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PubMedDate not supplied

Radiochemical investigations of [188Re(H2O)(CO)3-diaminopropionic acid-SSS-bombesin(7-14)NH2]: syntheses, radiolabeling and in vitro/in vivo GRP receptor targeting studies.

BACKGROUND: Bombesin (BBN), a 14 amino acid peptide, is an analogue of human gastrin-releasing peptide (GRP) that binds to GRP receptors (GRPr) with high affinity and specificity. The GRPr is over-expressed on a variety of human cancer cells including prostate, breast, lung, and pancreatic cancers. The specific aim of this study was to develop a 188Re(I)-radiolabeled BBN analogue that maintains high specificity for the GRPr in vivo. MATERIALS AND METHODS: A preselected synthetic sequence via solid phase peptide synthesis (SPPS) was designed to produce a Dpr-BBN (Dpr = Diaminopropionic acid) conjugate with the following general structure: Dpr-X-Q-W-A-V-G-H-L-M-(NH2), where the spacer group, X = Serylserylserine. The new BBN-construct was purified by reversed phase-HPLC (RP-HPLC). The non-radioactive Re(I)-BBN conjugate was prepared by the reaction of [Re(Br)3(CO)3]2- and Dpr-SSS-bombesin(7-14)NH2 with heating. ES-MS was used to determine the molecular constitution of the non-metallated and metallated Re (I)--conjugates. The 188 Re-conjugate was prepared at the tracer level by the pre-conjugation, postlabeling approach from the reaction of [188Re(H2O)3(CO)3]+ and corresponding ligand. RESULTS: The 188Re- and non-radioactive Re(I)conjugate behaved similarly under identical RP-HPLC conditions. In vitro cell displacement assays showed that the new conjugate has an IC50 value of approximately 1 nM. In vitro cell binding assays showed that the new conjugate is rapidly internalized and exhibits long-term retention, demonstrating the agonistic efficacy of the radiolabel. In vivo targeting of human prostate, PC-3 tumor xenografts indicated uptake and retention of the new radioconjugate for time-point < or = 24 hours. CONCLUSION: Results from in vitro and in vivo models demonstrated the ability of these derivatives to specifically target GRP receptors on human, prostate and cancerous PC-3 cells. This new construct holds potential for the development of a therapeutic entity for the treatment of prostate cancer.

Animals↗
PubMed2002

Electrophilic chelating agents for irreversible binding of metal chelates to engineered antibodies.

Radiolabeled monoclonal antibodies are widely used in the detection and treatment of cancer. However, several problems still prevent full clinical exploitation of these reagents. Low tumor/background ratios in radioimmunoscintigraphy and high background radioactivity in therapy are the foremost among these. The strategy of pretargeting which separates the tumor-targeting step from radiolocalization step may overcome these limitations. One pretargeting approach, based on the streptavidin-biotin system, has been demonstrated to successfully treat cancer in preclinical models (Proc. Natl. Acad. Sci. 97 (2000) 1802). In this report we describe the synthesis of several electrophilic chelates, designed for use in vivo. In this new pretargeting approach, we have used protein engineering to prepare an antibody that can bind selectively and irreversibly to certain of these metal chelates. This improves upon approaches based on the immunogenic protein streptavidin and the endogenous ligand biotin.

Animals↗
PubMed1996

Thermodynamic approach to the selection of polyuronide sequestrants for preventive and medicinal nutrition.

