RESUMEN
The direct estimation of the value of the diffusion component of mass transfer of pollutants in arable soil horizons is an important task of scientific and applied importance. The values of effective diffusion coefficients of 60Co radionuclide (Deff) in water-saturated samples of different soils with disturbed structure and the same initial bulk density were obtained during the laboratory experiment. Of particular interest is the assessment of the contribution of individual specific characteristics of soils that have undergone the gleying process to the regulation of Deff60Co.There was noted a significant variability of Deff60Co for investigated soils due to different soil characteristics. To assess this, influence a statistical approach has been used, where edaphic factors representing the most important characteristics of the soils acted as independent variables (predictors), and the dependent (resulting) variable was Deff60Co. The contributions of each of the selected indicators of soils state (independent variables) in varying of Deff60Co were also identified. During the experiments, there was revealed a particularly strong increase in the Deff60Co for soils with a high Eh, ΣFr.<0.01 mm and decrease in the absolute value of the dependent variable with two predictors: pHH2O and P2O5mobile in conditions of excessive moisture. Based on the study of the dependence between the main physicochemical soil properties and the magnitude of effective diffusion coefficients (Deff60Co), the selected physicochemical characteristics of soils were ranked by the degree of influence on the value of the dependent variable: pHH2O > Eh > ΣFr.<0.01 mm > P2O5mobile > Corg.At the same time, the multiple linear regression analysis of the obtained data showed statistical significance for two independent predictors of the model (pHH2O and ΣFr.<0.01 mm). As a result, semi-partial determination coefficients responsible for the share of the total variation of the dependent variable due to the statistically significant corresponding independent variables (pHH2O and ΣFr.<0.01 mm) were calculated based on the data presented.
Asunto(s)
Radioisótopos de Cobalto/farmacocinética , Contaminantes Radiactivos/farmacocinética , Suelo/química , DifusiónRESUMEN
Gastrin-releasing peptide receptors (GRPRs) are promising targets in oligometastatic prostate cancer. We have recently used 55Co (T1/2 = 17.5 h) as a label for next day PET imaging of GRPR expression obtaining high imaging contrast. The radionuclide-chelator combination can significantly influence the biodistribution of radiopeptides. Therefore, in this study, we hypothesized that the properties of 55Co-labeled PEG2-RM26 can be improved by identifying the optimal macrocyclic chelator. All analogues (X-PEG2-RM26, X = NOTA,NODAGA,DOTA,DOTAGA) were successfully labeled with radiocobalt with high yields and demonstrated high stability. The radiopeptides bound specifically and with picomolar affinity to GRPR and their cellular processing was characterized by low internalization. The best binding capacity was found for DOTA-PEG2-RM26. Ex vivo biodistribution in PC-3 xenografted mice was characterized by rapid blood clearance via renal excretion. Tumor uptake was similar for all conjugates at 3 h pi, exceeding the uptake in all other organs. Higher kidney uptake and longer retention were associated with N-terminal negative charge (DOTAGA-containing conjugate). Tumor-to-organ ratios increased over time for all constructs, although significant chelator-dependent differences were observed. Concordant with affinity measurements, DOTA-analog had the best retention of activity in tumors, resulting in the highest tumor-to-blood ratio 24 h pi, which translated into high contrast PET/CT imaging (using 55Co).
