-
Regulatory Toxicology and Pharmacology... Aug 2018Aminocarboxylic acid (ethylenediamine-based) chelating agents, such as DTPA and EDTA, are widely used in a variety of products and processes. Recently the European RAC... (Review)
Review
Aminocarboxylic acid (ethylenediamine-based) chelating agents, such as DTPA and EDTA, are widely used in a variety of products and processes. Recently the European RAC proposed to classify DTPA as a developmental toxicant Category 1B according to CLP. This paper provides unequivocal and significant evidence that developmental effects cannot be considered an intrinsic property of the chelating substances themselves since: (1) animals fed a zinc deficient diet during gestation exhibit developmental toxicity of a similar nature and severity to that observed in studies involving such chelates, (2) sufficient supplementation of zinc in the diet, or administration of zinc bound chelates, completely negates the developmental effects. Moreover, the bioavailability of DTPA is very low with >95% of oral doses excreted unchanged via the feces within 24 h. If DTPA would possess the intrinsic property to be developmentally toxic, simple zinc supplementation should not be sufficient to negate these effects. Furthermore, the relevance of classification is highly questionable since worker or consumer exposure could not lead to a scenario whereby sufficient zinc deficiency would manifest itself. Therefore classification of DTPA for such effects is not protective of human health; instead it leads to onerous and disproportionate restrictions being placed on this substance.
Topics: Animals; Chelating Agents; Humans; Pentetic Acid; Zinc
PubMed: 29964121
DOI: 10.1016/j.yrtph.2018.06.019 -
British Journal of Pharmacology Sep 2004Trastuzumab (Herceptin) is a recombinant humanised IgG1 monoclonal antibody against the human epidermal growth factor receptor 2 (HER2), used for metastatic breast...
Trastuzumab (Herceptin) is a recombinant humanised IgG1 monoclonal antibody against the human epidermal growth factor receptor 2 (HER2), used for metastatic breast cancer treatment. Radiolabelled trastuzumab may have several future applications for diagnostic use. The aim of the present study was to develop clinical grade (111)Indium ((111)In) radiolabelled trastuzumab, to evaluate the stability and immunoreactivity of the tracer and to perform a biodistribution study in human tumour-bearing mice. Trastuzumab was radiolabelled with (111)In using DTPA as a chelator. (111)In-DTPA-trastuzumab (labelling yield 92.3+/-2.3%, radiochemical purity 97.0+/-1.5%) is stable in PBS when stored at 4 degrees C for more than 14 days. The immunoreactive fraction determined by cell-binding assays, using the HER2-overexpressing human ovarian SK-OV-3 tumour cell line, was 0.87+/-0.06. Biodistribution and tumour targeting were studied in HER2 receptor-positive and -negative tumour-bearing athymic mice. The HER2-positive tumour showed (9.77+/-1.14% injected dose per gram (ID g(-1))) substantial uptake of the labelled antibody already after 5 h. The difference in uptake between HER2-positive versus -negative tumours was even more pronounced 3 days after injection (16.30+/-0.64% ID g(-1)), and was visualised by radioimmunoscintigraphy. Liver, spleen and kidney showed marked tracer uptake. In summary, trastuzumab can be efficiently radiolabelled with (111)In with high labelling yields and high stability. (111)In-DTPA-trastuzumab selectively binds to the human HER2 receptor both in vitro and in vivo in animals. Therefore, (111)In-DTPA-trastuzumab appears suitable for clinical use.
Topics: Animals; Breast Neoplasms; Drug Stability; Immunohistochemistry; Indium; Isotope Labeling; Mice; Mice, Nude; Neoplasm Transplantation; Pentetic Acid; Quality Control; Radiopharmaceuticals; Tissue Distribution
PubMed: 15289297
DOI: 10.1038/sj.bjp.0705915 -
Analytical Chemistry Nov 2018Macroautophagy is a complex degradative intracellular process by which long-lived proteins and damaged organelles are cleared. Common methods for the analysis of...
Macroautophagy is a complex degradative intracellular process by which long-lived proteins and damaged organelles are cleared. Common methods for the analysis of autophagy are bulk measurements which mask organelle heterogeneity and complicate the analysis of interorganelle association and trafficking. Thus, methods for individual organelle quantification are needed to address these deficiencies. Current techniques for quantifying individual autophagy organelles are either low through-put or are dimensionally limited. We make use of the multiparametric capability of mass cytometry to investigate phenotypic heterogeneity in autophagy-related organelle types that have been isolated from murine brain, liver, and skeletal muscle. Detection and phenotypic classification of individual organelles were accomplished through the use of a lanthanide-chelating membrane stain and organelle-specific antibodies. Posthoc sample matrix background correction and nonspecific antibody binding corrections provide measures of interorganelle associations and heterogeneity. This is the first demonstration of multiparametric individual organelle analysis via mass cytometry. The method described here illustrates the potential for further investigation of the inherently complex interorganelle associations, trafficking, and heterogeneity present in most eukaryotic biological systems.