An approach to the analysis of isotherms of cooperative binding is developed that allows to calculate approximately affinity profiles, i.e. dependencies of binding constants on binding densities. The comparison of the affinity profiles of the interactions of Ca2+ and Sr2+ ions with sodium pectate as well as sodium alginates with the different content of the blocks of alpha-L-guluronic acid residues (GG-blocks) and blocks of mixed composition showed that (1) pectate has higher affinity to both ions as compared with alginates; (2) the affinity of pectate to Ca2+ ions is comparable to its affinity to Sr2+ ions but in the case of Ca2+ ions the maximum of the affinity profile falls on the substantially lesser value of the binding density in comparison to Sr2+ ions that seems to be unfavorable from the standpoint of the use of this polyuronide in preventive or medicinal nutrition; (3) the affinity of both alginates to Sr2+ ions at relatively low binding densities exceeds their affinity to Ca2+ ions; (4) the affinity of alginates to Sr2+ ions increases with the increase in the content of GG-blocks, whereas the affinity to Ca2+ ions practically does not depend on the composition of the alginate; (5) the maximum binding density of Sr2+ ions to the alginates approximately corresponds to the content of GG-blocks. These results corroborate the practice of the use of alginates rich in residues of alpha-L-guluronic acid for the removal of radioactive strontium from the digestive tract. The binding constants of Pb2+ ions to pectate over a wide range of binding densities are more than an order of magnitude greater than those of alkali-earth metal ions.

Alginates↗
PubMed2001

Separation of metal ions by capillary electrophoresis--diversity, advantages, and drawbacks of detection methods.

Capillary electrophoresis (CE) has been applied to metal-ion analysis during the last 10 years. To improve sensitivity and selectivity different modes of detection have been adapted or developed. The selection of commercially available detection systems for metal-ion analysis is still primarily limited to UV-Vis detection, although other commercial systems, e.g. fluorescence, conductivity, or interfaces for coupling to mass spectrometry (MS) or inductively coupled plasma mass spectrometry (ICP-MS) are becoming available. High demands are made on any detector used in CE, because the analytical signal has to be extracted from less than 1 nL of sample, which corresponds to a total amount of < or = 10(-12) to 10(-15) mol analyte. This paper compares currently available and recently developed detection methods for CE as applied to the analysis of metal ions. Commercially available techniques, for example UV-Vis, fluorescence, or mass spectrometry, and other new detection methods including electrochemistry, radioactivity, and XRF, are discussed and future trends are anticipated.

Journal Article↗
PubMed1990

Purification to homogeneity and properties of mannosidase II from mung bean seedlings.

Mannosidase II was purified from mung bean seedlings to apparent homogeneity by using a combination of techniques including DEAE-cellulose and hydroxyapatite chromatography, gel filtration, lectin affinity chromatography, and preparative gel electrophoresis. The release of radioactive mannose from GlcNAc[3H]Man5GlcNAc was linear with time and protein concentration with the purified protein, did not show any metal ion requirement, and had a pH optimum of 6.0. The purified enzyme showed a single band on SDS gels that migrated with the Mr 125K standard. The enzyme was very active on GlcNAcMan5GlcNAc but had no activity toward Man5GlcNAc, Man9GlcNAc, Glc3Man9GlcNAc, or other high-mannose oligosaccharides. It did show slight activity toward Man3GlcNAc. The first product of the reaction of enzyme with GlcNAcMan5GlcNAc, i.e., GlcNAcMan4GlcNAc, was isolated by gel filtration and subjected to digestion with endoglucosaminidase H to determine which mannose residue had been removed. This GlcNAcMan4GlcNAc was about 60% susceptible to Endo H indicating that the mannosidase II preferred to remove the alpha 1,6-linked mannose first, but 40% of the time removed the alpha 1,3-linked mannose first. The final product of the reaction, GlcNAcMan3GlcNAc, was characterized by gel filtration and various enzymatic digestions. Mannosidase II was very strongly inhibited by swainsonine and less strongly by 1,4-dideoxy-1,4-imino-D-mannitol. It was not inhibited by deoxymannojirimycin.

1-Deoxynojirimycin↗
PubMed1987

Paramagnetic complexes of manganese(II), iron(III), and gadolinium(III) as contrast agents for magnetic resonance imaging. The influence of stability constants on the biodistribution of radioactive aminopolycarboxylate complexes.

