reduction waves assignable to the Tc/TcIITc [Tc6(24e/25e)] process were observed for the novel complexes. Density functional theory (DFT) calculations of the hexanuclear technetium complexes showed a smaller energy gap between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) of the hexanuclear technetium complexes compared to those of the rhenium analogues. The electronic transitions of the new technetium complexes shifted to lower energy compared to the isotypic rhenium complexes.