Asunto(s)
Bombesina/farmacocinética , Radioisótopos de Cobalto/farmacocinética , Compuestos Macrocíclicos/química , Compuestos Organometálicos/química , Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/patología , Receptores de Bombesina/antagonistas & inhibidores , Animales , Apoptosis , Bombesina/análogos & derivados , Bombesina/farmacología , Proliferación Celular , Quelantes/química , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Neurotransmisores/química , Neurotransmisores/farmacocinética , Neurotransmisores/farmacología , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND AND MOTIVATION: While small molecules can be used in cancer diagnosis there is a need for imageable diagnostic NanoParticles (NPs) that act as surrogates for the therapeutic NPs. Many NPs are composed of hydrophobic materials so the challenge is to formulate hydrophobic imaging agents. To develop individualized medical treatments based on NP, a first step should be the selection of patients who are likely responders to the treatment as judged by imaging tumor accumulation of NPs. This requires NPs with the same size and structure as the subsequent therapeutic NPs but labelled with a long-lived radionuclide. Cobalt isotopes are good candidates for NP labelling since 55Co has half-life of 17.5â¯h and positron energy of 570â¯keV while 57Co (t1/2 271.6 d) is an isotope suited for preclinical single photon emission tomography (SPECT) to visualize biodistribution and pharmacokinetics of NPs. We used the hydrophobic octaethyl porphyrin (OEP) to chelate cobalt and to encapsulate it inside hydrophobic liquid NPs (LNPs). We hypothesized that at least two additional hydrophobic axial ligands (oleylamine, OA) must be provided to the OEP-Co complex in order to encapsulate and retain Co inside LNP. RESULTS: 1. Cobalt chelation by OEP and OA. The association constant of cobalt to OEP was 2.49â¯×â¯105 M-1 and the formation of the hexacoordinate complex OEP-Co-4OA was measured by spectroscopy. 2. NP formulation and characterization: LNPs were prepared by the fast ethanol injection method and were composed of a liquid core (triolein) surrounded by a lipid monolayer (DSPC:Cholesterol:DSPE-PEG2000). The size of the LNPs loaded with the cobalt complex was 40⯱â¯5â¯nm, 3. Encapsulation of OEP-Co-OA: The loading capacity of OEP-Co-OA in LNP was 5â¯mol%. 4. Retention of OEP-57Co-4OA complex in the LNPs: the positive effect of the OA ligands was demonstrated on the stability of the OEP-57Co-4OA complex, providing a half-life for retention in PBS of 170â¯h (7â¯days) while in the absence of the axial OA ligands was only 22â¯h. 5 Biodistribution Study: the in vivo biodistribution of LNP was studied in AR42J pancreatic tumor-bearing mice. The estimated half-life of LNPs in blood was about 7.2â¯h. Remarkably, the accumulation of LNPs in the tumor was as high as 9.4% ID/g 24â¯h after injection with a doubling time for tumor accumulation of 3.22â¯h. The most important result was that the nanoparticles could indeed accumulate in the AR42J tumors up to levels greater than those of other NPs previously measured in the same tumor model, and at about half the values reported for the molecular agent 57Co-DOTATATE. CONCLUSIONS: The additional hydrophobic chelator OA was indeed needed to obtain a stable octahedral OEP-Co-4OA. Cobalt was actually well-retained inside LNP in the OEP-Co-4OA complex. The method described in the present work for the core-labelling of LNPs with cobalt is now ready for labeling of NPs with 55Co, or indeed other hexadentate radionuclides of interest for preclinical in vivo PET-imaging and radio-therapeutics.
Asunto(s)
Aminas/análisis , Quelantes/análisis , Radioisótopos de Cobalto/análisis , Nanopartículas/análisis , Neoplasias/diagnóstico por imagen , Porfirinas/análisis , Tomografía Computarizada de Emisión de Fotón Único/métodos , Aminas/farmacocinética , Animales , Quelantes/farmacocinética , Radioisótopos de Cobalto/farmacocinética , Interacciones Hidrofóbicas e Hidrofílicas , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Porfirinas/farmacocinética , Distribución TisularRESUMEN
High gastrin releasing peptide receptor (GRPR) expression is associated with numerous cancers including prostate and breast cancer. The aim of the current study was to develop a 55Co-labeled PET agent based on GRPR antagonist RM26 for visualization of GRPR-expressing tumors. Labeling with 57Co and 55Co, stability, binding specificity, and in vitro and in vivo characteristics of 57Co-NOTA-PEG2-RM26 were studied. NOTA-PEG2-RM26 was successfully radiolabeled with 57Co and 55Co with high yields and demonstrated high stability. The radiopeptide showed retained binding specificity to GRPR in vitro and in vivo. 57Co-NOTA-PEG2-RM26 biodistribution in mice was characterized by rapid clearance of radioactivity from blood and normal non-GRPR-expressing organs and low hepatic uptake. The clearance was predominantly renal with a low degree of radioactivity reabsorption. Tumor-to-blood ratios were approximately 200 (3 h pi) and 1000 (24 h pi). The favorable biodistribution of cobalt-labeled NOTA-PEG2-RM26 translated into high contrast preclinical PET/CT (using 55Co) and SPECT/CT (using 57Co) images of PC-3 xenografts. The initial biological results suggest that 55Co-NOTA-PEG2-RM26 is a promising tracer for PET visualization of GRPR-expressing tumors.