Topics: Animals; Antibodies; Autophagy; Chelating Agents; Female; Flow Cytometry; Intracellular Membranes; Mass Spectrometry; Mice, Inbred C57BL; Organelles; Pentetic Acid; Terbium
PubMed: 30350631
DOI: 10.1021/acs.analchem.8b02790 -
International Journal of Nanomedicine 2019Niosomes are nonionic surfactant-based vesicles that exhibit certain unique features which make them favorable nanocarriers for sustained drug delivery in cancer...
BACKGROUND AND PURPOSE
Niosomes are nonionic surfactant-based vesicles that exhibit certain unique features which make them favorable nanocarriers for sustained drug delivery in cancer therapy. Biodistribution studies are critical in assessing if a nanocarrier system has preferential accumulation in a tumor by enhanced permeability and retention effect. Radiolabeling of nanocarriers with radioisotopes such as Technetium-99m (Tc) will allow for the tracking of the nanocarrier noninvasively via nuclear imaging. The purpose of this study was to formulate, characterize, and optimize Tc-labeled niosomes.
METHODS
Niosomes were prepared from a mixture of sorbitan monostearate 60, cholesterol, and synthesized D-α-tocopherol polyethylene glycol 1000 succinate-diethylenetriaminepentaacetic acid (synthesis confirmed by H and C nuclear magnetic resonance spectroscopy). Niosomes were radiolabeled by surface chelation with reduced Tc. Parameters affecting the radiolabeling efficiency such as concentration of stannous chloride (SnCl·HO), pH, and incubation time were evaluated. In vitro stability of radiolabeled niosomes was studied in 0.9% saline and human serum at 37°C for up to 8 hours.
RESULTS
Niosomes had an average particle size of 110.2±0.7 nm, polydispersity index of 0.229±0.008, and zeta potential of -64.8±1.2 mV. Experimental data revealed that 30 µg/mL of SnCl·HO was the optimal concentration of reducing agent required for the radiolabeling process. The pH and incubation time required to obtain high radiolabeling efficiency was pH 5 and 15 minutes, respectively. Tc-labeled niosomes exhibited high radiolabeling efficiency (>90%) and showed good in vitro stability for up to 8 hours.
CONCLUSION
To our knowledge, this is the first study published on the surface chelation of niosomes with Tc. The formulated Tc-labeled niosomes possessed high radiolabeling efficacy, good stability in vitro, and show good promise for potential use in nuclear imaging in the future.
Topics: Animals; Carbon-13 Magnetic Resonance Spectroscopy; Humans; Hydrogen-Ion Concentration; Liposomes; Particle Size; Pentetic Acid; Proton Magnetic Resonance Spectroscopy; Radiopharmaceuticals; Spectroscopy, Fourier Transform Infrared; Static Electricity; Surface-Active Agents; Technetium; Time Factors; Tissue Distribution; Vitamin E
PubMed: 30863048
DOI: 10.2147/IJN.S184912 -
The Western Journal of Medicine Jan 1988Smoke inhalation causes most of the deaths in fire-related injuries, with pulmonary edema as a major determinant in the outcome of smoke-inhalation injury. The... (Review)
Review
Smoke inhalation causes most of the deaths in fire-related injuries, with pulmonary edema as a major determinant in the outcome of smoke-inhalation injury. The pathophysiology of pulmonary edema is thought to be related to the products of incomplete combustion. Damage to the integrity of the alveolar epithelium is one of the determinants of the development of smoke-induced pulmonary edema. In recent studies using lung clearance of aerosolized pentetic acid (DTPA [diethylenetriaminepentaacetic acid]) labeled with technetium Tc 99m to assess the permeability of the alveolar epithelium, several factors were identified that may increase a person's susceptibility to smoke-induced acute lung injury. These are increased initial alveolar permeability and alterations in the number and activity of alveolar macrophages. Clinical measurement of (99m)TcDTPA clearance may provide a sensitive and convenient method for the early detection and serial assessment of smoke-induced alveolar epithelial permeability changes.
Topics: Animals; Burns, Inhalation; Humans; Organometallic Compounds; Pentetic Acid; Pulmonary Edema; Rabbits; Technetium Tc 99m Pentetate
PubMed: 3277334
DOI: No ID Found -
Calcified Tissue International Nov 2013Elastin-specific medial vascular calcification, termed "Monckeberg's sclerosis," has been recognized as a major risk factor for various cardiovascular events. We...
