Development of Methods to Evaluate Several Levels of Uranium Concentrations in Drainage Water Using Total Reflection X-Ray Fluorescence Technique

As a country's law stipulates the effluent standard uranium concentration in drainage water, the uranium concentration must be determined when drainage water is released from a uranium handling facility, such as the Fukushima Daiichi nuclear power plant. The maximum allowable limit for uranium release at each facility is defined taking into consideration the situation of the facility, such as 1/10 to 1/100 of this effluent standard value. Currently, the uranium concentration of drainage water is commonly determined by α-particle spectrometry, in which several liters of drainage water must be evaporated, requiring about half of a day followed by 2–3 h of measurements, due to the low specific radioactivity of uranium. This work proposes a new methodology for the rapid and simple measurement of several levels of uranium in drainage water by a total reflection X-ray fluorescence (TXRF) analysis. Using a portable device for TXRF measurements was found to enable measurements with 1/10 the sensitivity of the effluent standard value by 10 times condensation of the uranium-containing sample solution; a benchtop device is useful to measure uranium concentrations <1/100 of the effluent standard value. Therefore, the selective usage of methods by a portable and benchtop devices allows for screening and precise evaluation of uranium concentrations in drainage water

Reduction of 223Ra retention in the Large Intestine During Targeted Alpha Therapy with 223RaCl2 by Oral BaSO4 Administration in Mice

Background: Targeted alpha therapy with 223RaCl2 is used to treat skeletal metastases of hormone-refractory prostate cancer. The intravenous injection of 223RaCl2 causes gastrointestinal disorders such as nausea, abdominal discomfort, and diarrhea as frequent clinical adverse events caused by radiation. BaSO4 is known to display Ra2+ ion uptake in its structure and is clinically used as a contrast agent for X-ray imaging following oral administration. Here, we investigated the feasibility of a method to reduce 223Ra retention in the large intestine with BaSO4 by biodistribution studies in mice. Methods: 223RaCl2 biodistribution was examined in ddY mice after intravenous administration (10 kBq/mouse).BaSO4 (100 mg/mouse) was orally administered 1 h before 223RaCl2 injection. We also investigated the effect of laxative treatment on BaSO4 activity, since laxatives are clinically used with BaSO4 to avoid impaction in the large intestine. Results: BaSO4 significantly reduced 223Ra retention in the large intestine after 223RaCl2 injection in mice when compared with the control without BaSO4 administration (P < 0.05). Excretion of 223Ra into the feces was significantly increased by BaSO4 administration (P < 0.05). Laxative treatment did not affect BaSO4 activity in reducing 223Ra retention, although no additional effect of laxative treatment to 223Ra excretion was observed in mice. Conclusions. BaSO4 administration was effective in reducing 223Ra retention in the large intestine during 223RaCl2 therapy, and laxative treatment did not attenuate BaSO4 activity. This method could be useful in reducing adverse events caused by radiation exposure to the large intestine during 223RaCl2 therapy

In Vivo Simultaneous Imaging of Vascular Pool and Hypoxia with a HT-29 Tumor Model: the Application of Dual-Isotope SPECT/PET/CT

