177Lu-DOTA-Bevacizumab: Radioimmunotherapy Agent for Melanoma.

Science.gov (United States)

Camacho, Ximena; Calzada, Victoria; Fernandez, Marcelo; Alonso, Omar; Chammas, Roger; Riva, Eloisa; Gambini, Juan Pablo; Cabral, Pablo

2017-01-01

Vascular endothelial growth factor (VEGF) is one of the classic factors to tumor-induced angiogenesis in several types, including melanoma. Bevacizumab is a humanized monoclonal antibody directed against VEGF. To radiolabel Bevacizumab with 177-Lutetium as a potential radioimmunotherapy agent for melanoma. Bevacizumab was derivatized with DOTA-NHS-ester at 4 ºC for 18 h. DOTABevacizumab was radiolabeled with 177LuCl3 (15 MBq/mg) at 37 ºC for 1 h. The studies were performed in healthy and B16F1 tumor-bearing C57BL/6J mice at 24 and 48 h (n = 5). Scinthigraphic imaging studies were performed at 24 h to determine the radiochemical stability, targeting specificity and pharmacokinetics of the 177Lutetium-labeled antibody. DOTA-Bevacizumab was efficiently labeled with 177LuCl3 at 37 °C. The in-vitro stability of labeled product was optimal over 72 h. In-vivo biodistribution studies showed a high liver and tumor uptake of 177Lu-DOTA-Bevacizumab, with tumor-to-muscle ratios of 11.58 and 6.37 at 24 and 48 h p.i. Scintigraphic imaging of melanoma tumor-bearing C57BL/6J mice showed liver and a high tumor selective uptake of 177Lu-DOTA-Bevacizumab at 24 h. Our results support the potential role of 177Lu-DOTA-Bevacizumab as a novel radioimmunotherapy agent for melanoma. We hope that these novel molecular imaging agents will open the path to new diagnostic and therapeutic strategies for Melanoma disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Ga(III) chelates of amphiphilic DOTA-based ligands: synthetic route and in vitro and in vivo studies

International Nuclear Information System (INIS)

Fontes, Andre; Prata, M. Isabel M.; Geraldes, Carlos F.G.C.; Andre, Joao P.

2011-01-01

In this work, we report on a synthetic strategy using amphiphilic DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-based chelators bearing a variable-sized α-alkyl chain at one of the pendant acetate arms (from 6 to 14 carbon atoms), compatible with their covalent coupling to amine-bearing biomolecules. The amphiphilic behavior of the micelles-forming Ga(III) chelates (critical micellar concentration), their stability in blood serum and their lipophilicity (logP) were investigated. Biodistribution studies with the 67 Ga-labeled chelates were performed in Wistar rats, which showed a predominant liver uptake with almost no traces of the radiochelates in the body after 24 h.

Gd (III) chelates adsorbed on TiO2 nanoparticles - promising MRI contrast agent

International Nuclear Information System (INIS)

Rehor, Ivan; Lukes, Ivan; Peters, Joop A.; Jirak, Daniel

2009-01-01

Full text: The project deals with a new contrast agent (CA) for magnetic resonance imaging (MRI). The CA consists of two main parts - diamagnetic core (TiO 2 nanoparticle) and Gd (III) chelates grafted on its surface. The presence of the nanoparticle core is responsible for significant increase of r1 millimolar relaxivity (which corresponds to the efficiency of the CA) due to the slowing down the rotation of the complex in solution. It also affects the biodistribution characteristics of the CA - the ability to penetrate through cell membranes is well known for nanoparticles, making them useful for cell labeling. The structure of the chelate is derived from DOTA ligand, whose Gd (III) complexes are commercially used as MRI CA in human medicine. The connection of the complex to the surface is realized via penylphosphonate, which is attached to the pendant arm of the ligand. Strong interaction of the phosphonate with the TiO 2 surface results in the full surface coverage. The complexation and MRI properties of Gd chelate were studied and exhibit analogy to the complexes of DOTA, The millimolar relaxivity (r1) of the Gd (III) complex significantly increases upon adsorption on the TiO 2 nanoparticles. PVA was added to the colloidal solutions of CA to stabilize them under biological conditions and such stabilized CA was utilized for MRI visualization of rat pancreatic islets (P1). The labeled islets were detected on MR images as hyperintense area and therefore our CA seems to be promising material for cellular MRI

Ga(III) chelates of amphiphilic DOTA-based ligands: synthetic route and in vitro and in vivo studies

Energy Technology Data Exchange (ETDEWEB)

Fontes, Andre [Centro de Quimica, Campus de Gualtar, Universidade do Minho, 4710-057, Braga (Portugal); Prata, M. Isabel M. [IBILI, Faculdade de Medicina, Universidade de Coimbra, 3548, Coimbra (Portugal); Geraldes, Carlos F.G.C. [Departamento de Ciencias da Vida, Faculdade de Ciencias e Tecnologia, Universidade de Coimbra, 3001-401, Coimbra (Portugal); Centro de Neurociencias e Biologia Celular, Universidade de Coimbra, 3001-401, Coimbra (Portugal); Andre, Joao P., E-mail: jandre@quimica.uminho.p [Centro de Quimica, Campus de Gualtar, Universidade do Minho, 4710-057, Braga (Portugal)

2011-04-15

In this work, we report on a synthetic strategy using amphiphilic DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-based chelators bearing a variable-sized {alpha}-alkyl chain at one of the pendant acetate arms (from 6 to 14 carbon atoms), compatible with their covalent coupling to amine-bearing biomolecules. The amphiphilic behavior of the micelles-forming Ga(III) chelates (critical micellar concentration), their stability in blood serum and their lipophilicity (logP) were investigated. Biodistribution studies with the {sup 67}Ga-labeled chelates were performed in Wistar rats, which showed a predominant liver uptake with almost no traces of the radiochelates in the body after 24 h.

SU-C-204-03: DFT Calculations of the Stability of DOTA-Based-Radiopharmaceuticals

Energy Technology Data Exchange (ETDEWEB)

Khabibullin, A.R.; Woods, L.M. [University of South Florida, Tampa, Florida (United States); Karolak, A.; Budzevich, M.M.; Martinez, M.V. [H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States); McLaughlin, M.L.; Morse, D.L. [University of South Florida, Tampa, Florida (United States); H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States)

2016-06-15

Purpose: Application of the density function theory (DFT) to investigate the structural stability of complexes applied in cancer therapy consisting of the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelated to Ac225, Fr221, At217, Bi213, and Gd68 radio-nuclei. Methods: The possibility to deliver a toxic payload directly to tumor cells is a highly desirable aim in targeted alpha particle therapy. The estimation of bond stability between radioactive atoms and the DOTA chelating agent is the key element in understanding the foundations of this delivery process. Thus, we adapted the Vienna Ab-initio Simulation Package (VASP) with the projector-augmented wave method and a plane-wave basis set in order to study the stability and electronic properties of DOTA ligand chelated to radioactive isotopes. In order to count for the relativistic effect of radioactive isotopes we included Spin-Orbit Coupling (SOC) in the DFT calculations. Five DOTA complex structures were represented as unit cells, each containing 58 atoms. The energy optimization was performed for all structures prior to calculations of electronic properties. Binding energies, electron localization functions as well as bond lengths between atoms were estimated. Results: Calculated binding energies for DOTA-radioactive atom systems were −17.792, −5.784, −8.872, −13.305, −18.467 eV for Ac, Fr, At, Bi and Gd complexes respectively. The displacements of isotopes in DOTA cages were estimated from the variations in bond lengths, which were within 2.32–3.75 angstroms. The detailed representation of chemical bonding in all complexes was obtained with the Electron Localization Function (ELF). Conclusion: DOTA-Gd, DOTA-Ac and DOTA-Bi were the most stable structures in the group. Inclusion of SOC had a significant role in the improvement of DFT calculation accuracy for heavy radioactive atoms. Our approach is found to be proper for the investigation of structures with DOTA

Comparison of MRI properties between derivatized DTPA and DOTA gadolinium-dendrimer conjugates.

Science.gov (United States)

Nwe, K; Bernardo, M; Regino, C A S; Williams, M; Brechbiel, M W

2010-08-15

In this report we directly compare the in vivo and in vitro MRI properties of gadolinium-dendrimer conjugates of derivatized acyclic diethylenetriamine-N,N',N',N'',N''-pentaacetic acid (1B4M-DTPA) and macrocyclic 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (C-DOTA). The metal-ligand chelates were pre-formed in alcohol prior to conjugation to the generation 4 PAMAM dendrimer (G4D), and the dendrimer-based agents were purified by Sephadex(R) G-25 column. The analysis and SE-HPLC data indicated chelate to dendrimer ratios of 30:1 and 28:1, respectively. Molar relaxivity measured at pH 7.4, 22 degrees C, and 3T are comparable (29.5 vs 26.9 mM(-1)s(-1)), and both conjugates are equally viable as MRI contrast agents based on the images obtained. The macrocyclic agent however exhibits a faster rate of clearance in vivo (t(1/2)=16 vs 29 min). Our conclusion is that the macrocyclic-based agent is the more suitable agent for in vivo use for these reasons combined with kinetic inertness associated with the Gd(III) DOTA complex stability properties. Published by Elsevier Ltd.

Fluid extraction using carbon dioxide and organophosphorus chelating agents

Science.gov (United States)

Smart, Neil G.; Wai, Chien M.; Lin, Yuehe; Kwang, Yak Hwa

1998-01-01

Methods for extracting metalloid and metal species from a solid or liquid material by exposing the material to a fluid solvent, particularly supercritical CO.sub.2, and a chelating agent are described. The chelating agent forms a chelate with the species, the chelate being soluble in the fluid to allow removal of the species from the material. In preferred embodiments the extraction solvent is supercritical CO.sub.2 and the chelating agent comprises an organophosphorous chelating agent, particularly sulfur-containing organophosphorous chelating agents, including mixtures of chelating agents. Examples of chelating agents include monothiophosphinic acid, di-thiophosphinic acid, phosphine sulfite, phosphorothioic acid, and mixtures thereof. The method provides an environmentally benign process for removing metal and metalloids from industrial waste solutions, particularly acidic solutions. Both the chelate and the supercritical fluid can be regenerated and the contaminant species recovered to provide an economic, efficient process.

Development of 90Y-DOTA-nimotuzumab Fab fragment for radioimmunotherapy

International Nuclear Information System (INIS)

Alonso Martinez, L.M.; Marylaine Perez-Malo Cruz; Rene Leyva Montana; Calzada Falcon, V.N.; Minely Zamora Barrabi; Alejandro Arbesu Valdivia; Ignacio Hernandez Gonzalez; Mariela Leon Perez

2014-01-01

Yttrium-90-( 90 Y) labeled monoclonal antibodies prepared with a chelating agent, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), have been used for radioimmunotherapy of cancer. In the present work, the Fab fragment of anti-EGFR monoclonal antibody nimotuzumab was prepared with high purity, integrity and biological activity. The Fab fragment with high specific recognition of EGFR in NCI-H125 human lung adenocarcinoma cells was derivatized with DOTA-NHS applying a simple procedure. DOTA-nimotuzumab Fab fragment was successfully radiolabeled with 90 Y with high radiochemical yield. The in vitro stability of labeled product was optimal over 24 h in buffered solution at 37 deg C. Biodistribution and pharmacokinetic studies correctly evaluated the in vivo non-tumor uptake, dosage regimen and excretion pathway in normal Wistar rats. (author)

Investigation of DOTA-Metal Chelation Effects on the Chemical Shift of ¹²⁹ Xe

Energy Technology Data Exchange (ETDEWEB)

Jeong, K; Slack, CC; Vassiliou, CC; Dao, P; Gomes, MD; Kennedy, DJ; Truxal, AE; Sperling, LJ; Francis, MB; Wemmer, DE; Pines, A

2015-09-17

Recent work has shown that xenon chemical shifts in cryptophane-cage sensors are affected when tethered chelators bind to metals. Here in this paper, we explore the xenon shifts in response to a wide range of metal ions binding to diastereomeric forms of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) linked to cryptophane-A. The shifts induced by the binding of Ca²⁺, Cu²⁺, Ce³⁺, Zn²⁺, Cd²⁺, Ni²⁺, Co²⁺, Cr²⁺, Fe³⁺, and Hg²⁺ are distinct. In addition, the different responses of the diastereomers for the same metal ion indicate that shifts are affected by partial folding with a correlation between the expected coordination number of the metal in the DOTA complex and the chemical shift of ¹²⁹Xe. Lastly, these sensors may be used to detect and quantify many important metal ions, and a better understanding of the basis for the induced shifts could enhance future designs.

The ubiquitous DOTA and its derivatives: the impact of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid on biomedical imaging.

Science.gov (United States)

Stasiuk, Graeme J; Long, Nicholas J

2013-04-07

Over the last twenty-five years 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) has made a significant impact on the field of diagnostic imaging. DOTA is not the only metal chelate in use in medical diagnostics, but it is the only one to significantly impact on all of the major imaging modalities Magnetic Resonance (MR), Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), and Fluorescence imaging. This crossover of modalities has been possible due to the versatility of DOTA firstly, to complex a variety of metal ions and secondly, the ease with which it can be modified for different disease states. This has driven research over the last two decades into the chemistry of DOTA and the modification of the substituent pendant arms of this macrocycle to create functional, targeted and dual-modal imaging agents. The primary use of DOTA has been with the lanthanide series of metals, gadolinium for MRI, europium and terbium for fluorescence and neodymium for near infra-red imaging. There are now many research groups dedicated to the use of lanthanides with DOTA although other chelates such as DTPA and NOTA are being increasingly employed. The ease with which DOTA can be conjugated to peptides has given rise to targeted imaging agents seen in the PET, SPECT and radiotherapy fields. These modalities use a variety of radiometals that complex with DOTA, e.g.(64)Cu and (68)Ga which are used in clinical PET scans, (111)In, and (90)Y for SPECT and radiotherapy. In this article, we will demonstrate the remarkable versatility of DOTA, how it has crossed the imaging modality boundaries and how it has been successfully transferred into the clinic.

Use of chelating agents as immovable phase in extraction chromatography

International Nuclear Information System (INIS)

Sebesta, F.

1978-01-01

Extraction chromatography using chelating agents is reviewed. The theory of element extraction by chelating agents and factors influencing this process (pH, extracting agent concentration in organic phase, masking agent concentration in aqueous phase) are briefly considered. The effect of kinetic factors on the extraction chromatography process is discussed. Ways of preparing columns are emphasized. Examples of using chelating reagents in various extraction chromatography systems are given. β-Diketones, oximes, hydroxamic acids, dithizon, diethyl dithiocarbamic acid are chosen as chelating agents

Chelating agents in pharmacology, toxicology and therapeutics

International Nuclear Information System (INIS)

1988-01-01

The proceedings contain 71 abstracts of papers. Fourteen abstracts were inputted in INIS. The topics covered include: the effects of chelating agents on the retention of 63 Ni, 109 Cd, 203 Hg, 144 Ce, 95 Nb and the excretion of 210 Po, 63 Ni, 48 V, 239 Pu, 241 Am, 54 Mn; the applications of tracer techniques for studies of the efficacy of chelation therapy in patients with heart and brain disorders; and the treatment of metal poisoning with chelating agents. (J.P.)

3-hydroxy-2(1H)-pyridinone chelating agents

Science.gov (United States)

Raymond, K.; Xu, J.

1999-04-06

Disclosed is a series of improved chelating agents and the chelates formed from these agents, which are highly effective upon both injection and oral administration. Several of the most effective are of low toxicity. These chelating agents incorporate within their structure 3-hydroxy-2-pyridinone (3,2-HOPO) moieties with a substituted carbamoyl group ortho to the hydroxy group of the hydroxypyridinone ring. The electron-withdrawing carbamoyl group increases the acidity, as well as the chemical stability towards oxidation and reduction, of the hydroxypyridinones. In the metal complexes of the chelating agents, the amide protons form very strong hydrogen bonds with the adjacent HOPO oxygen donor, making these complexes very stable at physiological conditions. The terminal N-substituents provide a certain degree of lipophilicity to the 3,2-HOPO, increasing oral activity. 2 figs.

Evaluation of Ga-DOTA-(D-Asp)n as bone imaging agents: D-aspartic acid peptides as carriers to bone.

Science.gov (United States)

Ogawa, Kazuma; Ishizaki, Atsushi; Takai, Kenichiro; Kitamura, Yoji; Makino, Akira; Kozaka, Takashi; Kiyono, Yasushi; Shiba, Kazuhiro; Odani, Akira

2017-10-25

67 Ga-DOTA-(L-Asp) 11 and 67 Ga-DOTA-(L-Asp) 14 , which have been developed as bone imaging agents, showed a high accumulation in bone and a rapid blood clearance in mice. However, peptides composed of D-amino acids are more stable in vivo than those composed of their L-equivalents. In this study, 67 Ga-DOTA-(D-Asp) n (n = 2, 5, 8, 11, or 14) were synthesized using the Fmoc-based solid-phase methodology and evaluated. In hydroxyapatite binding assay, binding of 67 Ga-DOTA-(D-Asp) n tended to increase with increasing length of the amino acid chain. 67 Ga-DOTA-(D-Asp) 11 and 67 Ga-DOTA-(D-Asp) 14 caused a high accumulation of radioactivity in the bones of the mice. However, the results for 67 Ga-DOTA-(D-Asp) n and 67 Ga-DOTA-(L-Asp) n were comparable. In urine analyses, the proportion of intact complex after injection of 67 Ga-DOTA-(D-Asp) 14 was significantly higher than that of 67 Ga-DOTA-(L-Asp) 14 . Although 67 Ga-DOTA-(D-Asp) 14 was more stable than 67 Ga-DOTA-(L-Asp) 14 , the properties of 67 Ga-DOTA-(D-Asp) n and 67 Ga-DOTA-(L-Asp) n as bone imaging agents may be comparable.

Positron emission tomography based analysis of long-circulating cross-linked triblock polymeric micelles in a U87MG mouse xenograft model and comparison of DOTA and CB-TE2A as chelators of copper-64.

Science.gov (United States)

Jensen, Andreas I; Binderup, Tina; Kumar EK, Pramod; Kjær, Andreas; Rasmussen, Palle H; Andresen, Thomas L

2014-05-12

Copolymers of ABC-type (PEG-PHEMA-PCMA) architecture were prepared by atom transfer radical polymerization and formulated as micelles with functionalizable primary alcohols in the shell-region (PHEMA-block) to which the metal-ion chelators DOTA or CB-TE2A were conjugated. Using this micelle system we compared the in vivo stabilities of DOTA and CB-TE2A as chelators of (64)Cu in micelle nanoparticles. The coumarin polymer (PCMA-block) micelle core was cross-linked by UV irradiation at 2 W/cm(2) for 30 min. The cross-linked micelles were labeled with (64)Cu at room temperature for 2 h (DOTA) or 80 °C for 3 h (CB-TE2A), giving labeling efficiencies of 60-76% (DOTA) and 40-47% (CB-TE2A). (64)Cu-micelles were injected into tumor-bearing mice (8 mg/kg) and PET/CT scans were carried out at 1, 22, and 46 h postinjection. The micelles showed good blood stability (T1/2: 20-26 h) and tumor uptake that was comparable with other nanoparticle systems. The DOTA micelles showed a biodistribution similar to the CB-TE2A micelles and the tumor uptake was comparable for both micelle types at 1 h (1.9% ID/g) and 22 h (3.9% ID/g) but diverged at 46 h with 3.6% ID/g (DOTA) and 4.9% ID/g (CB-TE2A). On the basis of our data, we conclude that cross-linked PEG-PHEMA-PCMA micelles have long circulating properties resulting in tumor accumulation and that DOTA and CB-TE2A (64)Cu-chelates show similar in vivo stability for the studied micelle system.

Improved tumor-targeting MRI contrast agents: Gd(DOTA) conjugates of a cycloalkane-based RGD peptide

International Nuclear Information System (INIS)

Park, Ji-Ae; Lee, Yong Jin; Ko, In Ok; Kim, Tae-Jeong; Chang, Yongmin; Lim, Sang Moo; Kim, Kyeong Min; Kim, Jung Young

2014-01-01

Highlights: • Development of improved tumor-targeting MRI contrast agents. • To increase the targeting ability of RGD, we developed cycloalkane-based RGD peptides. • Gd(DOTA) conjugates of cycloalkane-based RGD peptide show improved tumor signal enhancement in vivo MR images. - Abstract: Two new MRI contrast agents, Gd-DOTA-c(RGD-ACP-K) (1) and Gd-DOTA-c(RGD-ACH-K) (2), which were designed by incorporating aminocyclopentane (ACP)- or aminocyclohexane (ACH)-carboxylic acid into Gd-DOTA (gadolinium-tetraazacyclo dodecanetetraacetic acid) and cyclic RGDK peptides, were synthesized and evaluated for tumor-targeting ability in vitro and in vivo. Binding affinity studies showed that both 1 and 2 exhibited higher affinity for integrin receptors than cyclic RGDyK peptides, which were used as a reference. These complexes showed high relaxivity and good stability in human serum and have the potential to improve target-specific signal enhancement in vivo MR images

Improved tumor-targeting MRI contrast agents: Gd(DOTA) conjugates of a cycloalkane-based RGD peptide

Energy Technology Data Exchange (ETDEWEB)

Park, Ji-Ae, E-mail: jpark@kirams.re.kr [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Lee, Yong Jin; Ko, In Ok [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Tae-Jeong; Chang, Yongmin [Institute of Biomedical Engineering, Kyungpook National University, Daegu (Korea, Republic of); Lim, Sang Moo [Department of Nuclear Medicine, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Kyeong Min [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Jung Young, E-mail: jykim@kirams.re.kr [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

2014-12-12

Highlights: • Development of improved tumor-targeting MRI contrast agents. • To increase the targeting ability of RGD, we developed cycloalkane-based RGD peptides. • Gd(DOTA) conjugates of cycloalkane-based RGD peptide show improved tumor signal enhancement in vivo MR images. - Abstract: Two new MRI contrast agents, Gd-DOTA-c(RGD-ACP-K) (1) and Gd-DOTA-c(RGD-ACH-K) (2), which were designed by incorporating aminocyclopentane (ACP)- or aminocyclohexane (ACH)-carboxylic acid into Gd-DOTA (gadolinium-tetraazacyclo dodecanetetraacetic acid) and cyclic RGDK peptides, were synthesized and evaluated for tumor-targeting ability in vitro and in vivo. Binding affinity studies showed that both 1 and 2 exhibited higher affinity for integrin receptors than cyclic RGDyK peptides, which were used as a reference. These complexes showed high relaxivity and good stability in human serum and have the potential to improve target-specific signal enhancement in vivo MR images.

TmDOTA-tetraglycinate encapsulated liposomes as pH-sensitive LipoCEST agents.

Directory of Open Access Journals (Sweden)

Ana Christina L Opina

Full Text Available Lanthanide DOTA-tetraglycinate (LnDOTA-(gly₄⁻ complexes contain four magnetically equivalent amide protons that exchange with protons of bulk water. The rate of this base catalyzed exchange process has been measured using chemical exchange saturation transfer (CEST NMR techniques as a function of solution pH for various paramagnetic LnDOTA-(gly₄⁻ complexes to evaluate the effects of lanthanide ion size on this process. Complexes with Tb(III, Dy(III, Tm(III and Yb(III were chosen because these ions induce large hyperfine shifts in all ligand protons, including the exchanging amide protons. The magnitude of the amide proton CEST exchange signal differed for the four paramagnetic complexes in order, Yb>Tm>Tb>Dy. Although the Dy(III complex showed the largest hyperfine shift as expected, the combination of favorable chemical shift and amide proton CEST linewidth in the Tm(III complex was deemed most favorable for future in vivo applications where tissue magnetization effects can interfere. TmDOTA-(gly₄⁻ at various concentrations was encapsulated in the core interior of liposomes to yield lipoCEST particles for molecular imaging. The resulting nanoparticles showed less than 1% leakage of the agent from the interior over a range of temperatures and pH. The pH versus amide proton CEST curves differed for the free versus encapsulated agents over the acidic pH regions, consistent with a lower proton permeability across the liposomal bilayer for the encapsulated agent. Nevertheless, the resulting lipoCEST nanoparticles amplify the CEST sensitivity by a factor of ∼10⁴ compared to the free, un-encapsulated agent. Such pH sensitive nano-probes could prove useful for pH mapping of liposomes targeted to tumors.

DOTA-derivatives of octreotide dicarba-analogues with high affinity for somatostatin sst2,5 receptors

Science.gov (United States)

Pratesi, Alessandro; Ginanneschi, Mauro; Lumini, Marco; Papini, Anna M.; Novellino, Ettore; Brancaccio, Diego; Carotenuto, Alfonso

2017-02-01

In vivo somatostatin receptor scintigraphy is a valuable method for the visualization of human endocrine tumours and their metastases. In fact, peptide ligands of somatostatin receptors (sst’s) conjugated with chelating agents are in clinical use. We have recently developed octreotide dicarba-analogues, which show interesting binding profiles at sst’s. In this context, it was mandatory to explore the possibility that our analogues could maintain their activity also upon conjugation with DOTA. In this paper, we report and discuss the synthesis, binding affinity and conformational preferences of three DOTA-conjugated dicarba-analogues of octreotide. Interestingly, two conjugated analogues exhibited nanomolar affinities on sst2 and sst5 somatostatin receptor subtypes.

Chelating agents as stationary phase in extraction chromatography, ch. 11

International Nuclear Information System (INIS)

Sebesta, F.

1975-01-01

Chelating agents have been used largely in extraction chromatography for separations related to activation analysis, for concentration of metals from dilute solutions, and for preparation of radiochemically pure or carrier-free radionuclides. This review deals with the theory of extraction by chelating agents, the experimental technique, and the chelating agents and systems used (β-diketones, oximes, hydroxamic acid, dithizone and diethyldithiocarbamic acid)

Positron Emission Tomography Based Analysis of Long-Circulating Cross-Linked Triblock Polymeric Micelles in a U87MG Mouse Xenograft Model and Comparison of DOTA and CB-TE2A as Chelators of Copper-64

DEFF Research Database (Denmark)

Jensen, Andreas Tue Ingemann; Binderup, Tina; Ek, Pramod Kumar

2014-01-01

Copolymers of ABC-type (PEG-PHEMA-PCMA) architecture were prepared by atom transfer radical polymerization and formulated as micelles with functionalizable primary alcohols in the shell-region (PHEMA-block) to which the metal-ion chelators DOTA or CB-TE2A were conjugated. Using this micelle system...... we compared the in vivo stabilities of DOTA and CB-TE2A as chelators of 64Cu in micelle nanoparticles. The coumarin polymer (PCMA-block) micelle core was cross-linked by UV irradiation at 2 W/cm2 for 30 min. The cross-linked micelles were labeled with 64Cu at room temperature for 2 h (DOTA) or 80 °C...... for 3 h (CB-TE2A), giving labeling efficiencies of 60–76% (DOTA) and 40–47% (CB-TE2A). 64Cu-micelles were injected into tumor-bearing mice (8 mg/kg) and PET/CT scans were carried out at 1, 22, and 46 h postinjection. The micelles showed good blood stability (T1/2: 20–26 h) and tumor uptake...

The chemical fate of 212Bi-DOTA formed by β- decay of 212Pb(DOTA)2-

International Nuclear Information System (INIS)

Mirzadeh, S.; Kumar, K.; Gansow, O.A.

1993-01-01

The increasing use of inert metal complexes in radioimmunotherapy prompted us to explore the potential use of 212 Pb chelates. Herein, we report a study of the chemical fate of the 212 Bi-DOTA complex formed by β - decay of 212 Pb(DOTA) 2- (H 4 DOTA = 1,4,7,10-tetraazacyclododecanetetraacetic acid). To assure that both parent and daughter complexes were thermally stable, kinetic studies were performed with 203 Pb(II) and 206 Bi(III) which showed that both lead and bismuth complexes with DOTA undergo chemical exchange only very slowly in aqueous solution at pH 4-10. To investigate whether the complex ion which results from decay of 212 Pb(DOTA) 2- was intact and also stable, solutions initially containing only this ion were analyzed for amounts of DOTA-complexed and uncomplexed 212 Bi after attaining transient equilibrium with 212 Bi. The fraction of 212 Bi radioactivity not complexed to DOTA, vide infra, was found to be 36±2%. This value represents the fraction of breakup of 212 Bi(DOTA) - formed from β - decay of the parent complex. By considering the various extranuclear processes responsible for kinetic and electronic excitation of the 212 Bi daughter, break-up of the 212 Bi-DOTA complex is ascribed to the internal conversion of γ-rays emitted by the excited 212 Bi nuclide. (orig.)

Synthesis and stability test of radioimmunoconjugate 177Lu-DOTA-F(ab′2-trastuzumab for theranostic agent of HER2 positive breast cancer

Directory of Open Access Journals (Sweden)

Sandra Hermanto

2016-10-01

Full Text Available The use of trastuzumab as intact IgG labeling radionuclide for HER2 positive breast cancer theranostic agent is not ideal because it is slowly eliminated from the blood and normal tissues resulting in low tumor/blood (T/B and tumor/normal tissue (T/NT ratios. To overcome this limitation, we developed the trastuzumab F(ab′2 fragments and radiolabeling of the fragments by β and γ-particle of Lutetium-177. F(ab2 fragments were produced by digestion of trastuzumab IgG (Herceptin with pepsin for 18 h at 37 °C. The F(ab′2 fragment fractionated in PD-10 column, followed by the conjugation with 2-(4-isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA as a metal chelator and radiolabeling with 177LuCl3. Molecular weight of fragments was calculated by LCMS (Liquid Chromatography Mass Spectroscopy and the radiochemical purity was evaluated by ITLC-SG (Instan Thin Layer Chromatography. Our study showed that the purity of F(ab′2 fragment generated by PD-10 fractions was >98% and the molecular weight of F(ab′2 was 98.35 kDa. The average numbers of pSCN-Bn-DOTA chelates per antibody fragment were 5.03 ± 1.5 and the optimum conjugation reactions was performed at molar ratio 20:1 (chelator to antibody. The stability test of the radioimmunoconjugate in the human serum albumin (HSA at 37 °C showed the radiochemical purity was 91.96 ± 0.26% after 96 h storage. This indicated that the radioimmunoconjugate is relatively stable when applied to the human body's physiological condition.

Olivine-type cathode for rechargeable batteries: Role of chelating agents

International Nuclear Information System (INIS)

Kandhasamy, Sathiyaraj; Singh, Pritam; Thurgate, Stephen; Ionescu, Mihail; Appadoo, Dominique; Minakshi, Manickam

2012-01-01

Highlights: ► Olivine powder was synthesized by sol–gel method using a range of chelating agents. ► Role of chelating agents in olivine cathode was investigated for battery application. ► Battery was fabricated with olivine cathode, Zn anode and aqueous electrolyte. ► Synergetic effect of additives (CA + TEA + PVP) led to improved storage capacity. - Abstract: Olivine (LiCo 1/3 Mn 1/3 Ni 1/3 PO 4 ) powders were synthesized at 550–600 °C for 6 h in air by a sol–gel method using multiple chelating agents and used as a cathode material for rechargeable batteries. Range of chelating agents like a weak organic acid (citric acid – CA), emulsifier (triethanolamine – TEA) and non-ionic surfactant (polyvinylpyrrolidone – PVP) in sol–gel wet chemical synthesis were used. The dependence of the physicochemical properties of the olivine powders such as particle size, morphology, structural bonding and crystallinity on the chelating agent was extensively investigated. Among the chelating agents used, unique cycling behavior (75 mAh/g after 25 cycles) is observed for the PVP assisted olivine. This is due to volumetric change in trapped organic layer for first few cycles. The trapped organic species in the electrode–electrolyte interface enhances the rate of lithium ion diffusion with better capacity retention. In contrast, CA and TEA showed a gradual capacity fade of 30 and 38 mAh/g respectively after multiple cycles. The combination of all the three mixed chelating agents showed an excellent electrochemical behavior of 100 mAh/g after multiple cycles and the synergistic effect of these agents are discussed.

Bifunctional chelates of Rh-105 and Au-199 as potential radiotherapeutic agents

International Nuclear Information System (INIS)

Troutner, D.E.; Schlemper, E.O.

1990-01-01

Since last year we have: continued the synthesis of pentadentate bifunctional chelating agents based on diethylene triamine; studied the chelation Rh-105, Au-198 (as model for Au-199) and Tc-99m with these agents as well as chelation of Pd-109, Cu-67, In-111, and Co-57 with some of them; synthesized a new class of potential bifunctional chelating agents based on phenylene diamine; investigated the behavior of Au-198 as a model for Au-199; begun synthesis of bifunctional chelating agents based on terpyridly and similar ligands; and continued attempts to produce tetradentate bifunctional chelates based on diaminopropane. Each of these will be addressed in this report

Development of 177Lu-DOTA-anti-CD20 for radioimmunotherapy

International Nuclear Information System (INIS)

Hassan Yousefnia; Amir Reza Jalilian; Ali Bahrami-Samani; Simindokht Shirvani-Arani; Mohammad Ghannadi-Maragheh; Azim Arbabi; Edalat Radfar

2011-01-01

Rituximab was successively labeled with 177 Lu-lutetium chloride. 177 Lu chloride was obtained by thermal neutron flux (4 x 1013 n cm -2 s -1 ) of natural Lu 2 O 3 sample with a specific activity of 2.6-3 GBq/mg. The macrocyclic bifunctional chelating agent, N-succinimidyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA-NHS) was prepared at 25 deg C using DOTA, N-hydroxy succinimide (NHS) in CH 2 Cl 2 . DOTA-rituximab was obtained by the addition of 1 mL of a rituximab pharmaceutical solution (5 mg/mL, in phosphate buffer, pH 7.8) to a glass tube pre-coated with DOTA-NHS (0.01-0.1 mg) at 25 deg C with continuous mild stirring for 15 h. Radiolabeling was performed at 37 deg C in 24 h. Radio-thin layer chromatography showed an overall radiochemical purity of >98% at optimized conditions (specific activity = 444 MBq/mg, labeling efficacy; 82%). The final isotonic 177 Lu-DOTA-rituximab complex was checked by gel electrophoresis for structure integrity control. Radio-TLC was performed to ensure that only one species was present after filtration through a 0.22 μm filter. Preliminary biodistribution studies in normal rats were carried out to determine complex distribution of the radioimmunoconjugate up to 168 h. The biodistribution data were in accordance with other antiCD20 radioimmunoconjugates already reported. (author)

Remote-loading of liposomes with manganese-52 and in vivo evaluation of the stabilities of 52Mn-DOTA and 64Cu-DOTA using radiolabelled liposomes and PET imaging.

Science.gov (United States)

Jensen, Andreas I; Severin, Gregory W; Hansen, Anders E; Fliedner, Frederikke P; Eliasen, Rasmus; Parhamifar, Ladan; Kjær, Andreas; Andresen, Thomas L; Henriksen, Jonas R

2018-01-10

Liposomes are nanoparticles used in drug delivery that distribute over several days in humans and larger animals. Radiolabeling with long-lived positron emission tomography (PET) radionuclides, such as manganese-52 ( 52 Mn, T½=5.6days), allow the imaging of this biodistribution. We report optimized protocols for radiolabeling liposomes with 52 Mn, through both remote-loading and surface labeling. For comparison, liposomes were also remote-loaded and surface labeled with copper-64 ( 64 Cu, T½=12.7h) through conventional means. The chelator DOTA was used in all cases. The in vivo stability of radiometal chelates is widely debated but studies that mimic a realistic in vivo setting are lacking. Therefore, we employed these four radiolabeled liposome types as platforms to demonstrate a new concept for such in vivo evaluation, here of the chelates 52 Mn-DOTA and 64 Cu-DOTA. This was done by comparing "shielded" remote-loaded with "exposed" surface labeled variants in a CT26 tumor-bearing mouse model. Remote loading (90min at 55°C) and surface labeling (55°C for 2h) of 52 Mn gave excellent radiolabeling efficiencies of 97-100% and 98-100% respectively, and the liposome biodistribution was imaged by PET for up to 8days. Liposomes with surface-conjugated 52 Mn-DOTA exhibited a significantly shorter plasma half-life (T ½ =14.4h) when compared to the remote-loaded counterpart (T ½ =21.3h), whereas surface-conjugated 64 Cu-DOTA cleared only slightly faster and non-significantly, when compared to remote-loaded (17.2±2.9h versus 20.3±1.2h). From our data, we conclude the successful remote-loading of liposomes with 52 Mn, and furthermore that 52 Mn-DOTA may be unstable in vivo whereas 64 Cu-DOTA appears suitable for quantitative imaging. Copyright © 2017 Elsevier B.V. All rights reserved.

Extracellular gadolinium contrast agents: Differences in stability

International Nuclear Information System (INIS)

Morcos, S.K.