Asunto(s)
Bombesina/antagonistas & inhibidores , Radioisótopos de Cobalto/farmacocinética , Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Receptores de Bombesina/antagonistas & inhibidores , Receptores de Bombesina/análisis , Animales , Xenoinjertos , Humanos , Masculino , Ratones , Receptores de Bombesina/metabolismo , Distribución TisularRESUMEN
This study investigated the human gastrointestinal uptake (f1) and subsequent whole-body retention of orally administered inorganic radioactive cobalt. Of eight adult volunteers aged between 24 and 68 years, seven were given solutions of (57)Co (T1/2 = 272 d) containing a stable cobalt carrier, and six were given carrier-free (58)Co (T1/2 = 71 d). The administered activities ranged between 25 and 103 kBq. The observed mean f1, based on 6 days accumulated urinary excretion sampling and whole-body counting, was 0.028 ± 0.0048 for carrier-free (58)Co, and 0.016 ± 0.0021 for carrier-associated (57)Co. These values were in reasonable agreement with values reported from previous studies involving a single intake of inorganic cobalt. The time pattern of the total retention (including residual cobalt in the GI tract) included a short-term component with a biological half-time of 0.71 ± 0.03 d (average ± 1 standard error of the mean for the two nuclides), an intermediate component with a mean half-time of 32 ± 8.5 d, and a long-term component (observed in two volunteers) with half-times ranging from 80 to 720 d for the two isotopes. From the present data we conclude that for the short-lived (57)Co and (58)Co, more than 95% of the internal absorbed dose was delivered within 7 days following oral intake, with a high individual variation influenced by the transit time of the unabsorbed cobalt through the gastro-intestinal tract.
Asunto(s)
Radioisótopos de Cobalto/farmacocinética , Cobalto/farmacocinética , Administración Oral , Adulto , Anciano , Isótopos de Cobalto/farmacocinética , Femenino , Absorción Gastrointestinal , Humanos , Masculino , Distribución Tisular , Adulto JovenRESUMEN
The focus of this article was to explore the translocation of (109)Cd, (57)Co, (65)Zn, (63)Ni, and (134)Cs via xylem and phloem in the newly found hyperaccumulator Solanum nigrum L. Two experiments with the uptake via the roots and transport of (109)Cd, (57)Co, and (65)Zn labeled by roots, and the redistribution of (109)Cd, (65)Zn, (57)Co, (63)Ni, and (134)Cs using flap label in S. nigrum in a hydroponic culture with a standard nutrient solution were conducted. The results showed that (109)Cd added for 24 h to the nutrient medium of young plants was rapidly taken up, transferred to the shoot, and accumulated in the cotyledons and the oldest leaves but was not efficiently redistributed within the shoot afterward leading to a rather low content in the fruits. In contrast, (57)Co was more slowly taken up and released to the shoot, but afterward, this element was redistributed from older leaves to younger leaves and maturing fruits. (65)Zn was rapidly taken up and transferred to the shoot (mainly to the youngest leaves and not to the cotyledons). Afterward, this radionuclide was redistributed within the shoot to the youngest organs and finally accumulated in the maturing fruits. After flap labeling, all five heavy metals tested ((109)Cd, (57)Co, (65)Zn, (63)Ni, (134)Cs) were exported from the labeled leaf and redistributed within the plant. The accumulation in the fruits was most pronounced for (63)Ni and (65)Zn, while a relatively high percentage of (57)Co was finally found in the roots. (134)Cs was roughly in the middle of them. The transport of (109)Cd differed from that previously reported for wheat or lupin and might be important for the potential of S. nigrum to hyperaccumulate cadmium.
Asunto(s)
Metales Pesados/farmacocinética , Solanum nigrum/metabolismo , Radioisótopos de Cadmio/metabolismo , Radioisótopos de Cesio/farmacocinética , Radioisótopos de Cobalto/farmacocinética , Hidroponía , Níquel/farmacocinética , Floema/metabolismo , Hojas de la Planta/metabolismo , Raíces de Plantas/metabolismo , Radioisótopos/farmacocinética , Xilema/metabolismo , Radioisótopos de Zinc/farmacocinéticaRESUMEN
The mechanistic understanding of nanotoxicity requires the physico-chemical characterisation of nanoparticles (NP), and their comparative investigation relative to the corresponding ions and microparticles (MP). Following this approach, the authors studied the dissolution, interaction with medium components, bioavailability in culture medium, uptake and intracellular distribution of radiolabelled Co forms (CoNP, CoMP and Co(2+)) in Balb/3T3 mouse fibroblasts. Co(2+) first saturates the binding sites of molecules in the extracellular milieu (e.g., albumin and histidine) and on the cell surface. Only after saturation, Co(2+) is actively uptaken. CoNP, instead, are predicted to be internalised by endocytosis. Dissolution of Co particles allows the formation of Co compounds (CoNP-rel), whose mechanism of cellular internalisation is unknown. Co uptake (ranking CoMP > CoNP > Co(2+)) reached maximum at 4 h. Once inside the cell, CoNP spread into the cytosol and organelles. Consequently, massive amounts of Co ions and CoNP-rel can reach subcellular compartments normally unexposed to Co(2+). This could explain the fact that the nuclear and mitochondrial Co concentrations resulted significantly higher than those obtained with Co(2+).