Paramagnetic complexes of manganese(II), iron(III), and gadolinium(III) with many ligands appear to undergo ligand substitution in vivo, producing biodistribution data similar to the hydrated metal ions. To identify ligands likely to be valuable in the preparation of paramagnetic contrast agents, a series of aminopolycarboxylate complexes with stability constants increasing in the order iminodiacetic acid (IDA) less than nitrilotriacetic acid (NTA) less than EDTA less than CDTA less than or equal to DTPA was prepared with 54Mn(II), 59Fe(III), and 153Gd(III) at both tracer and carrier levels. Biodistribution studies in mice suggested that complexes remained unchanged in vivo if their stability constants (K1) were approximately greater than 10(16) for Mn(II) and Gd(III) and greater than 10(22) for Fe(III) complexes at tracer levels. Metal complexes with added carrier appeared to be effectively more stable in vivo, possibly due to dissociation and saturation of metal-binding sites. To avoid the accumulation of metal ions in tissues, new paramagnetic contrast agents containing these metal ions will require stability constants equal to or greater than those identified here.

Animals↗
PubMed1987

[Whole-body transmission scintigraphy using a line source].

Transmission scanning was proposed to be a useful adjunct to conventional emission scanning for accurately keying radionuclide deposition to radiographic anatomy. After introduction of a scintillation camera, transmission whole-body scintigraphy using a flood source has been performed in a patient with differentiated thyroid carcinoma. Recently immunoscintigraphy with radiolabeled monoclonal anti-tumor antibodies has become popular and transmission whole-body scintigraphy has been re-evaluated to make diagnosis for laterality of metastases. However, there are several problems to handle a flood source for preparation and shielding. We developed a special line source for transmission whole-body scintigraphy. The line source is composed of a plastic tube (inner diameter: 3 mm) with three-way stop in a U-shaped metal. There are several advantages to use this line source as compared to a flood one; (1) a small volume of radioactive solution (less than 5 ml), (2) easy preparation and setting, and (3) less radiation. Moreover good quality of transmission image is obtained using this line source.

Humans↗
PubMed1999

Chromosomal aberrations and sister-chromatid exchanges in Lithuanian populations: effects of occupational and environmental exposures.

Cytogenetic analysis of chromosomal aberrations (CA) in 175,229 cells from 1113 individuals, both unexposed and occupationally or environmentally exposed to heavy metals (mercury and lead), organic (styrene, formaldehyde, phenol and benzo(a)pyrene) and inorganic (sulfur and nitrogen oxides, hydrogen and ammonium fluorides) volatile substances and/or ionizing radiation was performed. In addition, 11,250 cells from 225 individuals were scored for the frequency of sister-chromatid exchanges (SCE). Increased frequencies of CA were found in all occupationally exposed groups. A principal difference between the exposure to heavy metals and organic substances was found: increase in the CA frequency was dependent on duration of exposure to mercury but not dependent on duration of exposure to styrene, formaldehyde and phenol. A higher CA incidence was found in lymphocytes of children living in the vicinity of a plant manufacturing phosphate fertilizers. This indicates that children are a sensitive study group for the assessment of environmental exposure. However, the results of SCE analysis in these children were inconclusive. Exposure to ionizing radiation was found to cause chromosome breaks and chromatid exchanges in Chernobyl clean-up workers and chromatid breaks, chromatid exchanges, dicentric chromosomes and chromosome translocations in workers from the Ignalina Nuclear Power Plant. The increased frequency of chromatid exchanges in individuals exposed to ionizing radiation was quite unexpected. This may be attributed to the action of some unrecognized life-style or occupational factors, or to be a result of radiation-induced genomic instability. Also an increased SCE frequency was found in lymphocytes of Chernobyl clean-up workers.

Adolescent↗
PubMed1987

Antibodies labeled with metallic radionuclides: influence of nuclide chemistry on dose distribution.