2008-01-01

Extracellular gadolinium contrast agents (Gd-CA) are either linear or macrocyclic chelates available as ionic or non-ionic preparations. The molecular structure whether cyclic or linear and ionicity determines the stability of Gd-CA. Linear chelates are flexible open chains which do not offer a strong binding to Gd 3+ . In contrast, the macrocyclic chelates offer a strong binding to Gd 3+ by the virtue of being preorganized rigid rings of almost optimal size to cage the gadolinium atom. Non-ionic preparations are also less stable in comparison to the ionic ones as the binding between Gd 3+ with the negatively charged carboxyl groups is stronger in comparison to that with amides or alcohol in the non-ionic preparations. According to stability constants and kinetic measurements, the most stable Gd-CM is the ionic-macrocyclic chelate Gd-DOTA and the least stable agents are the non-ionic linear chelates gadodiamide and gadoversetamide. In vivo data confirmed the low stability of non-ionic linear chelates but no significant difference was observed amongst the macrocyclic agents whether ionic (Gd-DOTA) or non-ionic such as Gd-HP-DO3A and Gd-BT-DO3A. The stability of Gd-CA seems to be an important factor in the pathogenesis of the serious complication of nephrogenic systemic fibrosis. Gd-CA of low stability are likely to undergo transmetallation and release free Gd ions that deposit in tissue and attract circulating fibrocytes to initiate the process of fibrosis. No cases of NSF have been observed so far after the exclusive use of the stable macrocyclic Gd-CA

Comparative evaluation of synthetic anti-HER2 Affibody molecules site-specifically labelled with {sup 111}In using N-terminal DOTA, NOTA and NODAGA chelators in mice bearing prostate cancer xenografts

Energy Technology Data Exchange (ETDEWEB)

Malmberg, Jennie; Varasteh, Zohreh; Orlova, Anna [Uppsala University, Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala (Sweden); Perols, Anna; Braun, Alexis; Eriksson Karlstroem, Amelie [AlbaNova University Centre, Division of Molecular Biotechnology, School of Biotechnology, KTH Royal Institute of Technology, Stockholm (Sweden); Altai, Mohamed; Tolmachev, Vladimir [Uppsala University, Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden); Sandstroem, Mattias [Uppsala University Hospital, Section of Medical Physics, Department of Oncology, Uppsala (Sweden); Garske, Ulrike [Uppsala University Hospital, Department of Medical Sciences, Section of Nuclear Medicine, Uppsala (Sweden)

2012-03-15

In disseminated prostate cancer, expression of human epidermal growth factor receptor type 2 (HER2) is one of the pathways to androgen independence. Radionuclide molecular imaging of HER2 expression in disseminated prostate cancer might identify patients for HER2-targeted therapy. Affibody molecules are small (7 kDa) targeting proteins with high potential as tracers for radionuclide imaging. The goal of this study was to develop an optimal Affibody-based tracer for visualization of HER2 expression in prostate cancer. A synthetic variant of the anti-HER2 Z{sub HER2:342} Affibody molecule, Z{sub HER2:S1}, was N-terminally conjugated with the chelators DOTA, NOTA and NODAGA. The conjugated proteins were biophysically characterized by electrospray ionization mass spectroscopy (ESI-MS), circular dichroism (CD) spectroscopy and surface plasmon resonance (SPR)-based biosensor analysis. After labelling with {sup 111}In, the biodistribution was assessed in normal mice and the two most promising conjugates were further evaluated for tumour targeting in mice bearing DU-145 prostate cancer xenografts. The HER2-binding equilibrium dissociation constants were 130, 140 and 90 pM for DOTA-Z{sub HER2:S1}, NOTA-Z{sub HER2:S1} and NODAGA-Z{sub HER2:S1}, respectively. A comparative study of {sup 111}In-labelled DOTA-Z{sub HER2:S1}, NOTA-Z{sub HER2:S1} and NODAGA-Z{sub HER2:S1} in normal mice demonstrated a substantial influence of the chelators on the biodistribution properties of the conjugates. {sup 111}In-NODAGA-Z{sub HER2:S1} had the most rapid clearance from blood and healthy tissues. {sup 111}In-NOTA-Z{sub HER2:S1} showed high hepatic uptake and was excluded from further evaluation. {sup 111}In-DOTA-Z{sub HER2:S1} and {sup 111}In-NODAGA-Z{sub HER2:S1} demonstrated specific uptake in DU-145 prostate cancer xenografts in nude mice. The tumour uptake of {sup 111}In-NODAGA-Z{sub HER2:S1}, 5.6 {+-} 0.4%ID/g, was significantly lower than the uptake of {sup 111}In-DOTA-Z{sub HER2:S1

Review of actinide decorporation with chelating agents

Energy Technology Data Exchange (ETDEWEB)

Ansoborlo, E. [CEA Valrho, Dir. de l' Energie Nucleaire (DEN/DRCP/CETAMA), 30 - Marcoule (France); Amekraz, B.; Moulin, Ch. [CEA Saclay, Dept. de Physico-Chimie (DEN/DPC/SECR), 91 - Gif sur Yvette (France); Moulin, V. [CEA Saclay, Dir. du Developpement et de l' Innovation Nucleares (DEN/DDIN/MR), 91 - Gif Sur Yvette (France); Taran, F. [CEA Saclay (DSV/DBJC/SMMCB), 91 - Gif-sur-Yvette (France); Bailly, Th.; Burgada, R. [Centre National de la Recherche Scientifique (CNRS/LCSB/UMR 7033), 93 - Bobigny (France); Henge-Napoli, M.H. [CEA Valrho, Site de Marcoule (INSTN), 30 (France); Jeanson, A.; Den Auwer, Ch.; Bonin, L.; Moisy, Ph. [CEA Valrho, Dir. de l' Energie Nucleaire (DEN/DRCP/SCPS), 30 - Marcoule (France)

2007-10-15

In case of accidental release of radionuclides in a nuclear facility or in the environment, internal contamination (inhalation, ingestion or wound) with actinides represents a severe health risk to human beings. It is therefore important to provide effective chelation therapy or decorporation to reduce acute radiation damage, chemical toxicity, and late radiation effects. Speciation governs bioavailability and toxicity of elements and it is a prerequisite tool for the design and success of new ligands or chelating agents. The purpose of this review is to present the state-of-the-art of actinide decorporation within biological media, to recall briefly actinide metabolism, to list the basic constraints of actinide-ligand for development, to describe main tools developed and used for decorporation studies, to review mainly the chelating agents tested for actinides, and finally to conclude on the future trends in this field. (authors)

Evaluation of Ga-DOTA-(D-Asp)n as bone imaging agents: D-aspartic acid peptides as carriers to bone

OpenAIRE

Ogawa, Kazuma; Ishizaki, Atsushi; Takai, Kenichiro; Kitamura, Yoji; Makino, Akira; Kozaka, Takashi; Kiyono, Yasushi; Shiba, Kazuhiro; Odani, Akira

2017-01-01

67Ga-DOTA-(L-Asp)11 and 67Ga-DOTA-(L-Asp)14, which have been developed as bone imaging agents, showed a high accumulation in bone and a rapid blood clearance in mice. However, peptides composed of D-amino acids are more stable in vivo than those composed of their L-equivalents. In this study, 67Ga-DOTA-(D-Asp)n (n = 2, 5, 8, 11, or 14) were synthesized using the Fmoc-based solid-phase methodology and evaluated. In hydroxyapatite binding assay, binding of 67Ga-DOTA-(D-Asp)n tended to increase ...

Phenolic aminocarboxylic acids - new chelating agents for modifying gallium-67 biodistribution

Energy Technology Data Exchange (ETDEWEB)

Hunt, F.C.; Maddalena, D.J. (Australian Atomic Energy Commission Research Establishment, Lucas Heights)

The chelating agents EDDHA and HBED were synthesised with carboxyl or sulphonyl groups in the phenolic ring to favour urinary excretion on complexing with gallium. Carboxyl EDDMA was administered to tumor-bearing rats, and its concentration in the tumours and other tissues determined by scintigraphic imaging. The chelating agents increase tumour to blood ratios by chelating gallium in vivo.

Interaction of chelating agents with cadmium in mice and rats

International Nuclear Information System (INIS)

Eybl, V.; Sykora, J.; Koutensky, J.; Caisova, D.; Schwartz, A.; Mertl, F.

1984-01-01

The influence of several chelating agents (CaDTPA, ZnDTPA, CaEDTA, ZnEDTA, DMSA, D-penicillamine and DMPS, DMP and DDC) on the acute toxicity of CdCl 2 and on the whole body retention and tissue distribution of cadmium after the IV application of /sup 115mCdCl 2 was compared in mice. The chelating agents were applied immediately after the application of cadmium. CaDTPA, ZnDTPA and DMSA appeared to be the most effective antidotes. However, DMSA increased the amount of cadmium retained in kidneys. The treatement of cadmium-poisoned mice with the combination of DMSA (IP) and ZnDTPA (SC) (all the compounds were injected in equimolar dose) decreased the toxicity of cadmium more than treatment with one chelating agents (given in a 2:1 dose). However, by studying the effect of these chelating agents and their combination application of the antidotes showed little or no improvement over the results obtained with the most effective of the individual components. In the urine of rats injected with CdCl 2 and treated with the chelating agents (CaDTPA, ZnDTPA, DMSA), the presence of cadmium complexes was demonstrated. The formation of mixed ligand chelates in vivo was not proved. Experiments in mice given a single injection of /sup 115m/Cd-labeled Cd complexes of DMPS, DMSA and DTPA showed a high retention of cadmium in the organisms after the IV application of CdDMPS and CdDMSA complexes

Phenolic aminocarboxylic acids - new chelating agents for modifying gallium-67 biodistribution

International Nuclear Information System (INIS)

Hunt, F.C.; Maddalena, D.J.

1982-01-01

The chelating agents EDDHA and HBED were synthesised with carboxyl or sulphonyl groups in the phenolic ring to favour urinary excretion on complexing with gallium. Carboxyl EDDMA was administered to tumor-bearing rats, and its concentration in the tumours and other tissues determined by scintigraphic imaging. The chelating agents increase tumour to blood ratios by chelating gallium in vivo. (U.K.)

Preclinical evaluation of somatostatin analogs bearing two macrocyclic chelators for high specific activity labeling with radiometals

International Nuclear Information System (INIS)

Storch, D.; Schmitt, J.S.; Waldherr, C.; Maecke, H.R.; Waser, B.; Reubi, J.C.

2007-01-01

Radiometallated analogues of the regulatory peptide somatostatin are of interest in the in vivo localization and targeted radiotherapy of somatostatin receptor-overexpressing tumors. An important aspect of their use in vivo is a fast and efficient labeling (complexation) protocol for radiometals along with a high specific activity. We describe in this manuscript synthetic methods for the coupling of two chelators (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid = DOTA) to the bioactive peptide [Tyr 3 ,Thr 8 ]-octreotide (TATE) in order to increase the specific activity (radioactivity in Bq per mole peptide). The full chelator-linker-peptide conjugate was assembled on solid support using standard Fmoc chemistry. Two DOTA-chelators were linked to the peptide using lysine or N,N'-bis(3-aminopropyl)-glycine (Apg); in addition, pentasarcosine (Sar 5 ) was used as a spacer between the chelators and the peptide to probe its influence on biology and pharmacology. Complexation rates with In 3+ and Y 3+ salts and the corresponding radiometals were high, the bis-DOTA-derivatives showed higher complexation rates and gave higher specific activity than DOTA-TATE. Pharmacological and biological data of the complexed molecules did not show significant differences if compared to the parent peptide [ 111/nat In-DOTA]-TATE except for [( 111/nat In-DOTA) 2 -Apg]-TATE which showed a lower binding affinity and rate of internalization into tumor cells. The biodistribution of [( 111/nat In-DOTA)-Lys( 111/nat In-DOTA)]-TATE in the rat tumor model (AR4-2J) showed a high and specific (as shown by a blocking experiment) tracer uptake in somatostatin receptor-positive tissue but a lower tumor uptake compared to [ 111/nat In-DOTA]-TATE. (orig.)

Preparation and evaluation of a radiogallium complex-conjugated bisphosphonate as a bone scintigraphy agent

International Nuclear Information System (INIS)

Ogawa, Kazuma; Takai, Kenichiro; Kanbara, Hiroya; Kiwada, Tatsuto; Kitamura, Yoji; Shiba, Kazuhiro; Odani, Akira

2011-01-01

Introduction: 68 Ga is a radionuclide of great interest as a positron emitter for positron emission tomography (PET). To develop a new bone-imaging agent with radiogallium, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was chosen as a chelating site and Ga-DOTA complex-conjugated bisphosphonate, which has a high affinity for bone, was prepared and evaluated. Although we are interested in developing 68 Ga-labeled bone imaging agents for PET, in these initial studies 67 Ga was used because of its longer half-life. Methods: DOTA-conjugated bisphosphonate (DOTA-Bn-SCN-HBP) was synthesized by conjugation of 2-(4-isothiocyanatebenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7, 10-tetraacetic acid to 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (alendronate). 67 Ga-DOTA-Bn-SCN-HBP was prepared by coordination with 67 Ga, and its in vitro and in vivo evaluations were performed. Results: 67 Ga-DOTA-Bn-SCN-HBP was prepared with a radiochemical purity of over 95% without purification. 67 Ga-DOTA-Bn-SCN-HBP had great affinity for hydroxyapatite in binding assay. In biodistribution experiments, 67 Ga-DOTA-Bn-SCN-HBP accumulated in bone rapidly but was hardly observed in tissues other than bone. Pretreatment of an excess amount of alendronate inhibited the bone accumulation of 67 Ga-DOTA-Bn-SCN-HBP. Conclusions: 67 Ga-DOTA-Bn-SCN-HBP showed ideal biodistribution characteristics as a bone-imaging agent. These findings should provide useful information on the drug design of bone imaging agents for PET with 68 Ga.

Interaction of chelating agents with cadmium in mice and rats.

Science.gov (United States)

Eybl, V; Sýkora, J; Koutenský, J; Caisová, D; Schwartz, A; Mertl, F

1984-01-01

The influence of several chelating agents (CaDTPA, ZnDTPA, CaEDTA, ZnEDTA, DMSA, D-penicillamine and DMPS, DMP and DDC) on the acute toxicity of CdCl2 and on the whole body retention and tissue distribution of cadmium after the IV application of 115mCdCl2 was compared in mice. The chelating agents were applied immediately after the application of cadmium. CaDTPA, ZnDTPA and DMSA appeared to be the most effective antidotes. However, DMSA increased the amount of cadmium retained in kidneys. The treatment of cadmium-poisoned mice with the combination of DMSA (IP) and ZnDTPA (SC) (all the compounds were injected in equimolar dose) decreased the toxicity of cadmium more than treatment with one chelating agents (given in a 2:1 dose). However, by studying the effect of these chelating agents and their combination of the retention and distribution of Cd in mice, it was demonstrated that the combined application of the antidotes showed little or no improvement over the results obtained with the most effective of the individual components. In the urine of rats injected with CdCl2 and treated with the chelating agents (CaDTPA, ZnDTPA, DMSA), the presence of cadmium complexes was demonstrated. The formation of mixed ligand chelates in vivo was not proved. Experiments in mice given a single injection of 115mCd-labeled Cd complexes of DMPS, DMSA and DTPA showed a high retention of cadmium in the organisms after the IV application of CdDMPS and CdDMSA complexes. PMID:6734561

A simplified suite of methods to evaluate chelator conjugation of antibodies: effects on hydrodynamic radius and biodistribution

International Nuclear Information System (INIS)

Al-Ejeh, Fares; Darby, Jocelyn M.; Thierry, Benjamin; Brown, Michael P.

2009-01-01

Introduction: Antibodies covalently conjugated with chelators such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) are required for radioimmunoscintigraphy and radioimmunotherapy, which are of growing importance in cancer medicine. Method: Here, we report a suite of simple methods that provide a preclinical assessment package for evaluating the effects of DOTA conjugation on the in vitro and in vivo performance of monoclonal antibodies. We exemplify the use of these methods by investigating the effects of DOTA conjugation on the biochemical properties of the DAB4 clone of the La/SSB-specific murine monoclonal autoantibody, APOMAB (registered) , which is a novel malignant cell death ligand. Results: We have developed a 96-well microtiter-plate assay to measure directly the concentration of DOTA and other chelators in antibody-chelator conjugate solutions. Coupled with a commercial assay for measuring protein concentration, the dual microtiter-plate method can rapidly determine chelator/antibody ratios in the same plate. The biochemical properties of DAB4 immunoconjugates were altered as the DOTA/Ab ratio increased so that: (i) mass/charge ratio decreased; (ii) hydrodynamic radius increased; (iii) antibody immunoactivity decreased; (iv) rate of chelation of metal ions and specific radioactivity both increased and in vivo, (v) tumor uptake decreased as nonspecific uptake by liver and spleen increased. Conclusion: This simplified suite of methods readily identifies biochemical characteristics of the DOTA-immunoconjugates such as hydrodynamic diameter and decreased mass/charge ratio associated with compromised immunotargeting efficiency and, thus, may prove useful for optimizing conjugation procedures in order to maximize immunoconjugate-mediated radioimmunoscintigraphy and radioimmunotherapy.

Synthesis and Characterization of a Gd-DOTA-D-Permeation Peptide for Magnetic Resonance Relaxation Enhancement of Intracellular Targets

Directory of Open Access Journals (Sweden)

Andrew M. Prantner

2003-10-01

Full Text Available Many MR contrast agents have been developed and proven effective for extracellular nontargeted applications, but exploitation of intracellular MR contrast agents has been elusive due to the permeability barrier of the plasma membrane. Peptide transduction domains can circumvent this permeability barrier and deliver cargo molecules to the cell interior. Based upon enhanced cellular uptake of permeation peptides with D-amino acid residues, an all-D Tat basic domain peptide was conjugated to DOTA and chelated to gadolinium. Gd-DOTA-D-Tat peptide in serum at room temperature showed a relaxivity of 7.94 ± 0.11 mM−1 sec−1 at 4.7 T. The peptide complex displayed no significant binding to serum proteins, was efficiently internalized by human Jurkat leukemia cells resulting in intracellular T1 relaxation enhancement, and in preliminary T1-weighted MRI experiments, significantly enhanced liver, kidney, and mesenteric signals.

Position for Site-Specific Attachment of a DOTA Chelator to Synthetic Affibody Molecules Has a Different Influence on the Targeting Properties of 68Ga-Compared to 111In-Labeled Conjugates

Directory of Open Access Journals (Sweden)

Hadis Honarvar

2014-12-01

Full Text Available Affibody molecules, small (7 kDa scaffold proteins, are a promising class of probes for radionuclide molecular imaging. Radiolabeling of Affibody molecules with the positron-emitting nuclide 68Ga would permit the use of positron emission tomography (PET, providing better resolution, sensitivity, and quantification accuracy than single-photon emission computed tomography (SPECT. The synthetic anti-HER2 ZHER2:S1 Affibody molecule was conjugated with DOTA at the N-terminus, in the middle of helix 3, or at the C-terminus. The biodistribution of 68Ga- and 111In-labeled Affibody molecules was directly compared in NMRI nu/nu mice bearing SKOV3 xenografts. The position of the chelator strongly influenced the biodistribution of the tracers, and the influence was more pronounced for 68Ga-labeled Affibody molecules than for the 111In-labeled counterparts. The best 68Ga-labeled variant was 68Ga-[DOTA-A1]-ZHER2:S1 which provided a tumor uptake of 13 ± 1 %ID/g and a tumor to blood ratio of 39 ± 12 at 2 hours after injection. 111In-[DOTA-A1]-ZHER2:S1 and 111In-[DOTA-K58]-ZHER2:S1 were equally good at this time point, providing a tumor uptake of 15 to 16 %ID/g and a tumor to blood ratio in the range of 60 to 80. In conclusion, the selection of the best position for a chelator in Affibody molecules can be used for optimization of their imaging properties. This may be important for the development of Affibody-based and other protein-based imaging probes.

Preparation and evaluation of a radiogallium complex-conjugated bisphosphonate as a bone scintigraphy agent

Energy Technology Data Exchange (ETDEWEB)

Ogawa, Kazuma, E-mail: kogawa@p.kanazawa-u.ac.jp [Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192 (Japan); Takai, Kenichiro; Kanbara, Hiroya; Kiwada, Tatsuto [Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192 (Japan); Kitamura, Yoji; Shiba, Kazuhiro [Advanced Science Research Center, Kanazawa University, Kanazawa 920-8640 (Japan); Odani, Akira [Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192 (Japan)

2011-07-15

Introduction: {sup 68}Ga is a radionuclide of great interest as a positron emitter for positron emission tomography (PET). To develop a new bone-imaging agent with radiogallium, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was chosen as a chelating site and Ga-DOTA complex-conjugated bisphosphonate, which has a high affinity for bone, was prepared and evaluated. Although we are interested in developing {sup 68}Ga-labeled bone imaging agents for PET, in these initial studies {sup 67}Ga was used because of its longer half-life. Methods: DOTA-conjugated bisphosphonate (DOTA-Bn-SCN-HBP) was synthesized by conjugation of 2-(4-isothiocyanatebenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7, 10-tetraacetic acid to 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (alendronate). {sup 67}Ga-DOTA-Bn-SCN-HBP was prepared by coordination with {sup 67}Ga, and its in vitro and in vivo evaluations were performed. Results: {sup 67}Ga-DOTA-Bn-SCN-HBP was prepared with a radiochemical purity of over 95% without purification. {sup 67}Ga-DOTA-Bn-SCN-HBP had great affinity for hydroxyapatite in binding assay. In biodistribution experiments, {sup 67}Ga-DOTA-Bn-SCN-HBP accumulated in bone rapidly but was hardly observed in tissues other than bone. Pretreatment of an excess amount of alendronate inhibited the bone accumulation of {sup 67}Ga-DOTA-Bn-SCN-HBP. Conclusions: {sup 67}Ga-DOTA-Bn-SCN-HBP showed ideal biodistribution characteristics as a bone-imaging agent. These findings should provide useful information on the drug design of bone imaging agents for PET with {sup 68}Ga.

Preclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic Infection Imaging Agent.

Science.gov (United States)

Ebenhan, Thomas; Mokaleng, Botshelo Brenda; Venter, Jacobus Daniel; Kruger, Hendrik Gert; Zeevaart, Jan Rijn; Sathekge, Mike

2017-08-24

The study assessed a radiolabeled depsipeptide conjugate ( 68 Ga-DOTA-TBIA101) for its potential as an imaging agent targeting infection or infection-associated inflammation. 68 Ga-labeled DOTA-TBIA101 imaging was performed in (NZR1) healthy rabbits; (NZR2) rabbits bearing muscular sterile inflammation and Staphylococcus aureus (SA) infection; and (NZR3) rabbits infected with Mycobacterium tuberculosis (MTB) combined with a subcutaneous scruff infection of SA in the same animal. All animals were imaged using a PET/CT scanner at 5 and 60 min post injection. Images showed elevated accumulation of 68 Ga-DOTA-TBIA101 in the sterile muscular inflammation site (T/NT ratio = 2.6 ± 0.37 (5 min) and 2.8 ± 2.3 (60 min)) and muscles infected with MTB (T/NT ratio = 2.6 ± 0.35 (5 min) and 2.8 ± 0.16 (60 min)). The findings suggest that 68 Ga-DOTA-TBIA101-PET/CT may detect MTB-associated inflammation, although more foundational studies need to be performed to rationalize the diagnostic value of this technique.

On-load chelating agent treatments for conventional and nuclear power stations

International Nuclear Information System (INIS)

Turner, D.J.

1978-01-01

The paper is concerned with the application of on-load chelating agent treatments to those types of water circuit for which they are not currently available: high pressure drum boilers, sub-critical once-through boilers and water reactors. An attempt was made to see whether the most thermally stable types of chelating agent are likely to be sufficiently strong chelating agents either to dissolve established Fe 3 O 4 deposits or to prevent their precipitation from solution. It seems likely that they are strong enough to prevent Fe 3 O 4 depositing in a once-through boiler, through some may require that mildly reducing conditions are maintained. They would not be effective in a high pressure drum boiler (at 350 0 C) unless much more strongly reducing conditions could be maintained. For such boilers it would probably be better to seek multidentate ligands of less than maximum thermal stability. There are some indications that chelating agents based on carbon chains are more stable than NTA or EDTA so that citric acid or some of the unidentified chelating agents recently found to be produced radiolytically may have potential in the treatment of high pressure drum boilers. The prospects for periodic full-load cleaning seem less good for both types of boiler. There may also be a role for radiolytically produced chelating agents in alleviating some of the problems caused by the deposition of radioactive corrosion products in water reactor circuits. The chances for successful development fall from quite good to very low down the series SGHWR moderator circuit, PWR primary circuit, ammonia dosed BWR, neutral chemistry BWR (including SGHWR). (author)

Imaging Tumor Vasculature Noninvasively with Positron Emission Tomography and RGD Peptides Labeled with Copper 64 Using the Bifunctonal Chelates DOTA, Oxo-DO3A. and PCTA

Directory of Open Access Journals (Sweden)

Donald T.T. Yapp

2013-06-01

Full Text Available Two novel bifunctional chelates, 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15,11,13-triene-3,6,9-triacetic acid (PCTA and 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (Oxo-DO3A, were found to radiolabel antibodies with copper 64 (64Cu well for positron emission tomography (PET. In this study, the same chelators were used to radiolabel peptides with 64Cu for PET imaging of angiogenesis. PCTA, Oxo-DO3A, and 1,4,7,10-tetraazacyclododecane-N,N‘,N“,N”’-tetraacetic acid (DOTA were conjugated to cyclic-(RGDyK, and their binding affinities were confirmed. Conditions for 64Cu radiolabeling were optimized for maximum yield and specific activity. The in vitro stability of the radiolabeled compounds was challenged with serum incubation. PET studies were carried out in a non-αvβ3-expressing tumor model to evaluate the compounds' specificity for proliferating tumor vasculature and their in vivo pharmacokinetics. The PCTA and Oxo-DO3A bioconjugates were labeled with 64Cu at higher effective specific activity and radiochemical yield than the DOTA bioconjugate. In the imaging studies, all the 64Cu bioconjugates could be used to visualize the tumor and the radiotracer uptake was blocked with cyclic-(RGDyK. Target uptake of each bioconjugate was similar, but differences in other tissues were observed. 64Cu-PCTA-RGD showed the best clearance from nontarget tissue and the highest tumor to nontarget ratios. PCTA was the most promising bifunctional chelate for 64Cu peptide imaging and warrants further investigation.

Enhancement of 67Ga tumor-to-blood ratios by chelating agent

International Nuclear Information System (INIS)

Saji, Hideo; Yokoyama, Akira; Hata, Naotaka; Misaki, Atsushi; Tanaka, Hisashi.

1980-01-01

Chelating agent, such as, CaEDTA, CaDTPA, D-penicillamine, DMSA, desferoxamine, NTA, cysteine ethyl ester, BAL, α-MPG, phthalein complexone, were tested as a possible contrast enhancing agent for tumor imaging with 67 Ga-citrate. The intravenous administration of a chelating agent to Ehrlich's tumor bearing mice, one hour after the injection of 67 Ga-citrate, accelerated the blood clearance with only a very slight change of activity in the target, increasing the tumor-to-blood ratio, and consequently achieving a better visualization. Among the tested chelating agents, D-penicillamine showed the highest target-to-nontarget ratio at a shorter time: a good tumor-to-blood ratio, performed after 24 hr with non-treated animals, was achieved in only 1-3 hr with post-treated animals. Thus, D-penicillamine hold a considerable promise as a contrast enhancing agent for future clinical use. (author)

Towards the Rational Design of MRI Contrast Agents: Electron Spin Relaxation Is Largely Unaffected by the Coordination Geometry of Gadolinium(III)–DOTA-Type Complexes

Science.gov (United States)

Bean, Jonathan F.; Clarkson, Robert B.; Helm, Lothar; Moriggi, Loïck; Sherry, A. Dean

2009-01-01

Electron-spin relaxation is one of the determining factors in the efficacy of MRI contrast agents. Of all the parameters involved in determining relaxivity it remains the least well understood, particularly as it relates to the structure of the complex. One of the reasons for the poor understanding of electron-spin relaxation is that it is closely related to the ligand-field parameters of the Gd3+ ion that forms the basis of MRI contrast agents and these complexes generally exhibit a structural isomerism that inherently complicates the study of electron spin relaxation. We have recently shown that two DOTA-type ligands could be synthesised that, when coordinated to Gd3+, would adopt well defined coordination geometries and are not subject to the problems of intramolecular motion of other complexes. The EPR properties of these two chelates were studied and the results examined with theory to probe their electron-spin relaxation properties. PMID:18283704

Decorporation of metal ions by chelating agents

International Nuclear Information System (INIS)

Koenig, T.

1978-01-01

Simple model designs to simulate the effect of therapeutical chelating agents on the behaviour of metals in mammal organisms with and without excretion have been derived and analytical solutions given for the corresponding differential equations. The possibilities of these models in the short-term description of plasma kinetics of various metals, the competition of the therapeutical ligands with proteins for the metal and of the metabolism of chelating agents were tested and the properties applying extreme conceivable parameters were analyzed. The simple models were successsively expanded in logical sequence, so that it was possible to qualitatively well describe over a long period of time, the metallic kinetics in plasma, organs and urine, the retention of the ligands and their effect on the metal excretion. Two suggestions were given to describe the so-called after-effect, an increased excretion of the metal at times when the ligand is almost completely excreted and their different behaviour after injecting the metal chelate is given. Calculations on the therapy with several ligand data as well as on dose fractionation are described resting on the ratios in the plutonium-239 chosen model parameters and the determining mechanisms analyzed. (orig./MG) [de

Remote-loading of liposomes with manganese-52 and in vivo evaluation of the stabilities of 52Mn-DOTA and 64Cu-DOTA using radiolabelled liposomes and PET imaging

DEFF Research Database (Denmark)

Jensen, Andreas I.; Severin, Gregory W.; Hansen, Anders Elias

2018-01-01

to 8days. Liposomes with surface-conjugated 52Mn-DOTA exhibited a significantly shorter plasma half-life (T½=14.4h) when compared to the remote-loaded counterpart (T½=21.3h), whereas surface-conjugated 64Cu-DOTA cleared only slightly faster and non-significantly, when compared to remote-loaded (17.2±2.......9h versus 20.3±1.2h). From our data, we conclude the successful remote-loading of liposomes with 52Mn, and furthermore that 52Mn-DOTA may be unstable in vivo whereas 64Cu-DOTA appears suitable for quantitative imaging....... protocols for radiolabeling liposomes with 52Mn, through both remote-loading and surface labeling. For comparison, liposomes were also remote-loaded and surface labeled with copper-64 (64Cu, T½=12.7h) through conventional means. The chelator DOTA was used in all cases. The in vivo stability of radiometal...

Synthesis and characterization of dihexyldithiocarbamate as a chelating agent in extraction of gold(III)

Energy Technology Data Exchange (ETDEWEB)

Fatimah, Soja Siti, E-mail: soja-sf@upi.edu [Departemen Pendidikan Kimia, Universitas Pendidikan Indonesia, Jl. Dr. Setiabudhi No. 229, Bandung 40154 (Indonesia); Department of Chemistry, Faculty of Mathematics and Natural Sciences, Padjadjaran University, Jl. Raya Bandung-Sumedang, Km. 21, Jatinangor (Indonesia); Bahti, Husein H.; Hastiawan, Iwan [Department of Chemistry, Faculty of Mathematics and Natural Sciences, Padjadjaran University, Jl. Raya Bandung-Sumedang, Km. 21, Jatinangor (Indonesia); Permanasari, Anna [Departemen Pendidikan Kimia, Universitas Pendidikan Indonesia, Jl. Dr. Setiabudhi No. 229, Bandung 40154 (Indonesia)

2016-02-08

The use of dialkyldithiocarbamates as chelating agents of transition metals have been developing for decades. Many chelating agents have been synthesized and used in the extraction of the metals. Studies on particular aspects of extraction of the metals, such as the effect of increasing hydrophobicity of chelating agents on the effectiveness of the extraction, have been done. However, despite the many studies on the synthesis and applications of this type of chelating agents, interests in the aspect of molecular structure of the synthesized ligands and of their complexes, have been limited. This study aimed at synthesizing and characterizing dihexylthiocarbamate, and using the ligand for the extraction of gold III). Characterization of the ligand and of its metal complex were done by using elemental analysis, DTG, and spectroscopic methods to include NMR, ({sup 1}H, and {sup 13}C), FTIR, and MS-ESI. Data on the synthesis, characterization, and the application of the ligand as a chelating agent are presented.

Synthesis and characterization of dihexyldithiocarbamate as a chelating agent in extraction of gold(III)

Science.gov (United States)

Fatimah, Soja Siti; Bahti, Husein H.; Hastiawan, Iwan; Permanasari, Anna

2016-02-01

The use of dialkyldithiocarbamates as chelating agents of transition metals have been developing for decades. Many chelating agents have been synthesized and used in the extraction of the metals. Studies on particular aspects of extraction of the metals, such as the effect of increasing hydrophobicity of chelating agents on the effectiveness of the extraction, have been done. However, despite the many studies on the synthesis and applications of this type of chelating agents, interests in the aspect of molecular structure of the synthesized ligands and of their complexes, have been limited. This study aimed at synthesizing and characterizing dihexylthiocarbamate, and using the ligand for the extraction of gold III). Characterization of the ligand and of its metal complex were done by using elemental analysis, DTG, and spectroscopic methods to include NMR, (1H, and 13C), FTIR, and MS-ESI. Data on the synthesis, characterization, and the application of the ligand as a chelating agent are presented.

Radiolabeling of NOTA and DOTA with Positron Emitting {sup 68}Ga and Investigation of In Vitro Properties

Energy Technology Data Exchange (ETDEWEB)

Jeong, Jae Min; Kim, Young Ju; Lee, Yun Sang; Lee, Dong Soo; Chung, June Key; Lee, Myung Chul [Seoul National University College of Medicine, Seoul (Korea, Republic of)

2009-08-15

We established radiolabeling conditions of NOTA and DOTA with a generator-produced PET radionuclide {sup 68}Ga and studied in vitro characteristics such as stability, serum protein binding, octanol/water distribution, and interference with other metal ions. Various concentrations of NOTA{center_dot}3HCl and DOTA{center_dot}4HCl were labeled with 1 mL {sup 68}GaCl{sub 3} (0.18{approx}5.75 mCi in 0.1 M HCl) in various pH. NOTA{center_dot}3HCl (0.373 mM) was labeled with {sup 68}GaCl{sub 3} (0.183{approx}0.232 mCi/0.1 M HCl 1.0 mL) in the presence of CuCl{sub 2}, FeCl{sub 2}, InCl{sub 3}, FeCl{sub 3}, GaCl{sub 3}, MgCl{sub 2} or CaCl{sub 2} (0{approx}6.07 mM) at room temperature. The labeling efficiencies of {sup 68}Ga-NOTA and {sup 68}Ga-DOTA were checked by ITLC-SG using acetone or saline as mobile phase. Stabilities, protein bindings, and octanol distribution coefficients of the labeled compounds also were investigated. {sup 68}Ga-NOTA and {sup 68}Ga-DOTA were labeled optimally at pH 6.5 and pH 3.5, respectively, and the chelates were stable for 4 hr either in the reaction mixture at room temperature or in the human serum at 37 .deg. C. NOTA was labeled at room temperature while DOTA required heating for labeling. {sup 68}Ga-NOTA labeling efficiency was reduced by CuCl{sub 2}, FeCl{sub 2}, InCl{sub 2}, FeCl{sub 3} or GaCl{sub 3}, however, was not influenced by MgCl{sub 2} or CaCl{sub 2}. The protein binding was low (2.04{approx}3.32%). Log P value of {sup 68}Ga-NOTA was -3.07 indicating high hydrophilicity. We found that NOTA is a better bifunctional chelating agent than DOTA for {sup 68}Ga labeling. Although, {sup 68}Ga-NOTA labeling is interfered by various metal ions, it shows high stability and low serum protein binding.

Development of 68Ga-SCN-DOTA-Capsaicin as an Imaging Agent Targeting Apoptosis and Cell Cycle Arrest in Breast Cancer.