Asunto(s)
Radioisótopos de Cobalto/farmacocinética , Cobalto/farmacocinética , Espacio Intracelular/química , Espacio Intracelular/metabolismo , Nanopartículas del Metal/química , Células 3T3 , Animales , Cobalto/química , Radioisótopos de Cobalto/química , Medios de Cultivo/química , Medios de Cultivo/metabolismo , ADN/química , ADN/metabolismo , RatonesRESUMEN
Measurements for internal dose assessment are required to be conducted based on the distribution of radionuclides in the body, which may change depending on the lapsed time. In this study, a biokinetic analysis code, which can be used in practical radiation control is developed, and the results of (60)Co and (137)Cs biokinetics are visualised as examples by drawing the depositions for each organ and tissue in a figure of the body as a function of lapsed time. In addition, based on visualised biokinetics, precautions for in vivo measurements are also discussed. These discussions led to the conclusion that the information of visualised biokinetics is useful for actual measurements in practical radiation control.
Asunto(s)
Algoritmos , Radioisótopos de Cesio/farmacocinética , Radioisótopos de Cobalto/farmacocinética , Exposición a Riesgos Ambientales/análisis , Modelos Biológicos , Protección Radiológica/normas , Radioisótopos de Cesio/análisis , Radioisótopos de Cobalto/análisis , Simulación por Computador , Sistema Digestivo/efectos de la radiación , Humanos , Cinética , Efectividad Biológica Relativa , Sistema Respiratorio/efectos de la radiación , Distribución TisularRESUMEN
Cobalamin (Cbl) utilization as a cofactor for methionine synthase and methylmalonyl-CoA mutase is dependent on the transport of Cbl through lysosomes and its subsequent delivery to the cytosol and mitochondria. We speculated that neuropathological conditions that impair lysosomal function (e.g., age-related lipofuscinosis and specific neurodegenerative diseases) might impair lysosomal Cbl transport. To address this question, an appropriate method to quantify intracellular Cbl transport in neuronal cell types and brain tissue is required. Thus, we developed methods to measure [57Co] Cbl levels in lysosomes, mitochondria and cytosol obtained from in vitro and in vivo sources. Human SH-SY5Y neurons or HT1080 fibroblasts were labeled with [57Co] Cbl and homogenized using a ball-bearing homogenizer, and the lysates were separated into 10 fractions using ultracentrifugation in an OptiPrep density gradient. Lysosomes were recovered from the top of the gradient (fractions 1-5), which were clearly separated from mitochondria (fractions 7-9) on the basis of the expression of the marker proteins, LAMP2 and VDAC1. The isolated lysosomes were intact based on their colocalization with acid phosphatase activity. The lysosomal and mitochondrial fractions were free of the cytosolic markers beta-actin and methionine synthase. The relative distribution of [57Co] Cbl in both neurons and fibroblasts was as follows: 6% in the lysosomes, 14% in the mitochondria and 80% in the cytosol. This technique was also used to fractionate organelles from mouse brain, where marker proteins were detected in the gradient at positions similar to those observed for the cell lines, and the relative distribution of [57Co] Cbl was as follows: 12% in the lysosomes, 15% in the mitochondria and 73% in the cytosol. These methods provide a useful tool for the investigation of intracellular Cbl trafficking in a neurobiological setting.
Asunto(s)
Encéfalo/metabolismo , Neuronas/metabolismo , Fracciones Subcelulares/metabolismo , Vitamina B 12/farmacocinética , Animales , Línea Celular , Radioisótopos de Cobalto/farmacocinética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Radiofármacos/farmacocinética , Distribución TisularRESUMEN
The efficiency calibration of whole-body counters (WBCs) for monitoring of internal contaminations is usually performed with anthropomorphic physical phantoms assuming homogeneous activity distribution. Besides the inherent limitations of these phantoms in resembling the human anatomy, they do not represent a realistic activity distribution, since in real situations each incorporated radionuclide has its particular biodistribution after entering the systemic circulation. Moreover, the activity content in the different organs and tissues comprising the biokinetics is time dependent. This work aims at assessing the whole-body counting efficiency deviations arising from considering a detailed voxel phantom instead of a standard physical phantom (BOMAB) and at evaluating the effect of the anatomical differences between both phantoms. It also aims at studying the efficiency considering the biodistribution of a set of radionuclides of interest incorporated in the scope of environmental and occupational exposures (inhalation and ingestion) and at computing the time-dependent efficiency correction factors to account for the biodistribution variation over time. For the purpose, Monte Carlo (MC) simulations were performed to simulate the whole-body counting efficiencies and biokinetic models were used to estimate the radionuclides' biokinetic behaviour in the human body after intake. The comparison between the efficiencies obtained with BOMAB and the voxel phantom showed deviations between 1.8 and 11.7 %, proving the adequacy of the BOMAB for WBC calibration. The obtained correction factors show that the effect of the biodistribution in the whole-body counting efficiency is more pronounced in cases of acute activity uptake and long-term retention in certain organs than in cases of homogeneous distribution in body tissues, for which the biokinetics influence can be neglected. This work further proves the powerful combination of MC simulation methods using voxel phantoms and biokinetic models for internal dosimetry studies.