Investigation of vascularity and hypoxia in tumors is important in understanding cancer biology to developthe therapeutic strategies in cancer treatment. ------------------------------------------------------------------------ *Corresponding author . Recently, an imaging technology with the VECTor SPECT/PET/CT small-animal scanner (MILabs) has been developed to obtain simultaneous images usingtwodifferent tracers labeled with SPECT and PET nuclides, respectively. In this study, we developed amethod to simultaneously visualize vascularity and hypoxia witha human colon carcinoma HT-29tumor-bearing mouse model with 99mTc-labeled human serum albumin (99mTc-HSA) to detect blood pool, and 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM) to detect the over-reduced conditionsunder hypoxia, by applying this SPECT/PET/CT technology.Prior to the in vivo experiments, a phantom study was conducted to confirmquantitativity of the 99mTc/64Cu dual-isotope imaging with the SPECT/PET/CT system,by comparing radioactivities detected by SPECT/PET/CT system and those of standards under the conditions of wide range of radioactivities and various content ratios, in our settings. An in vivoimaging study was conducted with HT-29 tumor-bearing mice. Both 64Cu-ATSM (37 MBq) and 99mTc-HSA (18.5 MBq) were intravenously injected into a mouse (n = 4) at 1 h and 10 min, respectively, before scanning for 20 min; the 99mTc/64Cu dual-isotope SPECT/PET/CT images were then obtained.The phantom study demonstrated that this system has high quantitativity, even when 2 isotopes co-existed and the content ratio was changed over a wide range, indicating the feasibility for in vivo experiments. In vivoSPECT/PET/CT imaging with 64Cu-ATSM and 99mTc-HSA visualized the distribution of each probe and showed that 64Cu-ATSM high-uptake regions barely overlapped with 99mTc-HSA high-uptake regions within HT-29 tumors.We developed a method to simultaneously visualize vascularity and hypoxia within HT-29tumors using in vivodual-isotope SPECT/PET/CT imaging. This methodology would be useful for studies oncancer biology with mouse tumor models anddevelopment of the treatment strategies against cancer. Examination of vascularity and hypoxia within in vivotumors is important in understanding the biology of cancer anddevelopmentof the therapeutic strategies in cancer treatment. For hypervascular tumors, antiangiogenic therapy and antivascular therapy are promising approaches. For antiangiogenic therapy, the anti-vascular endothelial growth factor antibody bevacizumab is now clinically used worldwide [1-4], and for antivascular therapy, a clinical trial withcombrestatin A4 phosphate is conducted[5]. For hypovascular tumor, which is usually associated with hypoxia, intensive treatment is necessary, since tumor hypoxia is reportedly resistant to chemotherapy and radiotherapy [6-8]. In recent years, several therapeutic methods have been proposedto damage to hypoxic regions within tumors, such as intensity modulated radiation therapy with hypoxia positron emission tomography (PET) imaging [9, 10], and carbon-ion radiotherapy, which is able to damage tumor cells even in the absence of oxygen by high linear energy transfer beam [11, 12]. However, considering the difficulty of cancer radical cure at the present moment, more effective drugs and treatment methods for antiangiogenic, antivascular, and antihypoxia therapies need to be developed. In addition, combinations of these therapies would be effective approaches, since they can attacktumor vascularity and hypoxia closely linked each other.However, it is still difficult to observe tumor vascularity and hypoxia both coincidently and concisely in in vivo tumor-bearing mouse model. Recently, a technology of single-photon emission computed tomography/positron emission tomography/computed tomography(SPECT/PET/CT) imaging with the VECTor small-animal scanner, launched from MILabs (Utrecht, Netherlands), has been reportedto obtain truly simultaneous images with twotracers labeled with SPECT and PET nuclides, respectively. Conventionally, dual-isotope imaging studies with SPECT and PET have been performed by obtaining each image independently with 2 separate systems [13, 14]. In contrast, the VECTor system is equipped with a clustered pinhole collimator, which dramatically reduces pinhole-edge penetration of high-energy annihilation ?-photons from PET nuclides and enables it to detect high-energy ?-photons derived from PET nuclides, in a manner similar to SPECT nuclides, and to obtain high-resolution images from positron emitters and single-photon emitters at the same time by separating the images based on the photon energy [15, 16]. Thus, this system has a novel concept to make images of PET nuclides, compared to the typical PET system, which measures the coincidence of annihilation ?-photons. Goorden et al. have reported that this system shows high spatial resolution, with 0.8 mm for PET nuclides and 0.5 mm for SPECT nuclides [15]. Miwa et al. also confirmed its performance in simultaneous detection of 99mTc and 18F using this system [17]. In this study, we developed a methodology to easily observe intratumoralvascularity and hypoxia in a simultaneous manner,by applyingthis SPECT/PET/CT technology. We used 99mTc-labeled human serum albumin (99mTc-HSA) labeled with a SPECT nuclide 99mTc (half-life = 6.0 h; 140 keV ?-ray: 89%) to visualize tumor vascularity by detecting blood pool [18]. The 99mTc-HSAhas been reported to detect tumor blood pool in many types of cancer, including colon cancer, renal cell carcinoma, and liver tumor in both preclinical and clinical studies [19-21]. We also used 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM), labeled with a PET nuclide 64Cu (half-life = 12.7 h; ?+-decay: 17.4%; ??-decay: 38.5%; and electron capture: 43%) [22], to detect tumor hypoxia. The Cu-ATSM, labeled with Cu radioisotopes, such as 60Cu, 62Cu, and 64Cu, has been developed as an imaging agent targeting hypoxic regions in tumors for use with PET [23-26].Many studies have demonstrated that Cu-ATSM accumulation is associated with hypoxic conditions of tumor in vitro and in vivo[26-29]. The mechanism of radiolabeled Cu-ATSM accumulation has been studied: Cu-ATSM has small molecular sizeand high membrane permeability, and thus rapidly diffuses into cells and is reduced and trapped within cells under highly reduced intracellular conditions such as hypoxia [24, 29-31]. A clinical study with 62Cu-ATSM demonstrated that high levels of hypoxia-inducible factor-1? (HIF-1?) expression were found in Cu-ATSM uptake regions in the tumors of patients with glioma [32]. In this study, we performed simultaneous in vivo imaging using a SPECT/PET/CT with 99mTc-HSA and 64Cu-ATSM for detecting tumor vascularity and hypoxia with a HT-29 tumor-bearing mouse model