Science.gov (United States)

Lee, Jun Young; Lee, Sang-Yeun; Kim, Gun Gyun; Hur, Min Goo; Yang, Seung Dae; Park, Jeong-Hoon; Kim, Sang Wook

2017-06-01

68 Ga-labeled capsaicin using a DOTA (1,4,7,10-tetraazocyclododecane-N,N',N″,N'″-tetraacetic acid) derivative [ 68 Ga-SCN-Benzyl(Bn)-DOTA-capsaicin] was studied for the diagnosis of breast cancers, such as MCF-7 and SK-BR-3. The standard compound, 69 Ga-SCN-Bn-DOTA-capsaicin, was also prepared and characterized by spectroscopic analysis. The binding affinity of 68 Ga-SCN-Bn-DOTA-capsaicin was evaluated by using breast cancer cell lines (MCF-7, SK-BR-3) and colon cancer cell (CT-26); the biodistribution was carried out by using MCF-7-bearing nude mice, after which the positron emission tomography (PET) images were obtained at different time intervals (15-120 minutes). 68 Ga-SCN-Bn-DOTA-capsaicin showed a cellular uptake of 0.93% Injected Dose (ID) after 30 minutes of incubation, whereas 68 Ga-SCN-Bn-DOTA showed a lower uptake of 0.25% ID. The tumor-to-blood ID/g% ratios increased and were found to be 0.49, 0.22, and 0.77 for 15, 30, and 60 minutes, respectively. The small-animal PET study showed that the uptake of 68 Ga-SCN-Bn-DOTA-capsaicin was higher in the tumor regions even at 30 minutes after injection. These results suggest that 68 Ga-SCN-Bn-DOTA-capsaicin is a potential targeting agent for PET imaging of MCF-7.

Rates of nickel(II) capture from complexes with NTA, EDDA, and related tetradentate chelating agents by the hexadentate chelating agents EDTA and CDTA: Evidence of a "semijunctive" ligand exchange pathway

Science.gov (United States)

Boland, Nathan E.; Stone, Alan T.

2017-09-01

Many siderophores and metallophores produced by soil organisms, as well as anthropogenic chelating agent soil amendments, rely upon amine and carboxylate Lewis base groups for metal ion binding. UV-visible spectra of metal ion-chelating agent complexes are often similar and, as a consequence, whole-sample absorbance measurements are an unreliable means of monitoring the progress of exchange reactions. In the present work, we employ capillary electrophoresis to physically separate Ni(II)-tetradentate chelating agent complexes (NiL) from Ni(II)-hexadentate chelating agent complexes (NiY) prior to UV detection, such that progress of the reaction NiL + Y → NiY + L can be conveniently monitored. Rates of ligand exchange for Ni(II) are lower than for other +II transition metal ions. Ni(II) speciation in environmental media is often under kinetic rather than equilibrium control. Nitrilotriacetic acid (NTA), with three carboxylate groups all tethered to a central amine Lewis base group, ethylenediamine-N,N‧-diacetic acid (EDDA), with carboxylate-amine-amine-carboxylate groups arranged linearly, plus four structurally related compounds, are used as tetradentate chelating agents. Ethylenediaminetetraacetic acid (EDTA) and the structurally more rigid analog trans-cyclohexaneethylenediaminetetraacetic acid (CDTA) are used as hexadentate chelating agents. Effects of pH and reactant concentration are explored. Ni(II) capture by EDTA was consistently more than an order of magnitude faster than capture by CDTA, and too fast to quantify using our capillary electrophoresis-based technique. Using NiNTA as a reactant, Ni(II) capture by CDTA is independent of CDTA concentration and greatly enhanced by a proton-catalyzed pathway at low pH. Using NiEDDA as reactant, Ni(II) capture by CDTA is first order with respect to CDTA concentration, and the contribution from the proton-catalyzed pathway diminished by CDTA protonation. While the convention is to assign either a disjunctive

Synthesis and stability test of radiogadolinium(III-DOTA-PAMAM G3.0-trastuzumab as SPECT-MRI molecular imaging agent for diagnosis of HER-2 positive breast cancer

Directory of Open Access Journals (Sweden)

Hardiani Rahmania

2015-01-01

Full Text Available Nonivasive diagnosis of cancer can be provided by molecular imaging using hybrid modality to obtain better sensitivity, specificity and depiction localization of the disease. In this study, we developed a new molecular imaging agent, radiogadolinium(III-DOTA-PAMAM G3.0-trastuzumab in the form of 147Gd-DOTA-PAMAM G3.0-trastuzumab, that can be both target-specific radiopharmaceutical in SPECT as well as targeted contrast agent in MRI for the purpose of diagnosis of HER-2 positive breast cancer. 147Gd radionuclide emits γ-rays that can be used in SPECT modality, but because of technical constraint, 147Gd radionuclide was simulated by its radioisotope, 153Gd. Gd-DOTA complex has also been known as good MRI contrast agent. PAMAM G3.0 is useful to concentrate Gd-DOTA compelexes in large quantities, thus minimizing the number of trastuzumab molecules used. Trastuzumab is human monoclonal antibody that can spesifically interact with HER-2. Synthesis of radiogadolinium(III-DOTA-PAMAM G3.0-trastuzumab was initiated by conjugating DOTA NHS ester ligand with PAMAM G3.0 dendrimer. The DOTA-PAMAM G3.0 produced was conjugated to trastuzumab molecule and labeled with 153Gd. Characterization DOTA-PAMAM G3.0-trastuzumab immunoconjugate was performed using HPLC system equipped with SEC. The formation of immunoconjugate was indicated by the shorter retention time (6.82 min compared to that of trastuzumab (7.06 min. Radiochemical purity of radiogadolinium(III-DOTA-PAMAM G3.0-trastuzumab was >99% after purification process by PD-10 desalting column. Radiogadolinium(III-DOTA-PAMAM G3.0-trastuzumab compound was stable at room temperature and at 2–8 0C as indicated by its radiochemical purity 97.6 ± 0.5%–99.1 ± 0.5% after 144 h storage.

Study of chelating agent as a surface modifier for retarding corrosion attack on ferrous metal

International Nuclear Information System (INIS)

Nur Ubaidah Saidin; Muhamad Daud; Siti Radiah Mohd Kamarudin; Zaifol Samsu; Azali Muhamad; Rusni Rejab; Mohd Saari Ripin; Mohd Shariff Sattar

2010-01-01

A different concentration of chelating agents in electrolyte of 3.5 % NaCl was applied to bare ferrous metal and tested for their effectiveness as a corrosion retardant. The performance of the samples was measured using corrosion measurement system. The results indicated that the contribution of chelating agent was expediting the reduction of the passive film. The anodic behavior was clearly found to be influenced by the concentration of the chelating agent. It was also found that some of the corrosion was apparently converted to protective layer over a period of time. Excessive moisture caused breakdown of film by removing the unreacted chelating agent and causing regrowth of the existing rust. (author)

DOTA-PESIN, a DOTA-conjugated bombesin derivative designed for the imaging and targeted radionuclide treatment of bombesin receptor-positive tumours

International Nuclear Information System (INIS)

Zhang, Hanwen; Maecke, Helmut R.; Schuhmacher, Jochen; Eisenhut, Michael; Waser, Beatrice; Reubi, Jean Claude; Wild, Damian

2007-01-01

We aimed at designing and developing a novel bombesin analogue, DOTA-PEG 4 -BN(7-14) (DOTA-PESIN), with the goal of labelling it with 67/68 Ga and 177 Lu for diagnosis and radionuclide therapy of prostate and other human cancers overexpressing bombesin receptors. The 8-amino acid peptide bombesin (7-14) was coupled to the macrocyclic chelator DOTA via the spacer 15-amino-4,7,10,13-tetraoxapentadecanoic acid (PEG 4 ). The conjugate was complexed with Ga(III) and Lu(III) salts. The GRP receptor affinity and the bombesin receptor subtype profile were determined in human tumour specimens expressing the three bombesin receptor subtypes. Internalisation and efflux studies were performed with the human GRP receptor cell line PC-3. Xenografted nude mice were used for biodistribution. [Ga III /Lu III ]-DOTA-PESIN showed good affinity to GRP and neuromedin B receptors but no affinity to BB3. [ 67 Ga/ 177 Lu]-DOTA-PESIN internalised rapidly into PC-3 cells whereas the efflux from PC-3 cells was relatively slow. In vivo experiments showed a high and specific tumour uptake and good retention of [ 67 Ga/ 177 Lu]-DOTA-PESIN. [ 67 Ga/ 177 Lu]-DOTA-PESIN highly accumulated in GRP receptor-expressing mouse pancreas. The uptake specificity was demonstrated by blocking tumour uptake and pancreas uptake. Fast clearance was found from blood and all non-target organs except the kidneys. High tumour-to-normal tissue ratios were achieved, which increased with time. PET imaging with [ 68 Ga]-DOTA-PESIN was successful in visualising the tumour at 1 h post injection. Planar scintigraphic imaging showed that the 177 Lu-labelled peptide remained in the tumour even 3 days post injection. The newly designed ligands have high potential with regard to PET and SPECT imaging with 68/67 Ga and targeted radionuclide therapy with 177 Lu. (orig.)

Standardization of Procedures for the Preparation of (177)Lu- and (90)Y-labeled DOTA-Rituximab Based on the Freeze-dried Kit Formulation.

Science.gov (United States)

Wojdowska, Wioletta; Karczmarczyk, Urszula; Maurin, Michal; Garnuszek, Piotr; Mikołajczak, Renata

2015-01-01

Rituximab when radiolabelled with (177)Lu or (90)Y has been investigated for the treatment of patients with Non-Hodgkin's Lymphoma. In this study, we optimized the preparation of antibody conjugates with chelating agent in the freeze-dried kit. It shortens procedures needed for the successful radiolabeling with lutetium-177 and yttrium-90 and assures reproducible labelling yields. Various molar ratios of Rituximab:DOTA (from 1:5 to 1:100) were used at the conjugation step and different purification method to remove unbound DOTA were investigated (size-exclusion chromatography, dialysis, ultrafiltration). The final monoclonal antibody concentration was quantified by Bradford method, and the number of DOTA molecules was determined by radiolabeling assay using (64)Cu. The specific activity of (177)Lu-DOTA-Rituximab and (90)Y-DOTA-Rituximab were optimized using various amounts of radiometal. Quality control (SE-HPLC, ITLC) and stability study were performed. An average of 4.2 ± 0.8 p-SCN-Bz-DOTA molecules could be randomly conjugated to a single molecule of Rituximab. The ultrafiltration system was the most efficient for purification and resulted in the highest recovery efficiency (77.2%). At optimized conditions the (177)Lu-DOTARituximab and (90)Y-DOTA-Rituximab were obtained with radiochemical purity >99% and specific activity ca. 600 MBq/mg. The radioimmunoconjugates were stable in human serum and 0.9% NaCl. After 72 h of incubation the radiochemical purity of (177)Lu-DOTA-Rituximab decreased to 94% but it was still more than 88% for (90)Y-DOTA-Rituximab. The radioimmunoconjugate showed stability after six months storage at 2 - 8(0)C, as a lyophilized formulation. Our study shows that Rituximab-DOTA can be efficiently radiolabeled with (177)Lu and (90)Y via p-SCN-Bn-DOTA using a freezedried kit.

A study on the adsorption and subsurface transport of radioactive solutes in the presence of chelating agents

International Nuclear Information System (INIS)

Baik, Min Hoon

1994-02-01

In this study, adsorption and transport models were developed to analyze the effect of chelating agents on the adsorption and subsurface transport of radioactive solutes. The effect of chelating agents on the adsorption of radioactive solutes was analyzed by developing an adsorption model based upon the extended concept of distribution coefficient reflecting the presence of chelating agents. Also, a batch adsorption experiment was conducted in order to validate the developed adsorption model and to investigate the effect of chelating agent on the adsorption of radioactive metal solutes. In this experiment, a Cobalt(II)/EDTA/Bentonite system was considered as a representative chelation/adsorption system. It was found from the results that the presence of chelating agents significantly reduced the adsorbing capacity of geologic media such as clay minerals and soils. Thus it was concluded that the presence of chelating agents even in a small amount could contribute to the mobilization of radioactive solutes from radioactive waste burial sites by reducing the adsorbing capacity of geologic media. The effect of chelating agents on the transport of radioactive solutes in subsurface porous media was analyzed by formulating an advective-dispersive transport model which incorporated chelate formation, adsorption, decay, and degradations and by introducing the concept of a tenad. Particularly the governing equation for the tenad of radioactive solutes, M, was presented as a linear partial differential form by introducing the extended distribution coefficient, K D . The calculated results from the model showed that the transport rate of the chelated radionuclides was much greater than that of the free ionic radionuclides. This much faster transport of the chelated radionuclides was found to be due to the lower retardation factor of the chelated radionuclides than the free ionic radionuclides. The effect of parameters on the transport of radioactive solutes was also analyzed

[(64) Cu]-labelled trastuzumab: optimisation of labelling by DOTA and NODAGA conjugation and initial evaluation in mice.

Science.gov (United States)

Schjoeth-Eskesen, Christina; Nielsen, Carsten Haagen; Heissel, Søren; Højrup, Peter; Hansen, Paul Robert; Gillings, Nic; Kjaer, Andreas

2015-05-30

The human epidermal growth factor receptor-2 (HER2) is overexpressed in 20-30% of all breast cancer cases, leading to increased cell proliferation, growth and migration. The monoclonal antibody, trastuzumab, binds to HER2 and is used for treatment of HER2-positive breast cancer. Trastuzumab has previously been labelled with copper-64 by conjugation of a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator. The aim of this study was to optimise the (64) Cu-labelling of DOTA-trastuzumab and as the first to produce and compare with its 1,4,7-triazacyclononane, 1-glutaric acid-5,7 acetic acid (NODAGA) analogue in a preliminary HER2 tumour mouse model. The chelators were conjugated to trastuzumab using the activated esters DOTA mono-N-hydroxysuccinimide (NHS) and NODAGA-NHS. (64) Cu-labelling of DOTA-trastuzumab was studied by varying the amount of DOTA-trastuzumab used, reaction temperature and time. Full (64) Cu incorporation could be achieved using a minimum of 10-µg DOTA-trastuzumab, but the fastest labelling was obtained after 15 min at room temperature using 25 µg of DOTA-trastuzumab. In comparison, 80% incorporation was achieved for (64) Cu-labelling of NODAGA-trastuzumab. Both [(64) Cu]DOTA-trastuzumab and [(64) Cu]NODAGA-trastuzumab were produced after purification with radiochemical purities of >97%. The tracers were injected into mice with HER2 expressing tumours. The mice were imaged by positron emission tomography and showed high tumour uptake of 3-9% ID/g for both tracers. © 2015 The Authors Journal of Labelled Compounds and Radiopharmaceuticals published by John Wiley & Sons Ltd.

Studies of the competition for thorium ion between chelating agents and bovine serum albumin

International Nuclear Information System (INIS)

Luo Meichu; Zhang Meizhen; Sun Meizhen; Chen Shijie

1995-01-01

Fourteen chelation agents (polyaminopolcarboxylate type--TTHA, DTPA, EDTA; phenolicpolycarboxylate type--811, 8102, 7601, 7602, 7603, 7616, 7711, 7724, 7803, 7804, 8307) were studied their competitive ability to mobilize the thorium with bovine serum albumin (BSA). The experimental results showed that the competitive ability of TTHA, 8102, 811 to chelate Thorium with BSA were the strongest, and EDTA was the worst in all chelating agents. The measured order of the competitive ability of chelators is basically consistent with animal experimental results in vivo. The parameter F is defined as the competitive ability of chelators. F is taken as a screening criterion for de-corporate thorium which is simple, quick and effective method in vitro

AAZTA: an ideal chelating agent for the development of {sup 44}Sc PET imaging agents

Energy Technology Data Exchange (ETDEWEB)

Nagy, Gabor; Szikra, Dezso; Trencsenyi, Gyoergy [Scanomed Ltd., Debrecen (Hungary); University of Debrecen, Medical Imaging Clinic (Hungary); Fekete, Aniko [University of Debrecen, Medical Imaging Clinic (Hungary); Garai, Ildiko [Scanomed Ltd., Debrecen (Hungary); Giani, Arianna M.; Negri, Roberto [Dipartimento di Scienze del Farmaco, Universita del Piemonte Orientale, Novara (Italy); Masciocchi, Norberto [Dipartimento di Scienza e Alta Tecnologia e To.Sca.Lab, Universita degli Studi dell' Insubria, Como (Italy); Maiocchi, Alessandro; Uggeri, Fulvio [Bracco Imaging spa, Bracco Research Centre, Colleretto Giacosa (Italy); Toth, Imre [Department of Inorganic and Analytical Chemistry, University of Debrecen (Hungary); Aime, Silvio [Dipartimento di Biotecnologie Molecolari e Scienze della Salute, Centro di Imaging Molecolare e Preclinico, Universita degli Studi di Torino (Italy); Giovenzana, Giovanni B. [Dipartimento di Scienze del Farmaco, Universita del Piemonte Orientale, Novara (Italy); CAGE Chemicals srl, Novara (Italy); Baranyai, Zsolt [Bracco Imaging spa, Bracco Research Centre, Colleretto Giacosa (Italy); Department of Inorganic and Analytical Chemistry, University of Debrecen (Hungary)

2017-02-13

Unprecedented fast and efficient complexation of Sc{sup III} was demonstrated with the chelating agent AAZTA (AAZTA=1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)] amino-6-methylperhydro-1,4-d iazepine) under mild experimental conditions. The robustness of the {sup 44}Sc(AAZTA){sup -} chelate and conjugated biomolecules thereof is further shown by in vivo PET imaging in healthy and tumor mice models. The new results pave the way towards development of efficient Sc-based radiopharmaceuticals using the AAZTA chelator. (copyright 2017 Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim)

Development of radioactively labelled cancer seeking biomolecules for targeted therapy

International Nuclear Information System (INIS)

Pillai, M.R.A.

2000-01-01

The work done towards the development of bifunctional chelating agents, modified peptide and their radiolabelling studies with 90 Y and 188 Re are reported. Bifunctional chelating agents DOTA, TETA and DAHPES were synthesised. DOTA-Lanreotide (Mauritius) was synthesised from lanreotide. 90 Y and 188 Re used in the studies were obtained from 90 Sr- 90 Y and 188 W- 188 Re generators. Complexation studies of DOTA and Mauritius with 90 Y and that of DAHPES and EC with 188 Re were carried out. Cell labelling of 90 Y-DOTA-Lanreotide with a cell line expressing somatostatin receptors was also carried out

Development of radioactively labelled cancer seeking biomolecules for targeted therapy. India

International Nuclear Information System (INIS)

Pillai, M.R.A.

2000-01-01

The work done towards the development of bifunctional chelating agents, modified peptide and their radiolabelling studies with 90 Y and 188 Re are reported. Bifunctional chelating agents DOTA, TETA and DAHPES were synthesised. DOTA-Lanreotide (Mauritius) was synthesised from Lanreotide. 90 Y and 188 Re used in the studies were obtained from 90 Sr- 90 Y and 188 W- 188 Re generators. Complexation studies of DOTA and Mauritius with 90 Y and that of DAHPES and EC with 188 Re were carried out. Cell labelling of 90 Y-DOTA-Lanreotide with a cell line expressing somatostatin receptors was also carried out

Synthesis of a Fluorescently Labeled 68Ga-DOTA-TOC Analog for Somatostatin Receptor Targeting.

Science.gov (United States)

Ghosh, Sukhen C; Hernandez Vargas, Servando; Rodriguez, Melissa; Kossatz, Susanne; Voss, Julie; Carmon, Kendra S; Reiner, Thomas; Schonbrunn, Agnes; Azhdarinia, Ali

2017-07-13

Fluorescently labeled imaging agents can identify surgical margins in real-time to help achieve complete resections and minimize the likelihood of local recurrence. However, photon attenuation limits fluorescence-based imaging to superficial lesions or lesions that are a few millimeters beneath the tissue surface. Contrast agents that are dual-labeled with a radionuclide and fluorescent dye can overcome this limitation and combine quantitative, whole-body nuclear imaging with intraoperative fluorescence imaging. Using a multimodality chelation (MMC) scaffold, IRDye 800CW was conjugated to the clinically used somatostatin analog, 68 Ga-DOTA-TOC, to produce the dual-labeled analog, 68 Ga-MMC(IRDye 800CW)-TOC, with high yield and specific activity. In vitro pharmacological assays demonstrated retention of receptor-targeting properties for the dual-labeled compound with robust internalization that was somatostatin receptor (SSTR) 2-mediated. Biodistribution studies in mice identified the kidneys as the primary excretion route for 68 Ga-MMC(IRDye 800CW)-TOC, along with clearance via the reticuloendothelial system. Higher uptake was observed in most tissues compared to 68 Ga-DOTA-TOC but decreased as a function of time. The combination of excellent specificity for SSTR2-expressing cells and suitable biodistribution indicate potential application of 68 Ga-MMC(IRDye 800CW)-TOC for intraoperative detection of SSTR2-expressing tumors.

Mercury removal in utility wet scrubber using a chelating agent

Science.gov (United States)

Amrhein, Gerald T.

2001-01-01

A method for capturing and reducing the mercury content of an industrial flue gas such as that produced in the combustion of a fossil fuel or solid waste adds a chelating agent, such as ethylenediaminetetraacetic acid (EDTA) or other similar compounds like HEDTA, DTPA and/or NTA, to the flue gas being scrubbed in a wet scrubber used in the industrial process. The chelating agent prevents the reduction of oxidized mercury to elemental mercury, thereby increasing the mercury removal efficiency of the wet scrubber. Exemplary tests on inlet and outlet mercury concentration in an industrial flue gas were performed without and with EDTA addition. Without EDTA, mercury removal totaled 42%. With EDTA, mercury removal increased to 71%. The invention may be readily adapted to known wet scrubber systems and it specifically provides for the removal of unwanted mercury both by supplying S.sup.2- ions to convert Hg.sup.2+ ions into mercuric sulfide (HgS) and by supplying a chelating agent to sequester other ions, including but not limited to Fe.sup.2+ ions, which could otherwise induce the unwanted reduction of Hg.sup.2+ to the form, Hg.sup.0.

Isolation and Utilization of Corn Cobs Hemisellulose as Chelating Agent for Lead Ions

International Nuclear Information System (INIS)

Muchlisyam; Harahap, U; Silalahi, J.; Zul Alfian

2013-01-01

Corn cobs is an agricultural byproduct containing polysaccharide composed of cellulose, hemicelluloses and lignin. Hemicelluloses has a hydroxyl and carbonyl functional groups which can be used as chelating agent for metal ions. The purpose of this study was to isolate and evaluate corncobs hemicelluloses as a chelating agent toward lead ion. Graphite furnace spectrophotometry at 283.3 nm was used to determine the residual lead ion in solution. The research's result showed that the highest yield of hemicelluloses (12.04 %) was obtained from delignication with 0,03 M NaOH in 60 % ethanol and 3 % H 2 O 2 , hemicelluloses isolation with 500 ml of 0.2 M NaOH, and precipitation with 1:4 ratio of 10 % acetic acid in 95 % ethanol. The 300 mg corn cobs hemicelluloses has chelating effect for 40 mg lead solution at (39.52±0.1350) mg or 98.80 %, that the corn cobs hemicelluloses can be used as a chelating agent for lead. (author)

Bifunctional chelating agent for the design and development of site specific radiopharmaceuticals and biomolecule conjugation strategy

Science.gov (United States)

Katti, Kattesh V.; Prabhu, Kandikere R.; Gali, Hariprasad; Pillarsetty, Nagavara Kishore; Volkert, Wynn A.

2003-10-21

There is provided a method of labeling a biomolecule with a transition metal or radiometal in a site specific manner to produce a diagnostic or therapeutic pharmaceutical compound by synthesizing a P.sub.2 N.sub.2 -bifunctional chelating agent intermediate, complexing the intermediate with a radio metal or a transition metal, and covalently linking the resulting metal-complexed bifunctional chelating agent with a biomolecule in a site specific manner. Also provided is a method of synthesizing the --PR.sub.2 containing biomolecules by synthesizing a P.sub.2 N.sub.2 -bifunctional chelating agent intermediate, complexing the intermediate with a radiometal or a transition metal, and covalently linking the resulting radio metal-complexed bifunctional chelating agent with a biomolecule in a site specific manner. There is provided a therapeutic or diagnostic agent comprising a --PR.sub.2 containing biomolecule.

DOTA-PESIN, a DOTA-conjugated bombesin derivative designed for the imaging and targeted radionuclide treatment of bombesin receptor-positive tumours

Energy Technology Data Exchange (ETDEWEB)

Zhang, Hanwen; Maecke, Helmut R. [University Hospital Basel, Division of Radiological Chemistry, Department of Radiology, Basel (Switzerland); Schuhmacher, Jochen; Eisenhut, Michael [German Cancer Research Centre, Department of Radiopharmaceutical Chemistry, Heidelberg (Germany); Waser, Beatrice; Reubi, Jean Claude [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, P.O. Box 62, Berne (Switzerland); Wild, Damian [University Hospital, Clinic and Institute of Nuclear Medicine, Department of Radiology, Basel (Switzerland)

2007-08-15

We aimed at designing and developing a novel bombesin analogue, DOTA-PEG{sub 4}-BN(7-14) (DOTA-PESIN), with the goal of labelling it with {sup 67/68}Ga and {sup 177}Lu for diagnosis and radionuclide therapy of prostate and other human cancers overexpressing bombesin receptors. The 8-amino acid peptide bombesin (7-14) was coupled to the macrocyclic chelator DOTA via the spacer 15-amino-4,7,10,13-tetraoxapentadecanoic acid (PEG{sub 4}). The conjugate was complexed with Ga(III) and Lu(III) salts. The GRP receptor affinity and the bombesin receptor subtype profile were determined in human tumour specimens expressing the three bombesin receptor subtypes. Internalisation and efflux studies were performed with the human GRP receptor cell line PC-3. Xenografted nude mice were used for biodistribution. [Ga{sup III}/Lu{sup III}]-DOTA-PESIN showed good affinity to GRP and neuromedin B receptors but no affinity to BB3. [{sup 67}Ga/{sup 177}Lu]-DOTA-PESIN internalised rapidly into PC-3 cells whereas the efflux from PC-3 cells was relatively slow. In vivo experiments showed a high and specific tumour uptake and good retention of [{sup 67}Ga/{sup 177}Lu]-DOTA-PESIN. [{sup 67}Ga/{sup 177}Lu]-DOTA-PESIN highly accumulated in GRP receptor-expressing mouse pancreas. The uptake specificity was demonstrated by blocking tumour uptake and pancreas uptake. Fast clearance was found from blood and all non-target organs except the kidneys. High tumour-to-normal tissue ratios were achieved, which increased with time. PET imaging with [{sup 68}Ga]-DOTA-PESIN was successful in visualising the tumour at 1 h post injection. Planar scintigraphic imaging showed that the {sup 177}Lu-labelled peptide remained in the tumour even 3 days post injection. The newly designed ligands have high potential with regard to PET and SPECT imaging with {sup 68/67}Ga and targeted radionuclide therapy with {sup 177}Lu. (orig.)

Glyphosate, a chelating agent-relevant for ecological risk assessment?

Science.gov (United States)

Mertens, Martha; Höss, Sebastian; Neumann, Günter; Afzal, Joshua; Reichenbecher, Wolfram

2018-02-01

Glyphosate-based herbicides (GBHs), consisting of glyphosate and formulants, are the most frequently applied herbicides worldwide. The declared active ingredient glyphosate does not only inhibit the EPSPS but is also a chelating agent that binds macro- and micronutrients, essential for many plant processes and pathogen resistance. GBH treatment may thus impede uptake and availability of macro- and micronutrients in plants. The present study investigated whether this characteristic of glyphosate could contribute to adverse effects of GBH application in the environment and to human health. According to the results, it has not been fully elucidated whether the chelating activity of glyphosate contributes to the toxic effects on plants and potentially on plant-microorganism interactions, e.g., nitrogen fixation of leguminous plants. It is also still open whether the chelating property of glyphosate is involved in the toxic effects on organisms other than plants, described in many papers. By changing the availability of essential as well as toxic metals that are bound to soil particles, the herbicide might also impact soil life, although the occurrence of natural chelators with considerably higher chelating potentials makes an additional impact of glyphosate for most metals less likely. Further research should elucidate the role of glyphosate (and GBH) as a chelator, in particular, as this is a non-specific property potentially affecting many organisms and processes. In the process of reevaluation of glyphosate its chelating activity has hardly been discussed.

Bone targeting compounds for radiotherapy and imaging: *Me(III)-DOTA conjugates of bisphosphonic acid, pamidronic acid and zoledronic acid.

Science.gov (United States)

Meckel, M; Bergmann, R; Miederer, M; Roesch, F

2017-01-01

Bisphosphonates have a high adsorption on calcified tissues and are commonly used in the treatment of bone disorder diseases. Conjugates of bisphosphonates with macrocyclic chelators open new possibilities in bone targeted radionuclide imaging and therapy. Subsequent to positron emission tomography (PET) examinations utilizing 68 Ga-labelled analogues, endoradiotheraphy with 177 Lu-labelled macrocyclic bisphosphonates may have a great potential in the treatment of painful skeletal metastases. Based on the established pharmaceuticals pamidronate and zoledronate two new DOTA-α-OH-bisphosphonates, DOTA PAM and DOTA ZOL (MM1.MZ) were successfully synthesized. The ligands were labelled with the positron emitting nuclide 68 Ga and the β - emitting nuclide 177 Lu and compared in in vitro studies and in ex vivo biodistribution studies together with small animal PET and single photon emission computed tomography (SPECT) studies against [ 18 F]NaF and a known DOTA-α-H-bisphosphonate conjugate (BPAPD) in healthy Wistar rats. The new DOTA-bisphosphonates can be labelled in high yield of 80 to 95 % in 15 min with post-processed 68 Ga and >98 % with 177 Lu. The tracers showed very low uptake in soft tissue, a fast renal clearance and a high accumulation on bone. The best compound was [ 68 Ga]DOTA ZOL (SUV Femur  = 5.4 ± 0.6) followed by [ 18 F]NaF (SUV Femur  = 4.8 ± 0.2), [ 68 Ga]DOTA PAM (SUV Femur  = 4.5 ± 0.2) and [ 68 Ga]BPAPD (SUV Femur  = 3.2 ± 0.3). [ 177 Lu]DOTA ZOL showed a similar distribution as the diagnostic 68 Ga complex. The 68 Ga labelled compounds showed a promising pharmacokinetics, with similar uptake profile and distribution kinetics. Bone accumulation was highest for [ 68 Ga]DOTA ZOL , which makes this compound probably an interesting bone targeting agent for a therapeutic approach with 177 Lu. The therapeutic compound [ 177 Lu]DOTA ZOL showed a high target-to-background ratio. SPECT experiments showed concordance

Development of [⁶⁴Cu]-DOTA-PR81 radioimmunoconjugate for MUC-1 positive PET imaging.

Science.gov (United States)

Alirezapour, Behrouz; Rasaee, Mohammad Javad; Jalilian, Amir Reza; Rajabifar, Saeed; Mohammadnejad, Javad; Paknejad, Malihe; Maadi, Ehsan; Moradkhani, Sedigheh

2016-01-01

Breast cancer radioimmunoscintigraphy targeting MUC1 expression is a growing field of work in nuclear medicine research. PR81 is a monoclonal antibody that binds with high affinity to MUC1, which is over expressed on breast tumors. In this study, we report production, quality control and preclinical qualifications of a copper-64 labeled PR81 for PET imaging of breast cancer. PR81 was conjugated with DOTA-NHS-ester and purified by molecular filtration followed by chelate:mAb ratio determination by spectrophotometric method. DOTA-PR81 was labeled with (64)Cu followed by radiochemical purity, in vitro stability, in vitro internalization and immunoreactivity determination. The tissue biodistribution of the (64)Cu-DOTA-PR81 and (64)Cu-DOTA-hIgG was evaluated in BALB/c mice with breast carcinoma tumors using tissue counting and imaging. The radiochemical purity of radioimmunoconjugate was >95±1.9% (ITLC) (specific activity; 4.6 μCi/μg). The average number of chelators per antibody was 3.4±0.3:1. The (64)Cu-DOTA-PR81 showed immunoreactivity towards MUC1 antigen and MCF7 cell line with significant in vitro stability (>89% in PBS and 78±0.5% in human serum) over 48 h. Maximum internalized activity of radiolabeled PR81 in 4-8 h was 81.5%. The biodistribution and scintigraphy studies showed the accumulation of the complex at the site of tumors with high sensitivity and specificity compared to control probes. The results showed that (64)Cu-DOTA-PR81 may be considered as a potential PET tracer for diagnosis and follow-up of MUC1 expression in oncology. Copyright © 2015 Elsevier Inc. All rights reserved.

Targeted Catalytic Inactivation of Angiotensin Converting Enzyme by Lisinopril-Coupled Transition Metal Chelates

Science.gov (United States)

Joyner, Jeff C.; Hocharoen, Lalintip; Cowan, J. A.

2012-01-01

A series of compounds that target reactive transition metal chelates to somatic Angiotensin Converting Enzyme (sACE-1) have been synthesized. Half maximal inhibitory concentrations (IC50) and rate constants for both inactivation and cleavage of full length sACE-1 have been determined and evaluated in terms of metal-chelate size, charge, reduction potential, coordination unsaturation, and coreactant selectivity. Ethylenediamine-tetraacetic acid (EDTA), nitrilotriacetic acid (NTA), 1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetic acid (DOTA), and tripeptide GGH were linked to the lysine sidechain of lisinopril by EDC/NHS coupling. The resulting amide-linked chelate-lisinopril (EDTA-lisinopril, NTA-lisinopril, DOTA-lisinopril, and GGH-lisinopril) conjugates were used to form coordination complexes with iron, cobalt, nickel and copper, such that lisinopril could mediate localization of the reactive metal chelates to sACE-1. ACE activity was assayed by monitoring cleavage of the fluorogenic substrate Mca-RPPGFSAFK(Dnp)-OH, a derivative of bradykinin, following pre-incubation with metal-chelate-lisinopril compounds. Concentration-dependent inhibition of sACE-1 by metal-chelate-lisinopril complexes revealed IC50 values ranging from 44 nM to 4,500 nM for Ni-NTA-lisinopril and Ni-DOTA-lisinopril, respectively, versus 1.9 nM for lisinopril. Stronger inhibition was correlated with smaller size and lower negative charge of the attached metal chelates. Time-dependent inactivation of sACE-1 by metal-chelate-lisinopril complexes revealed a remarkable range of catalytic activities, with second order rate constants as high as 150,000 M−1min−1 (Cu-GGH-lisinopril), while catalyst-mediated cleavage of sACE-1 typically occurred at much lower rates, indicating that inactivation arose primary from sidechain modification. Optimal inactivation of sACE-1 was observed when the reduction potential for the metal center was poised near 1000 mV, reflecting the difficulty of protein

Targeted catalytic inactivation of angiotensin converting enzyme by lisinopril-coupled transition-metal chelates.

Science.gov (United States)

Joyner, Jeff C; Hocharoen, Lalintip; Cowan, J A

2012-02-22

A series of compounds that target reactive transition-metal chelates to somatic angiotensin converting enzyme (sACE-1) have been synthesized. Half-maximal inhibitory concentrations (IC(50)) and rate constants for both inactivation and cleavage of full-length sACE-1 have been determined and evaluated in terms of metal chelate size, charge, reduction potential, coordination unsaturation, and coreactant selectivity. Ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and tripeptide GGH were linked to the lysine side chain of lisinopril by 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride/N-hydroxysuccinimide coupling. The resulting amide-linked chelate-lisinopril (EDTA-lisinopril, NTA-lisinopril, DOTA-lisinopril, and GGH-lisinopril) conjugates were used to form coordination complexes with iron, cobalt, nickel, and copper, such that lisinopril could mediate localization of the reactive metal chelates to sACE-1. ACE activity was assayed by monitoring cleavage of the fluorogenic substrate Mca-RPPGFSAFK(Dnp)-OH, a derivative of bradykinin, following preincubation with metal chelate-lisinopril compounds. Concentration-dependent inhibition of sACE-1 by metal chelate-lisinopril complexes revealed IC(50) values ranging from 44 to 4500 nM for Ni-NTA-lisinopril and Ni-DOTA-lisinopril, respectively, versus 1.9 nM for lisinopril. Stronger inhibition was correlated with smaller size and lower negative charge of the attached metal chelates. Time-dependent inactivation of sACE-1 by metal chelate-lisinopril complexes revealed a remarkable range of catalytic activities, with second-order rate constants as high as 150,000 M(-1) min(-1) (Cu-GGH-lisinopril), while catalyst-mediated cleavage of sACE-1 typically occurred at much lower rates, indicating that inactivation arose primarily from side chain modification. Optimal inactivation of sACE-1 was observed when the reduction potential for the

The use of radiocobalt as a label improves imaging of EGFR using DOTA-conjugated Affibody molecule

DEFF Research Database (Denmark)

Garousi, Javad; Andersson, Ken G; Dam, Johan H

2017-01-01

-expressing xenografts in mice. An optimal combination of radionuclide, chelator and targeting protein may further improve the contrast of radionuclide imaging. The aim of this study was to evaluate the targeting properties of radiocobalt-labelled DOTA-ZEGFR:2377. DOTA-ZEGFR:2377 was labelled with (57)Co (T1/2 = 271.8 d......), (55)Co (T1/2 = 17.5 h), and, for comparison, with the positron-emitting radionuclide (68)Ga (T1/2 = 67.6 min) with preserved specificity of binding to EGFR-expressing A431 cells. The long-lived cobalt radioisotope (57)Co was used in animal studies. Both (57)Co-DOTA-ZEGFR:2377 and (68)Ga-DOTA......Several anti-cancer therapies target the epidermal growth factor receptor (EGFR). Radionuclide imaging of EGFR expression in tumours may aid in selection of optimal cancer therapy. The (111)In-labelled DOTA-conjugated ZEGFR:2377 Affibody molecule was successfully used for imaging of EGFR...