Elastin-specific medial vascular calcification, termed "Monckeberg's sclerosis," has been recognized as a major risk factor for various cardiovascular events. We hypothesize that chelating agents, such as disodium ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), and sodium thiosulfate (STS) might reverse elastin calcification by directly removing calcium from calcified tissues into soluble calcium complexes. We assessed the chelating ability of EDTA, DTPA, and STS on removal of calcium from hydroxyapatite (HA) powder, calcified porcine aortic elastin, and calcified human aorta in vitro. We show that both EDTA and DTPA could effectively remove calcium from HA and calcified tissues, while STS was not effective. The tissue architecture was not altered during chelation. In the animal model of aortic elastin-specific calcification, we further show that local periadventitial delivery of EDTA loaded in to poly(lactic-co-glycolic acid) nanoparticles regressed elastin-specific calcification in the aorta. Collectively, the data indicate that elastin-specific medial vascular calcification could be reversed by chelating agents.
Topics: Aged; Animals; Aortic Diseases; Calcium; Chelating Agents; Drug Evaluation, Preclinical; Edetic Acid; Female; Humans; Male; Middle Aged; Pentetic Acid; Rats; Rats, Sprague-Dawley; Swine; Treatment Outcome; Vascular Calcification
PubMed: 23963635
DOI: 10.1007/s00223-013-9780-0 -
Molecular Imaging and Biology Feb 2011Recent preclinical and clinical studies show that dyes that excite and fluoresce in the near-infrared range may be used for tracking and detecting disease targets in...
PURPOSE
Recent preclinical and clinical studies show that dyes that excite and fluoresce in the near-infrared range may be used for tracking and detecting disease targets in vivo. A method for quantifying free dye molecules in antibody conjugate preparations is required for agent batch release and for translation into the clinic.
PROCEDURES
Herein, we developed and validated a SDS-PAGE method to determine the percentage of free IRDye 800 CW in (DTPA)(n)-trastuzumab-(IRDye 800)(m) conjugate sample preparations in which high-performance liquid chromatography (HPLC) assessment of free dye was not possible.
RESULTS
The SDS-PAGE assay was accurate and valid for free IRDye 800 CW amounts between 38 and 4 mol% of total dye. Gel sample preparation reagent affected the specificity of the assay, and lower and upper limits of quantitation and detection were determined.
CONCLUSION
This method may be applicable to other near-infrared dye-conjugated antibody-based imaging agents in which HPLC assessment of purity is not feasible. This validated method for quality assurance will facilitate the translation of dual-labeled antibody conjugates for nuclear and optical imaging.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Calibration; Chromatography, High Pressure Liquid; Coloring Agents; Electrophoresis, Polyacrylamide Gel; Indicators and Reagents; Indium Radioisotopes; Limit of Detection; Pentetic Acid; Solutions; Spectroscopy, Near-Infrared; Trastuzumab
PubMed: 20458634
DOI: 10.1007/s11307-010-0328-7 -
International Journal of Radiation... Jul 2012The open structure of euchromatin renders it susceptible to DNA damage by ionizing radiation (IR) compared with compact heterochromatin. The effect of chromatin...
PURPOSE
The open structure of euchromatin renders it susceptible to DNA damage by ionizing radiation (IR) compared with compact heterochromatin. The effect of chromatin configuration on the efficacy of Auger electron radiotherapy was investigated.
METHODS AND MATERIALS
Chromatin structure was altered in MDA-MB-468 and 231-H2N human breast cancer cells by suberoylanilide hydroxamic acid (SAHA), 5-aza-2-deoxycytidine, or hypertonic treatment. The extent and duration of chromatin structural changes were evaluated using the micrococcal nuclease assay. DNA damage (γH2AX assay) and clonogenic survival were evaluated after exposure to (111)In-DTPA-hEGF, an Auger electron-emitting radiopharmaceutical, or IR. The intracellular distribution of (111)In-DTPA-hEGF after chromatin modification was investigated in cell fractionation experiments.
RESULTS
Chromatin remained condensed for up to 20 minutes after NaCl and in a relaxed state 24 hours after SAHA treatment. The number of γH2AX foci per cell was greater in MDA-MB-468 and 231-H2N cells after IR (0.5 Gy) plus SAHA (1 μM) compared with IR alone (16 ± 0.6 and 14 ± 0.3 vs. 12 ± 0.4 and 11 ± 0.2, respectively). More γH2AX foci were observed in MDA-MB-468 and 231-H2N cells exposed to (111)In-DTPA-hEGF (6 MBq/μg) plus SAHA vs. (111)In-DTPA-hEGF alone (11 ± 0.3 and 12 ± 0.7 vs. 9 ± 0.4 and 7 ± 0.3, respectively). 5-aza-2-deoxycytidine enhanced the DNA damage caused by IR and (111)In-DTPA-hEGF. Clonogenic survival was reduced in MDA-MB-468 and 231-H2N cells after IR (6 Gy) plus SAHA (1 μM) vs. IR alone (0.6% ± 0.01 and 0.3% ± 0.2 vs. 5.8% ± 0.2 and 2% ± 0.1, respectively) and after (111)In-DTPA-hEGF plus SAHA compared to (111)In-DTPA-hEGF alone (21% ± 0.4% and 19% ± 4.6 vs. 33% ± 2.3 and 32% ± 3.7). SAHA did not affect (111)In-DTPA-hEGF nuclear localization. Hypertonic treatment resulted in fewer γH2AX foci per cell after IR and (111)In-DTPA-hEGF compared to controls but did not significantly alter clonogenic survival.