Asunto(s)
Radioisótopos de Cesio/farmacocinética , Radioisótopos de Cobalto/farmacocinética , Fantasmas de Imagen , Monitoreo de Radiación , Recuento Corporal Total/métodos , Simulación por Computador , Humanos , Cinética , Masculino , Método de Montecarlo , Dosis de Radiación , Protección Radiológica , Distribución TisularRESUMEN
LBERI, a member of the Medical Countermeasures to Radiologic Threats (MCART) consortium funded by NIAID, was tasked to develop biokinetic models for the distribution of radionuclide threats using the most likely routes of incorporation in both small and large animals. In this paper, the biokinetics of systemically administered soluble (60)Co have been examined. Male and female jugular-vein-catheterized (JVC) F344 rats received intravenous (IV) doses of 11.2 kBq of (60)CoCl2. The distribution of the radiocobalt was followed for 28 d with tissue sampling done at 1 and 4 h, and at 1, 2, 4, 8, 16, and 28 d. Urine and feces were collected daily. Tissues and excreta were analyzed by gamma pulse height analysis. Within 8 d, 93% of the cobalt was eliminated from the body, primarily though urine. The highest tissue burdens were found in the liver, gastrointestinal (GI) tract, and muscle shortly after administration. These tissues cleared quickly, so that by the conclusion of the 28-d study, less than 3% of the injected dose remained in the body. The results are comparable to published literature values for tissue content of (60)Co and for excretion patterns up to 30 d after injection. These results will provide the data needed to construct a biokinetic model for the unperturbed biokinetics of (60)Co in rats, which will subsequently be used to evaluate the impact of administered decorporating agents on organ radiation doses. The animal model described in this paper is representative of that used for other routes of radionuclide administration, such as inhalation, ingestion, and wound contamination, that have been studied at LBERI in support of the MCART and NIAID programs.
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Radioisótopos de Cobalto/efectos adversos , Radioisótopos de Cobalto/farmacocinética , Traumatismos Experimentales por Radiación/etiología , Traumatismos Experimentales por Radiación/metabolismo , Recuento Corporal Total , Animales , Descontaminación/métodos , Femenino , Humanos , Masculino , Tasa de Depuración Metabólica , Especificidad de Órganos , Dosis de Radiación , Traumatismos Experimentales por Radiación/prevención & control , Ratas , Ratas Endogámicas F344 , Distribución TisularRESUMEN
The terrorist use of a radiological dispersal device (RDD) has been described as "not if, but when" (). Exposures from such an event could occur by a number of routes including inhalation, wound contamination, or embedded fragments. Several of the radionuclides thought to be potential RDD components are metals or ceramic material. The use of such material would increase the potential for wounds from embedded fragments of radioactive material. To date, most research in this area has focused on inhalation exposures, while the consequence of embedded fragment exposure has not been investigated. This study modified a previously used rodent model in order to determine the biokinetics of intramuscularly implanted nonradioactive surrogate RDD material. Cobalt, iridium, or strontium titanate was embedded into the gastrocnemius muscle of Sprague Dawley rats. The rats were euthanized at 1, 3, or 6 mo post-implantation. Tissue metal analysis showed that iridium did not solubilize from the implanted pellet, while cobalt and strontium did so rapidly. Cobalt was found in all tissues analyzed, but it was localized mainly to kidney and liver as well as being excreted in the urine. Strontium was found in lung, liver, and spleen, as well as being deposited in bone. However, the greatest strontium concentrations were found in the popliteal lymph nodes, the lymph nodes responsible for draining the area of the gastrocnemius. These results indicate that, depending upon the material, a variety of treatment strategies will be needed when dealing with embedded fragment wounds from a radiological dispersal device event.