An antibody with human CEA specificity has been labeled with either yttrium-90, scandium-47, or indium-111, via a diethylenetriamine pentaacetic acid (DTPA) link covalently bound to the protein. The clearance of these proteins from the blood of mice can be described by a single exponential; the half-life decreases in the order indium-111 greater than yttrium-90 greater than scandium-47. Associated with the blood clearance is an uptake of radioactivity into the liver; scandium-47 has the highest concentration, indium-111 has the least, and yttrium-90 is intermediate. There is no correlation between these results and the equilibrium stability constants of the metals with DTPA-like ligands. The results obtained show that, in vivo, scandium-47 and yttrium-90 are more easily displaced from DTPA by other ions than is indium-111. They also show that free DTPA is able to extract yttrium-90 and scandium-47, but not indium-111, from the liver of treated animals, indicating that indium-111 is resistant to ligand exchange reactions in vivo. These data indicate that 1) the equilibrium stability constant is not a good indicator of the in vivo stability of metal-labeled proteins and 2) it is possible to manipulate the ion distribution and therefore the dose from scandium-47 and yttrium-90 after injection of the labeled proteins.

Animals↗
PubMed2005

Genotoxicity and cytotoxicity assay of water sampled from the underground nuclear explosion site in the north of the Perm region (Russia).

The results of our study revealed a local biologically relevant surface water contamination in the radionuclide anomaly in the north of Russia (Perm region) by means of Allium schoenoprasum L. anaphase-telophase chromosome aberration assay. This radionuclide anomaly was formed in 1971 as a result of an underground nuclear explosion with soil excavation. Specific activities of main dose-forming radionuclides in all examined reservoirs are below intervention levels officially adopted in Russia for drinking water. We found that (90)Sr significantly contributes to induction of cytogenetic disturbances. Our previous data and the data described here suggest that metal and radionuclide combined exposure (with the dose below permissible exposure limits for human) may cause substantial biological effects. These effects are in part due to synergic response. The findings described here indicated that development of a new concept of radiation protection for humans and biota should be based on the clear understanding of biological effects of low doses of radiation in chronic exposure to multi-pollutant mixtures.

Cesium Radioisotopes↗
PubMed2001

Distribution of organic carbon, selected stable elements and artificial radionuclides among dissolved, colloidal and particulate phases in the Rhône River (France): preliminary results.

The behaviour of radionuclides discharged from nuclear facilities in the Rhône River depends on their distribution among the dissolved, colloidal and particulate phases. A large water sample was fractionated using sequential ultrafiltration. Size distributions of organic carbon, Fe, Al, Si, Ca, Mg, Cu, Zn, 137Cs, 60Co and 106Ru were obtained. Our results show that organic colloids account for 11% of the total organic carbon content. Approximately 20% of the dissolved (< 450 nm) Fe and Al are in colloidal classes. 137Cs is not significantly transferred by the colloidal phase while 25% of 60Co or 106Ru is associated with organic and inorganic colloids.

Carbon↗
PubMed1991

Biodistribution and tumor uptake of [67Ga]chlorogallium-tetraoctadecyloxy phthalocyanine and its sulfonation products in tumor bearing C3H mice.

To evaluate the biodistribution and tumor uptake of chlorogallium tetraoctadecycloxy phthalocyanine, a potential new drug for the photodynamic therapy of cancer, we prepared the radioactive 67Ga-labeled complex and its water soluble sulfonated derivative. The non-sulfonated dye was obtained by condensation of octadecyloxyphthalonitrile in the presence of a mixture of 67Ga and 69Ga chloride. The sulfonated derivative was obtained by treatment of the condensation product with oleum. As singlet molecular oxygen has been implicated in the photodynamic action of phthalocyanines (Pcs), the quantum yield of singlet oxygen (phi delta) was evaluated for chlorogallium tetraoctadecyloxy Pc, and also its zinc, aluminum and metal free analogues. After intraperitoneal administration of the non-sulfonated dye into RIF tumor bearing C3H mice, a very high 67Ga-uptake was observed in the spleen, while tumor radioactivity remained low during the 3 day study. The in vivo stability of the 67Ga-phthalocyanine complex was confirmed by comparing the distribution pattern with that of 67Ga-citrate, which proved to be significantly different. Intravenous injection of the sulfonated dye resulted in an overall lowering of 67Ga-uptake by most tissues, particularly in the spleen, while tumor radioactivities were slightly higher. These data suggest that amphiphilic photosensitizers, containing both polar sulfonate groups and long aliphatic substituents, exhibit the best distribution pattern for both imaging and photodynamic therapy of tumors.