Production of chelating agents by Pseudomonas aeruginosa grown in the presence of thorium and uranium

International Nuclear Information System (INIS)

Premuzic, E.T.; Lin, M.; Francis, A.J.; Schubert, J.

1986-01-01

Chelating agents produced by microorganisms enhance the dissolution of iron increasing the mobility and bioavailability of the metal. Since some similarities exist in the biological behavior of ferric, thorium and uranyl ions, microorganisms resistant to these metals and which grow in their presence may produce sequestering agents of Th and U, and other metals in a manner similar to the complexation of iron by siderophores. The ability of P. aeruginosa to elaborate sequestering agents in medium containing thorium or uranium salts was tested. Uranium has a stronger inhibitory effect on growth of the organism than thorium at similar concentrations. Analyses of the culture media have shown, that relative to the control, and under the experimental conditions used, the microorganisms have produced several new chelating agents for thorium and uranium. Extracts containing these chelating agents have been tested for their decorporation potential. In vitro mouse liver bioassay and in vivo mouse toxicity tests indicate that their efficiency is comparable to DTPA and DFOA and that they are virtually non-toxic to mice. The bacterially produced compounds resemble, but are not identical to the known iron chelating siderophores isolated from microorganisms. Some of their chemical properties are also discussed. (author)

Preparation and biological studies of 68Ga-DOTA-alendronate

Directory of Open Access Journals (Sweden)

Ashraf Fakhari

2016-07-01

Full Text Available Objective(s: In line with previous research on the development of conjugated bisphosphonate ligands as new bone-avid agents, in this study, DOTA conjugated alendronate (DOTA-ALN was synthesized and evaluated after labeling with gallium-68 (68Ga.Methods: DOTA-ALN was synthesized and characterized, followed by 68Ga-DOTA-ALN preparation, using DOTA-ALN and 68GaCl3 (pH: 4-5 at 92-95°C for 10 min. Stability tests, hydroxyapatite assay, partition coefficient calculation,biodistribution studies, and imaging were performed on the developed agent in normal rats.Results: The complex was prepared with high radiochemical purity (>99% as depicted by radio thin-layer chromatography; specific activity: 310-320GBq/mmol after solid phase purification and was stabilized for up to 90 min with a logP value of -2.91. Maximum ligand binding (65% was observed in the presence of 50 mg of hydroxyapatite; a major portion of the activity was excreted through the kidneys. With the exception of excretory organs, gastrointestinal tract organs, including the liver, intestine, and colon, showed significant uptake; however, the bone uptake was low (

Inositol hexa-phosphate: a potential chelating agent for uranium

International Nuclear Information System (INIS)

Cebrian, D.; Tapia, A.; Real, A.; Morcillo, M.A.

2007-01-01

Chelation therapy is an optimal method to reduce the radionuclide-related risks. In the case of uranium incorporation, the treatment of choice is so far i.v infusion of a 1.4% sodium bicarbonate solution, but the efficacy has been proved to be not very high. In this study, we examine the efficacy of some substances: bicarbonate, citrate, diethylenetriamine pentaacetic acid (DTPA), ethidronate (EHBP) and inositol hexa-phosphate (phytic acid) to chelate uranium using a test developed by Braun et al. Different concentrations of phytic acid, an abundant component of plant seeds that is widely distributed in animal cells and tissues in substantial levels, were tested and compared to the same concentrations of sodium citrate, bicarbonate, EHBP and DTPA. The results showed a strong affinity of inositol hexa-phosphate for uranium, suggesting that it could be an effective chelating agent for uranium in vivo. (authors)

Macromolecular and dendrimer-based magnetic resonance contrast agents

Energy Technology Data Exchange (ETDEWEB)

Bumb, Ambika; Brechbiel, Martin W. (Radiation Oncology Branch, National Cancer Inst., National Inst. of Health, Bethesda, MD (United States)), e-mail: pchoyke@mail.nih.gov; Choyke, Peter (Molecular Imaging Program, National Cancer Inst., National Inst. of Health, Bethesda, MD (United States))

2010-09-15

Magnetic resonance imaging (MRI) is a powerful imaging modality that can provide an assessment of function or molecular expression in tandem with anatomic detail. Over the last 20-25 years, a number of gadolinium-based MR contrast agents have been developed to enhance signal by altering proton relaxation properties. This review explores a range of these agents from small molecule chelates, such as Gd-DTPA and Gd-DOTA, to macromolecular structures composed of albumin, polylysine, polysaccharides (dextran, inulin, starch), poly(ethylene glycol), copolymers of cystamine and cystine with GD-DTPA, and various dendritic structures based on polyamidoamine and polylysine (Gadomers). The synthesis, structure, biodistribution, and targeting of dendrimer-based MR contrast agents are also discussed

New method for studying the efficiency of chelating agents of the polyamine acid series for internal decontamination

International Nuclear Information System (INIS)

Lafuma, J.; Nenot, J.C.; Morin, M.

1968-01-01

We followed the biological fate of a complex formed on one side with either a rare earth (cerium-144) or a transuranium element (plutonium-239), and on the other side with a chelating agent of the polyamino acid series (EDTA, BAETA, DTPA, TTHA). This method allowed to study: 1 - the in vivo stability of the various complexes and to compare them; 2 - the stability of the complexes as a function of the isotope - chelating agent weight relationships; 3 - the metabolism of the chelating agents resulting in stable complexes, i. e. DTPA and TTHA mainly. This simple method brought out the higher efficiency, of DTPA in chelating rare earths and plutonium and for therapeutic purposes. (authors) [fr

of radioconjugated DOTA-1-Nal3-octreotide labeled with gallium-68 using non-aqueous solvents

International Nuclear Information System (INIS)

Pérez-Malo Cruz, Marylaine; Leyva Montaña, René

2016-01-01

Neuroendocrine tumors specifically over-expressing somatostatin receptors. Diagnosis has expanded due to radiolabelling of DOTA-peptides such as somatostatin analogue DOTA-1-Nal 3 -Octreotide (DOTA-NOC) conjugated to β+ emitting radionuclides such as 68 Ga, which has very favorable physics-nuclear properties. This paper describes the radiolabeling procedures of DOTA-NOC with 68 Ga, in pure aqueous medium and in presence of non-aqueous solvents as well as the methods used for quality control where a formulation is obtained with a radiochemical yield exceeding 95%. The addition of ethanol (30% - v / v) to reaction mixture allowed to increase the specific activity of 68 Ga-DOTA-NOC radioconjugate, reaching a value of 182 MBq / nmol, higher than reported in the literature (50 MBq / nmol ) for labeling in pure aqueous medium. Stability studies are also presented (in presence of saline solution and saline phosphate buffer, transmetallation studies in Fe 3+ , Ca 2+ , Mg 2+ and Zn 2+ solutions, challenges competition against EDTA and DTPA chelators and in vitro stability in human transferrin) performed to 68Ga-DOTA-NOC radioconjugated, showing its high stability (> 95%). (author)

44Sc for labeling of DOTA- and NODAGA-functionalized peptides: preclinical in vitro and in vivo investigations.

Science.gov (United States)

Domnanich, Katharina A; Müller, Cristina; Farkas, Renata; Schmid, Raffaella M; Ponsard, Bernard; Schibli, Roger; Türler, Andreas; van der Meulen, Nicholas P

2017-01-01

Recently, 44 Sc (T 1/2  = 3.97 h, Eβ + av  = 632 keV, I = 94.3 %) has emerged as an attractive radiometal candidate for PET imaging using DOTA-functionalized biomolecules. The aim of this study was to investigate the potential of using NODAGA for the coordination of 44 Sc. Two pairs of DOTA/NODAGA-derivatized peptides were investigated in vitro and in vivo and the results obtained with 44 Sc compared with its 68 Ga-labeled counterparts.DOTA-RGD and NODAGA-RGD, as well as DOTA-NOC and NODAGA-NOC, were labeled with 44 Sc and 68 Ga, respectively. The radiopeptides were investigated with regard to their stability in buffer solution and under metal challenge conditions using Fe 3+ and Cu 2+ . Time-dependent biodistribution studies and PET/CT imaging were performed in U87MG and AR42J tumor-bearing mice. Both RGD- and NOC-based peptides with a DOTA chelator were readily labeled with 44 Sc and 68 Ga, respectively, and remained stable over at least 4 half-lives of the corresponding radionuclide. In contrast, the labeling of NODAGA-functionalized peptides with 44 Sc was more challenging and the resulting radiopeptides were clearly less stable than the DOTA-derivatized matches. 44 Sc-NODAGA peptides were clearly more susceptible to metal challenge than 44 Sc-DOTA peptides under the same conditions. Instability of 68 Ga-labeled peptides was only observed if they were coordinated with a DOTA in the presence of excess Cu 2+ . Biodistribution data of the 44 Sc-labeled peptides were largely comparable with the data obtained with the 68 Ga-labeled counterparts. It was only in the liver tissue that the uptake of 68 Ga-labeled DOTA compounds was markedly higher than for the 44 Sc-labeled version and this was also visible on PET/CT images. The 44 Sc-labeled NODAGA-peptides showed a similar tissue distribution to those of the DOTA peptides without any obvious signs of in vivo instability. Although DOTA revealed to be the preferred chelator for stable coordination of 44

Gd-labeled glycol chitosan as a pH-responsive magnetic resonance imaging agent for detecting acidic tumor microenvironments.

Science.gov (United States)

Nwe, Kido; Huang, Ching-Hui; Tsourkas, Andrew

2013-10-24

Neoplastic lesions can create a hostile tumor microenvironment with low extracellular pH. It is commonly believed that these conditions can contribute to tumor progression as well as resistance to therapy. We report the development and characterization of a pH-responsive magnetic resonance imaging contrast agent for imaging the acidic tumor microenvironment. The preparation included the conjugation of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid 1-(2,5-dioxo-1-pyrrolidinyl) ester (DOTA-NHS) to the surface of a water-soluble glycol chitosan (GC) polymer, which contains pH-titrable primary amines, followed by gadolinium complexation (GC-NH2-GdDOTA). GC-NH2-GdDOTA had a chelate-to-polymer ratio of approximately1:24 and a molar relaxivity of 9.1 mM(-1) s(-1). GC-NH2-GdDOTA demonstrated pH-dependent cellular association in vitro compared to the control. It also generated a 2.4-fold enhancement in signal in tumor-bearing mice 2 h postinjection. These findings suggest that glycol chitosan coupled with contrast agents can provide important diagnostic information about the tumor microenvironment.

Gd-DOTA enhancement of cerebral and spinal tumors on MR imaging

International Nuclear Information System (INIS)

Berry, I.; Manelfe, C.; Chastin, I.; Arrue, P.; Prere, J.

1987-01-01

The use of Gd-DOTA as a contrast agent in MR imaging to improve the diagnosis of cerebral and spinal tumors was assessed in 20 patients, ten with brain tumors and ten with spinal tumors. Imaging was performed with a 0.5-T Magniscan 5000 unit. T1-weighted (spin-echo and gradient-echo) and T2-weighted (spin-echo) images were acquired before and after intravenous injection of Gd-DOTA, 0.1 mmol/kg. On T1-weighted images, Gd-DOTA enhanced sites of presumed disruption of the blood-brain barrier. This made some brain tumors more conspicuous and helped target biopsies, but did not reveal any additional lesions. On the other hand, the use of Gd-DOTA significantly improved the reliability of spinal tumor imaging compared to imaging performed without contrast agent, allowing delineation of abnormalities on T1-weighted images, which frequently contain fewer artifacts than the most sensitive T2-weighted images. Images obtained with Gd-DOTA could be used by the physician to rule out residual tumor after surgery and to assess recurrences. Additional work should be done to discover whether spinal tumor exploration with MR imaging could include solely T1-weighted sequences, performed before and after contrast agent administration, without T2-weighted sequences

Hyperpolarized 89Y NMR spectroscopic detection of yttrium ion and DOTA macrocyclic ligand complexation: pH dependence and Y-DOTA intermediates

Science.gov (United States)

Ferguson, Sarah; Kiswandhi, Andhika; Niedbalski, Peter; Parish, Christopher; Kovacs, Zoltan; Lumata, Lloyd

Dissolution dynamic nuclear polarization (DNP) is a rapidly emerging physics technique used to enhance the signal strength in nuclear magnetic resonance (NMR) and imaging (MRI) experiments for nuclear spins such as yttrium-89 by >10,000-fold. One of the most common and stable MRI contrast agents used in the clinic is Gd-DOTA. In this work, we have investigated the binding of the yttrium and DOTA ligand as a model for complexation of Gd ion and DOTA ligand. The macrocyclic ligand DOTA is special because its complexation with lanthanide ions such as Gd3+ or Y3+ is highly pH dependent. Using this physics technology, we have tracked the complexation kinetics of hyperpolarized Y-triflate and DOTA ligand in real-time and detected the Y-DOTA intermediates. Different kinds of buffers were used (lactate, acetate, citrate, oxalate) and the pseudo-first order complexation kinetic calculations will be discussed. The authors would like to acknowledge the support by US Dept of Defense Award No. W81XWH-14-1-0048 and Robert A. Welch Foundation Grant No. AT-1877.

Characterization of radionuclide-chelating agent complexes found in low-level radioactive decontamination waste. Literature review

International Nuclear Information System (INIS)

Serne, R.J.; Felmy, A.R.; Cantrell, K.J.; Krupka, K.M.; Campbell, J.A.; Bolton, H. Jr.; Fredrickson, J.K.

1996-03-01

The US Nuclear Regulatory Commission is responsible for regulating the safe land disposal of low-level radioactive wastes that may contain organic chelating agents. Such agents include ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), picolinic acid, oxalic acid, and citric acid, and can form radionuclide-chelate complexes that may enhance the migration of radionuclides from disposal sites. Data from the available literature indicate that chelates can leach from solidified decontamination wastes in moderate concentration (1--100 ppm) and can potentially complex certain radionuclides in the leachates. In general it appears that both EDTA and DTPA have the potential to mobilize radionuclides from waste disposal sites because such chelates can leach in moderate concentration, form strong radionuclide-chelate complexes, and can be recalcitrant to biodegradation. It also appears that oxalic acid and citric acid will not greatly enhance the mobility of radionuclides from waste disposal sites because these chelates do not appear to leach in high concentration, tend to form relatively weak radionuclide-chelate complexes, and can be readily biodegraded. In the case of picolinic acid, insufficient data are available on adsorption, complexation of key radionuclides (such as the actinides), and biodegradation to make definitive predictions, although the available data indicate that picolinic acid can chelate certain radionuclides in the leachates

Characterization of radionuclide-chelating agent complexes found in low-level radioactive decontamination waste. Literature review

Energy Technology Data Exchange (ETDEWEB)

Serne, R.J.; Felmy, A.R.; Cantrell, K.J.; Krupka, K.M.; Campbell, J.A.; Bolton, H. Jr.; Fredrickson, J.K. [Pacific Northwest National Lab., Richland, WA (United States)

1996-03-01

The US Nuclear Regulatory Commission is responsible for regulating the safe land disposal of low-level radioactive wastes that may contain organic chelating agents. Such agents include ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), picolinic acid, oxalic acid, and citric acid, and can form radionuclide-chelate complexes that may enhance the migration of radionuclides from disposal sites. Data from the available literature indicate that chelates can leach from solidified decontamination wastes in moderate concentration (1--100 ppm) and can potentially complex certain radionuclides in the leachates. In general it appears that both EDTA and DTPA have the potential to mobilize radionuclides from waste disposal sites because such chelates can leach in moderate concentration, form strong radionuclide-chelate complexes, and can be recalcitrant to biodegradation. It also appears that oxalic acid and citric acid will not greatly enhance the mobility of radionuclides from waste disposal sites because these chelates do not appear to leach in high concentration, tend to form relatively weak radionuclide-chelate complexes, and can be readily biodegraded. In the case of picolinic acid, insufficient data are available on adsorption, complexation of key radionuclides (such as the actinides), and biodegradation to make definitive predictions, although the available data indicate that picolinic acid can chelate certain radionuclides in the leachates.

Development of novel radiogallium-labeled bone imaging agents using oligo-aspartic acid peptides as carriers.

Directory of Open Access Journals (Sweden)

Kazuma Ogawa

Full Text Available (68Ga (T 1/2 = 68 min, a generator-produced nuclide has great potential as a radionuclide for clinical positron emission tomography (PET. Because poly-glutamic and poly-aspartic acids have high affinity for hydroxyapatite, to develop new bone targeting (68Ga-labeled bone imaging agents for PET, we used 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA as a chelating site and conjugated aspartic acid peptides of varying lengths. Subsequently, we compared Ga complexes, Ga-DOTA-(Aspn (n = 2, 5, 8, 11, or 14 with easy-to-handle (67Ga, with the previously described (67Ga-DOTA complex conjugated bisphosphonate, (67Ga-DOTA-Bn-SCN-HBP. After synthesizing DOTA-(Aspn by a Fmoc-based solid-phase method, complexes were formed with (67Ga, resulting in (67Ga-DOTA-(Aspn with a radiochemical purity of over 95% after HPLC purification. In hydroxyapatite binding assays, the binding rate of (67Ga-DOTA-(Aspn increased with the increase in the length of the conjugated aspartate peptide. Moreover, in biodistribution experiments, (67Ga-DOTA-(Asp8, (67Ga-DOTA-(Asp11, and (67Ga-DOTA-(Asp14 showed high accumulation in bone (10.5 ± 1.5, 15.1 ± 2.6, and 12.8 ± 1.7% ID/g, respectively but were barely observed in other tissues at 60 min after injection. Although bone accumulation of (67Ga-DOTA-(Aspn was lower than that of (67Ga-DOTA-Bn-SCN-HBP, blood clearance of (67Ga-DOTA-(Aspn was more rapid. Accordingly, the bone/blood ratios of (67Ga-DOTA-(Asp11 and (67Ga-DOTA-(Asp14 were comparable with those of (67Ga-DOTA-Bn-SCN-HBP. In conclusion, these data provide useful insights into the drug design of (68Ga-PET tracers for the diagnosis of bone disorders, such as bone metastases.

Chelation Therapy for Mercury Poisoning

Directory of Open Access Journals (Sweden)

Rong Guan

2009-01-01

Full Text Available Chelation therapy has been the major treatment for heavy metal poisoning. Various chelating agents have been developed and tested for treatment of heavy metal intoxications, including mercury poisoning. It has been clearly shown that chelating agents could rescue the toxicity caused by heavy metal intoxication, but the potential preventive role of chelating agents against heavy metal poisoning has not been explored much. Recent paper by Siddiqi and colleagues has suggested a protective role of chelating agents against mercury poisoning, which provides a promising research direction for broader application of chelation therapy in prevention and treatment of mercury poisoning.

Preparation of 177Lu-DOTA/DTPA-Bz-Cys-RGD dimer and biodistribution evaluation in normal mice

International Nuclear Information System (INIS)

Sheng Feng; Jia Bing; Wang Fan; He Weiwei; Liu Zhaofei; Zhao Huiyun

2008-01-01

177 Lu-DOTA-Bz-Cys-RGD dimer and 177 Lu-DTPA-Bz-Cys-RGD dimer were prepared, and the in vitro and in vivo properties were compared. TLC and HPLC show that the labeling yields of two radiolabeled compounds are more than 95% under optimal conditions (pH=5.0, reacting at 100 degree C for 15-20 min), and the two radiolabeled compounds show pretty good in vitro stability. HPLC analyses and lg P values reveal that lipophilicity of 177 Lu-DOTA-Bz-Cys- RGD dimer is higher than 177 Lu-DTPA-Bz-Cys-RGD dimer. The uptake of 177 Lu-DTPA-Bz-Cys- RGD dimer in other tissues is significantly higher than that of 177 Lu-DOTA-Bz-Cys-RGD dimer at 4 h postinjection, except for blood and spleen. The in vivo stability of 177 Lu-DOTA-Bz-Cys-RGD dimer is much better than 177 Lu-DTPA-Bz-Cys-RGD dimer. Bz-DOTA is an ideal bifunctional chelator for 177 Lu labeling of RGD dimer. (authors)

Positron emission tomography study on pancreatic somatostatin receptors in normal and diabetic rats with {sup 68}Ga-DOTA-octreotide: A potential PET tracer for beta cell mass measurement

Energy Technology Data Exchange (ETDEWEB)

Sako, Takeo [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Division of Molecular Imaging, Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017 (Japan); Hasegawa, Koki; Nishimura, Mie; Kanayama, Yousuke; Wada, Yasuhiro; Hayashinaka, Emi; Cui, Yilong; Kataoka, Yosky [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Senda, Michio [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Division of Molecular Imaging, Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017 (Japan); Watanabe, Yasuyoshi, E-mail: yywata@riken.jp [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan)

2013-12-06

Highlights: •PET images showed high uptake of {sup 68}Ga-DOTA-octreotide in the normal pancreas. •{sup 68}Ga-DOTA-octreotide specifically binds to somatostatin receptors in the pancreas. •The pancreatic uptake of {sup 68}Ga-DOTA-octreotide was decreased in the diabetic rats. •{sup 68}Ga-DOTA-octreotide could be a candidate PET probe to measure the beta cell mass. -- Abstract: Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, and the loss or dysfunction of pancreatic beta cells has been reported before the appearance of clinical symptoms and hyperglycemia. To evaluate beta cell mass (BCM) for improving the detection and treatment of DM at earlier stages, we focused on somatostatin receptors that are highly expressed in the pancreatic beta cells, and developed a positron emission tomography (PET) probe derived from octreotide, a metabolically stable somatostatin analog. Octreotide was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a chelating agent, and labeled with {sup 68}Gallium ({sup 68}Ga). After intravenous injection of {sup 68}Ga-DOTA-octreotide, a 90-min emission scan of the abdomen was performed in normal and DM model rats. The PET studies showed that {sup 68}Ga-DOTA-octreotide radioactivity was highly accumulated in the pancreas of normal rats and that the pancreatic accumulation was significantly reduced in the rats administered with an excess amount of unlabeled octreotide or after treatment with streptozotocin, which was used for the chemical induction of DM in rats. These results were in good agreement with the ex vivo biodistribution data. These results indicated that the pancreatic accumulation of {sup 68}Ga-DOTA-octreotide represented specific binding to the somatostatin receptors and reflected BCM. Therefore, PET imaging with {sup 68}Ga-DOTA-octreotide could be a potential tool for evaluating BCM.

Searching for new aluminium chelating agents: a family of hydroxypyrone ligands.

Science.gov (United States)

Toso, Leonardo; Crisponi, Guido; Nurchi, Valeria M; Crespo-Alonso, Miriam; Lachowicz, Joanna I; Mansoori, Delara; Arca, Massimiliano; Santos, M Amélia; Marques, Sérgio M; Gano, Lurdes; Niclós-Gutíerrez, Juan; González-Pérez, Josefa M; Domínguez-Martín, Alicia; Choquesillo-Lazarte, Duane; Szewczuk, Zbigniew

2014-01-01

Attention is devoted to the role of chelating agents in the treatment of aluminium related diseases. In fact, in spite of the efforts that have drastically reduced the occurrence of aluminium dialysis diseases, they so far constitute a cause of great medical concern. The use of chelating agents for iron and aluminium in different clinical applications has found increasing attention in the last thirty years. With the aim of designing new chelators, we synthesized a series of kojic acid derivatives containing two kojic units joined by different linkers. A huge advantage of these molecules is that they are cheap and easy to produce. Previous works on complex formation equilibria of a first group of these ligands with iron and aluminium highlighted extremely good pMe values and gave evidence of the ability to scavenge iron from inside cells. On these bases a second set of bis-kojic ligands, whose linkers between the kojic chelating moieties are differentiated both in terms of type and size, has been designed, synthesized and characterized. The aluminium(III) complex formation equilibria studied by potentiometry, electrospray ionization mass spectroscopy (ESI-MS), quantum-mechanical calculations and (1)H NMR spectroscopy are here described and discussed, and the structural characterization of one of these new ligands is presented. The in vivo studies show that these new bis-kojic derivatives induce faster clearance from main organs as compared with the monomeric analog. © 2013.

Comparative study on DOTA-derivatized bombesin analog labeled with 90Y and 177Lu: in vitro and in vivo evaluation

International Nuclear Information System (INIS)

Koumarianou, Eftychia; Mikolajczak, Renata; Pawlak, Dariusz; Zikos, Xhristos; Bouziotis, Pinelopi; Garnuszek, Piotr; Karczmarczyk, Urszula; Maurin, Michal; Archimandritis, Spyridon C.

2009-01-01

Introduction: The aim of the study was to compare in vitro and in vivo a novel DOTA-chelated bombesin (BN) analog of the amino acid sequence, QRLGNQWAVGHLM-CONH 2 (BN[2-14]NH 2 ), labeled with 90 Y and 177 Lu, for its potential use in targeted radiotherapy of tumors expressing gastrin releasing peptide (GRP) receptors. The same amino acid sequence, but with different chelator, referred as BN1.1 (Gly-Gly-Cys-Aca-QRLGNQWAVGHLM-CONH 2 ), has already been studied and reported; however, the DOTA-chelated one, suitable for labeling with M +3 type radiometals, was not yet described. Methods: The conditions for labeling of DOTA-BN[2-14]NH 2 with noncarrier added 90 Y and with 177 Lu [specific activity (SA), 15 Ci/mg Lu] were investigated and optimized to provide 90 Y-DOTA-BN[2-14]NH 2 and 177 Lu-DOTA-BN[2-14]NH 2 of high SA. The stability of the radiolabeled compounds in human serum was evaluated over a period of 24 h. The human prostate cancer cell line PC-3, known to express GRP receptors, was used for in vitro evaluation of radiolabeled peptide affinity to GRP receptors and for assessment of cytotoxicity of both nonlabeled and radiolabeled peptide. Biodistribution accompanied by receptor blocking was studied in normal Swiss mice. Results: 90 Y-DOTA-BN[2-14]NH 2 and 177 Lu-DOTA-BN[2-14]NH 2 were obtained with radiochemical yield >98% and high SA (67.3 GBq 90 Y/μmol and 33.6 GBq 177 Lu/μmol, respectively). They were stable when incubated in human serum for up to 24 h. The binding affinities of DOTA-BN[2-14]NH 2 and both nat Y- and nat Lu-labeled analogs to GRP receptors were high (IC 50 =1.78, 1.99, and 1.34 nM, respectively), especially for the nat Lu-DOTA-BN[2-14]NH 2 complex. The cytotoxicity study of DOTA-BN[2-14]NH 2 to PC-3 cells revealed an IC 50 =6300 nM after 72 h of exposition, while the labeled derivatives showed no significant cytotoxic effect. The internalization rate to PC-3 cells was more rapid for 177 Lu-labeled peptide (84.87%) than for the 90 Y

Preparation and Biological Study of (68)Ga-DOTA-alendronate.

Science.gov (United States)

Fakhari, Ashraf; Jalilian, Amir R; Johari-Daha, Fariba; Shafiee-Ardestani, Mehdi; Khalaj, Ali

2016-01-01

In line with previous research on the development of conjugated bisphosphonate ligands as new bone-avid agents, in this study, DOTA-conjugated alendronate (DOTA-ALN) was synthesized and evaluated after labeling with gallium-68 ((68)Ga). DOTA-ALN was synthesized and characterized, followed by (68)Ga-DOTA-ALN preparation, using DOTA-ALN and (68)GaCl3 (pH: 4-5) at 92-95° C for 10 min. Stability tests, hydroxyapatite assay, partition coefficient calculation, biodistribution studies, and imaging were performed on the developed agent in normal rats. The complex was prepared with high radiochemical purity (>99% as depicted by radio thin-layer chromatography; specific activity: 310-320 GBq/mmol) after solid phase purification and was stabilized for up to 90 min with a log P value of -2.91. Maximum ligand binding (65%) was observed in the presence of 50 mg of hydroxyapatite; a major portion of the activity was excreted through the kidneys. With the exception of excretory organs, gastrointestinal tract organs, including the liver, intestine, and colon, showed significant uptake; however, the bone uptake was low (<1%) at 30 min after the injection. The data were also confirmed by sequential imaging at 30-90 min following the intravenous injection. The high solubility and anionic properties of the complex led to major renal excretion and low hydroxyapatite uptake; therefore, the complex failed to demonstrate bone imaging behaviors.

Design, Synthesis, and Biological Evaluation of 68Ga-DOTA-PA1 for Lung Cancer: A Novel PET Tracer for Multiple Somatostatin Receptor Imaging.

Science.gov (United States)

Liu, Fei; Liu, Teli; Xu, Xiaoxia; Guo, Xiaoyi; Li, Nan; Xiong, Chiyi; Li, Chun; Zhu, Hua; Yang, Zhi

2018-02-05

Most of the radiolabeled somatostatin analogues (SSAs) are specific for subtype somatostatin receptor 2 (SSTR 2 ). Lack of ligands targeting other subtypes of SSTRs, especially SSTR 1, SSTR 3 , and SSTR 5 , limited their applications in tumors of low SSTR 2 expression, including lung tumor. In this study, we aimed to design and synthesize a positron emission tomography (PET) radiotracer targeting multi-subtypes of SSTRs for PET imaging. PA1 peptide and its conjugate with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator or fluorescein isothiocyanate (FITC) at the N-terminal of the lysine position were synthesized. 68 Ga was chelated to DOTA-PA1 to obtain 68 Ga-DOTA-PA1 radiotracer. The stability, lipophilicity, binding affinity, and binding specificity of 68 Ga-DOTA-PA1 and FITC-PA1 were evaluated by various in vitro experiments. Micro-PET imaging of 68 Ga-DOTA-PA1 was performed in nude mice bearing A549 lung adenocarcinoma, as compared with 68 Ga-DOTA-(Tyr3)-octreotate ( 68 Ga-DOTA-TATE). Histological analysis of SSTR expression in A549 tumor tissues and human tumor tissues was conducted using immunofluorescence staining and immunohistochemical assay. 68 Ga-DOTA-PA1 had high radiochemical yield and radiochemical purity of over 95% and 99%, respectively. The radiotracer was stable in vitro in different buffers over a 2 h incubation period. Cell uptake of 68 Ga-DOTA-PA1 was 1.31-, 1.33-, and 1.90-fold that of 68 Ga-DOTA-TATE, which has high binding affinity only for SSTR 2 , after 2 h incubation in H520, PG, and A549 lung cancer cell lines, respectively. Micro-PET images of 68 Ga-DOTA-PA1 showed that the PET imaging signal correlated with the total expression of SSTRs, instead of SSTR 2 only, which was measured by Western blotting and immunofluorescence analysis in mice bearing A549 tumors. In summary, a novel PET radiotracer, 68 Ga-DOTA-PA1, targeting multi-subtypes of SSTRs, was successfully synthesized and was confirmed to be useful for PET

Positron emission tomography study on pancreatic somatostatin receptors in normal and diabetic rats with 68Ga-DOTA-octreotide: a potential PET tracer for beta cell mass measurement.

Science.gov (United States)

Sako, Takeo; Hasegawa, Koki; Nishimura, Mie; Kanayama, Yousuke; Wada, Yasuhiro; Hayashinaka, Emi; Cui, Yilong; Kataoka, Yosky; Senda, Michio; Watanabe, Yasuyoshi

2013-12-06

Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, and the loss or dysfunction of pancreatic beta cells has been reported before the appearance of clinical symptoms and hyperglycemia. To evaluate beta cell mass (BCM) for improving the detection and treatment of DM at earlier stages, we focused on somatostatin receptors that are highly expressed in the pancreatic beta cells, and developed a positron emission tomography (PET) probe derived from octreotide, a metabolically stable somatostatin analog. Octreotide was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a chelating agent, and labeled with (68)Gallium ((68)Ga). After intravenous injection of (68)Ga-DOTA-octreotide, a 90-min emission scan of the abdomen was performed in normal and DM model rats. The PET studies showed that (68)Ga-DOTA-octreotide radioactivity was highly accumulated in the pancreas of normal rats and that the pancreatic accumulation was significantly reduced in the rats administered with an excess amount of unlabeled octreotide or after treatment with streptozotocin, which was used for the chemical induction of DM in rats. These results were in good agreement with the ex vivo biodistribution data. These results indicated that the pancreatic accumulation of (68)Ga-DOTA-octreotide represented specific binding to the somatostatin receptors and reflected BCM. Therefore, PET imaging with (68)Ga-DOTA-octreotide could be a potential tool for evaluating BCM. Copyright © 2013 Elsevier Inc. All rights reserved.

Development of a large peptoid-DOTA combinatorial library.

Science.gov (United States)

Singh, Jaspal; Lopes, Daniel; Gomika Udugamasooriya, D

2016-09-01

Conventional one-bead one-compound (OBOC) library synthesis is typically used to identify molecules with therapeutic value. The design and synthesis of OBOC libraries that contain molecules with imaging or even potentially therapeutic and diagnostic capacities (e.g. theranostic agents) has been overlooked. The development of a therapeutically active molecule with a built-in imaging component for a certain target is a daunting task, and structure-based rational design might not be the best approach. We hypothesize to develop a combinatorial library with potentially therapeutic and imaging components fused together in each molecule. Such molecules in the library can be used to screen, identify, and validate as direct theranostic candidates against targets of interest. As the first step in achieving that aim, we developed an on-bead library of 153,600 Peptoid-DOTA compounds in which the peptoids are the target-recognizing and potentially therapeutic components and the DOTA is the imaging component. We attached the DOTA scaffold to TentaGel beads using one of the four arms of DOTA, and we built a diversified 6-mer peptoid library on the remaining three arms. We evaluated both the synthesis and the mass spectrometric sequencing capacities of the test compounds and of the final library. The compounds displayed unique ionization patterns including direct breakages of the DOTA scaffold into two units, allowing clear decoding of the sequences. Our approach provides a facile synthesis method for the complete on-bead development of large peptidomimetic-DOTA libraries for screening against biological targets for the identification of potential theranostic agents in the future. © 2016 The Authors. Biopolymers Published by Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 673-684, 2016. © 2016 The Authors. Biopolymers Published by Wiley Periodicals, Inc.

Detoxication and removal of uranium by phenolic chelating agents

International Nuclear Information System (INIS)

Luo Meichu; Chen Guibao; Li Landi

1992-01-01

The use of phenolic chelating agents for detoxication and removal of uranyl nitrate in mice and rats is reported. Antidotal test: 8102, 7601 and 811 were given 2 mM/kg subcutaneously to mice and 1 mM/kg intramuscularly to rats when the animals were injected i.p. with different doses (100-500 mg/kg) of uranyl nitrate. The results showed that the antidotal effects of 8102 and 7601 were better than 811 in augmenting survival, survival time (day) and renal factor (kidney weight/body weight x100). 8102 was superior to 7601 against higher dose of uranyl nitrate intoxication. Removal test: five phenolic chelating agents (8102, 7601, 811, 7603 and 8307) were studied in rats. The results obtained demonstrated that 8102 and 7601 were better than 811, 7603 and 8307 in increasing U excretion in the urine after acute uranyl nitrate intoxication. The effects of different doses (300-1000 μM/kg) of 8102 was superior to 7601 in increasing U excretion in the urine and decreasing U deposition in the tissues. The toxicity and dose of 8102 in treating uranium intoxication are discussed

Iron-chelating agents never suppress Fenton reaction but participate in quenching spin-trapped radicals

International Nuclear Information System (INIS)

Li Linxiang; Abe, Yoshihiro; Kanagawa, Kiyotada; Shoji, Tomoko; Mashino, Tadahiko; Mochizuki, Masataka; Tanaka, Miho; Miyata, Naoki

2007-01-01

Hydroxyl radical formation by Fenton reaction in the presence of an iron-chelating agent such as EDTA was traced by two different assay methods; an electron spin resonance (ESR) spin-trapping method with 5,5-dimethyl-1-pyrroline N-oxide (DMPO), and high Performance liquid chromatography (HPLC)-fluorescence detection with terephthalic acid (TPA), a fluorescent probe for hydroxyl radicals. From the ESR spin-trapping measurement, it was observed that EDTA seemed to suppress hydroxyl radical formation with the increase of its concentration. On the other hand, hydroxyl radical formation by Fenton reaction was not affected by EDTA monitored by HPLC assay. Similar inconsistent effects of other iron-chelating agents such as nitrylotriacetic acid (NTA), diethylenetriamine penta acetic acid (DTPA), oxalate and citrate were also observed. On the addition of EDTA solution to the reaction mixture 10 min after the Fenton reaction started, when hydroxyl radical formation should have almost ceased but the ESR signal of DMPO-OH radicals could be detected, it was observed that the DMPO-OH· signal disappeared rapidly. With the simultaneous addition of Fe(II) solution and EDTA after the Fenton reaction ceased, the DMPO-OH· signal disappeared more rapidly. The results indicated that these chelating agents should enhance the quenching of [DMPO-OH]· radicals by Fe(II), but they did not suppress Fenton reaction by forming chelates with iron ions

Chelation Therapy for Mercury Poisoning

OpenAIRE

Rong Guan; Han Dai

2009-01-01

Chelation therapy has been the major treatment for heavy metal poisoning. Various chelating agents have been developed and tested for treatment of heavy metal intoxications, including mercury poisoning. It has been clearly shown that chelating agents could rescue the toxicity caused by heavy metal intoxication, but the potential preventive role of chelating agents against heavy metal poisoning has not been explored much. Recent paper by Siddiqi and colleagues has suggested a protective role o...