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Metales Pesados/farmacocinética , Radioisótopos/farmacocinética , Animales , Radioisótopos de Cobalto/farmacocinética , Radioisótopos de Iridio/farmacocinética , Masculino , Metales Pesados/toxicidad , Músculo Esquelético/metabolismo , Ratas , Ratas Sprague-Dawley , Radioisótopos de Estroncio/farmacocinética , Terrorismo , Distribución TisularRESUMEN
Although the presence of manufactured nanoparticles in the aquatic environment is still largely undocumented, their release could certainly occur in the future, particularly via municipal treatment plant effluents of cities supporting nano-industries. To get an initial estimate of the environmental behavior of nanomaterials, we investigated the distribution and accumulation of ceria nanoparticles in simulated aquatic ecosystems which included aquatic plant, shellfish, fish, water, and sediment using a radiotracer technique. Radioactive ceria (141CeO2) nanoparticles with a diameter of ca. 7 nm were synthesized by a precipitation method and added to the simulated aquatic ecosystems. The results indicate that the concentration of ceria nanoparticles in water decreased to a steady-state value after 3 days; meanwhile, the concentrations of ceria nanoparticles in the aquatic plant and sediment increased to their highest values. The distribution and accumulation characteristics of ceria nanoparticles in various aquatic organisms were different. Ceratophyllum demersum showed a high ability of accumulation of ceria nanoparticles from water.
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Organismos Acuáticos/metabolismo , Cerio/farmacocinética , Radioisótopos de Cobalto/farmacocinética , Sedimentos Geológicos/química , Nanopartículas del Metal/química , Organismos Acuáticos/química , Disponibilidad Biológica , Cerio/química , Radioisótopos de Cobalto/química , Ecosistema , Microscopía Electrónica de Transmisión , Modelos Biológicos , Tamaño de la PartículaRESUMEN
The acknowledged risk of deliberate release of radionuclides into local environments by terrorist activities has prompted a drive to improve novel materials and methods for removing internally deposited radionuclides. These decorporation treatments will also benefit workers in the nuclear industry, should an exposure occur. Cuprimine and Syprine are oral therapeutics based on the active ingredients D-penicillamine and N,N'-bis-(2-aminoethyl)-1,2-ethanediamine dihydrochloride, respectively. These therapeutic drugs have been used for several decades to treat Wilson's disease, a genetic defect leading to copper overload, by chelation and accelerated excretion of internally deposited copper. Studies were undertaken to evaluate these FDA-approved drugs for the in vivo decorporation of radioactive cobalt (Co) and polonium (Po) using male Wistar-Han rats. In these studies, Co or Po was administered to animals by IV injection, followed by oral gavage doses of either Cuprimine or Syprine. Control animals received the radionuclide alone. For Co studies, animals received a single dose of Cuprimine or Syprine, while for Po studies animals were repeatedly dosed at 24-h intervals for a total of 5 doses. Results show that Syprine significantly increased urinary elimination and skeletal concentrations of Co compared to controls. While Cuprimine had little effect on total excretion of Co, the skeletal, kidney, liver, muscle, and stomach tissues had significantly lower radioactivity compared to control animals. The low overall excretion of Po made it difficult to reliably measure urinary or fecal radioactivity and draw a definitive conclusion on the effect of Cuprimine or Syprine treatment on excretion. However, Cuprimine treatment was effective at reducing spleen levels of Po compared to controls. Similarly, Syprine treatment produced statistically significant reductions of Po in the spleen and skeletal tissues compared to control animals. Based on these promising findings, further studies to evaluate the dose-response pharmacokinetic profiles for decorporation are warranted.
Asunto(s)
Radioisótopos de Cobalto/aislamiento & purificación , Penicilamina/química , Penicilamina/farmacología , Polonio/química , Polonio/aislamiento & purificación , Trientina/química , Trientina/farmacología , Animales , Quelantes/administración & dosificación , Quelantes/química , Quelantes/farmacología , Radioisótopos de Cobalto/química , Radioisótopos de Cobalto/farmacocinética , Humanos , Masculino , Penicilamina/administración & dosificación , Polonio/farmacocinética , Ratas , Ratas Wistar , Distribución Tisular , Trientina/administración & dosificaciónRESUMEN
This report provides a comparison of the oral decorporation efficacy of L-glutathione (GSH), L-cysteine (Cys), and a liposomal GSH formulation (ReadiSorb) toward systemic (60)Co to that observed following intravenous administration of GSH and Cys in F344 rats. Aminoacid L-histidine (His) containing no thiol functionality was tested intravenously to compare in vivo efficacy of the aminothiol (GSH, Cys) chelators with that of the aminoimidazole (His) chelator. In these studies, (60)Co was administered to animals by intravenous injection, followed by intravenous or oral gavage doses of a chelator repeated at 24-h intervals for a total of 5 doses. The results suggest that GSH and Cys are potent decorporation agents for (60)Co in the rat model, although the efficacy of treatment depends largely on the systemic availability of the chelator. The intravenous route of administration of GSH or Cys was most effective in reducing tissue (60)Co levels and in increasing excretion of radioactivity compared to control animals. Liposomal encapsulation was found to markedly enhance the oral bioavailability of GSH compared to non-formulated GSH. The oral administration of liposomal GSH reduced (60)Co levels in nearly all tissues by 12-43% compared to that observed for non-formulated GSH. Efficacy of oral Cys was only slightly reduced in comparison with intravenous Cys. Further studies to optimize the dosing regimen in order to maximize decorporation efficiency are warranted.