Animals↗
PubMed2005

Characterisation and evaluation of metal-loaded iminodiacetic acid-silica of different porosity for the selective enrichment of phosphopeptides.

Silica particles of different porosity were functionalised with iminodiacetic acid (IDA) and loaded with Fe(III) to yield immobilised metal affinity chromatography stationary phases (Fe(III)-IDA-silica) for phosphopeptide enrichment. The elution step of bound phosphopeptides was optimised with a 32P radioactive labelled peptide by a comprehensive study. Several elution systems, including phosphate buffers of different pH and concentration and ethylenediaminetetraacetic acid solutions were employed. Furthermore the effect of support porosity on elution behaviour was investigated. Under best conditions recoveries higher than 90% were achieved. A solid-phase extraction (SPE) protocol was developed for fractionation of phosphorylated and non-phosphorylated peptides and desalting of the fractions which is essential for subsequent mass spectrometric analysis by the combination of Fe(III)-IDA-silica and C18-silica particles. The pH of the loading buffer was found to be a critical parameter for the efficiency of the SPE protocol. As tryptic digests of alpha-lactalbumin, lysozyme and ribonuclease A mixed with three synthetic phosphopeptides were fractionated, pH 2.5 provided minimal proportion of unspecific bound peptides when comparing the fractions after mu-LC-electrospray ionization MS separation. The effect of a sample derivatisation reaction (methylation) on the efficiency of phosphopeptide enrichment was further investigated. Blocking carboxylate groups by methyl ester formation totally prevented unspecific interaction with the immobilised Fe(III) ions, but generated partially methylated phosphopeptides that increased the complexity of the phosphorylated fraction.

Chromatography, Affinity↗
PubMed2006

LH release by Cu and Ni salts and metal-GnRH complexes, in vitro.

The present studies were undertaken to examine the effect of copper and nickel salts and their complexes with GnRH on LH release from the pig anterior pituitary cells in vitro. The potency of Cu-GnRH and Ni-GnRH binding to GnRH receptors with iodinated GnRH as a radioactive tracer was also verified. The incubation of pig pituitary cells with Cu and Ni acetate salts showed no effect of the studied ions on LH release at any concentration used. However, nickel salt at a lower dose (10(-10) and 10(-9) M) tended to decrease LH output. By contrast, the native GnRH as well as its metal complexes significantly stimulated LH release after three hours of treatment and Cu-GnRH was found to be the most effective. The results showed that Cu and Ni complexes with GnRH but not their acetate salts are effective in LH release from pig pituitary cells collected from adult female pigs.

Acetates↗
PubMed2001

A mechanistic model for the uptake of waterborne strontium in the common carp (Cyprinus carpio L.).

The release of radioactive strontium to the environment is of concern due to the strong accumulation of this calcium resembling element in the bone and other tissues. To predict the effects of changes in environmental conditions on the uptake of Sr2+ and Ca2+ by freshwater fish, a Michaelis-Menten type model is introduced that accounts for the effects of chemical speciation, hydrogen ion activity, and metal ion competition. The uptake kinetics were characterized in vivo from short-term exposure experiments using the common carp (Cyprinus carpio) as the model organism. Fish were exposed to a wide range of waterborne Sr2+ (0.2-10,000 microM) and Ca2+ (10-10,000 microM) concentrations and water pH (5.0-8.5). Strontium uptake by the whole body of fish increased with increasing Sr2+ activity, displaying saturation kinetics, but decreased significantly with increasing Ca2+ and H+ activities in the water. Likewise, calcium uptake by the fish decreased with increasing Sr2+ and H+ activities in the water. The model fitted to the pooled data explains 97.5% of the variation in Sr2+ uptake and 86% in Ca2+ uptake over the wide range of exposure conditions and reveals that Sr2+ and Ca2+ inhibit each other completely competitively, while H+ inhibits the uptake of both metal ions in a partially noncompetitive way. This model can be used as a mechanistic tool to predict the uptake of these metals in carp under variable conditions.

Animals↗