Comparative study on DOTA-derivatized bombesin analog labeled with {sup 90}Y and {sup 177}Lu: in vitro and in vivo evaluation

Energy Technology Data Exchange (ETDEWEB)

Koumarianou, Eftychia [Institute R-RP, NCSR ' Demokritos' , Athens (Greece); IAE, Radioisotope Centre POLATOM, 05-400 Swierk-Otwock (Poland)], E-mail: eytyxiak@yahoo.com; Mikolajczak, Renata; Pawlak, Dariusz [IAE, Radioisotope Centre POLATOM, 05-400 Swierk-Otwock (Poland); Zikos, Xhristos; Bouziotis, Pinelopi [Institute R-RP, NCSR ' Demokritos' , Athens (Greece); Garnuszek, Piotr; Karczmarczyk, Urszula; Maurin, Michal [Department of Radiopharmaceuticals, National Medicines Institute, Chelmska 30/34, 00-725 Warsaw (Poland); Archimandritis, Spyridon C. [Institute R-RP, NCSR ' Demokritos' , Athens (Greece)

2009-08-15

Introduction: The aim of the study was to compare in vitro and in vivo a novel DOTA-chelated bombesin (BN) analog of the amino acid sequence, QRLGNQWAVGHLM-CONH{sub 2} (BN[2-14]NH{sub 2}), labeled with {sup 90}Y and {sup 177}Lu, for its potential use in targeted radiotherapy of tumors expressing gastrin releasing peptide (GRP) receptors. The same amino acid sequence, but with different chelator, referred as BN1.1 (Gly-Gly-Cys-Aca-QRLGNQWAVGHLM-CONH{sub 2}), has already been studied and reported; however, the DOTA-chelated one, suitable for labeling with M{sup +3} type radiometals, was not yet described. Methods: The conditions for labeling of DOTA-BN[2-14]NH{sub 2} with noncarrier added {sup 90}Y and with {sup 177}Lu [specific activity (SA), 15 Ci/mg Lu] were investigated and optimized to provide {sup 90}Y-DOTA-BN[2-14]NH{sub 2} and {sup 177}Lu-DOTA-BN[2-14]NH{sub 2} of high SA. The stability of the radiolabeled compounds in human serum was evaluated over a period of 24 h. The human prostate cancer cell line PC-3, known to express GRP receptors, was used for in vitro evaluation of radiolabeled peptide affinity to GRP receptors and for assessment of cytotoxicity of both nonlabeled and radiolabeled peptide. Biodistribution accompanied by receptor blocking was studied in normal Swiss mice. Results: {sup 90}Y-DOTA-BN[2-14]NH{sub 2} and {sup 177}Lu-DOTA-BN[2-14]NH{sub 2} were obtained with radiochemical yield >98% and high SA (67.3 GBq {sup 90}Y/{mu}mol and 33.6 GBq {sup 177}Lu/{mu}mol, respectively). They were stable when incubated in human serum for up to 24 h. The binding affinities of DOTA-BN[2-14]NH{sub 2} and both {sup nat}Y- and {sup nat}Lu-labeled analogs to GRP receptors were high (IC{sub 50}=1.78, 1.99, and 1.34 nM, respectively), especially for the {sup nat}Lu-DOTA-BN[2-14]NH{sub 2} complex. The cytotoxicity study of DOTA-BN[2-14]NH{sub 2} to PC-3 cells revealed an IC{sub 50}=6300 nM after 72 h of exposition, while the labeled derivatives showed no

Labelling of the peptide Dota-Octreotate with Lutetium 177; Marcado del peptido Dota-Octreotate con Lutecio 177

Energy Technology Data Exchange (ETDEWEB)

Hernandez B, C.A

2004-07-01

In this work is described the optimization of the reaction conditions to obtain the complex {sup 177} Lu-Dota-TATE with a radiochemical purity > 95%, even so the studies of stability In vitro to the dilution in saline solution, stability in human serum and challenge to the cystein. The biodistribution studies are presented in mice Balb-C and the tests of biological recognition using one lines cellular of pancreatic adenoma (AR42-J). The obtained results show a high stability of the radio complex in vitro, since it doesn't suffer trans chelation from the Lutetium-177 to plasmatic proteins. The biodistribution tests in mice Balb-C demonstrated an appropriate lipophilly of the complex to be excreted in more proportion by the kidneys without significant accumulation in healthy tissues. It is necessary to mention that the drop activity specifies (3.54 {mu}g / 37 MBq) obtained in the irradiation of {sup 176} Lu{sub 2}O{sub 3} it allowed to verify the union of the {sup 177}Lu-Dota-Tate to membrane receivers but without being able to obtain the saturation curves and competition required to characterize quantitatively the biological recognition. (Author)

The use of radiocobalt as a label improves imaging of EGFR using DOTA-conjugated Affibody molecule.

Science.gov (United States)

Garousi, Javad; Andersson, Ken G; Dam, Johan H; Olsen, Birgitte B; Mitran, Bogdan; Orlova, Anna; Buijs, Jos; Ståhl, Stefan; Löfblom, John; Thisgaard, Helge; Tolmachev, Vladimir

2017-07-20

Several anti-cancer therapies target the epidermal growth factor receptor (EGFR). Radionuclide imaging of EGFR expression in tumours may aid in selection of optimal cancer therapy. The 111 In-labelled DOTA-conjugated Z EGFR:2377 Affibody molecule was successfully used for imaging of EGFR-expressing xenografts in mice. An optimal combination of radionuclide, chelator and targeting protein may further improve the contrast of radionuclide imaging. The aim of this study was to evaluate the targeting properties of radiocobalt-labelled DOTA-Z EGFR:2377 . DOTA-Z EGFR:2377 was labelled with 57 Co (T 1/2  = 271.8 d), 55 Co (T 1/2  = 17.5 h), and, for comparison, with the positron-emitting radionuclide 68 Ga (T 1/2  = 67.6 min) with preserved specificity of binding to EGFR-expressing A431 cells. The long-lived cobalt radioisotope 57 Co was used in animal studies. Both 57 Co-DOTA-Z EGFR:2377 and 68 Ga-DOTA-Z EGFR:2377 demonstrated EGFR-specific accumulation in A431 xenografts and EGFR-expressing tissues in mice. Tumour-to-organ ratios for the radiocobalt-labelled DOTA-Z EGFR:2377 were significantly higher than for the gallium-labelled counterpart already at 3 h after injection. Importantly, 57 Co-DOTA-Z EGFR:2377 demonstrated a tumour-to-liver ratio of 3, which is 7-fold higher than the tumour-to-liver ratio for 68 Ga-DOTA-Z EGFR:2377 . The results of this study suggest that the positron-emitting cobalt isotope 55 Co would be an optimal label for DOTA-Z EGFR:2377 and further development should concentrate on this radionuclide as a label.

High-performance lithium-rich layered oxide materials: Effects of chelating agents on microstructure and electrochemical properties

International Nuclear Information System (INIS)

Li, Lingjun; Xu, Ming; Chen, Zhaoyong; Zhou, Xiang; Zhang, Qiaobao; Zhu, Huali; Wu, Chun; Zhang, Kaili

2015-01-01

The mechanisms and effects of three typical chelating agents, namely glucose, citric acid and sucrose on the sol-gel synthesis process, electrochemical degradation and structural evolution of 0.5Li 2 MnO 3 ·0.5LiNi 0.5 Co 0.2 Mn 0.3 O 2 (LLMO) materials are systematically compared for the first time. X-ray diffraction, scanning electron microscopy, X-ray photoelectron spectroscopy and high-resolution transmission electron microscopy analysis indicate that the sample synthesized from sucrose owns well structure, homogenous distribution, low Ni 3+ concentration and good surface structural stability during cycling, respectively. Electrochemical tests further prove that the LLMO material obtained from sucrose maintains 258.4 mAh g −1 with 94.8% capacity retention after 100 cycles at 0.2 C. The superior electrochemical performance can be ascribed to the exceptional complexing mechanism of sucrose, compared to those of the glucose and citric acid. Namely, one mole sucrose can be hydrolyzed into two different monosaccharides and further chelates three M (Li, Ni, Co and Mn) ions to form a more uniform ion-chelated matrix during sol-gel process. This discovery is an important step towards understanding the selection criterion of chelating agents for sol-gel method, that chelating agent with excellent complexing capability is beneficial to the distribution, structural stability and electrochemical properties of advanced lithium-rich layered materials

Comparison of bifunctional chelates for {sup 64}Cu antibody imaging

Energy Technology Data Exchange (ETDEWEB)

Ferreira, Cara L.; Crisp, Sarah; Bensimon, Corinne [MDS Nordion, Vancouver, BC (Canada); Yapp, Donald T.T.; Ng, Sylvia S.W. [British Columbia Cancer Agency Research Centre, Vancouver, BC (Canada); University of British Columba, The Faculty of Pharmaceutical Sciences, Vancouver, BC (Canada); Sutherland, Brent W. [British Columbia Cancer Agency Research Centre, Vancouver, BC (Canada); Gleave, Martin [Prostate Centre at Vancouver General Hospital, Vancouver, BC (Canada); Jurek, Paul; Kiefer, Garry E. [Macrocyclics Inc., Dallas, TX (United States)

2010-11-15

Improved bifunctional chelates (BFCs) are needed to facilitate efficient {sup 64}Cu radiolabeling of monoclonal antibodies (mAbs) under mild conditions and to yield stable, target-specific agents. The utility of two novel BFCs, 1-Oxa-4,7,10-triazacyclododecane-5-S-(4-isothiocyanatobenzyl)-4,7,10-triacetic acid (p-SCN-Bn-Oxo-DO3A) and 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-4-S-(4-isothiocyanatobenzyl)-3,6,9-triacetic acid (p-SCN-Bn-PCTA), for mAb imaging with {sup 64}Cu were compared to the commonly used S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (p-SCN-Bn-DOTA). The BFCs were conjugated to trastuzumab, which targets the HER2/neu receptor. {sup 64}Cu radiolabeling of the conjugates was optimized. Receptor binding was analyzed using flow cytometry and radioassays. Finally, PET imaging and biodistribution studies were done in mice bearing either HER2/neu-positive or HER2/neu-negative tumors. {sup 64}Cu-Oxo-DO3A- and PCTA-trastuzumab were prepared at room temperature in >95% radiochemical yield (RCY) in <30 min, compared to only 88% RCY after 2 h for the preparation of {sup 64}Cu-DOTA-trastuzumab under the same conditions. Cell studies confirmed that the immunoreactivity of the mAb was retained for each of the bioconjugates. In vivo studies showed that {sup 64}Cu-Oxo-DO3A- and PCTA-trastuzumab had higher uptake than the {sup 64}Cu-DOTA-trastuzumab at 24 h in HER2/neu-positive tumors, resulting in higher tumor to background ratios and better tumor images. By 40 h all three of the {sup 64}Cu-BFC-trastuzumab conjugates allowed for clear visualization of the HER2/neu-positive tumors but not the negative control tumor. The antibody conjugates of PCTA and Oxo-DO3A were shown to have superior {sup 64}Cu radiolabeling efficiency and stability compared to the analogous DOTA conjugate. In addition, {sup 64}Cu-PCTA and Oxo-DO3A antibody conjugates may facilitate earlier imaging with greater target to background ratios than

Chelation in Metal Intoxication

Directory of Open Access Journals (Sweden)

Swaran J.S. Flora

2010-06-01

Full Text Available Chelation therapy is the preferred medical treatment for reducing the toxic effects of metals. Chelating agents are capable of binding to toxic metal ions to form complex structures which are easily excreted from the body removing them from intracellular or extracellular spaces. 2,3-Dimercaprol has long been the mainstay of chelation therapy for lead or arsenic poisoning, however its serious side effects have led researchers to develop less toxic analogues. Hydrophilic chelators like meso-2,3-dimercaptosuccinic acid effectively promote renal metal excretion, but their ability to access intracellular metals is weak. Newer strategies to address these drawbacks like combination therapy (use of structurally different chelating agents or co-administration of antioxidants have been reported recently. In this review we provide an update of the existing chelating agents and the various strategies available for the treatment of heavy metals and metalloid intoxications.

Synthesis and in vivo evaluation of 201Tl(III)-DOTA complexes for applications in SPECT imaging

NARCIS (Netherlands)

Hijnen, N.M.; Vries, de A.; Blange, R.; Burdinski, D.; Grüll, H.

2010-01-01

Introduction The aim of this study was to assess the use of 201thallium3+ (201Tl3+) as a radiolabel for nuclear imaging tracers. Methods for labeling of 1,4,7,10-tetraazacyclododecane-N,N',N¿,N'¿ tetraacetic acid (DOTA) and diethylenetriaminepentaacetic acid (DTPA) chelators with 201Tl3+ were

Article Commentary: Chelation Therapy for Mercury Poisoning

Directory of Open Access Journals (Sweden)

Rong Guan

2009-01-01

Full Text Available Chelation therapy has been the major treatment for heavy metal poisoning. Various chelating agents have been developed and tested for treatment of heavy metal intoxications, including mercury poisoning. It has been clearly shown that chelating agents could rescue the toxicity caused by heavy metal intoxication, but the potential preventive role of chelating agents against heavy metal poisoning has not been explored much. Recent paper by Siddiqi and colleagues has suggested a protective role of chelating agents against mercury poisoning, which provides a promising research direction for broader application of chelation therapy in prevention and treatment of mercury poisoning.

Synthesis and spectroscopic investigations of hydroxyapatite using a green chelating agent as template

Science.gov (United States)

Gopi, D.; Bhuvaneshwari, N.; Indira, J.; Kavitha, L.

2013-03-01

Hydroxyapatite [Ca10(PO4)6(OH)2, HAP] particles have been successfully synthesized by a cost-effective, eco-friendly green template method using natural and commercially available sucrose as a chelating agent. The sucrose used in this method has been extracted from various sources, three from natural and one from commercially available sources are exploited in our study to achieve a controlled crystallinity, particle size as well as uniform morphology. Spectral characterizations involving Fourier transform infrared spectroscopy (FT-IR) for the functional group analysis of sucrose and HAP; carbon-13 nuclear magnetic resonance spectroscopy (13C NMR) for the identification of the carbon atoms in sucrose and in HAP; liquid chromatography/mass spectrometry (LC-MS) for the determination of the hydrolyzed products of sucrose; and X-ray diffraction (XRD) techniques for the phase identification of the HAP particles were performed. The morphology of the HAP particles were assessed thoroughly using a scanning electron microscope (SEM) equipped with energy dispersive X-ray analysis (EDAX). The experimental results indicate that the obtained HAP using the natural sucrose as a chelating agent is of phase pure, with a well defined morphology having discrete particles without any agglomeration than the HAP from commercially available sucrose. Further, the reduced particle size can be achieved from the stem sugarcane extract as the source of the chelating agent.

Synthesis and spectroscopic investigations of hydroxyapatite using a green chelating agent as template.

Science.gov (United States)

Gopi, D; Bhuvaneshwari, N; Indira, J; Kavitha, L

2013-03-01

Hydroxyapatite [Ca(10)(PO(4))(6)(OH)(2), HAP] particles have been successfully synthesized by a cost-effective, eco-friendly green template method using natural and commercially available sucrose as a chelating agent. The sucrose used in this method has been extracted from various sources, three from natural and one from commercially available sources are exploited in our study to achieve a controlled crystallinity, particle size as well as uniform morphology. Spectral characterizations involving Fourier transform infrared spectroscopy (FT-IR) for the functional group analysis of sucrose and HAP; carbon-13 nuclear magnetic resonance spectroscopy ((13)C NMR) for the identification of the carbon atoms in sucrose and in HAP; liquid chromatography/mass spectrometry (LC-MS) for the determination of the hydrolyzed products of sucrose; and X-ray diffraction (XRD) techniques for the phase identification of the HAP particles were performed. The morphology of the HAP particles were assessed thoroughly using a scanning electron microscope (SEM) equipped with energy dispersive X-ray analysis (EDAX). The experimental results indicate that the obtained HAP using the natural sucrose as a chelating agent is of phase pure, with a well defined morphology having discrete particles without any agglomeration than the HAP from commercially available sucrose. Further, the reduced particle size can be achieved from the stem sugarcane extract as the source of the chelating agent. Copyright © 2012 Elsevier B.V. All rights reserved.

Robust labeling and comparative preclinical characterization of DOTA-TOC and DOTA-TATE

International Nuclear Information System (INIS)

Velikyan, Irina; Xu Hui; Nair, Manoj; Hall, Håkan

2012-01-01

Objectives: Various radionuclide-labeled somatostatin analogues are used currently for diagnosis and therapy of neuroendocrine tumors. In particular, [ 68 Ga]Ga-DOTA-TOC is commonly used for diagnosis, while [ 177 Lu]Lu-DOTA-TATE is used for therapy. With the development of theranostics and personalized medicine where the imaging diagnosis is tailored to the subsequent radiotherapy, it is of paramount importance to investigate the relevance of the ligand exchange. The aim of this study was to compare binding capacity of [ 67/68 Ga]Ga-DOTA-TOC ([ 67/68 Ga]Ga-N-(4,7,10-(tris(carboxymethyl)-1,4,7, 10-tetraazacyclododecan-1-yl) acetyl-D-Phe-c[Cys-D-Tyr-Trp-Lys-Thr-Cys]-Thr(ol)) and [ 67/68 Ga]Ga-DOTA-TATE ([ 67/68 Ga]Ga-N-(4,7,10-(tris(carboxymethyl)-1,4,7, 10-tetraazacyclododecan-1-yl)acetyl-D-Phe-c[Cys-D-Tyr-Trp-Lys-Thr-Cys]-Thr) in vitro in monkey brain cryosections and in vivo in the rat, where, in contrast to transfected cell lines, there is a heterogeneous distribution of somatostatin receptor (SSTR) subtypes. The influence of various production methods of [ 68 Ga]Ga-DOTA-TOC and [ 68 Ga]Ga-DOTA-TATE on the biological performance of the tracers was also studied. Material and Methods: [ 67 Ga]Ga-DOTA-TOC, [ 68 Ga]Ga-DOTA-TOC, [ 67 Ga]Ga-DOTA-TATE and [ 68 Ga]Ga-DOTA-TATE were synthesized including preconcentration and purification of the generator eluate. The binding of the radioligands was assessed in vitro using autoradiography on cryosections of Rhesus monkey brains and in vivo/ex vivo using organ distribution studies in rats. Results and Discussion: The tracer production method was improved in terms of higher robustness, simplification and good manufacturing practice (GMP) relevance. The synthesis variation did not influence the biological performance of the tracers. There was no statistically significant difference observed in the binding of [ 67/68 Ga]Ga-DOTA-TOC and [ 67/68 Ga]Ga-DOTA-TATE either in brain cortex in vitro or in rat biodistribution and uptake

Robust labeling and comparative preclinical characterization of DOTA-TOC and DOTA-TATE.

Science.gov (United States)

Velikyan, Irina; Xu, Hui; Nair, Manoj; Hall, Håkan

2012-07-01

Various radionuclide-labeled somatostatin analogues are used currently for diagnosis and therapy of neuroendocrine tumors. In particular, [68Ga]Ga-DOTA-TOC is commonly used for diagnosis, while [177Lu]Lu-DOTA-TATE is used for therapy. With the development of theranostics and personalized medicine where the imaging diagnosis is tailored to the subsequent radiotherapy, it is of paramount importance to investigate the relevance of the ligand exchange. The aim of this study was to compare binding capacity of [67/68Ga]Ga-DOTA-TOC ([67/68Ga]Ga-N-(4,7,10-(tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetyl-D-Phe-c[Cys-D-Tyr-Trp-Lys-Thr-Cys]-Thr(ol)) and [67/68Ga]Ga-DOTA-TATE ([67/68Ga]Ga-N-(4,7,10-(tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetyl-D-Phe-c[Cys-D-Tyr-Trp-Lys-Thr-Cys]-Thr) in vitro in monkey brain cryosections and in vivo in the rat, where, in contrast to transfected cell lines, there is a heterogeneous distribution of somatostatin receptor (SSTR) subtypes. The influence of various production methods of [68Ga]Ga-DOTA-TOC and [68Ga]Ga-DOTA-TATE on the biological performance of the tracers was also studied. [67Ga]Ga-DOTA-TOC, [68Ga]Ga-DOTA-TOC, [67Ga]Ga-DOTA-TATE and [68Ga]Ga-DOTA-TATE were synthesized including preconcentration and purification of the generator eluate. The binding of the radioligands was assessed in vitro using autoradiography on cryosections of Rhesus monkey brains and in vivo/ex vivo using organ distribution studies in rats. The tracer production method was improved in terms of higher robustness, simplification and good manufacturing practice (GMP) relevance. The synthesis variation did not influence the biological performance of the tracers. There was no statistically significant difference observed in the binding of [67/68Ga]Ga-DOTA-TOC and [67/68Ga]Ga-DOTA-TATE either in brain cortex in vitro or in rat biodistribution and uptake in SSTR-positive tissues such as pancreas, adrenals and pituitary. The uptake in these

Mono(pyridine-N-oxide) DOTA analog and its G1/G4-PAMAM dendrimer conjugates labeled with 177Lu: Radiolabeling and biodistribution studies

International Nuclear Information System (INIS)

Laznickova, A.; Biricova, V.; Laznicek, M.; Hermann, P.

2014-01-01

177 Lu radiolabeling of the first (G1-) or fourth (G4-) generation polyaminoamide (PAMAM) dendrimer conjugates with DOTA-like bifunctional chelator with one methylenepyridine-N-oxide pendant arm (DO3A-py NO-C ) stability of the radiolabeled species and their pharmacokinetic characteristics were evaluated in preclinical experiments. The results showed that the G1- and G4-dendrimer conjugates, modified in average with 7.5 or 57 DO3A-py NO-C chelating units, respectively, can also be labeled with 177 Lu with a high specific activity and radiochemical purity even at 37 °C. The radiolabeled species were stable for at least 24 h. Distribution profile of G1-dendrimer conjugate in organs and tissues of rats was more favorable than that of G4 one. On the other hand, the later dendrimer conjugate bears a substantially higher number of metal chelators per molecule enabling binding of a considerably larger number of radiometals. Our results indicate that an employment of dendrimer-chelate conjugates with bound radiometals might represent a prospective way for radiolabeling of biologically active target-specific macromolecules to obtain markedly high specific activity. - Highlights: • Chelation of DOTA-like ligands suitable for biomacromolecules modification. • Radiolabeling of modified PAMAM-dendrimers with 177 Lu. • Determination of stability of the labeled conjugates. • Pharmacokinetic characteristics evaluated in preclinical experiments

Enhanced in vitro activity of tigecycline in the presence of chelating agents.

Science.gov (United States)

Deitchman, Amelia N; Singh, Ravi Shankar Prasad; Rand, Kenneth H; Derendorf, Hartmut

2018-05-01

The lack of availability of novel antibiotic agents and the rise of resistance to existing therapies has led clinicians to utilise combination therapy to adequately treat bacterial infections. Here we examined how chelators may impact the in vitro activity of tigecycline (TIG) against Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae. Minimum inhibitory concentrations (MICs) were determined by broth dilution with and without various combinations of chelators (EDTA and other tetracyclines) and metal ions (i.e. calcium, magnesium). Trimethoprim (TMP) was used as a non-chelating control. Addition of metal ions led to increases in MICs, whilst addition of EDTA led to decreases in MICs. The chelating effects of EDTA were reversed by addition of magnesium and most profoundly calcium. Similar effects of EDTA and calcium were observed for tetracycline (TET) and TMP. When other tetracyclines (TET, oxytetracycline (OXY) and chlortetracycline (CHL)) were used as chelators at concentrations below their MICs, TIG MICs decreased for P. aeruginosa but not for E. coli. Some decreases in TIG MICs were observed for K. pneumoniae when TET and CHL were added. A dose-dependent decrease in TIG MIC was observed for TET and was reversed by the addition of calcium. The presence of effects of EDTA and calcium on TMP MICs indicates that mechanisms outside of TIG chelation likely play a role in enhanced activity. Full characterisation of an unexpected interaction such as TIG-TET with different microorganisms could provide valuable insights into the underlying mechanisms and design of physiologically viable chelators as candidates for future combinations regimens. Copyright © 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Diagnostic PET Imaging of Mammary Microcalcifications Using 64Cu-DOTA-Alendronate in a Rat Model of Breast Cancer.

Science.gov (United States)

Ahrens, Bradley J; Li, Lin; Ciminera, Alexandra K; Chea, Junie; Poku, Erasmus; Bading, James R; Weist, Michael R; Miller, Marcia M; Colcher, David M; Shively, John E

2017-09-01

The development of improved breast cancer screening methods is hindered by a lack of cancer-specific imaging agents and effective small-animal models to test them. The purpose of this study was to evaluate 64 Cu-DOTA-alendronate as a mammary microcalcification-targeting PET imaging agent, using an ideal rat model. Our long-term goal is to develop 64 Cu-DOTA-alendronate for the detection and noninvasive differentiation of malignant versus benign breast tumors with PET. Methods: DOTA-alendronate was synthesized, radiolabeled with 64 Cu, and administered to normal or tumor-bearing aged, female, retired breeder Sprague-Dawley rats for PET imaging. Mammary tissues were subsequently labeled and imaged with light, confocal, and electron microscopy to verify microcalcification targeting specificity of DOTA-alendronate and elucidate the histologic and ultrastructural characteristics of the microcalcifications in different mammary tumor types. Tumor uptake, biodistribution, and dosimetry studies were performed to evaluate the efficacy and safety of 64 Cu-DOTA-alendronate. Results: 64 Cu-DOTA-alendronate was radiolabeled with a 98% yield. PET imaging using aged, female, retired breeder rats showed specific binding of 64 Cu-DOTA-alendronate in mammary glands and mammary tumors. The highest uptake of 64 Cu-DOTA-alendronate was in malignant tumors and the lowest uptake in benign tumors and normal mammary tissue. Confocal analysis with carboxyfluorescein-alendronate confirmed the microcalcification binding specificity of alendronate derivatives. Biodistribution studies revealed tissue alendronate concentrations peaking within the first hour, then decreasing over the next 48 h. Our dosimetric analysis demonstrated a 64 Cu effective dose within the acceptable range for clinical PET imaging agents and the potential for translation into human patients. Conclusion: 64 Cu-DOTA-alendronate is a promising PET imaging agent for the sensitive and specific detection of mammary tumors as

[Bifunctional chelates of Rh-105, Au-199, and other metallic radionuclides as potential radiotherapeutic agents

International Nuclear Information System (INIS)

1991-01-01

Progress during this period is reported under the following headings: Diethylenetriamine based and related bifunctional chelating agents and their complexation with Rh-105, Au-198, Pd-109, cu-67, In-111, and Co-57; studies of Pd-109, Rh-105 and Tc-99m with bifunctional chelates based on phenylenediamine; establishment of an appropriate protein assay method for conjugated proteins; studies of new bifunctional Bi, Tri and tetradentate amine oxime ligands with Rh-105; IgG and antibody B72.3 conjugation studies by HPLC Techniques with bifunctional metal chelates; and progress on ligand systems for Au(III)

[Bifunctional chelates of Rh-105, Au-199, and other metallic radionuclides as potential radiotherapeutic agents

Energy Technology Data Exchange (ETDEWEB)

1991-12-31

Progress during this period is reported under the following headings: Diethylenetriamine based and related bifunctional chelating agents and their complexation with Rh-105, Au-198, Pd-109, cu-67, In-111, and Co-57; studies of Pd-109, Rh-105 and Tc-99m with bifunctional chelates based on phenylenediamine; establishment of an appropriate protein assay method for conjugated proteins; studies of new bifunctional Bi, Tri and tetradentate amine oxime ligands with Rh-105; IgG and antibody B72.3 conjugation studies by HPLC Techniques with bifunctional metal chelates; and progress on ligand systems for Au(III).

(Bifunctional chelates of Rh-105, Au-199, and other metallic radionuclides as potential radiotherapeutic agents)

Energy Technology Data Exchange (ETDEWEB)

1991-01-01

Progress during this period is reported under the following headings: Diethylenetriamine based and related bifunctional chelating agents and their complexation with Rh-105, Au-198, Pd-109, cu-67, In-111, and Co-57; studies of Pd-109, Rh-105 and Tc-99m with bifunctional chelates based on phenylenediamine; establishment of an appropriate protein assay method for conjugated proteins; studies of new bifunctional Bi, Tri and tetradentate amine oxime ligands with Rh-105; IgG and antibody B72.3 conjugation studies by HPLC Techniques with bifunctional metal chelates; and progress on ligand systems for Au(III).

Radiolabeling of DOTA-like conjugated peptides with generator-produced 68Ga and using NaCl-based cationic elution method

Science.gov (United States)

Mueller, Dirk; Breeman, Wouter A P; Klette, Ingo; Gottschaldt, Michael; Odparlik, Andreas; Baehre, Manfred; Tworowska, Izabela; Schultz, Michael K

2017-01-01

Gallium-68 (68Ga) is a generator-produced radionuclide with a short half-life (t½ = 68 min) that is particularly well suited for molecular imaging by positron emission tomography (PET). Methods have been developed to synthesize 68Ga-labeled imaging agents possessing certain drawbacks, such as longer synthesis time because of a required final purification step, the use of organic solvents or concentrated hydrochloric acid (HCl). In our manuscript, we provide a detailed protocol for the use of an advantageous sodium chloride (NaCl)-based method for radiolabeling of chelator-modified peptides for molecular imaging. By working in a lead-shielded hot-cell system, 68Ga3+ of the generator eluate is trapped on a cation exchanger cartridge (100 mg, ∼8 mm long and 5 mm diameter) and then eluted with acidified 5 M NaCl solution directly into a sodium acetate-buffered solution containing a DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) or DOTA-like chelator-modified peptide. The main advantages of this procedure are the high efficiency and the absence of organic solvents. It can be applied to a variety of peptides, which are stable in 1 M NaCl solution at a pH value of 3–4 during reaction. After labeling, neutralization, sterile filtration and quality control (instant thin-layer chromatography (iTLC), HPLC and pH), the radiopharmaceutical can be directly administered to patients, without determination of organic solvents, which reduces the overall synthesis-to-release time. This procedure has been adapted easily to automated synthesis modules, which leads to a rapid preparation of 68Ga radiopharmaceuticals (12–16 min). PMID:27172166

Preparation & in vitro evaluation of 90Y-DOTA-rituximab

Science.gov (United States)

Kameswaran, Mythili; Pandey, Usha; Dash, Ashutosh; Samuel, Grace; Venkatesh, Meera

2016-01-01

Background & objectives: Radioimmunotherapy is extensively being used for the treatment of non-Hodgkin's lymphoma (NHL). Use of rituximab, a chimeric anti-CD20 antibody directed against the CD20 antigen in combination with suitable beta emitters is expected to result in good treatment response by its cross-fire and bystander effects. The present work involves the conjugation of p-isothiocyanatobenzyl DOTA (p-SCN-Bn-DOTA) to rituximab, its radiolabelling with 90Y and in vitro and in vivo evaluation to determine its potential as a radioimmunotherapeutic agent. Methods: Rituximab was conjugated with p-SCN-Bn-DOTA at 1:1 antibody: DOTA molar ratio. The number of DOTA molecules linked to one molecule of rituximab was determined by radioassay and spectroscopic assay. Radiolabelling of rituximab with 90Y was carried out and its in vitro stability was evaluated. In vitro cell binding studies were carried out in Raji cells expressing CD20 antigen. Biodistribution studies were carried out in normal Swiss mice. Results: Using both radioassay and spectroscopic method, it was determined that about five molecules of DOTA were linked to rituximab. Radiolabelling of the rituximab conjugate with 90Y and subsequent purification on PD-10 column gave a product with radiochemical purity (RCP) > 98 per cent which was retained at > 90 per cent up to 72 h when stored at 37°C. In vitro cell binding experiments of 90Y-DOTA-rituximab with Raji cells exhibited specific binding of 20.7 ± 0.1 per cent with 90Y-DOTA-rituximab which reduced to 15.5 ± 0.2 per cent when incubated with cold rituximab. The equilibrium constant Kd for 90Y-DOTA-Rituximab was determined to be 3.38 nM. Radiolabelled antibody showed clearance via hepatobiliary and renal routes and activity in tibia was found to be quite low indicating in vivo stability of 90Y-DOTA-rituximab. Interpretation & conclusions: p-SCN-Bn-DOTA was conjugated with rituximab and radiolabelling with 90Y was carried out. In vitro studies carried

[Enhanced phytoextraction of heavy metal contaminated soil by chelating agents and auxin indole-3-acetic acid].

Science.gov (United States)

Zhou, Jian-min; Dang, Zhi; Chen, Neng-chang; Xu, Sheng-guang; Xie, Zhi-yi

2007-09-01

The environmental risk of chelating agents such as EDTA application to the heavy metals polluted soils and the stress on plant roots due to the abrupt increase metals concentration limit the wide commercial use of chelate-induced phytoextraction. Chelating agent ethylenediaminetetraacetic acid (EDTA) and nitrilotriacetic acid (NTA) and auxin indole-3-acetic acid (IAA) were used for enhancing heavy metals uptake from soils by Zea mays L. (corn) in pot experiments. The metals content in plant tissues was quantified using an inductively coupled plasma mass spectrometer (ICP-MS). The results showed that the combination of IAA and EDTA increased the biomass by about 40.0% and the contents of Cu, Zn, Cd and Pb in corn shoots by 27.0%, 26.8%, 27.5% and 32.8% respectively, as compared to those in EDTA treatment. While NTA&IAA treatment increased the biomass by about 29.9% and the contents of Cu, Zn, Cd and Pb in corn shoots by 31.8%, 27.6%, 17.0% and 26.9% respectively, as compared to those in NTA treatment. These results indicated that corn growth was promoted, and the biomass and the accumulation of heavy metals in plant shoots were increased significantly with the addition of IAA, which probably helps to change the cell membrane properties and the biomass distribution, resulting in the alleviation of the phytotoxicity of metals and the chelating agents.

Comparison of the stability of Y-90-, Lu-177- and Ga-68- labeled human serum albumin microspheres (DOTA-HSAM)

Energy Technology Data Exchange (ETDEWEB)

Wunderlich, Gerd [Department of Nuclear Medicine, University Hospital, 01307 Dresden (Germany); Schiller, Eik, E-mail: eisc@rotop-pharmaka.d [ROTOP Pharmaka AG, 01454 Radeberg (Germany); Bergmann, Ralf; Pietzsch, Hans-Juergen [Forschungszentrum Dresden-Rossendorf, Institute of Radiopharmacy, P.O. Box 510119, 01314 Dresden (Germany)

2010-11-15

Introduction: Microparticles derived from denatured human serum albumin (DOTA-derivatized human serum albumin microspheres, or DOTA-HSAM) are attractive carriers of radionuclides for both therapeutic and diagnostic purposes. In this article, we describe a labeling procedure for diagnostic (Ga-68) and therapeutic (Y-90, Lu-177) radionuclides and report on the results of stability studies of these products. Methods: DOTA-HSAM was labeled in 0.5 M ammonium acetate buffer, pH 5.0, containing 0.02 mg/ml detergent. After adding the radionuclide, the mixture was shaken for 15 min at 90{sup o}C. Labeling yields and in vitro stability were determined by thin-layer chromatography. For determination of the in vivo stability of Ga-68 and Y-90 DOTA-HSAM, the particles were injected intravenously in Wistar rats. Results: Labeling yields up to 95% in the case of Ga-68 and Lu-177 were achieved. Ga-68-labeled DOTA-HSAM showed high in vitro and in vivo stability. The amount of particle-bound radioactivity of Lu-177 DOTA-HSAM declines slowly in a linear manner to approximately 72% after 13 days. For Y-90, the labeling yield decreased with increasing radioactivity level. We presume radiolysis as the reason for these findings. Conclusion: The labeling of DOTA-HSAM with different radionuclides is easy to perform. The radiation-induced cleavage of the labeled chelator together with the rather short half-life of radioactivity fixation in vivo (3.7 days) is, in our opinion, opposed to therapeutic applications of DOTA-HSAM. On the other hand, the high stability of Ga-68 DOTA-HSAM makes them an attractive candidate for the measurement of regional perfusion by PET.