Asunto(s)
Radioisótopos de Cobalto/farmacocinética , Radioisótopos de Cobalto/toxicidad , Cisteína/administración & dosificación , Glutatión/administración & dosificación , Administración Oral , Animales , Antídotos/administración & dosificación , Quelantes/administración & dosificación , Quelantes/metabolismo , Radioisótopos de Cobalto/administración & dosificación , Cisteína/metabolismo , Glutatión/metabolismo , Histidina/metabolismo , Inyecciones Intravenosas , Liposomas , Masculino , Tasa de Depuración Metabólica/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Receptores de Superficie Celular/metabolismo , Terrorismo , Distribución TisularRESUMEN
With the increased threat of terrorist release of radioactive materials, there is a need for non-toxic decorporation agents to treat internal contamination with radionuclides. In this study, low molecular weight chitosan was evaluated for decorporation of radioactive cobalt (60Co). The affinity of chitosan for Co(II) was tested in vitro using spectrophotometric and potentiometric titration techniques. For in vivo studies, the effect of chitosan on ingested 60Co was evaluated using F344 rats administered a single dose followed by oral chitosan. Chitosan was also evaluated for systemic decorporation of 60Co following intravenous injection with repeated chitosan administration over 5 d. Control animals received 60Co without chelation treatment. Excreta and tissues were collected for analysis using gamma-counting techniques. Results from in vitro experiments confirmed the binding of Co(II) to chitosan, with the postulated formation of a mixed cobalt-chitosan-hydroxide complex species; a stability constant was calculated for this complex. For in vivo studies, oral administration of chitosan significantly reduced systemic absorption of orally administered 60Co as evidenced by an increase in fecal elimination and decrease in urinary elimination. However, oral administration of chitosan lactate slightly decreased fecal excretion of 60Co. Further, oral administration of chitosan significantly reduced 60Co levels in kidney, liver, and skeleton compared to control animals receiving 60Co alone. By the i.v. route, chitosan slightly reduced levels of 60Co in tissues compared to controls, although statistically significant reductions were only observed for blood and kidney. Overall, this commercially available chitosan oligosaccharide exhibited promising potential; further studies are warranted to evaluate the optimal dosing regimen and chemical modifications to increase effectiveness.
Asunto(s)
Quelantes/administración & dosificación , Quitosano/administración & dosificación , Radioisótopos de Cobalto/farmacocinética , Administración Oral , Animales , Huesos/metabolismo , Heces , Inyecciones Intravenosas , Absorción Intestinal , Riñón/metabolismo , Hígado/metabolismo , Masculino , Tasa de Depuración Metabólica , Ratas , Ratas Endogámicas F344 , Distribución TisularRESUMEN
Somatostatin-based radioligands have been shown to have sensitive imaging properties for neuroendocrine tumours and their metastases. The potential of [(55)Co(dotatoc)] (dotatoc =4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane-1-ylacetyl-D-Phe-(Cys-Tyr-D-Trp-Lys-Thr-Cys)-threoninol (disulfide bond)) as a new radiopharmaceutical agent for PET has been evaluated. (57)Co was used as a surrogate of the positron emitter (55)Co and the pharmacokinetics of [(57)Co(dotatoc)] were investigated by using two nude mouse models. The somatostatin receptor subtype (sst1-sst5) affinity profile of [(nat)Co(dotatoc)] on membranes transfected with human somatostatin receptor subtypes was assessed by using autoradiographic methods. These studies revealed that [(57)Co(dotatoc)] is an sst2-specific radiopeptide which presents the highest affinity ever found for the sst2 receptor subtype. The rate of internalisation into the AR4-2J cell line also was the highest found for any somatostatin-based radiopeptide. Biodistribution studies, performed in nude mice bearing an AR4-2J tumour or a transfected HEK-sst2 cell-based tumour, showed high and specific uptake in the tumour and in other sst-receptor-expressing tissues, which reflects the high receptor binding affinity and the high rate of internalisation. The pharmacologic differences between [(57)Co(dotatoc)] and [(67)Ga(dotatoc)] are discussed in terms of the structural parameters found for the chelate models [Co(II)(dota)](2-) and [Ga(III)(dota)](-) whose X-ray structures have been determined. Both chelates show six-fold coordination in pseudo-octahedral arrangements.