Cancer stem cell niche imaging with 64Cu-ATSM and the application for internal radiotherapy

2011 Workshop on Radiopharmaceuticals and Molecular Probe

X-ray fluorescence in biological sciences

For rapid detection of uranium contamination in wounds at a nuclear fuel handling facility, a technique for XRF analysis of blood collected on small filter paper was developed, and a minimum detectable radioactivity of 0.31 mBq was obtained. This is much smaller than the lower detection limit of 1 Bq of the α-particle survey meter. This very simple and rapid technique has enabled the detection of uranium contamination in wounds with much higher sensitivity

Is acetate metabolism a possible imaging marker for hypoxia-stimulating tumors?

Our previous study showed that acetate fixation into lipids is elevated in tumor cells: this characteristic underlies 11C-acetate PET of tumors. The pathway is considered to be driven by acetyl-CoA synthetase (Acss) converting acetate to acetyl-CoA. On the other hand, we found that tumor cells can also utilize a reverse reaction of Acss for ATP synthesis through acetate production, which resembles known pathway in ancient anaerobic organisms. These facts collectively point out that Acss manages both anabolism and catabolism of acetate coordinately in tumor cells.Additionally, we found that expression of Acss was increased significantly under hypoxia, which indicates that total activity of acetate metabolism is up-regulated in hypoxic tumor cells. In this study, to confirm the above supposition and propose acetate PET as a new tumor metabolic imaging, we examined the characteristics of tumor acetate uptake under hypoxia.We performed 14C-acetate uptake study using cultured mouse tumor cells in 24-well plates with fibroblast cells as control. Cells were incubated under normoxia for 24 h, then a part of them were treated by 2 h hypoxia. After preincubation, medium containing 1mu Ci 14C-acetate was added to each well and the cells were further incubated for 1 h under the same condition. After cell lyses, radioactivity was measured by a liquid scintillation counter. To verify the role of Acss, we also examined 14C-acetate uptake in Acss-knockdown tumor cells.Our data demonstrated that 14C-acetate uptake was higher under hypoxia than normoxia in tumor cells, but not in normal cells, and that knock down of Acss decreased 14C-acetate uptake in tumor cells. Based on these results, we concluded that tumor acetate metabolism mediated by Acss was up-regulated under hypoxia, which caused the increase of 14C-acetate uptake. These findings suggest a possibility that 11C-acetate PET is visualizing hypoxia-stimulated up-regulation of acetate metabolism in tumor cells.Joint Molecular Imaging Conferenc

Acceleration of tumor acetate uptake under hypoxia: A new perception of tumor imaging by acetate

Objectives: 11C-acetate PET is known as a useful tool for detecting various kinds of tumors. The acetate uptake in tumor cells is considered to be mediated by acetyl-CoA synthetase (Acss). On the other hand, our recent data showed that expression of Acss was up-regulated under hypoxia, which suggested that this enzyme plays important roles to control both anabolism and catabolism of acetate coordinately in tumor cells. In this study, we characterized tumor acetate uptake under hypoxia to propose a new perception of acetate tumor imaging. Methods: in vitro 14C-acetate uptake study was performed using four mouse tumor cell lines (lung carcinoma, melanoma, colon carcinoma, and mammary carcinoma) and a mouse fibroblast cell line as control. Cells were plated and incubated under normoxia for 24 h and some cells were treated by 2-6 h hypoxia, additionally. After the preincubation, medium containing 1 mu Ci 14C-acetate was added to each well of 24-well plates and respective cells were incubated for 1 h under the same condition. Then, medium was removed and cells were washed twice and lysed with 0.2N NaOH or processed by Bligh and Dyer extraction method to separate lipid- and water-soluble fractions. Radioactivity was measured by a liquid scintillation counter. The results were compared to Acss mRNA expression pattern. Results: 14C-acetate uptake was higher under hypoxia than normoxia in tumor cells, but not in normal cells. In tumor cell lines, ratio of 14C incorporation into lipid-soluble fraction to that into water-soluble fraction increased 2-3 times under hypoxia, compared to normoxia. The pattern of 14C-acetate uptake was correlated with that of Acss2 mRNA expression. Conclusions: As acetate metabolism catalyzed by Acss was up-regulated under hypoxia, incorporation of 14C-acetate increased in tumor cells. Most of the acetate taken up by tumor cells seemed to be consequently fixed into lipid-soluble fraction under hypoxia. These evidences suggest a possibility that 11C-acetate PET is visualizing hypoxic up-regulation of acetate metabolism in tumor cells.Society of nuclear medicine 54rd Annual Meetn