CONCLUSIONS
Chromatin structure affects DNA damage and cell survival after exposure to Auger electron radiation.
Topics: Analysis of Variance; Azacitidine; Cell Line, Tumor; Chromatin; DNA Damage; Decitabine; Electrons; Epidermal Growth Factor; ErbB Receptors; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Pentetic Acid; Radiation Tolerance; Radiopharmaceuticals; Radiotherapy; Sodium Chloride; Vorinostat
PubMed: 22336201
DOI: 10.1016/j.ijrobp.2011.09.051 -
AJNR. American Journal of Neuroradiology Jan 1996To describe the MR characteristics of optic neuropathy caused by vasculitis.
PURPOSE
To describe the MR characteristics of optic neuropathy caused by vasculitis.
METHODS
Nine cases of optic neuropathy with diagnosis of vasculitis (six with systemic lupus erythematosis and one each with rheumatoid arthritis, Sjögren disease, and radiation vasculitis) were reviewed retrospectively. Patients were 31 to 62 years old, and all but one were women. All patients had MR imaging through the orbits and anterior visual pathways, five with fat suppression, with and without gadopentetate dimeglumine. Five patients also had MR imaging of the entire brain. The size and enhancement of various segments of the optic nerve and anterior visual pathways were studied.
RESULTS
MR imaging with contrast material showed enhancement and enlargement of segments of the optic nerves and/or chiasm in six of the nine patients (all but three with systemic lupus erythematosis). Enlargement of a segment of the anterior visual pathway never occurred without enhancement, but enhancement alone did occur in three cases. Of the five patients who had MR imaging of the whole brain, abnormalities were seen in three: periventricular hyperintensity in two and a lacunar infarct in one; none had vessel abnormalities.
CONCLUSION
Because the MR enhancement seen represents disruption of the blood-brain barrier within the optic nerve, MR imaging with gadopentetate dimeglumine and fat suppression should be performed to detect increased permeability of the blood-brain barrier in acute optic neuropathy.
Topics: Adult; Arthritis, Rheumatoid; Blood-Brain Barrier; Contrast Media; Drug Combinations; Female; Gadolinium DTPA; Humans; Image Enhancement; Lupus Erythematosus, Systemic; Magnetic Resonance Imaging; Male; Meglumine; Middle Aged; Optic Nerve; Optic Neuritis; Organometallic Compounds; Pentetic Acid; Retrospective Studies; Vasculitis
PubMed: 8770262
DOI: No ID Found -
Biomolecules Oct 2022Speciation of actinides, and more particularly bioligand-binding ability, influences in vivo behavior. Understanding these interactions is essential for estimation of...
Speciation of actinides, and more particularly bioligand-binding ability, influences in vivo behavior. Understanding these interactions is essential for estimation of radiological dose and improvement of decorporation strategies for accidentally contaminated victims. Because the handling of actinides imposes overwhelming difficulties, in vitro assays carried out in physiological conditions are lacking and data regarding such interactions are scarce. In this study, we used a bi-compartmental and dynamic assay, providing physiological conditions (presence of inorganic ions, pH, temperature) to explore interactions between the actinides plutonium (Pu) and americium (Am) and endogenous (proteins transferrin and ferritin) or exogenous ligands (the chelating agent diethylenetriaminpentaacetic acid, DTPA). In this assay, an agarose gel represents the retention compartment of actinides and a dynamic fluid phase, the transfer compartment. The proportion of actinides transferred from static to dynamic phase reflects interactions between Pu/Am and various ligands. The results show differences in the formation of actinide-protein or actinide-DTPA complexes in physiologically relevant media depending on which ligand is present and where. We observed differential behavior for Pu and Am similar to in vivo studies. Thus, our assay may be used to determine the ability of various actinides to interact with specific proteins or with drug candidates for decorporation in complex physiologically relevant environments.
Topics: Ligands; Actinoid Series Elements; Americium; Plutonium; Pentetic Acid
PubMed: 36358903
DOI: 10.3390/biom12111553