Comparison of the stability of Y-90-, Lu-177- and Ga-68- labeled human serum albumin microspheres (DOTA-HSAM)

International Nuclear Information System (INIS)

Wunderlich, Gerd; Schiller, Eik; Bergmann, Ralf; Pietzsch, Hans-Juergen

2010-01-01

Introduction: Microparticles derived from denatured human serum albumin (DOTA-derivatized human serum albumin microspheres, or DOTA-HSAM) are attractive carriers of radionuclides for both therapeutic and diagnostic purposes. In this article, we describe a labeling procedure for diagnostic (Ga-68) and therapeutic (Y-90, Lu-177) radionuclides and report on the results of stability studies of these products. Methods: DOTA-HSAM was labeled in 0.5 M ammonium acetate buffer, pH 5.0, containing 0.02 mg/ml detergent. After adding the radionuclide, the mixture was shaken for 15 min at 90 o C. Labeling yields and in vitro stability were determined by thin-layer chromatography. For determination of the in vivo stability of Ga-68 and Y-90 DOTA-HSAM, the particles were injected intravenously in Wistar rats. Results: Labeling yields up to 95% in the case of Ga-68 and Lu-177 were achieved. Ga-68-labeled DOTA-HSAM showed high in vitro and in vivo stability. The amount of particle-bound radioactivity of Lu-177 DOTA-HSAM declines slowly in a linear manner to approximately 72% after 13 days. For Y-90, the labeling yield decreased with increasing radioactivity level. We presume radiolysis as the reason for these findings. Conclusion: The labeling of DOTA-HSAM with different radionuclides is easy to perform. The radiation-induced cleavage of the labeled chelator together with the rather short half-life of radioactivity fixation in vivo (3.7 days) is, in our opinion, opposed to therapeutic applications of DOTA-HSAM. On the other hand, the high stability of Ga-68 DOTA-HSAM makes them an attractive candidate for the measurement of regional perfusion by PET.

Design and synthesis of 225Ac radioimmunopharmaceuticals

International Nuclear Information System (INIS)

McDevitt, Michael R.; Ma, Dangshe; Simon, Jim; Frank, R. Keith; Scheinberg, David A.

2002-01-01

The alpha-particle-emitting radionuclides 213 Bi, 211 At, 224 Ra are under investigation for the treatment of leukemias, gliomas, and ankylosing spondylitis, respectively. 213 Bi and 211 At were attached to monoclonal antibodies and used as targeted immunotherapeutic agents while unconjugated 224 Ra chloride selectively seeks bone. 225 Ac possesses favorable physical properties for radioimmunotherapy (10 d half-life and 4 net alpha particles), but has a history of unfavorable radiolabeling chemistry and poor metal-chelate stability. We selected functionalized derivatives of DOTA as the most promising to pursue from out of a group of potential 225 Ac chelate compounds. A two-step synthetic process employing either MeO-DOTA-NCS or 2B-DOTA-NCS as the chelating moiety was developed to attach 225 Ac to monoclonal antibodies. This method was tested using several different IgG systems. The chelation reaction yield in the first step was 93±8% radiochemically pure (n=26). The second step yielded 225 Ac-DOTA-IgG constructs that were 95±5% radiochemically pure (n=27) and the mean percent immunoreactivity ranged from 25% to 81%, depending on the antibody used. This process has yielded several potential novel targeted 225 Ac-labeled immunotherapeutic agents that may now be evaluated in appropriate model systems and ultimately in humans

Design and synthesis of {sup 225}Ac radioimmunopharmaceuticals

Energy Technology Data Exchange (ETDEWEB)

McDevitt, Michael R.; Ma, Dangshe; Simon, Jim; Frank, R. Keith; Scheinberg, David A. E-mail: d-scheinberg@ski.mskcc.org

2002-12-01

The alpha-particle-emitting radionuclides {sup 213}Bi, {sup 211}At, {sup 224}Ra are under investigation for the treatment of leukemias, gliomas, and ankylosing spondylitis, respectively. {sup 213}Bi and {sup 211}At were attached to monoclonal antibodies and used as targeted immunotherapeutic agents while unconjugated {sup 224}Ra chloride selectively seeks bone. {sup 225}Ac possesses favorable physical properties for radioimmunotherapy (10 d half-life and 4 net alpha particles), but has a history of unfavorable radiolabeling chemistry and poor metal-chelate stability. We selected functionalized derivatives of DOTA as the most promising to pursue from out of a group of potential {sup 225}Ac chelate compounds. A two-step synthetic process employing either MeO-DOTA-NCS or 2B-DOTA-NCS as the chelating moiety was developed to attach {sup 225}Ac to monoclonal antibodies. This method was tested using several different IgG systems. The chelation reaction yield in the first step was 93{+-}8% radiochemically pure (n=26). The second step yielded {sup 225}Ac-DOTA-IgG constructs that were 95{+-}5% radiochemically pure (n=27) and the mean percent immunoreactivity ranged from 25% to 81%, depending on the antibody used. This process has yielded several potential novel targeted {sup 225}Ac-labeled immunotherapeutic agents that may now be evaluated in appropriate model systems and ultimately in humans.

Hyaluronic acid-modified manganese-chelated dendrimer-entrapped gold nanoparticles for the targeted CT/MR dual-mode imaging of hepatocellular carcinoma

Science.gov (United States)

Wang, Ruizhi; Luo, Yu; Yang, Shuohui; Lin, Jiang; Gao, Dongmei; Zhao, Yan; Liu, Jinguo; Shi, Xiangyang; Wang, Xiaolin

2016-09-01

Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver. The early and effective diagnosis has always been desired. Herein, we present the preparation and characterization of hyaluronic acid (HA)-modified, multifunctional nanoparticles (NPs) targeting CD44 receptor-expressing cancer cells for computed tomography (CT)/magnetic resonance (MR) dual-mode imaging. We first modified amine-terminated generation 5 poly(amidoamine) dendrimers (G5.NH2) with an Mn chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), fluorescein isothiocyanate (FI), and HA. Then, gold nanoparticles (AuNPs) were entrapped within the above raw product, denoted as G5.NH2-FI-DOTA-HA. The designed multifunctional NPs were formed after further Mn chelation and purification and were denoted as {(Au0)100G5.NH2-FI-DOTA(Mn)-HA}. These NPs were characterized via several different techniques. We found that the {(Au0)100G5.NH2-FI-DOTA(Mn)-HA} NPs exhibited good water dispersibility, stability under different conditions, and cytocompatibility within a given concentration range. Because both AuNPs and Mn were present in the product, {(Au0)100G5.NH2-FI-DOTA(Mn)-HA} displayed a high X-ray attenuation intensity and favorable r1 relaxivity, which are advantageous properties for targeted CT/MR dual-mode imaging. This approach was used to image HCC cells in vitro and orthotopically transplanted HCC tumors in a unique in vivo model through the CD44 receptor-mediated endocytosis pathway. This work introduces a novel strategy for preparing multifunctional NPs via dendrimer nanotechnology.

Cohort study of somatostatin-based radiopeptide therapy with [(90)Y-DOTA]-TOC versus [(90)Y-DOTA]-TOC plus [(177)Lu-DOTA]-TOC in neuroendocrine cancers.

Science.gov (United States)

Villard, Linda; Romer, Anna; Marincek, Nicolas; Brunner, Philippe; Koller, Michael T; Schindler, Christian; Ng, Quinn K T; Mäcke, Helmut R; Müller-Brand, Jan; Rochlitz, Christoph; Briel, Matthias; Walter, Martin A

2012-04-01

Radiopeptide therapy is commonly performed with a single radioisotope. We aimed to compare the effectiveness of somatostatin-based radiopeptide therapy with a single versus a combination of radioisotopes. In a cohort study, patients with metastasized neuroendocrine cancer were treated with repeated cycles of (90)yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide ([(90)Y-DOTA]-TOC) or with cycles alternating between [(90)Y-DOTA]-TOC and (177)lutetium-labeled DOTA-TOC ([(177)Lu-DOTA]-TOC) until tumor progression or permanent toxicity. Multivariable Cox regression and competing risk regression were used to study predictors of survival and renal toxicity in patients completing three or more treatment cycles. A total of 486 patients completed three or more treatment cycles; 237 patients received [(90)Y-DOTA]-TOC and 249 patients received [(90)Y-DOTA]-TOC + [(177)Lu-DOTA]-TOC. Patients receiving [(90)Y-DOTA]-TOC + [(177)Lu-DOTA]-TOC had a significantly longer survival than patients receiving [(90)Y-DOTA]-TOC alone (5.51 v 3.96 years; hazard ratio, 0.64; 95% CI, 0.47 to 0.88; P = .006). The rates of severe hematologic toxicities (6.3% v 4.4%; P = .25) and severe renal toxicity (8.9% v 11.2%; P = .47) were comparable in both groups. [(90)Y-DOTA]-TOC + [(177)Lu-DOTA]-TOC was associated with improved overall survival compared with [(90)Y-DOTA]-TOC alone in patients completing three or more cycles of treatment. Contrary to the current practice in radiopeptide therapy, our results suggest an advantage of using a combination of radioisotopes.

Self-diffusion coefficient of iron as affected by chelating agents using tracer technique

International Nuclear Information System (INIS)

Massoud, M.A.; Abd-El-Sabour, M.F.; Omar, M.A.

1983-01-01

The effect of Fe 2 (So 4 ) 3 , Fe-DTPA, and Fe-EDDHA on the self-diffusion coefficient of Fe in some soils of Egypt was studied. The effect of chelating compounds on the ratio between solid phase fraction of the labile Fe and its concentration in the soil solution (capacity factor) was also studied. The data reveals the following items of more interesting: 1) The use of chelating agents, i.e., DTPA and EDDHA increased the amount of Fe in soil solution, hence the capacity factor was decreased using these compounds. It seems that as the addition of Fe was in the chelated form in soil solution, the slight loss of 59Fe from solution when 59Fe - chelate was used could be attributed to the isotopic exchange with soil Fe. 2) It was found that the addition of either Fe-DTPA or Fe-EDDHA significantly increased the self-diffusion of Fe in soil as compared with Fe 2 (So 4 ) 3 . It was also noticed that the self-diffusion for Fe in the alluvial soil was greater than in the calcareous one due to the instance competition between Ca and Fe for the chelating ligands in the calcareous soil. It was also seen that soil texture affects Fe self-diffusion

Cell-permeable Ln(III) chelate-functionalized InP quantum dots as multimodal imaging agents.

Science.gov (United States)

Stasiuk, Graeme J; Tamang, Sudarsan; Imbert, Daniel; Poillot, Cathy; Giardiello, Marco; Tisseyre, Céline; Barbier, Emmanuel L; Fries, Pascal Henry; de Waard, Michel; Reiss, Peter; Mazzanti, Marinella

2011-10-25

Quantum dots (QDs) are ideal scaffolds for the development of multimodal imaging agents, but their application in clinical diagnostics is limited by the toxicity of classical CdSe QDs. A new bimodal MRI/optical nanosized contrast agent with high gadolinium payload has been prepared through direct covalent attachment of up to 80 Gd(III) chelates on fluorescent nontoxic InP/ZnS QDs. It shows a high relaxivity of 900 mM(-1) s(-1) (13 mM(-1 )s(-1) per Gd ion) at 35 MHz (0.81 T) and 298 K, while the bright luminescence of the QDs is preserved. Eu(III) and Tb(III) chelates were also successfully grafted to the InP/ZnS QDs. The absence of energy transfer between the QD and lanthanide emitting centers results in a multicolor system. Using this convenient direct grafting strategy additional targeting ligands can be included on the QD. Here a cell-penetrating peptide has been co-grafted in a one-pot reaction to afford a cell-permeable multimodal multimeric MRI contrast agent that reports cellular localization by fluorescence and provides high relaxivity and increased tissue retention with respect to commercial contrast agents.

Preparation & in vitro evaluation of ⁹⁰Y-DOTA-rituximab.

Science.gov (United States)

Kameswaran, Mythili; Pandey, Usha; Dash, Ashutosh; Samuel, Grace; Venkatesh, Meera

2016-01-01

Radioimmunotherapy is extensively being used for the treatment of non-Hodgkin's lymphoma (NHL). Use of rituximab, a chimeric anti-CD20 antibody directed against the CD20 antigen in combination with suitable beta emitters is expected to result in good treatment response by its cross-fire and bystander effects. The present work involves the conjugation of p-isothiocyanatobenzyl DOTA (p-SCN-Bn-DOTA) to rituximab, its radiolabelling with [90] Y and in vitro and in vivo evaluation to determine its potential as a radioimmunotherapeutic agent. Rituximab was conjugated with p-SCN-Bn-DOTA at 1:1 antibody: DOTA molar ratio. The number of DOTA molecules linked to one molecule of rituximab was determined by radioassay and spectroscopic assay. Radiolabelling of rituximab with 90 Y was carried out and its in vitro stability was evaluated. In vitro cell binding studies were carried out in Raji cells expressing CD20 antigen. Biodistribution studies were carried out in normal Swiss mice. Using both radioassay and spectroscopic method, it was determined that about five molecules of DOTA were linked to rituximab. Radiolabelling of the rituximab conjugate with [90] Y and subsequent purification on PD-10 column gave a product with radiochemical purity (RCP) > 98 per cent which was retained at > 90 per cent up to 72 h when stored at 37°C. In vitro cell binding experiments of 90 Y-DOTA-rituximab with Raji cells exhibited specific binding of 20.7 ± 0.1 per cent with [90] Y-DOTA-rituximab which reduced to 15.5 ± 0.2 per cent when incubated with cold rituximab. The equilibrium constant K d for 90 Y-DOTA-Rituximab was determined to be 3.38 nM. Radiolabelled antibody showed clearance via hepatobiliary and renal routes and activity in tibia was found to be quite low indicating in vivo stability of [90] Y-DOTA-rituximab. p-SCN-Bn-DOTA was conjugated with rituximab and radiolabelling with 90 Y was carried out. In vitro studies carried out in Raji cells showed the specificity of the

Solution mining dawsonite from hydrocarbon containing formations with a chelating agent

Science.gov (United States)

Vinegar, Harold J [Bellaire, TX

2009-07-07

A method for treating an oil shale formation comprising dawsonite includes providing heat from one or more heaters to the formation to heat the formation. Hydrocarbon fluids are produced from the formation. At least some dawsonite in the formation is decomposed with the provided heat. A chelating agent is provided to the formation to dissolve at least some dawsonite decomposition products. The dissolved dawsonite decomposition products are produced from the formation.

Self-diffusion coefficient of iron as affected by chelating agents using tracer technique

Energy Technology Data Exchange (ETDEWEB)

Massoud, M.A.; Abd-El-Sabour, M.F. (Agriculture Dept. for Soil and Water Research, Nuclear Research Centre, A.E.A., Cairo (Egypt)); Omar, M.A. (Ain Shams Univ., Cairo (Egypt). Faculty of Agriculture)

1983-01-01

The effect of Fe/sub 2/(So/sub 4/)/sub 3/, Fe-DTPA, and Fe-EDDHA on the self-diffusion coefficient of Fe in some soils of Egypt was studied. The effect of chelating compounds on the ratio between solid phase fraction of the labile Fe and its concentration in the soil solution (capacity factor) was also studied. The data reveals the following items of more interesting: 1) The use of chelating agents, i.e., DTPA and EDDHA increased the amount of Fe in soil solution, hence the capacity factor was decreased using these compounds. It seems that as the addition of Fe was in the chelated form in soil solution, the slight loss of 59Fe from solution when 59Fe - chelate was used could be attributed to the isotopic exchange with soil Fe. 2) It was found that the addition of either Fe-DTPA or Fe-EDDHA significantly increased the self-diffusion of Fe in soil as compared with Fe/sub 2/(So/sub 4/)/sub 3/. It was also noticed that the self-diffusion for Fe in the alluvial soil was greater than in the calcareous one due to the instance competition between Ca and Fe for the chelating ligands in the calcareous soil. It was also seen that soil texture affects Fe self-diffusion.

Surface modification of PLGA nanospheres with Gd-DTPA and Gd-DOTA for high-relaxivity MRI contrast agents

NARCIS (Netherlands)

Ratzinger, Gerda; Agrawal, Prashant; Körner, Wilfried; Lonkai, Julia; Sanders, Honorius M. H. F.; Terreno, Enzo; Wirth, Michael; Strijkers, Gustav J.; Nicolay, Klaas; Gabor, Franz

2010-01-01

The preparation of particulate contrast agents for magnetic resonance imaging (MRI) based on biodegradable poly(D,L-lactide-co-glycolide) (PLGA) nanocarriers is reported. By spacer-aided covalent surface-grafting of the prominent chelating ligands diethylenetriaminepentaacetic acid (DTPA) and

Surface modification of PLGA nanospheres with Gd-DTPA and Gd-DOTA for high-relaxivity MRI contrast agents

NARCIS (Netherlands)

Ratzinger, G.; Agrawal, P.; Koerner, W.; Lonkai, J.; Sanders, H.M.H.F.; Terreno, E.; Wirth, M.; Strijkers, G. J.; Nicolay, K.; Gabor, F.

2010-01-01

The preparation of particulate contrast agents for magnetic resonance imaging (MRI) based on biodegradable poly(d,l-lactide-co-glycolide) (PLGA) nanocarriers is reported. By spacer-aided covalent surface-grafting of the prominent chelating ligands diethylenetriaminepentaacetic acid (DTPA) and

Intrinsic dependence of the magnetic properties of CoFe{sub 2}O{sub 4} nanoparticles prepared via chemical methods with addition of chelating agents

Energy Technology Data Exchange (ETDEWEB)

Mendonça, E.C. [Núcleo de Pós-Graduação em Física, Campus Prof. José Aluísio de Campos, UFS, 49100-000 São Cristóvão, SE (Brazil); Tenório, Mayara A. [Departamento de Física, Campus Prof. Alberto Carvalho, UFS, 49500-000 Itabaiana, SE (Brazil); Mecena, S.G.; Zucolotto, B.; Silva, L.S. [Núcleo de Pós-Graduação em Física, Campus Prof. José Aluísio de Campos, UFS, 49100-000 São Cristóvão, SE (Brazil); Jesus, C.B.R. [Instituto de Física Gleb Wataghin, UNICAMP, C. P. 6165, 13083-970 Campinas, SP (Brazil); Meneses, C.T. [Núcleo de Pós-Graduação em Física, Campus Prof. José Aluísio de Campos, UFS, 49100-000 São Cristóvão, SE (Brazil); and others

2015-12-01

In this work, the effect of addition of different chelating agents on the magnetic properties of cobalt ferrite nanoparticles produced by the combining of both co-precipitation and hydrothermal methods is reported. The Rietveld analyses of X-ray diffraction patterns reveal that our samples are single phase (space group: Fd-3m) with small average sizes. The weight losses observed in the thermogravimetric measurements together with the M×H curves show that the organic contamination coming from chelating agent decomposition can give rise to misinterpretation of the magnetization measurements. Besides, analyses of the zero-field-cooled (ZFC) and field-cooled (FC) magnetization measurements and the M×H curves measured at room temperature allows us to state that both the average blocking temperature and particles size distribution are sensitive to the kind of chelating agent. - Highlights: Superparamagnetism. Chelating agents. Organic contamination.

Labelling of the peptide Dota-Octreotate with Lutetium 177

International Nuclear Information System (INIS)

Hernandez B, C.A.

2004-01-01

In this work is described the optimization of the reaction conditions to obtain the complex 177 Lu-Dota-TATE with a radiochemical purity > 95%, even so the studies of stability In vitro to the dilution in saline solution, stability in human serum and challenge to the cystein. The biodistribution studies are presented in mice Balb-C and the tests of biological recognition using one lines cellular of pancreatic adenoma (AR42-J). The obtained results show a high stability of the radio complex in vitro, since it doesn't suffer trans chelation from the Lutetium-177 to plasmatic proteins. The biodistribution tests in mice Balb-C demonstrated an appropriate lipophilly of the complex to be excreted in more proportion by the kidneys without significant accumulation in healthy tissues. It is necessary to mention that the drop activity specifies (3.54 μg / 37 MBq) obtained in the irradiation of 176 Lu 2 O 3 it allowed to verify the union of the 177 Lu-Dota-Tate to membrane receivers but without being able to obtain the saturation curves and competition required to characterize quantitatively the biological recognition. (Author)

Magnetic resonance characterization of tumor microvessels in experimental breast tumors using a slow clearance blood pool contrast agent (carboxymethyldextran-A2-Gd-DOTA) with histopathological correlation

International Nuclear Information System (INIS)

Preda, Anda; Novikov, Viktor; Moeglich, Martina; Turetschek, Karl; Shames, David M.; Roberts, Timothy P.L.; Brasch, Robert C.; Floyd, Eugenia; Carter, Wayne O.; Corot, Claire

2005-01-01

Carboxymethyldextran (CMD)-A2-Gd-DOTA, a slow clearance blood pool contrast agent with a molecular weight of 52.1 kDa, designed to have intravascular residence for more than 1 h, was evaluated for its potential to characterize and differentiate the microvessels of malignant and benign breast tumors. Precontrast single-slice inversion-recovery snapshot FLASH and dynamic contrast-enhanced MRI using an axial T1-weighted three-dimensional spoiled gradient recalled sequence was performed in 30 Sprague-Dawley rats with chemically induced breast tumors. Endothelial transfer coefficient and fractional plasma volume of the breast tumors were estimated from MRI data acquired with CMD-A2-Gd-DOTA enhancement injected at a dose of 0.1 mmol Gd/kg body weight using a two-compartment bidirectional model of the tumor tissue. The correlation between MRI microvessel characteristics and histopathological tumor grade was determined using the Scarff-Bloom-Richardson method. Using CMD-A2-Gd-DOTA, no significant correlations were found between the MR-estimated endothelial transfer coefficient or plasma volumes with histological tumor grade. Analysis of CMD-A2-Gd-DOTA-enhanced MR kinetic data failed to demonstrate feasibility for the differentiation of benign from malignant tumors or for image-based tumor grading. (orig.)

Mechanism and energetics for complexation of 90Y with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a model for cancer radioimmunotherapy

International Nuclear Information System (INIS)

Jang, Y.H.; Blanco, M.; Dasgupta, S.; Keire, D.A.; Shively, J.E.; Goddard, W.A. III

1999-01-01

A promising cancer therapy involves the use of the macrocyclic polyaminoacetate DOTA (1,4,6,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) attached to a tumor-targeting antibody complexed with the β emitter 90 Y 3+ . However, incorporation of the 90 Y into the DOTA conjugate is too slow. To identify the origins of this problem, ab initio quantum chemistry methods (B3LYP/:ACVP* and HF/LACVP*) were used to predict structures and energetics. The authors find that the initial complex YH 2 (DOTA) + is 4-coordinate (the four equivalent carboxylate oxygens), which transforms to YH(DOTA) (5-coordinate with one ring N and four carboxylate oxygens), and finally to Y(DOTA) - , which is 8-coordinate (four oxygens and four nitrogens). The rate-determining step is the conversion of YH(DOTA) to Y(DOTA) - , which was calculated to have an activation free energy (aqueous phase) of 8.4 kcal/mol, in agreement with experimental results (8.1--9.3 kcal/mol) for various metals to DOTA [Kumar, K.; Tweedle, M.F. Inorg. Chem. 1993, 32, 4193--4199; Wu, S.L.; Horrocks, W.D., Jr., Inorg. Chem. 1995, 34, 3724--2732]. On the basis of this mechanism the authors propose a modified chelate, DO3AlPr, which has calculated at a much faster rate of incorporation

Somatostatin-based radiopeptide therapy with [177Lu-DOTA]-TOC versus [90Y-DOTA]-TOC in neuroendocrine tumours

International Nuclear Information System (INIS)

Romer, A.; Seiler, D.; Brunner, P.; Ng, Q.K.T.; Mueller-Brand, J.; Marincek, N.; Walter, M.A.; Koller, M.T.; Maecke, H.R.; Rochlitz, C.; Briel, M.; Schindler, C.

2014-01-01

Somatostatin-based radiopeptide treatment is generally performed using the β-emitting radionuclides 90 Y or 177 Lu. The present study aimed at comparing benefits and harms of both therapeutic approaches. In a comparative cohort study, patients with advanced neuroendocrine tumours underwent repeated cycles of [ 90 Y-DOTA]-TOC or [ 177 Lu-DOTA]-TOC until progression of disease or permanent adverse events. Multivariable Cox regression and competing risks regression were employed to examine predictors of survival and adverse events for both treatment groups. Overall, 910 patients underwent 1,804 cycles of [ 90 Y-DOTA]-TOC and 141 patients underwent 259 cycles of [ 177 Lu-DOTA]-TOC. The median survival after [ 177 Lu-DOTA]-TOC and after [ 90 Y-DOTA]-TOC was comparable (45.5 months versus 35.9 months, hazard ratio 0.91, 95 % confidence interval 0.63-1.30, p = 0.49). Subgroup analyses revealed a significantly longer survival for [ 177 Lu-DOTA]-TOC over [ 90 Y-DOTA]-TOC in patients with low tumour uptake, solitary lesions and extra-hepatic lesions. The rate of severe transient haematotoxicities was lower after [ 177 Lu-DOTA]-TOC treatment (1.4 vs 10.1 %, p = 0.001), while the rate of severe permanent renal toxicities was similar in both treatment groups (9.2 vs 7.8 %, p = 0.32). The present results revealed no difference in median overall survival after [ 177 Lu-DOTA]-TOC and [ 90 Y-DOTA]-TOC. Furthermore, [ 177 Lu-DOTA]-TOC was less haematotoxic than [ 90 Y-DOTA]-TOC. (orig.)

Somatostatin-based radiopeptide therapy with [177Lu-DOTA]-TOC versus [90Y-DOTA]-TOC in neuroendocrine tumours.

Science.gov (United States)

Romer, A; Seiler, D; Marincek, N; Brunner, P; Koller, M T; Ng, Q K T; Maecke, H R; Müller-Brand, J; Rochlitz, C; Briel, M; Schindler, C; Walter, M A

2014-02-01

Somatostatin-based radiopeptide treatment is generally performed using the β-emitting radionuclides (90)Y or (177)Lu. The present study aimed at comparing benefits and harms of both therapeutic approaches. In a comparative cohort study, patients with advanced neuroendocrine tumours underwent repeated cycles of [(90)Y-DOTA]-TOC or [(177)Lu-DOTA]-TOC until progression of disease or permanent adverse events. Multivariable Cox regression and competing risks regression were employed to examine predictors of survival and adverse events for both treatment groups. Overall, 910 patients underwent 1,804 cycles of [(90)Y-DOTA]-TOC and 141 patients underwent 259 cycles of [(177)Lu-DOTA]-TOC. The median survival after [(177)Lu-DOTA]-TOC and after [(90)Y-DOTA]-TOC was comparable (45.5 months versus 35.9 months, hazard ratio 0.91, 95% confidence interval 0.63-1.30, p = 0.49). Subgroup analyses revealed a significantly longer survival for [(177)Lu-DOTA]-TOC over [(90)Y-DOTA]-TOC in patients with low tumour uptake, solitary lesions and extra-hepatic lesions. The rate of severe transient haematotoxicities was lower after [(177)Lu-DOTA]-TOC treatment (1.4 vs 10.1%, p = 0.001), while the rate of severe permanent renal toxicities was similar in both treatment groups (9.2 vs 7.8%, p = 0.32). The present results revealed no difference in median overall survival after [(177)Lu-DOTA]-TOC and [(90)Y-DOTA]-TOC. Furthermore, [(177)Lu-DOTA]-TOC was less haematotoxic than [(90)Y-DOTA]-TOC.

Nature of the bifunctional chelating agent used for radioimmunotherapy with yttrium-88 monoclonal antibodies: critical factors in determining in vivo survival and organ toxicity

Energy Technology Data Exchange (ETDEWEB)

Kozak, R.W.; Raubitschek, A.; Mirzadeh, S.; Brechbiel, M.W.; Junghaus, R.; Gansow, O.A.; Waldmann, T.A. (Center for Biologics Evaluation and Research, FDA, Bethesda, MD (USA))

1989-05-15

One factor that is critical to the potential effectiveness of radioimmunotherapy is the design of radiometal-chelated antibodies that will be stable in vivo. Stability in vivo depends on the condition that both the chelate linkage and radiolabeling procedures not alter antibody specificity and biodistribution. In addition, synthesis and selection of the chelating agent is critical for each radiometal in order to prevent inappropriate release of the radiometal in vivo. In the present study, we compare the in vivo stability of seven radioimmunoconjugates that use different polyaminocarboxylate chelating agents to complex yttrium-88 to the mouse anti-human interleukin-2 receptor monoclonal antibody, anti-Tac. Chelate linkage and radiolabeling procedures did not alter the immunospecificity of anti-Tac. In order to assess whether yttrium was inappropriately released from the chelate-coupled antibody in vivo, iodine-131-labeled and yttrium-88 chelate-coupled antibodies were simultaneously administered to the same animals to correlate the decline in yttrium and radioiodinated antibody activity. The four stable yttrium-88 chelate-coupled antibodies studied displayed similar iodine-131 and yttrium-88 activity, indicating minimal elution of yttrium-88 from the complex. In contrast, the unstable yttrium-88 chelate-coupled antibodies had serum yttrium-88 activities that declined much more rapidly than their iodine-131 activities, suggesting loss of the radiolabel yttrium-88 from the chelate. Furthermore, high rates of yttrium-88 elution correlated with deposition in bone. Four chelating agents emerged as promising immunotherapeutic reagents: isothiocyanate benzyl DTPA and its derivatives 1B3M, MX, and 1M3B.

Influence of macrocyclic chelators on the targeting properties of (68Ga-labeled synthetic affibody molecules: comparison with (111In-labeled counterparts.

Directory of Open Access Journals (Sweden)

Joanna Strand

Full Text Available Affibody molecules are a class of small (7 kDa non-immunoglobulin scaffold-based affinity proteins, which have demonstrated substantial potential as probes for radionuclide molecular imaging. The use of positron emission tomography (PET would further increase the resolution and quantification accuracy of Affibody-based imaging. The rapid in vivo kinetics of Affibody molecules permit the use of the generator-produced radionuclide (68Ga (T1/2=67.6 min. Earlier studies have demonstrated that the chemical nature of chelators has a substantial influence on the biodistribution properties of Affibody molecules. To determine an optimal labeling approach, the macrocyclic chelators 1,4,7,10-tetraazacylododecane-1,4,7,10-tetraacetic acid (DOTA, 1,4,7-triazacyclononane-N,N,N-triacetic acid (NOTA and 1-(1,3-carboxypropyl-1,4,7- triazacyclononane-4,7-diacetic acid (NODAGA were conjugated to the N-terminus of the synthetic Affibody molecule ZHER2:S1 targeting HER2. Affibody molecules were labeled with (68Ga, and their binding specificity and cellular processing were evaluated. The biodistribution of (68Ga-DOTA-ZHER2:S1, (68Ga-NOTA-ZHER2:S1 and (68Ga-NODAGA-ZHER2:S1, as well as that of their (111In-labeled counterparts, was evaluated in BALB/C nu/nu mice bearing HER2-expressing SKOV3 xenografts. The tumor uptake for (68Ga-DOTA-ZHER2:S1 (17.9 ± 0.7%IA/g was significantly higher than for both (68Ga-NODAGA-ZHER2:S1 (16.13 ± 0.67%IA/g and (68Ga-NOTA-ZHER2:S1 (13 ± 3%IA/g at 2 h after injection. (68Ga-NODAGA-ZHER2:S1 had the highest tumor-to-blood ratio (60 ± 10 in comparison with both (68Ga-DOTA-ZHER2:S1 (28 ± 4 and (68Ga-NOTA-ZHER2:S1 (42 ± 11. The tumor-to-liver ratio was also higher for (68Ga-NODAGA-ZHER2:S1 (7 ± 2 than the DOTA and NOTA conjugates (5.5 ± 0.6 vs.3.3 ± 0.6. The influence of chelator on the biodistribution and targeting properties was less pronounced for (68Ga than for (111In. The results of this study demonstrate that macrocyclic

Effect of pH on the release of radionuclides and chelating agents from cement-solidified decontamination ion-exchange resins collected from operating nuclear power stations

International Nuclear Information System (INIS)

McIsaac, C.V.; Akers, D.W.; McConnell, J.W.

1991-06-01

Data are presented on the physical stability and leachability of radionuclides and chelating agents from cement-solidified decontamination ion-exchange resin wastes collected from two operating commercial light water reactors. Small-scale waste--form specimens collected during solidifications performed at the Brunswick Steam Electric Plant Unit 1 and at the James A. FitzPatrick Nuclear Power Station were leach-tested and subjected to compressive strength testing in accordance with the Nuclear Regulatory Commission's ''Technical Position on Waste Form'' (Revision 1). Samples of untreated resin waste collected from each solidification vessel before the solidification process were analyzed for concentrations of radionuclides, selected transition metals, and chelating agents to determine the quantities of these chemicals in the waste-form specimens. The chelating agents included oxalic, citric, and picolinic acids. In order to determine the effect of leachant chemical composition and pH on the stability and leachability of the waste forms, waste-form specimens were leached in various leachants. Results of this study indicate that differences in pH do not affect releases from cement-solidified decontamination ion-exchange resin waste forms, but that differences in leachant chemistry and the presence of chelating agents may affect the releases of radionuclides and chelating agents. Also, this study indicates that the cumulative releases of radionuclides and chelating agents are similar for waste- form specimens that decomposed and those that retained their general physical form. 36 refs., 60 figs., 28 tabs

Chelating agents improve enzymatic solubilization of pectinaceous co-processing streams

DEFF Research Database (Denmark)

Ravn, Helle Christine; Meyer, Anne S.

2014-01-01

of different levels of ethylene-diaminetetraacetic acid (EDTA), citric acid, oxalic acid, and phosphate was assessed in relation to enzymatic solubilization of isopropanol precipitatable oligo- and polysaccharides from sugar beet pulp, citrus peel, and two types of potato pulp. The two types of potato pulp...... solubilization yields. The effect of the chelating agents correlated to their dissociation constants (pKa values) and calcium binding constants and citric acid and EDTA exerted highest effects. Maximum polysaccharide yield was obtained for FiberBind 400 where the enzymatic treatment in presence of citric acid...

Correlation of Somatostatin Receptor-2 Expression with Gallium-68-DOTA-TATE Uptake in Neuroblastoma Xenograft Models.

Science.gov (United States)

Zhang, Libo; Vines, Douglass C; Scollard, Deborah A; McKee, Trevor; Komal, Teesha; Ganguly, Milan; Do, Trevor; Wu, Bing; Alexander, Natasha; Vali, Reza; Shammas, Amer; Besanger, Travis; Baruchel, Sylvain

2017-01-01

Peptide-receptor imaging and therapy with radiolabeled somatostatin analogs such as 68 Ga-DOTA-TATE and 177 Lu-DOTA-TATE have become an effective treatment option for SSTR-positive neuroendocrine tumors. The purpose of this study was to evaluate the correlation of somatostatin receptor-2 (SSTR2) expression with 68 Ga-DOTA-TATE uptake and 177 Lu-DOTA-TATE therapy in neuroblastoma (NB) xenograft models. We demonstrated variable SSTR2 expression profiles in eight NB cell lines. From micro-PET imaging and autoradiography, a higher uptake of 68 Ga-DOTA-TATE was observed in SSTR2 high-expressing NB xenografts (CHLA-15) compared to SSTR2 low-expressing NB xenografts (SK-N-BE(2)). Combined autoradiography-immunohistochemistry revealed histological colocalization of SSTR2 and 68 Ga-DOTA-TATE uptake in CHLA-15 tumors. With a low dose of 177 Lu-DOTA-TATE (20 MBq/animal), tumor growth inhibition was achieved in the CHLA-15 high SSTR2 expressing xenograft model. Although, in vitro , NB cells showed variable expression levels of norepinephrine transporter (NET), a molecular target for 131 I-MIBG therapy, low 123 I-MIBG uptake was observed in all selected NB xenografts. In conclusion, SSTR2 expression levels are associated with 68 Ga-DOTA-TATE uptake and antitumor efficacy of 177 Lu-DOTA-TATE. 68 Ga-DOTA-TATE PET is superior to 123 I-MIBG SPECT imaging in detecting NB tumors in our model. Radiolabeled DOTA-TATE can be used as an agent for NB tumor imaging to potentially discriminate tumors eligible for 177 Lu-DOTA-TATE therapy.