Asunto(s)
Quelantes , Radioisótopos de Cobalto , Neoplasias/diagnóstico por imagen , Compuestos Organometálicos , Radiofármacos , Somatostatina/análogos & derivados , Animales , Quelantes/química , Quelantes/farmacocinética , Radioisótopos de Cobalto/química , Radioisótopos de Cobalto/farmacocinética , Cristalografía por Rayos X , Humanos , Marcaje Isotópico , Cinética , Ligandos , Ratones , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacocinética , Ensayo de Unión Radioligante , Cintigrafía , Radiofármacos/química , Radiofármacos/farmacocinética , Ratas , Sensibilidad y Especificidad , Somatostatina/química , Termodinámica , Distribución Tisular , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This paper reviews information on the biological behavior of inorganic cobalt in humans and laboratory animals and proposes a model of the systemic biokinetics of inorganic cobalt in adult humans. The model was developed as part of an effort to update the models of the International Commission on Radiological Protection (ICRP) for addressing intakes of radionuclides by workers but is also applicable to environmental or medical exposures to inorganic forms of radiocobalt. The model can be used in conjunction with any respiratory, gastrointestinal, or wound model that provides predictions of the time-dependent feed of cobalt to blood. In contrast to the ICRP's current systemic model for cobalt, which is a simple open catenary system, the proposed model is constructed within a physiologically realistic framework that depicts recycling of cobalt between blood and tissues and transfer from blood to excretion pathways. Compared with the ICRP's current model, the proposed model yields similar predictions of whole-body retention but substantially different predictions of the systemic distribution of cobalt as a function of time after uptake to blood.
Asunto(s)
Radioisótopos de Cobalto/farmacocinética , Cobalto/farmacocinética , Modelos Biológicos , Exposición Profesional/análisis , Animales , Cobalto/sangre , Radioisótopos de Cobalto/sangre , Humanos , Especificidad de la Especie , Distribución TisularRESUMEN
On leaving the irradiated fuel bay at Pickering A nuclear power station, a worker triggered a whole body monitor alarm with activity in or on his head, and despite careful decontamination techniques he subsequently swallowed a hot particle. Over the next 3 d, the radioactivity was tracked through the body. It was then excreted in a single faecal sample and recovered for physical and radiochemical analysis. This analysis demonstrated that the particle contained 330 kBq of 60Co and only traces of other radioactivity. Its dimensions were approximately 50-130 microm and its composition was consistent with that of Stellite 6. A dose assessment was carried out taking into account the residence time of the particle in the mouth and its transit through the body. The estimated committed effective dose was 1.4 mSv, and the equivalent dose to the maximally exposed 1 cm2 of skin, 81 mSv.
Asunto(s)
Radioisótopos de Cobalto/análisis , Radioisótopos de Cobalto/farmacocinética , Modelos Biológicos , Exposición Profesional/análisis , Radiometría/métodos , Recuento Corporal Total , Carga Corporal (Radioterapia) , Canadá , Radioisótopos de Cobalto/química , Simulación por Computador , Humanos , Reactores Nucleares , Especificidad de Órganos , Tamaño de la Partícula , Dosis de Radiación , Efectividad Biológica Relativa , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Intakes and doses are assessed for seven workers who accidentally inhaled particles containing Co in the same incident. Comprehensive whole body data to 15 y, and some early urine and fecal data, are available for each individual. The biokinetic and dosimetric models currently recommended by ICRP have been used to assess these cases. It was not possible to obtain good fits to the data using the ICRP models with their default parameter values. However, good fits to all the measurement data were obtained by varying parameter values following a procedure similar to that recommended in recently developed guidelines for assessment of internal doses from monitoring data. It was found that retention in the lungs was much longer than predicted by the ICRP Human Respiratory Tract Model, and so for each case it was necessary to reduce the particle transport clearance of material from the deep lungs. This reduction in lung clearance rates, and the use of specific AMAD values, were the dominating factors in changing assessed doses from those calculated using ICRP default values.