Correlation of Somatostatin Receptor-2 Expression with Gallium-68-DOTA-TATE Uptake in Neuroblastoma Xenograft Models

Directory of Open Access Journals (Sweden)

Libo Zhang

2017-01-01

Full Text Available Peptide-receptor imaging and therapy with radiolabeled somatostatin analogs such as 68Ga-DOTA-TATE and 177Lu-DOTA-TATE have become an effective treatment option for SSTR-positive neuroendocrine tumors. The purpose of this study was to evaluate the correlation of somatostatin receptor-2 (SSTR2 expression with 68Ga-DOTA-TATE uptake and 177Lu-DOTA-TATE therapy in neuroblastoma (NB xenograft models. We demonstrated variable SSTR2 expression profiles in eight NB cell lines. From micro-PET imaging and autoradiography, a higher uptake of 68Ga-DOTA-TATE was observed in SSTR2 high-expressing NB xenografts (CHLA-15 compared to SSTR2 low-expressing NB xenografts (SK-N-BE(2. Combined autoradiography-immunohistochemistry revealed histological colocalization of SSTR2 and 68Ga-DOTA-TATE uptake in CHLA-15 tumors. With a low dose of 177Lu-DOTA-TATE (20 MBq/animal, tumor growth inhibition was achieved in the CHLA-15 high SSTR2 expressing xenograft model. Although, in vitro, NB cells showed variable expression levels of norepinephrine transporter (NET, a molecular target for 131I-MIBG therapy, low 123I-MIBG uptake was observed in all selected NB xenografts. In conclusion, SSTR2 expression levels are associated with 68Ga-DOTA-TATE uptake and antitumor efficacy of 177Lu-DOTA-TATE. 68Ga-DOTA-TATE PET is superior to 123I-MIBG SPECT imaging in detecting NB tumors in our model. Radiolabeled DOTA-TATE can be used as an agent for NB tumor imaging to potentially discriminate tumors eligible for 177Lu-DOTA-TATE therapy.

Improving the efficiency of phytoremediation using electrically charged plant and chelating agents.

Science.gov (United States)

Tahmasbian, Iman; Safari Sinegani, Ali Akbar

2016-02-01

The low efficiency of phytoremediation is a considerable problem that limits the application of this environmentally friendly method on heavy metal-polluted soils. The combination of chelate-assisted phytoextraction and electrokinetic remediation could offer new opportunities to improve the effectiveness of phytoextraction. The current experiment aims to investigate the effects of electrical fields and chelating agents on phytoremediation efficiency. In a pot experiment using mine soil, poultry manure extract (PME), cow manure extract (CME), and ethylenediaminetetraacetic acid (EDTA) were applied to soil as chelating agents (2 g kg(-1)) at the beginning of the flowering stage. A week later, Helianthus annuus (sunflower) was negatively charged by inserting a stainless steel needle with 10 and 30 V DC electricity in the lowest part of the stems for 1 h each day for a 14-day period. At the end of the experiment, the shoot and root dry weight, lead (Pb) concentration in plant organs, translocation factor (TF), metal uptake index (UI), and soil available Pb (diethylene triamine pentaacetic acid (DTPA) extractable) were detected. Results indicated that the application of electrical fields had no significant impact on the shoot and root dry weights, while Pb concentration and UI increased in the 10-V EDTA treatment by 500 % compared to control. There was no significant difference between UI in 30- and 10-V EDTA treatments. Soil available Pb significantly increased in the 30-V treated soil. A positive correlation was observed between the available Pb in soil near the root and Pb concentration in shoot, its TF, and UI. In conclusion, a negatively charged plant along with the application of EDTA significantly increased the phytoremediation efficiency.

Chelation in metal intoxication

DEFF Research Database (Denmark)

Aaseth, Jan; Skaug, Marit Aralt; Cao, yang

2015-01-01

The present review provides an update of the general principles for the investigation and use of chelating agents in the treatment of intoxications by metals. The clinical use of the old chelators EDTA (ethylenediamine tetraacetate) and BAL (2,3-dimercaptopropanol) is now limited due to the incon......The present review provides an update of the general principles for the investigation and use of chelating agents in the treatment of intoxications by metals. The clinical use of the old chelators EDTA (ethylenediamine tetraacetate) and BAL (2,3-dimercaptopropanol) is now limited due...... to the inconvenience of parenteral administration, their own toxicity and tendency to increase the neurotoxicity of several metals. The hydrophilic dithiol chelators DMSA (meso-2,3-dimercaptosuccinic acid) and DMPS (2,3-dimercapto-propanesulphonate) are less toxic and more efficient than BAL in the clinical treatment...... of heavy metal poisoning, and available as capsules for oral use. In copper overload, DMSA appears to be a potent antidote, although d-penicillamine is still widely used. In the chelation of iron, the thiols are inefficient, since iron has higher affinity for ligands with nitrogen and oxygen, but the new...

Improved Efficacy of Synthesizing *MIII-Labeled DOTA Complexes in Binary Mixtures of Water and Organic Solvents. A Combined Radio- and Physicochemical Study.

Science.gov (United States)

Pérez-Malo, Marylaine; Szabó, Gergely; Eppard, Elisabeth; Vagner, Adrienn; Brücher, Ernő; Tóth, Imre; Maiocchi, Alessandro; Suh, Eul Hyun; Kovács, Zoltán; Baranyai, Zsolt; Rösch, Frank

2018-05-21

Typically, the synthesis of radiometal-based radiopharmaceuticals is performed in buffered aqueous solutions. We found that the presence of organic solvents like ethanol increased the radiolabeling yields of [ 68 Ga]Ga-DOTA (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacatic acid). In the present study, the effect of organic cosolvents [ethanol (EtOH), isopropyl alcohol, and acetonitrile] on the radiolabeling yields of the macrocyclic chelator DOTA with several trivalent radiometals (gallium-68, scandium-44, and lutetium-177) was systematically investigated. Various binary water (H 2 O)/organic solvent mixtures allowed the radiolabeling of DOTA at a significantly lower temperature than 95 °C, which is relevant for the labeling of sensitive biological molecules. Simultaneously, much lower amounts of the chelators were required. This strategy may have a fundamental impact on the formulation of trivalent radiometal-based radiopharmaceuticals. The equilibrium properties and formation kinetics of [M(DOTA)] - (M III = Ga III , Ce III , Eu III , Y III , and Lu III ) complexes were investigated in H 2 O/EtOH mixtures (up to 70 vol % EtOH). The protonation constants of DOTA were determined by pH potentiometry in H 2 O/EtOH mixtures (0-70 vol % EtOH, 0.15 M NaCl, 25 °C). The log K 1 H and log K 2 H values associated with protonation of the ring N atoms decreased with an increase of the EtOH content. The formation rates of [M(DOTA)] - complexes increase with an increase of the pH and [EtOH]. Complexation occurs through rapid formation of the diprotonated [M(H 2 DOTA)] + intermediates, which are in equilibrium with the kinetically active monoprotonated [M(HDOTA)] intermediates. The rate-controlling step is deprotonation (and rearrangement) of the monoprotonated intermediate, which occurs through H 2 O ( *M(HL) k H 2 O ) and OH - ( *M(HL) k OH ) assisted reaction pathways. The rate constants are essentially independent of the EtOH concentration, but the M(HL) k H2O

Preparation of Ga-67 labeled monoclonal antibodies using deferoxamine as a bifunctional chelating agent

International Nuclear Information System (INIS)

Endo, K.; Furukawa, T.; Ohmomo, Y.

1984-01-01

Ga-67 labeled monoclonal IgG or F(ab')/sub 2/ fragments against α-fetoprotein and β-subunit of human choriogonadotropin (HCG), were prepared using Deferoxamine (DFO) as a bifunctional chelating agent. DFO, a well-known iron chelating agent, was conjugated with monoclonal antibodies (Ab) by a glutaraldehyde two step method and the effect of conjugation on the Ab activities was examined by RIA and Scatchard plot analysis. In both monoclonal Ab preparations, the conjugation reaction was favored as the pH increased. However, Ab-binding activities decreased as the molecular ratios of DFO to Ab increased. Preserved Ab activities were observed when Ab contained DFO per Ab molecule less than 2.1. At a ratio of over 3.3 DFO molecules per Ab, the maximal binding capacity rather than the affinity constant decreased. The inter-molecular cross linkage seemed to be responsible for the deactivation of binding activities. The obtained DFO-Ab conjugates, were then easily labeled with high efficiency and reproducibility and Ga-67 DFO-Ab complexes were highly stable both in vitro and in vivo. Thus, biodistribution of Ga-67 labeled F(ab')/sub 2/ fragments of monoclonal Ab to HCG β-subunit was attempted in nude mice transplanted with HCG-producing human teratocarcinoma. Tumor could be visualized, in spite of relatively high background imaging of liver, kidney and spleen. The use of DFO as a bifunctional chelating agent provided good evidence for its applicability to labeling monoclonal Ab with almost full retention of Ab activities. Further, availability of Ga-68 will make Ga-68 DFO-monoclonal Ab a very useful tool for positron tomography imaging of various tumors

Role of different chelating agent in synthesis of copper doped tin oxide (Cu-SnO2) nanoparticles

Science.gov (United States)

Saravanakumar, B.; Anusiya, A.; Rani, B. Jansi; Ravi, G.; Yuvakkumar, R.

2018-05-01

An attempt was made to synthesis the copper doped tin oxide (Cu-SnO2) nanoparticles by adopting different chelating agents (NaOH, KOH and C2H2O4) by Sol-gel process. The synthesized products were characterized by XRD, Photoluminescence (PL), Infra- Red (FTIR) and SEM analysis. The XRD confirms the formation of Cu-SnO2 shows the maximum peak at 33.8° with lattice plane (101). The PL peak at 361 and 382 nm due to the recombination of electron in conduction band to valence band infers the optical properties. The IR spectra correspond to the peak at 551 and 620 cm-1 attributed to the characteristics peak for Cu-SnO2 nanoparticles. The SEM images for all three Cu-SnO2 nanoparticles formed by three chelating agent (NaOH, KOH and C2H2O4) facilitates the formation mechanism and the chelating agent Oxalic acid results in formation of nano flowers with diverse layers orientated in random direction. Further SEM studies reveal that, the Cu-SnO2 nanoparticles formed by oxalic acid could posses high surface area with large number layered structured enables the better electrochemical properties and its applications.

Organically complexed copper, zinc, and chelating agents in the rivers of Western Puerto Rico

International Nuclear Information System (INIS)

Montgomery, J.R.; Echevarria, J.E.

1975-01-01

The method for determining soluble chelators gives their concentration in copper-equivalent chelating capacity units in fresh or slightly brackish (less than 3 percent salinity) water. The mean concentration of chelators in the Rio Guanajibo for December 1973 and January 1974 was 0.4 mg of copper per liter of water (N = 21, SD = 0.2) and for February 1974, 0.9 mg/liter (N = 8, SD = 0.4). The combined mean for the Rio Anasco and Culebrinas was 0.5 mg/liter (N = 7, SD = 0.4) in January and February 1974. The mean concentration of ionic copper was 0.5 μg/liter (N = 7, SD = 0.6) and of ionic zinc, 0.2 μg/liter (N = 8, SD = 0.1) in the Rio Guanajibo from November 1972 to February 1973. The concentration of organically bound copper was 0.3 μ/liter (N = 7, SD = 0.2) and that of organically bound zinc was 0.6 μg/liter (N = 8, SD = 0.6); this indicates that there was more than a sufficient quantity of chelator available in the river to complex all the soluble copper. The presence of a high ratio of Ca 2+ to Cu 2+ probably prevents the formation of larger concentrations of organically complexed copper. The mean concentration of chelating agents in the Guanajibo River seems to be directly related to the increased organic input from municipalities and a sugar mill. The concentration of chelators in tropical rivers appears to be higher than that found in Canadian lakes. The mean concentration for particulate organic carbon (POC) was 3653 μg atoms/liter (SD = 3653, N = 29). The dissolved reactive phosphate (DRP) ranged from a mean of 1.1 μg atom/liter. No significant correlation could be found between POC, DRP, and the concentration of chelators

Somatostatin receptor PET in neuroendocrine tumours: 68Ga-DOTA0,Tyr3-octreotide versus 68Ga-DOTA0-lanreotide

International Nuclear Information System (INIS)

Putzer, Daniel; Kroiss, Alexander; Waitz, Dietmar; Gabriel, Michael; Uprimny, Christian; Guggenberg, Elisabeth von; Decristoforo, Clemens; Warwitz, Boris; Virgolini, Irene Johanna; Traub-Weidinger, Tatjana; Widmann, Gerlig

2013-01-01

The aim of this study was to evaluate the impact of 68 Ga-labelled DOTA 0 -lanreotide ( 68 Ga-DOTA-LAN) on the diagnostic assessment of neuroendocrine tumour (NET) patients with low to moderate uptake on planar somatostatin receptor (SSTR) scintigraphy or 68 Ga-labelled DOTA 0 ,Tyr 3 -octreotide ( 68 Ga-DOTA-TOC) positron emission tomography (PET). Fifty-three patients with histologically confirmed NET and clinical signs of progressive disease, who had not qualified for peptide receptor radionuclide therapy (PRRT) on planar SSTR scintigraphy or 68 Ga-DOTA-TOC PET (n = 38) due to lack of tracer uptake, underwent 68 Ga-DOTA-LAN PET to evaluate a treatment option with 90 Y-labelled lanreotide according to the MAURITIUS trial. The included patients received 150 ± 30 MBq of each radiopharmaceutical intravenously. PET scans were acquired 60-90 min after intravenous bolus injection. Image results from both PET scans were compared head to head, focusing on the intensity of tracer uptake in terms of treatment decision. CT was used for morphologic correlation of tumour lesions. To further evaluate the binding affinities of each tracer, quantitative and qualitative values were calculated for target lesions. 68 Ga-DOTA-LAN and 68 Ga-DOTA-TOC both showed equivalent findings in 24/38 patients when fused PET/CT images were interpreted. The sensitivity, specificity and accuracy of 68 Ga-DOTA-LAN in comparison to CT were 0.63, 0.5 and 0.62 (n = 53; p 68 Ga-DOTA-TOC in comparison to CT 0.78, 0.5 and 0.76 (n = 38; p 68 Ga-DOTA-TOC showed a significantly higher maximum standardized uptake value (SUV max ) regarding the primary tumour in 25 patients (p 68 Ga-DOTA-LAN. Corresponding values of both PET scans for tumour and liver did not show any significant correlation. 68 Ga-DOTA-TOC revealed more tumour sites than 68 Ga-DOTA-LAN (106 vs 53). The tumour to background ratios for tumour and liver calculated from SUV max measurements were significantly higher for 68 Ga-DOTA-TOC than 68 Ga-DOTA

Biliary excretion of cadmium in rat. III. Effects of chelating agents and change in intracellular thiol content on billiary transport and tissue distribution of cadmium

Energy Technology Data Exchange (ETDEWEB)

Cherian, M.G.

1980-03-01

The effects of changes in sulfur-containing intracellular ligands on biliary excretion of cadmium were studied in rats. Injection of zinc or copper salts 24 h before intravenous injection of /sup 109/CdCl/sub 2/ (1 mg/kg Cd) decreased biliary excretion of Cd. Pretreatment with cysteine (25 mg/kg) had a similar effect. Depletion of intracellular thiol by injection of diethylmaleate had little effect. The effect of chelating agents on the pharmacokinetics of Cd depended on time of administration of the agents after exposure to Cd. When chelating agents were administered 1/2 h after Cd injection (before the synthesis of metallothionein), the thiol-containing agents (2,3-dimercapto-1-propanol (BAL), DL-penicillamine, N-acetylpenicillamine, and dithioerythritol increased the biliary excretion of Cd, while the carboxyl-containing ones (EDTA and nitrilotriacetate) increased the urinary excretion of Cd. BAL was the most effective chelating agent, but there was also an increase in the renal concentration of Cd. However, when these chelating agents were administered 24 h after Cd injection (after the synthesis of metallothionein), only BAL increased the biliary excretion of Cd. Renal and hepatic Cd concentrations decreased concurrently after BAL treatment.

68Ga- and 111In-labelled DOTA-RGD peptides for imaging of αvβ3 integrin expression

International Nuclear Information System (INIS)

Decristoforo, Clemens; Hernandez Gonzalez, Ignacio; Rupprich, Marco; Virgolini, Irene; Carlsen, Janette; Huisman, Marc; Wester, Hans-Juergen; Haubner, Roland

2008-01-01

αvβ3 integrins are important cell adhesion receptors involved in angiogenic processes. Recently, we demonstrated using [ 18 F]Galacto-RGD that monitoring of αvβ3 expression is feasible. Here, we introduce 68 Ga- and 111 In-labelled derivatives and compare them with [ 18 F]Galacto-RGD. For radiolabelling, cyclo(RGDfK(DOTA)) was synthesised using SPPS. For in vitro characterisation determination of partition coefficients, protein binding, metabolic stability, αvβ3 affinity and cell uptake and for in vivo characterization, biodistribution studies and micro positron emission tomography (PET) imaging were carried out. For in vivo and in vitro studies, human melanoma M21 (αvβ3 positive) and M21-L (αvβ3 negative) cells were used. Both tracers can be synthesised straightforward. The compounds showed hydrophilic properties and high metabolic stability. Up to 23% protein-bound activity for [ 68 Ga]DOTA-RGD and only up to 1.4% for [ 111 In]DOTA-RGD was found. Cell uptake studies indicate receptor-specific accumulation. This is confirmed by the biodistribution data. One hour p.i. accumulation in αvβ3-positive tumours was 2.9 ± 0.3%ID/g and in αvβ3-negative tumours 0.8 ± 0.1%ID/g for [ 68 Ga]DOTA-RGD ([ 111 In]DOTA-RGD: 1.9 ± 0.3%ID/g and 0.5 ± 0.2%ID/g; [ 18 F]Galacto-RGD: 1.6 ± 0.2%ID/g and 0.4 ± 0.1%ID/g). Thus, tumour uptake ratios were comparable. Due to approx. 3-fold higher blood pool activities for [ 68 Ga]DOTA-RGD, tumour/blood ratios were higher for [ 111 In]DOTA-RGD and [ 18 F]Galacto-RGD. However, microPET studies demonstrated that visualisation of αvβ3-positive tumours using [ 68 Ga]DOTA-RGD is possible. Our data indicate that [ 68 Ga]DOTA-RGD allows monitoring of αvβ3 expression. Especially, the much easier radiosynthesis compared to [ 18 F]Galacto-RGD would make it an attractive alternative. However, due to higher blood pool activity, [ 18 F]Galacto-RGD remains superior for imaging αvβ3 expression. Introduction of alternative chelator

Somatostatin-based radiopeptide therapy with [{sup 177}Lu-DOTA]-TOC versus [{sup 90}Y-DOTA]-TOC in neuroendocrine tumours

Energy Technology Data Exchange (ETDEWEB)

Romer, A.; Seiler, D.; Brunner, P.; Ng, Q.K.T.; Mueller-Brand, J. [University Hospital Basel, Institute of Nuclear Medicine, Basel (Switzerland); Marincek, N.; Walter, M.A. [University Hospital Basel, Institute of Nuclear Medicine, Basel (Switzerland); University Hospital Bern, Institute of Nuclear Medicine, Bern (Switzerland); Koller, M.T. [University Hospital Basel, Basel Institute for Clinical Epidemiology and Biostatistics, Basel (Switzerland); Maecke, H.R. [University Hospital Basel, Division of Radiochemistry, Basel (Switzerland); Rochlitz, C. [University Hospital Basel, Department of Oncology, Basel (Switzerland); Briel, M. [University Hospital Bern, Institute of Nuclear Medicine, Bern (Switzerland); University Hospital Basel, Basel Institute for Clinical Epidemiology and Biostatistics, Basel (Switzerland); McMaster University, Department of Clinical Epidemiology and Biostatistics, Hamilton (Canada); Schindler, C. [University of Basel, Swiss Tropical and Public Health Institute, Basel (Switzerland)

2014-02-15

Somatostatin-based radiopeptide treatment is generally performed using the β-emitting radionuclides {sup 90}Y or {sup 177}Lu. The present study aimed at comparing benefits and harms of both therapeutic approaches. In a comparative cohort study, patients with advanced neuroendocrine tumours underwent repeated cycles of [{sup 90}Y-DOTA]-TOC or [{sup 177}Lu-DOTA]-TOC until progression of disease or permanent adverse events. Multivariable Cox regression and competing risks regression were employed to examine predictors of survival and adverse events for both treatment groups. Overall, 910 patients underwent 1,804 cycles of [{sup 90}Y-DOTA]-TOC and 141 patients underwent 259 cycles of [{sup 177}Lu-DOTA]-TOC. The median survival after [{sup 177}Lu-DOTA]-TOC and after [{sup 90}Y-DOTA]-TOC was comparable (45.5 months versus 35.9 months, hazard ratio 0.91, 95 % confidence interval 0.63-1.30, p = 0.49). Subgroup analyses revealed a significantly longer survival for [{sup 177}Lu-DOTA]-TOC over [{sup 90}Y-DOTA]-TOC in patients with low tumour uptake, solitary lesions and extra-hepatic lesions. The rate of severe transient haematotoxicities was lower after [{sup 177}Lu-DOTA]-TOC treatment (1.4 vs 10.1 %, p = 0.001), while the rate of severe permanent renal toxicities was similar in both treatment groups (9.2 vs 7.8 %, p = 0.32). The present results revealed no difference in median overall survival after [{sup 177}Lu-DOTA]-TOC and [{sup 90}Y-DOTA]-TOC. Furthermore, [{sup 177}Lu-DOTA]-TOC was less haematotoxic than [{sup 90}Y-DOTA]-TOC. (orig.)

Somatostatin receptor PET in neuroendocrine tumours: 68Ga-DOTA0,Tyr3-octreotide versus 68Ga-DOTA0-lanreotide.

Science.gov (United States)

Putzer, Daniel; Kroiss, Alexander; Waitz, Dietmar; Gabriel, Michael; Traub-Weidinger, Tatjana; Uprimny, Christian; von Guggenberg, Elisabeth; Decristoforo, Clemens; Warwitz, Boris; Widmann, Gerlig; Virgolini, Irene Johanna

2013-02-01

The aim of this study was to evaluate the impact of (68)Ga-labelled DOTA(0)-lanreotide ((68)Ga-DOTA-LAN) on the diagnostic assessment of neuroendocrine tumour (NET) patients with low to moderate uptake on planar somatostatin receptor (SSTR) scintigraphy or (68)Ga-labelled DOTA(0),Tyr(3)-octreotide ((68)Ga-DOTA-TOC) positron emission tomography (PET). Fifty-three patients with histologically confirmed NET and clinical signs of progressive disease, who had not qualified for peptide receptor radionuclide therapy (PRRT) on planar SSTR scintigraphy or (68)Ga-DOTA-TOC PET (n = 38) due to lack of tracer uptake, underwent (68)Ga-DOTA-LAN PET to evaluate a treatment option with (90)Y-labelled lanreotide according to the MAURITIUS trial. The included patients received 150 ± 30 MBq of each radiopharmaceutical intravenously. PET scans were acquired 60-90 min after intravenous bolus injection. Image results from both PET scans were compared head to head, focusing on the intensity of tracer uptake in terms of treatment decision. CT was used for morphologic correlation of tumour lesions. To further evaluate the binding affinities of each tracer, quantitative and qualitative values were calculated for target lesions. (68)Ga-DOTA-LAN and (68)Ga-DOTA-TOC both showed equivalent findings in 24/38 patients when fused PET/CT images were interpreted. The sensitivity, specificity and accuracy of (68)Ga-DOTA-LAN in comparison to CT were 0.63, 0.5 and 0.62 (n = 53; p < 0.0001) and for (68)Ga-DOTA-TOC in comparison to CT 0.78, 0.5 and 0.76 (n = 38; p < 0.013), respectively. (68)Ga-DOTA-TOC showed a significantly higher maximum standardized uptake value (SUV(max)) regarding the primary tumour in 25 patients (p < 0.003) and regarding the liver in 30 patients (p < 0.009) compared to (68)Ga-DOTA-LAN. Corresponding values of both PET scans for tumour and liver did not show any significant correlation. (68)Ga-DOTA-TOC revealed more tumour sites than (68)Ga-DOTA

Monitoring the effects of chelating agents and electrical fields on active forms of Pb and Zn in contaminated soil.

Science.gov (United States)

Tahmasbian, Iman; Safari Sinegani, Ali Akbar

2013-11-01

The application of electrical fields and chelating agents is an innovative hybrid technology used for the decontamination of soil polluted by heavy metals. The effects of four center-oriented electrical fields and chelating agents on active fractions of lead and zinc were investigated in this pot experiment. Ethylenediaminetetraacetic acid (EDTA) as a synthetic chelator and cow manure extract (CME) and poultry manure extract (PME) as natural chelators were applied to the pots (2 g kg(-1)) 30 days after the first irrigation. Two weeks later, four center-oriented electrical fields were applied in each pot (in three levels of 0, 10, and 30 V) for 1 h each day for 14 days. The soil near the cathode and anodes was collected and analyzed as cathodic and anodic soil, respectively. Results indicated that the soluble-exchangeable fraction of lead and zinc were decreased in the cathodic soil, while the carbonate-bound fractions were increased. In the anodic soil, however, the opposite result was observed. EDTA enhanced the soluble-exchangeable form of the metals in both anodic and cathodic soils. Furthermore, the amounts of carbonate-bound heavy metals were increased by the application of CME in both soils. The organic-bound fraction of the metals was increased by the application of natural chelators, while electrical fields had no significant impacts on this fraction.

64Cu-DOTA as a surrogate positron analog of Gd-DOTA for cardiac fibrosis detection with PET: pharmacokinetic study in a rat model of chronic MI.

Science.gov (United States)

Kim, Heejung; Lee, Sung-Jin; Davies-Venn, Cynthia; Kim, Jin Su; Yang, Bo Yeun; Yao, Zhengsheng; Kim, Insook; Paik, Chang H; Bluemke, David A

2016-02-01

The aim of this study was to investigate the pharmacokinetics of (64)Cu-DOTA (1,4,7,10-azacyclododecane-N,N',N'',N'''-tetraacetic acid), a positron surrogate analog of the late gadolinium (Gd)-enhancement cardiac magnetic resonance agent, Gd-DOTA, in a rat model of chronic myocardial infarction (MI) and its microdistribution in the cardiac fibrosis by autoradiography. DOTA was labeled with (64)Cu-acetate. CD rats (n=5) with MI by left anterior descending coronary artery ligation and normal rats (n=6) were injected intravenously with (64)Cu-DOTA (18.5 MBq, 0.02 mmol DOTA/kg). Dynamic PET imaging was performed for 60 min after injection. (18)F-Fluorodeoxyglucose ([(18)F]-FDG) PET imaging was performed to identify the viable myocardium. For the region of interest analysis, the (64)Cu-DOTA PET image was coregistered to the [(18)F]-FDG PET image. To validate the PET images, slices of heart samples from the base to the apex were analyzed using autoradiography and by histological staining with Masson's trichrome. (64)Cu-DOTA was rapidly taken up in the infarct area. The time-activity curves demonstrated that (64)Cu-DOTA concentrations in the blood, fibrotic tissue, and perfusion-rich organs peaked within a minute post injection; thereafter, it was rapidly washed out in parallel with blood clearance and excreted through the renal system. The blood clearance curve was biphasic, with a distribution half-life of less than 3 min and an elimination half-life of ∼21.8 min. The elimination half-life of (64)Cu-DOTA from the focal fibrotic tissue (∼22.4 min) and the remote myocardium (∼20.1 min) was similar to the blood elimination half-life. Consequently, the uptake ratios of focal fibrosis-to-blood and remote myocardium-to-blood remained stable for the time period between 10 and 60 min. The corresponding ratios obtained from images acquired from 30 to 60 min were 1.09 and 0.59, respectively, indicating that the concentration of (64)Cu-DOTA in the focal

DOTA-NOC, a high-affinity ligand of somatostatin receptor subtypes 2, 3 and 5 for labelling with various radiometals

International Nuclear Information System (INIS)

Wild, Damian; Schmitt, Joerg S.; Ginj, Mihaela; Maecke, Helmut R.; Bernard, Bert F.; Krenning, Eric; Jong, Marion de; Wenger, Sandra; Reubi, Jean-Claude

2003-01-01

Earlier studies have shown that modification of the octapeptide octreotide in positions 3 and 8 may result in compounds with increased somatostatin receptor affinity that, if radiolabelled, display improved uptake in somatostatin receptor-positive tumours. The aim of a recent research study in our laboratory was to employ the parallel peptide synthesis approach by further exchanging the amino acid in position 3 of octreotide and coupling the macrocyclic chelator DOTA(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to these peptides for labelling with radiometals like gallium-67 or -68, indium-111, yttrium-90 and lutetium-177. The purpose was to find radiopeptides with an improved somatostatin receptor binding profile in order to extend the spectrum of targeted tumours. A first peptide, [ 111 In, 90 Y-DOTA]-1-Nal 3 -octreotide ( 111 In, 90 Y-DOTA-NOC), was isolated which showed an improved profile. In III -DOTA-NOC exhibited the following IC 50 values (nM) when studied in competition with [ 125 I][Leu 8 , d-Trp 22 , Tyr 25 ]somatostatin-28 (values for Y III -DOTA-NOC are shown in parentheses): sstr2, 2.9±0.1 (3.3±0.2); sstr3, 8±2 (26±1.9); sstr5, 11.2±3.5 (10.4±1.6). Affinity towards sstr1 and 4 was very low or absent. In III -DOTA-NOC is superior to all somatostatin-based radiopeptides having this particular type of binding profile, including DOTA-lanreotide, and has three to four times higher binding affinity to sstr2 than In III ,Y III -DOTA-Tyr 3 -octreotide (In III ,Y III -DOTA-TOC). In addition, [ 111 In]DOTA-NOC showed a specific and high rate of internalization into AR4-2J rat pancreatic tumour cells which, after 4 h, was about two times higher than that of [ 111 In]DOTA-TOC and three times higher than that of [ 111 In]DOTA-octreotide ([ 111 In]DOTA-OC). The internalized radiopeptides were externalized intact upon 2 h of internalization followed by an acid wash. After 2-3 h of externalization a plateau is reached, indicating a steady

Subcritical wet air oxidation of organic solvents and chelating agents of the nuclear fuel

International Nuclear Information System (INIS)

Bachir, Souley

1999-01-01

This document deals with the environment control, more specially organic solvents and chelating agents destruction, employed in the nuclear industry. This work details the subcritical wet air oxidation process. Another part of the document deals with the possible coupling between this process and the biodegradation technic in the framework of the sewage sludges treatment. (A.L.B.)

Simultaneous (68)Ga-DOTA-TOC PET/MRI with gadoxetate disodium in patients with neuroendocrine tumor.

Science.gov (United States)

Hope, Thomas A; Pampaloni, Miguel Hernandez; Nakakura, Eric; VanBrocklin, Henry; Slater, James; Jivan, Salma; Aparici, Carina Mari; Yee, Judy; Bergsland, Emily

2015-08-01

To evaluate a simultaneous PET/MRI approach to imaging patients with neuroendocrine tumor using a combination of (68)Ga-DOTA-TOC as a PET contrast agent and gadoxetate disodium as a hepatobiliary MRI contrast agent. Ten patients with neuroendocrine tumor with known or suspected hepatic disease were imaged using a (68)Ga-DOTA-TOC PET/CT immediately followed by a 3.0T time-of-flight PET/MRI, using a combined whole body and liver specific imaging. The presence of lesions and DOTA-TOC avidity were assessed on CT, PET from PET/CT, diffusion weighted imaging, hepatobiliary phase imaging (HBP), and PET from PET/MRI. Maximum standardized uptake values (SUVmax) in hepatic lesions and nodal metastases were compared between PET/CT and PET/MRI, as were detection rates using each imaging approach. A total of 101 hepatic lesions were identified, 47 of which were DOTA-TOC avid and able to be individually measured on both PET/CT and PET/MRI. HBP imaging had a higher sensitivity for detection of hepatic lesions compared to CT or PET (99% vs. 46% and 64%, respectively; p values TOC and gadoxetate disodium was successful in whole body staging of patients with neuroendocrine tumor. HBP imaging had an increased detection rate for hepatic metastases.

Synthesis and Relaxivity Studies of a DOTA-Based Nanomolecular Chelator Assembly Supported by an Icosahedral Closo-B122− -Core for MRI: A Click Chemistry Approach

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Satish S. Jalisatgi

2013-07-01

Full Text Available An icosahedral closo-B122− scaffold based nano-sized assembly capable of carrying a high payload of Gd3+-chelates in a sterically crowded configuration is developed by employing the azide-alkyne click reaction. The twelve copies of DO3A-t-Bu-ester ligands were covalently attached to an icosahedral closo-B122− core via suitable linkers through click reaction. This nanomolecular structure supporting a high payload of Gd3+-chelate is a new member of the closomer MRI contrast agents that we are currently developing in our laboratory. The per Gd ion relaxivity (r1 of the newly synthesized MRI contrast agent was obtained in PBS, 2% tween/PBS and bovine calf serum using a 7 Tesla micro MRI instrument and was found to be slightly higher (r1 = 4.7 in PBS at 25 °C compared to the clinically used MRI contrast agents Omniscan (r1 = 4.2 in PBS at 25 °C and ProHance (r1 = 3.1 in PBS at 25 °C.

Peptide receptor radionuclide therapy (PRRT) using Lu-177 DOTA-NOC and Lu-177 DOTA-TATE: Comparative results

International Nuclear Information System (INIS)

Wehrmann, C.; Senftleben, S.; Baum, R.P.

2007-01-01

Full text: Aim: One of the few treatment options for inoperable neuroendocrine tumors (NET) is peptide receptor radiotherapy with somatostatin analogues. DOTA-NOC shows the highest affinity to the somatostatin receptors (sstr) 3 and 5 and a very high affinity to sstr 2. We compared the dosimetric parameters uptake, half-life (kinetics) and mean absorbed organ and tumor doses of 177 Lu DOTANOC and 177 Lu DOTA-TATE. Methods: 139 patients with neuroendocrine tumors with high sstr expression (verified by Ga-68 DOTA-NOC PET/CT) were studied. 130 patients (57m, 73f; aged 60±11a) were treated with 2.5-7.4 GBq Lu-177 DOTA-TATE and 9 patients (3m, 6f, aged 64±10a) with 3.6-7.4 GBq Lu-177 DOTA-NOC. Whole-body scans were performed after 0.5h, 3h, 24h, 48h, 72h and 96h p.i. Blood samples from 23 patients were obtained after therapy. By means of geometric mean and after background correction, ROI results were used to calculate the estimated absorbed organ and tumor doses according to the MIRD-scheme (OLINDA software). Results: Lu-177 DOTA-NOC showed a higher uptake as compared to Lu-177 DOTATATE (=100%): for whole-body about 38% and in normal tissue 36%, in the spleen 17% and in the kidneys 18%. The tumor uptake was about 5% higher for DOTA-TATE. The effective half-life for whole-body was comparable for both peptides (t1/2a NOC 2.9h vs. TATE 2.4h and t1/2b NOC 54h vs. TATE 56h). In normal tissue, t1/2a was similar (NOC 3.3h; TATE 2.6h) but the t1/2b was longer for DOTA-TATE (NOC 43h; TATE 48h). t1/2b was longer for DOTA-NOC in the spleen (NOC 81h; TATE 72h) and in the kidney (NOC 68.1h; TATE 65h). The mean absorbed dose in the kidney (TATE 5Sv; NOC 6Sv) and spleen (TATE 7Sv; NOC 8Sv) was higher for DOTA-NOC. In the tumor, the t1/2b was higher for DOTA-TATE (NOC 65h; TATE 77h). For DOTA-TATE the whole-body dose was lower (0.27Sv) as compared to DOTA-NOC (0.38 Sv) (significant by unpaired sign test). The estimated mean absorbed tumor doses were 47+/-66 Sv for DOTA-TATE and 35

PURWARUPA PORTAL MEMBER DOTA 2 INDONESIA

Directory of Open Access Journals (Sweden)

Yogi Anggoro

2017-11-01

Full Text Available Game di Indonesia sangatlah berkembang pesat, dari game offline maupun online. Penggemar game bukan hanya dari kalangan anak kecil, namun dari semua kalangan. Apalagi game online, sampai diperlombakan. Salah satunya yaitu game Dota 2, yang merupakan salah satu game online. Pada gamers bahkan tidak hanya di lingkup Indonesia saja, namun dapat tanding dengan negara manapun. Dari game ini muncul komunitas Dota 2, di Indonesia terdapat website yang memberikan informasi tentang Dota 2. Tetapi dari sekian website yang dikembangkan tidak ditemukan sebuah website yang mengakomodasi kebutuhan dari gamers. Tujuan dari penelitian ini adalah membuat sebuah wadah yang berfungsi sebagai sistem informasi untuk mengatur segala aktivitas gamers dalam bermain Dota 2. Purwarupa dalam penelitian ini mengakomodasi dalam pembuatan grup, mendapatkan pertandingan serta berpartisipasi dalam pertandingan ini. Di dalam purwarupa ini menjadi penting agar mempermudah pemain dalam bermain game Dota 2 ini. Dengan metode pengumpulan data literature, inisiasi, investigasi sampai pengembangan sistem dapat menghasilkan sebuah sistem informasi untuk komunitas Dota 2 di Indonesia.

Evaluation and comparison of Ga-68 DOTA-TATE and Ga-68 DOTA-NOC PET/CT imaging in well-differentiated thyroid cancer.

Science.gov (United States)

Ocak, Meltem; Demirci, Emre; Kabasakal, Levent; Aygun, Aslan; Tutar, Rumeysa O; Araman, Ahmet; Kanmaz, Bedii

2013-11-01

Somatostatin receptor (Sstr) scintigraphy with radiolabelled somatostatin analogues has been used extensively for the diagnosis and therapy of Sstr-expressing tumours. It has been shown that well-differentiated thyroid cancer (WDTC) cells have a high expression of Sstr2, Sstr3 and Sstr5. Hence, WDTC cells could be an ideal target for the evaluation of lesion uptake of Ga-68 DOTA-1-NaI3-octreotide (DOTA-NOC), which has a high affinity not only to Sstr2 but also to Sstr3 and Sstr5. The aim of the present study was to evaluate the value of Ga-68 DOTA-NOC as a target for Sstr2-expressing, Sstr3-expressing and Sstr5-expressing tumours in WDTC patients and to compare the results with those of Ga-68 DOTA-TATE in the same patient population. Thirteen patients with WDTC were included in our study: nine with papillary thyroid cancer, three with Hurthle cell carcinoma and one with follicular thyroid carcinoma. All patients had elevated serum thyroglobulin levels and negative post-therapeutic I-131 whole-body scans, which were obtained after the last radioiodine treatment. All patients had undergone two consecutive PET imaging studies with Ga-68 DOTA-D-Phe1-Tyr3-octreotate (DOTA-TATE) and Ga-68 DOTA-NOC, respectively. All images were evaluated visually, and maximum standardized uptake values were calculated. Both Ga-68 DOTA-TATE and Ga-68 DOTA-NOC PET images gave comparable results. Among the 13 patients, imaging with both Ga-68 DOTA-TATE and Ga-68 DOTA-NOC gave negative results in five (38%) patients and positive results in eight (62%) patients. A total of 45 lesions were identified on Ga-68 DOTA-TATE images and 42 on Ga-68 DOTA-NOC images; three lesions were missed. Lesion uptake was significantly higher on Ga-68 DOTA-TATE images. Maximum standardized uptake values of Ga-68 DOTA-TATE and Ga-68 DOTA-NOC were 12.9±9.1 and 6.3±4.1 (n=54, PDOTA-TATE has a higher lesion uptake even in WDTC patients and may have potential advantage over Ga-68 DOTA-NOC.

radiolabeling of DOTA-substance P with 177Lu and biodistribution of 177Lu-DOTA-substance P

International Nuclear Information System (INIS)

Liang Jixin; Li Hongyu; Xiang Xueqin; Luo Zhifu; Luo Hongyi; Hu Liansheng; Chen Yang; Zhuang Ling; Deng Xinrong

2012-01-01

The aim of this project is to evaluate the biodistribution of 177 Lu-DOTA-SP in normal mice and in PANC-1 tumor bearing nude mice and to pave the way for its potentially medical application. In this study, 177 Lu-DOTA-SP was successfully prepared with labeling yield of greater than 90% at optimized conditions and more than 98% of radiochemical purity after C18 Sep-Pak purification. 177 Lu-DOTA-SP showed good stability in saline and in 5% serum while it decomposed slowly in 10% serum. Biodistribution studies in normal mice showed high uptake of 177 Lu-DOTA-SP in the kidneys, indicating the excretion mainly by renal pathway. In addition, 177 Lu-DOTA-SP was washed out from the blood quickly. Bio- distribution of 177 Lu-DOTA-SP in PANC-1 tumor bearing mice showed higher uptake in pancreatic tumor than that in normal pancreas, indicating the presence of NK-1 receptors in PANC-1 pancreatic tumor. However, from SPECT image, no radioactivity accumulation was observed in PANC-1 tumor. Further evaluation is needed to confirm its potential application for radiotherapy of pancreatic cancers. (authors)

Representasi Hero Perempuan Dalam Game Dota 2

OpenAIRE

Handoko, Sofyan; Yuwono, Elisabeth Christine; Mardiono, Bambang

2016-01-01

Dota 2 merupakan video game yang sedang berkembang di Indonesia, adalah game yang mempertarungkan pemain-pemain yang terbagi kedalam dua tim yang berbeda. Dota 2 memperlihatkan bahwa meskipun game bertema perang, terdapat karakter-karakter yang biasa disebut hero, terdapat sosok perempuan pada game Dota 2. Studi dilakukan untuk melihat apakah hero perempuan dalam game Dota 2 telah direpresentasikan sesuai dengan atribut mereka masing-masing (Strength, Agility, dan Intellegence) dan melihat ma...

Comparison of 111In-DOTA-DPhe1-Tyr3-octreotide and 111In-DOTA-lanreotide scintigraphy and dosimetry in patients with neuroendocrine tumours

International Nuclear Information System (INIS)

Rodrigues, Margarida; Virgolini, Irene; Traub-Weidinger, Tatjana; Li, Shuren; Ibi, Bettina

2006-01-01

Somatostatin receptor scintigraphy with 111 In-DOTA-DPhe 1 -Tyr 3 -octreotide ( 111 In-DOTA-TOC) and 111 In-DOTA-lanreotide ( 111 In-DOTA-LAN) has been used for staging of neuroendocrine tumours (NETs). However, the comparative diagnostic value of these radioligands on a lesion basis has not yet been established. The aim of this study was to compare the diagnostic capacity of 111 In-DOTA-TOC and 111 In-DOTA-LAN scintigraphy in patients with NETs, evaluating whether significant differences exist in lesion imaging with these radioligands. Furthermore, dosimetric data were compared. Forty-five patients with NETs were investigated with 111 In-DOTA-TOC and 111 In-DOTA-LAN scintigraphy. Scintigraphic results were compared with those of conventional imaging and/or surgery in each patient, and also 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) in 20 patients. 111 In-DOTA-TOC and 111 In-DOTA-LAN scintigraphy were true positive in 42/45 (93%) and 39/45 (87%) patients, and imaged 74/91 (81%) and 73/91 (80%) tumour lesions, respectively. 111 In-DOTA-TOC and 111 In-DOTA-LAN detected liver metastases in 21 and 14 patients, mediastinal metastases in seven and 11 patients, and bone metastases in two and seven patients, respectively. These radioligands revealed lesions not seen by conventional imaging in seven and eight patients, respectively, or by 18 F-FDG-PET in eight and seven patients, respectively. The estimated tumour absorbed doses for 90 Y-DOTA-TOC were higher than those for 90 Y-DOTA-LAN in 14 patients, whereas the opposite was true in 12 patients. Both 111 In-DOTA-TOC and 111 In-DOTA-LAN are suitable for imaging tumour lesions in patients with NETs and can detect lesions that may not be seen by conventional imaging and 18 F-FDG-PET. Compared with 111 In-DOTA-LAN, 111 In-DOTA-TOC has a superior diagnostic capacity for liver metastases, but a lower diagnostic capacity for metastatic lesions in mediastinum and bone. (orig.)

Study on the mutagenic effects of a new chelating agent (7603) used for accelerating excretion of radionuclides

International Nuclear Information System (INIS)

Shen Binyuan; Luo Meichu; Zhen Guibao; Ruan Tianming; Feng Jialin; Cao Qunli

1989-01-01

The results of studies on the mutagenic effects of a new chelating agent, Suo An Quan (7603) or 5-methxlene Iminodiaeticaid Vanillin, was reported in this paper. For this agent, no mutagenesis was found by the reverse mutation test of Salmonella typhi munine (Amos test), the test of chromosome aberrations in Chinese hamster oocytes (CHO cells), and the test of micronucleus in polychromatic erythrocytes of the bone marrow in mice

Lanthanide ion (III) complexes of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaminophosphonate (DOTA-4AmP8−) for dual biosensing of pH with CEST (chemical exchange saturation transfer) and BIRDS (biosensor imaging of redundant deviation in shifts)

Science.gov (United States)

Huang, Yuegao; Coman, Daniel; Ali, Meser M.; Hyder, Fahmeed

2014-01-01

Relaxivity based magnetic resonance of phosphonated ligands chelated with gadolinium (Gd3+) shows promise for pH imaging. However instead of monitoring the paramagnetic effect of lanthanide complexes on the relaxivity of water protons, biosensor (or molecular) imaging with magnetic resonance is also possible by detecting either the non-exchangeable or the exchangeable protons on the lanthanide complexes themselves. The non-exchangeable protons (e.g., –CHx, where 3≥x≥1) are detected using a three-dimensional chemical shift imaging method called Biosensor Imaging of Redundant Deviation in Shifts (BIRDS), whereas the exchangeable protons (e.g., –OH or –NHy, where 2≥y≥1) are measured with Chemical Exchange Saturation Transfer (CEST) contrast. Here we tested the feasibility of BIRDS and CEST for pH imaging of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaminophosphonate (DOTA-4AmP8−) chelated with thulium (Tm3+) and ytterbium (Yb3+). BIRDS and CEST experiments show that both complexes are responsive to pH and temperature changes. Higher pH and temperature sensitivities are obtained with BIRDS for either complex when using the chemical shift difference between two proton resonances vs. using the chemical shift of a single proton resonance, thereby eliminating the need to use water resonance as reference. While CEST contrast for both agents is linearly dependent on pH within a relatively large range (i.e., 6.3-7.9), much stronger CEST contrast is obtained with YbDOTA-4AmP5− than with TmDOTA-4AmP5−. In addition, we demonstrate the prospect of using BIRDS to calibrate CEST as new platform for quantitative pH imaging. PMID:24801742

Effect of the ultrasound-Fenton oxidation process with the addition of a chelating agent on the removal of petroleum-based contaminants from soil.

Science.gov (United States)

Li, Ying; Li, Fangmin; Li, Fanxiu; Yuan, Fuqian; Wei, Pingfang

2015-12-01

The effects of ultrasonic irradiation, the chelating agent modified Fenton reaction, and a combination of ultrasound and the Fenton method in removing petroleum contaminants from a soil were studied. The results showed that the contaminant removal rate of the Fenton treatment combined with an oxalic acid chelating agent was 55.6% higher than that without a chelating agent. The average removal rate of the contaminants using the ultrasound-Fenton treatment was 59.0% higher than that without ultrasonic treatment. A combination of ultrasound and an Fe(2+)/Fe(3+)-oxalate complex-modified Fenton reagent resulted in significantly higher removal rates of n-alkanes (C(n)H(2n+2), n Fenton method. The Fenton reaction and the ultrasound-Fenton treatment can unselectively remove multiple components of residual hydrocarbons and a number of benzene rings in polycyclic aromatic hydrocarbons. The chemistry of the heterocyclic compounds and the position and number of substituents can affect the degradation process.

Effects of some chelating agents on the uptake and distribution of 54Mn(II) in the brown trout (Salmo trutta)

International Nuclear Information System (INIS)

Rouleau, C.; Tjaelve, H.; Pelletier, E.; Gottofrey, J.

1994-01-01

The effects of humic acids, which are natural metal-complexing compounds, and potassium ethylxanthate, sodium diethyldithiophosphate, sodium dimethyldithicarbamate, which are sulphur-containing man-made chelating agents, on the uptake and tissue distribution of 54 Mn(II) were studied in brown trout (Salmo trutta). Fish were exposed for 7 days to 0.1 μg Mn(II)x. -2 as NmCl 2 (l μCia 54 Mnxl -1 ) with or without chelat agents. Examination of the partition of Mn between octanol and a Tris-HCl buffer in the presence of these compounds was also performed. Humic acids had only small effects on Mn uptake and distribution in trout, probably because of the low stability of Mn-humate complexes. Partition of Mn in the presence of potassium ethylxanthate, sodium diethyldithiophosphate, sodium dimethyldithiocarbamate, and sodium diethyldithiocarbamate between octanol and Tris-HCl buffer showed formation of lipophilic complex with the latter two compounds, but not with the former. However, these four chelating agents all decreased Mn uptake in the trout by 40-45%. These substances also changed the distribution of Mn within the fish, with a higher proportion of the metal being present in some visceral organs and a smaller proportion being localized in some non-parenchymateous tissues, such as skin, fins and bones. The mechanisms underlying these effects are not known. however, the interaction of chelating agents with the Mn, although weak, may have partially withdrawn the metal from the uptake process inthe gills. The redistribution of Mn in the fish may be due to the binding of the metal to complexing compounds which have reached the intestinal lumen. Previous studies with other metals have shown increased or unchanged metal levels in tissues of fish at exposure together with potasium ethylxanthate, sodium diethyldithiophosphate, sodium dimethyldithiocarbamate, and sodium diethyldithiocarbamate, but decreased metal levels have not been observed before. (au) (37 refs.)

Role of chelates in magnetic resonance imaging studies

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Tripathi Laxmi

2009-01-01

Full Text Available Imaging studies are tests performed with a variety of techniques that produce pictures of the inside of a patient′s body. Magnetic resonance imaging (MRI is an imaging technique based on the principles of nuclear magnetic resonance. MRI uses a powerful magnetic field, radio waves, and a computer to produce detailed pictures of organs, soft tissues, bone, and virtually all other internal body structures. Chelates have a wide application in such imaging techniques. Chelates in imaging studies are used alone as radioactive agents or conjugated to monoclonal antibodies or to DNA as radioactive agents. Technetium chelates and gadolinium chelates are being widely used as magnetic resonance contrast media.

Optimization of reaction conditions for the radiolabeling of DOTA and DOTA-peptide with (44m/44)Sc and experimental evidence of the feasibility of an in vivo PET generator.

Science.gov (United States)

Huclier-Markai, S; Kerdjoudj, R; Alliot, C; Bonraisin, A C; Michel, N; Haddad, F; Barbet, J

2014-05-01

Among the number of generator systems providing radionuclides with decay parameters promising for imaging and treatment applications, there is the (44)Ti (T1/2=60 years)/(44)Sc (T1/2=3.97 h) generator. This generator provides a longer-lived daughter for extended PET/CT measurements compared to the chemically similar system (68)Ge/(68)Ga. Scandium also exists as (47)Sc, a potential therapeutic radionuclide. It is possible to produce (44)Sc in a cyclotron using, for example, the (44)Ca (d, n) (44)Sc nuclear reaction. In that case, the isomeric state (44 m)Sc (T1/2=58.6h) is co-produced and may be used as an in vivo(44 m)Sc/(44)Sc generator. The aim of this study is to evaluate the feasibility of this in vivo(44 m)Sc/(44)Sc generator and to demonstrate that the daughter radionuclide stays inside the chelator after decay of the parent radionuclide. Indeed, the physico-chemical process occurring after the primary radioactive decay (EC, IT, Auger electron …) has prevented in many cases the use of in-vivo generator, because of the post-effect as described in the literature. The DOTA macrocyclic ligand forms stable complexes with many cations and has been shown to be the most suitable chelating moiety for scandium. Initially, the radiolabeling of DOTA and a DOTA-peptide (DOTATATE) with Sc was performed and optimized as a function of time, pH, metal-to-ligand ratio and temperature. Next, the physico-chemical processes that could occur after the decay (post-effect) were studied. (44 m)Sc(III)-labeled DOTA-peptide was quantitatively adsorbed on a solid phase matrix through a hydrophobic interaction. Elutions were then performed at regular time intervals using a DTPA solution at various concentrations. Finally, the radiolabelled complex stability was studied in serum. Radiolabeling yields ranged from 90% to 99% for metal-to-ligand ratio ranging from 1:10 to 1:500 for DOTA or DOTATATE respectively. The optimum physico-chemical parameters were pH=4-6, t=20 min, T=70°C. Then

Sequestering agent for uranyl chelation: a new family of CAMS ligands

International Nuclear Information System (INIS)

Leydier, A.; Pellet-Rostaing, S.; Favre-Reguillon, A.; Lemaire, M.; Lecercle, D.; Taran, F.

2008-01-01

The synthesis of new dipodal bis-sulfo-catechol-amide uranophiles is presented. Their binding abilities for uranyl cation were determined by UV spectrophotometry in aqueous media under various pH conditions and further studied by 1 H NMR analysis of the resonance signal of both aromatic protons of the sulfo-catechol-amide groups. The results showed that the efficiency of these hydrosoluble chelating agents depends on the nature of the spacers. Each ligand shows a more or less pronounced affinity for uranium. The best receptor is the ligand CYCAMS 5d obtained as a mixture of cis/trans isomers, which achieves the best compromise between rigidity and steric hindrance. (authors)

Topical efficacy of dimercapto-chelating agents against lewisite-induced skin lesions in SKH-1 hairless mice

Energy Technology Data Exchange (ETDEWEB)

Mouret, Stéphane, E-mail: stephane.mouret@irba.fr [Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche (France); Wartelle, Julien; Emorine, Sandy; Bertoni, Marine; Nguon, Nina; Cléry-Barraud, Cécile [Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche (France); Dorandeu, Frédéric [Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche (France); Ecole du Val-de-Grâce, 1 place Alphonse Laveran, Paris (France); Boudry, Isabelle [Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche (France)

2013-10-15

Lewisite is a potent chemical warfare arsenical vesicant that can cause severe skin lesions. Today, lewisite exposure remains possible during demilitarization of old ammunitions and as a result of deliberate use. Although its cutaneous toxicity is not fully elucidated, a specific antidote exists, the British anti-lewisite (BAL, dimercaprol) but it is not without untoward effects. Analogs of BAL, less toxic, have been developed such as meso-2,3-dimercaptosuccinic acid (DMSA) and have been employed for the treatment of heavy metal poisoning. However, efficacy of DMSA against lewisite-induced skin lesions remains to be determined in comparison with BAL. We have thus evaluated in this study the therapeutic efficacy of BAL and DMSA in two administration modes against skin lesions induced by lewisite vapor on SKH-1 hairless mice. Our data demonstrate a strong protective efficacy of topical application of dimercapto-chelating agents in contrast to a subcutaneous administration 1 h after lewisite exposure, with attenuation of wound size, necrosis and impairment of skin barrier function. The histological evaluation also confirms the efficacy of topical application by showing that treatments were effective in reversing lewisite-induced neutrophil infiltration. This protective effect was associated with an epidermal hyperplasia. However, for all the parameters studied, BAL was more effective than DMSA in reducing lewisite-induced skin injury. Together, these findings support the use of a topical form of dimercaprol-chelating agent against lewisite-induced skin lesion within the first hour after exposure to increase the therapeutic management and that BAL, despite its side-effects, should not be abandoned. - Highlights: • Topically applied dimercapto-chelating agents reduce lewisite-induced skin damage. • One topical application of BAL or DMSA is sufficient to reverse lewisite effects. • Topical BAL is more effective than DMSA to counteract lewisite-induced skin damage.

Development of an inflammation imaging tracer, 111In-DOTA-DAPTA, targeting chemokine receptor CCR5 and preliminary evaluation in an ApoE-/- atherosclerosis mouse model.

Science.gov (United States)

Wei, Lihui; Petryk, Julia; Gaudet, Chantal; Kamkar, Maryam; Gan, Wei; Duan, Yin; Ruddy, Terrence D

2018-02-07

Chemokine receptor 5 (CCR5) plays an important role in atherosclerosis. Our objective was to develop a SPECT tracer targeting CCR5 for imaging plaque inflammation by radiolabeling D-Ala-peptide T-amide (DAPTA), a CCR5 antagonist, with 111 In. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) conjugated DAPTA (DOTA-DAPTA) was labeled with 111 In. Cell uptake studies were conducted in U87-CD4-CCR5 and U87-MG cells. Biodistribution was determined in C57BL/6 mice. Autoradiography, en face and Oil Red O (ORO) imaging studies were performed in ApoE -/- mice. DOTA-DAPTA was radiolabeled with 111 In with high radiochemical purity (> 98%) and specific activity (70 MBq·nmol). 111 In-DOTA-DAPTA exhibited fast blood and renal clearance and high spleen uptake. The U87-CD4-CCR5 cells had significantly higher uptake in comparison to the U87-MG cells. The cell uptake was reduced by three times with DAPTA, indicating the receptor specificity of the uptake. Autoradiographic images showed significantly higher lesion uptake of 111 In-DOTA-DAPTA in ApoE -/- mice than that in C57BL/6 mice. The tracer uptake in 4 month old ApoE -/- high fat diet (HFD) mice with blocking agent was twofold lower than the same mice without the blocking agent, demonstrating the specificity of the tracer for the CCR5 receptor. 111 In-DOTA-DAPTA, specifically targeting chemokine receptor CCR5, is a potential SPECT agent for imaging inflammation in atherosclerosis.

Comparison of Ga-68 DOTA-TATE and Ga-68 DOTA-LAN PET/CT imaging in the same patient group with neuroendocrine tumours: preliminary results.

Science.gov (United States)

Demirci, Emre; Ocak, Meltem; Kabasakal, Levent; Araman, Ahmet; Ozsoy, Yildiz; Kanmaz, Bedii

2013-08-01

Recent studies have suggested that PET imaging with Ga-68-labelled DOTA-somatostatin analogues such as octreotide and octreotate is useful in diagnosing neuroendocrine tumours (NETs) and has superior value over both computed tomography and planar and SPECT somatostatin receptor scintigraphy. The aim of the present study was to evaluate the role of Ga-68 DOTA-lanreotide (Ga-68-DOTA-LAN) in patients with somatostatin receptor (sst)-expressing tumours and to compare the results of Ga-68 DOTA-D-Phe1-Tyr3-octreotate (Ga-68-DOTA-TATE) in the same patient population. Twelve patients with NETs who were referred to our department for somatostatin receptor scintigraphy were included in the study. There were four patients with well-differentiated neuroendocrine tumour (WDNET) grade 1, two patients with WDNET grade 2, and three patients with poorly differentiated neuroendocrine carcinoma (PDNEC) grade 3. There was also one patient with medullary thyroid cancer, one patient with meningioma and one patient with MEN-1. All patients underwent two consecutive PET imaging studies with Ga-68-DOTA-TATE and Ga-68 DOTA-LAN. All images were evaluated visually, and maximum standardized uptake value was calculated for quantitative evaluation. On visual examination of maximum intensity projection images, GA-68 DOTA-LAN was seen to have high background activity and high bone marrow uptake. Both tracers defined 67 lesions. Ga-68 DOTA-TATE images revealed 63 (94%) clearly defined lesions, missing four lesions. In contrast, Ga-68 DOTA-LAN images defined only 23 (44%) lesions, missing 44 (56%) lesions. Thirty-two bone lesions were detected on Ga-68-DOTA-TATE images. Among them, only 11 (34%) were positive on Ga-68 DOTA-LAN images, whereas 21 (66%) were negative. When we evaluated liver, mediastinum and gastrointestinal tract lesions, Ga-68 DOTA-LAN was seen to be positive for 12 (34%) lesions and negative for 23 (66%) lesions. Although the results are preliminary, the image quality obtained by

Novel chelating agents for iron, manganese, zinc, and copper mixed fertilisation in high pH soil-less cultures.

Science.gov (United States)

López-Rayo, Sandra; Nadal, Paloma; Lucena, Juan J

2016-03-15

Studies about simultaneous fertilisation with several micronutrients have increased in recent years, as Fe, Mn and Zn deficiencies may appear in the same culture conditions. In fertigation, the replacement of sulfates by synthetic chelates is essential in areas with high pH irrigation water and substrates. Ethylenediamine-N-(2-hydroxyphenylacetic acid)-N'-(4-hydroxyphenylacetic acid) (o,p-EDDHA) and ethylenediamine disuccinic acid (EDDS) are novel chelating agents whose efficacy in simultaneous fertilisation of Zn, Mn and Cu is unknown. This work evaluates the effectiveness of both ligands compared to traditional ligands (EDTA, HEEDTA and DTPA) applied as micronutrient chelate mixtures to soybean and navy bean plants grown in soil-less cultures at high pH by analysing the SPAD and micronutrient nutritional status, including the Composition Nutritional Diagnosis (CND) analysis tool. The application of micronutrients using o,p-EDDHA was more effective in providing Mn and Zn than traditional ligands or sulfates. The application using EDDS increased the Zn nutrition. The results are well correlated with the chemical stability of the formulations. The combined application of Mn and Zn as o,p-EDDHA chelates can represent a more effective source than traditional chelates in micronutrient fertiliser mixtures in soil-less cultures at a high pH. © 2015 Society of Chemical Industry.

Effect of the tether on the Mg(II), Ca(II), Cu(II) and Fe(III) stability constants and pM values of chelating agents related to EDDHA.

Science.gov (United States)

Sierra, Miguel A; Gómez-Gallego, Mar; Alcázar, Roberto; Lucena, Juan J; Yunta, Felipe; García-Marco, Sonia

2004-11-07

The effect of the length and the structure of the tether on the chelating ability of EDDHA-like chelates have not been established. In this work, PDDHA (propylenediamine-N,N'-bis(o-hydroxyphenyl)acetic acid), BDDHA (butylenediamine-N,N'-bis(o-hydroxyphenyl)acetic acid) and XDDHA (p-xylylenediamine-N,N'-bis(o-hydroxyphenyl)acetic acid) have been obtained and their chemical behaviour has been studied and compared with that of EDDHA following our methodology. The purity of the chelating agents, and their protonation, Ca(II), Mg(II), Fe(III) and Cu(II) stability constants and pM values have been determined. The stability constants and pM values indicate that EDDHA forms the most stable chelates followed by PDDHA. However, the differences among the pFe values are small when a nutrient solution is used, and in these conditions the XDDHA/Fe(III) chelate is the most stable. The results obtained in this work indicate that all the chelating agents studied can be used as iron chlorosis correctors and they can be applied to soil/plant systems.

Treatment with tandem [90Y]DOTA-TATE and [177Lu]DOTA-TATE of neuroendocrine tumours refractory to conventional therapy.

Science.gov (United States)

Seregni, E; Maccauro, M; Chiesa, C; Mariani, L; Pascali, C; Mazzaferro, V; De Braud, F; Buzzoni, R; Milione, M; Lorenzoni, A; Bogni, A; Coliva, A; Lo Vullo, S; Bombardieri, E

2014-02-01

Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues has been demonstrated to be an effective therapeutic option in patients with disseminated neuroendocrine tumours (NET). Treatment with tandem [(90)Y]DOTA-TATE and [(177)Lu]DOTA-TATE may improve the efficacy of PRRT without increasing the toxicity. In a phase II study we evaluated the feasibility of combined PPRT with a high-energy beta emitter ((90)Y) and a medium-energy beta/gamma emitter ([(177)Lu) in patients with metastatic NET refractory to conventional therapy. A group of 26 patients with metastatic NET were treated with four therapeutic cycles of alternating [[(177)Lu]DOTA-TATE (5.55 GBq) and [(90)Y]DOTA-TATE (2.6 GBq). A dosimetric evaluation was carried out after administration of [[(177)Lu]DOTA-TATE to calculate the absorbed doses in healthy organs. The acute and long-term toxicities of repeated treatment were analysed. PRRT efficacy was evaluated according to RECIST. Administration of tandem [(90)Y]DOTA-TATE and [[(177)Lu]DOTA-TATE induced objective responses in 42.3 % of patients with metastatic NET with a median progression-free survival longer than 24 months. Of patients with pretreatment carcinoid syndrome, 90 % showed a symptomatic response or a reduction in tumour-associated pain. The cumulative biologically effective doses (BED) were below the toxicity limit in the majority of patients, in the absence of renal function impairment. The results of our study indicates that combined [(90)Y]DOTA-TATE and [(177)Lu]DOTA-TATE therapy is a feasible and effective therapeutic option in NET refractory to conventional therapy. Furthermore, the absence of kidney damage and the evaluated cumulative BEDs suggest that increasing the number of tandem administrations is an interesting approach.

Mechanisms of oxide dissolution by acid chelating agents

International Nuclear Information System (INIS)

Blesa, M.A.; Maroto, A.J.G.

1982-01-01

In this paper, the different possible rate controlling processes in the dissolution of metallic oxides are examined. In particular, the following situations are assessed: mass-transfer control; coupling of mass-transfer and reactions at the interface; interface equilibration with the solution; various interface disruption and reconstruction phenomena. For each of the above mentioned cases, the influence of variables such as reagent concentration, temperature, pH, fluid hydrodynamics and general and specific catalysts is discussed. Depending upon the particular situation it is found that a more rational basis for the development of reagent is given by these considerations. The influence of chelating agents on both the thermodynamics and kinetics of the process is discussed, and the results of experimental studies in batch on magnetite and various ferrites are presented and discussed. For this purpose, several reagents were studied, including some very effective ones like thioglycolic acid, and others commonly used in actual decontamination, like ethylenediaminetetraacetic acid and oxalic acid. The relation to other (reductive) chemical decontamination procedures is discussed. The relevance of these studies to decontamination of metallic surfaces is discussed

Dosimetric Studies in Normal Mice of 177Lu-DOTA-SP and 177Lu-DOTA-His2-MG

International Nuclear Information System (INIS)

Puerta Yepes, N.; Rojo, A.M.; Lopez Bularte, A.C.; Nevares, N.; Zapata, M.; Perez, J.H.; Crudo, J.

2010-01-01

DOTA-Substance-P (SP) and DOTA-minigastrin (His2-MG) labeled with 177 Lu could be used in peptide receptor radionuclide therapy (PRRT) for treatment of various tumour species. Biodistribution studies of both radiopharmaceuticals in normal mice were performed at different times. Absorbed doses in mouse organs were estimated and extrapolated to humans. Dosimetric calculations showed that kidneys received the highest dose, for both radiopharmaceuticals. The Maximum Tolerated Activity (MTA) of 177 Lu-DOTA-SP that can be administered without kidney toxicity are 414 and 422 MBq/kg for the standard adult man and woman, respectively. In the same way, the MTA of 177 Lu-DOTA-His2-MG are 488 and 518 MBq/kg for the standard adult man and woman, respectively. (authors)

Feasibility of tetracycline, a common antibiotic, as chelating agent for spectrophotometric determination of UO22+ after cloud point extraction

International Nuclear Information System (INIS)

Esra Bagda; Ebru Yabas; Nihat Karakus

2014-01-01

A cloud point extraction (CPE) procedure was presented for the preconcentration of UO 2 2+ ion in different water samples. Tetracycline (TC) is the second most widely used antibiotics in the world and is used as chelating agent. To the best of our knowledge, this is the first work that an antibiotic is used as a chelating agent for CPE of UO 2 2+ . Besides, the use of TC as complexing agent provides excellent chelating features. TC molecule has large numbers of functional groups (adjacent hydroxyl oxygen atoms and cyclohexanone oxygen atoms, amide groups) which can form stable complex with UO 2 2+ . After complexation with TC, UO 2 2+ ions were quantitatively recovered in Triton X-100 after cooling in the ice bath. 3.0 mL of acetate buffer was added to the surfactant-rich phase prior to its analysis by UV-Vis spectrophotometer. The influence of analytical parameters including pH, buffer volume, TC, Triton X-100 concentrations, bath temperature, incubation time were optimized. The effect of the matrix ions on the recovery of UO 2 2+ ions was investigated. The limit of detection was 0.0746 μg mL -1 along with enrichment factor of 14.3 with a R.S.D. of 3.6 %. The proposed procedure was applied to the analysis of various environmental water samples. On the other hand, the electronic distribution of TC molecule is investigated with their frontier molecular orbital density distributions. (author)

Somatostatin receptor PET in neuroendocrine tumours: {sup 68}Ga-DOTA{sup 0},Tyr{sup 3}-octreotide versus {sup 68}Ga-DOTA{sup 0}-lanreotide

Energy Technology Data Exchange (ETDEWEB)

Putzer, Daniel; Kroiss, Alexander; Waitz, Dietmar; Gabriel, Michael; Uprimny, Christian; Guggenberg, Elisabeth von; Decristoforo, Clemens; Warwitz, Boris; Virgolini, Irene Johanna [Innsbruck Medical University, Department of Nuclear Medicine, Innsbruck (Austria); Traub-Weidinger, Tatjana [Vienna Medical University, Department of Nuclear Medicine, Vienna (Austria); Widmann, Gerlig [Innsbruck Medical University, Department of Radiology, Innsbruck (Austria)

2013-03-15

The aim of this study was to evaluate the impact of {sup 68}Ga-labelled DOTA{sup 0}-lanreotide ({sup 68}Ga-DOTA-LAN) on the diagnostic assessment of neuroendocrine tumour (NET) patients with low to moderate uptake on planar somatostatin receptor (SSTR) scintigraphy or {sup 68}Ga-labelled DOTA{sup 0},Tyr{sup 3}-octreotide ({sup 68}Ga-DOTA-TOC) positron emission tomography (PET). Fifty-three patients with histologically confirmed NET and clinical signs of progressive disease, who had not qualified for peptide receptor radionuclide therapy (PRRT) on planar SSTR scintigraphy or {sup 68}Ga-DOTA-TOC PET (n = 38) due to lack of tracer uptake, underwent {sup 68}Ga-DOTA-LAN PET to evaluate a treatment option with {sup 90}Y-labelled lanreotide according to the MAURITIUS trial. The included patients received 150 {+-} 30 MBq of each radiopharmaceutical intravenously. PET scans were acquired 60-90 min after intravenous bolus injection. Image results from both PET scans were compared head to head, focusing on the intensity of tracer uptake in terms of treatment decision. CT was used for morphologic correlation of tumour lesions. To further evaluate the binding affinities of each tracer, quantitative and qualitative values were calculated for target lesions. {sup 68}Ga-DOTA-LAN and {sup 68}Ga-DOTA-TOC both showed equivalent findings in 24/38 patients when fused PET/CT images were interpreted. The sensitivity, specificity and accuracy of {sup 68}Ga-DOTA-LAN in comparison to CT were 0.63, 0.5 and 0.62 (n = 53; p < 0.0001) and for {sup 68}Ga-DOTA-TOC in comparison to CT 0.78, 0.5 and 0.76 (n = 38; p < 0.013), respectively. {sup 68}Ga-DOTA-TOC showed a significantly higher maximum standardized uptake value (SUV{sub max}) regarding the primary tumour in 25 patients (p < 0.003) and regarding the liver in 30 patients (p < 0.009) compared to {sup 68}Ga-DOTA-LAN. Corresponding values of both PET scans for tumour and liver did not show any significant correlation. {sup 68}Ga-DOTA

68Ga-DOTA-TOC Uptake in Pleomorphic Adenoma.

Science.gov (United States)

Laurens, S Tom; Netea-Maier, Romana T; Aarntzen, Erik J H G

2018-07-01

A 56-year-old man who was recently diagnosed with a carcinoid tumor of the os petrosum was referred for a Ga-DOTA-TOC PET/CT scan. Besides the moderately increased Ga-DOTA-TOC accumulation in the carcinoid tumor, the scan showed strongly increased and focal Ga-DOTA-TOC uptake in an additional lesion in the right parotid gland. The markedly different Ga-DOTA-TOC avidity suggested a different etiology, and histological examination demonstrated a pleomorphic adenoma.

Investigation of a potential macromolecular MRI contrast agent prepared from PPI (G = 2, polypropyleneimine, generation 2) dendrimer bifunctional chelates

Science.gov (United States)

Wang, Jianxin Steven

The long-term objective is to develop magnetic resonance (MR) contrast agents that actively and passively target tumors for diagnosis and therapy. Many diagnostic imaging techniques for cancer lack specificity. A dendrimer based magnetic resonance imaging contrast agent has been developed with large proton relaxation enhancements and high molecular relaxivities. A new type of linear dendrimer based MRI contrast agent that is built from the polypropyleneimine and polyamidoamine dendrimers in which free amines have been conjugated to the chelate DTPA, which further formed the complex with Gadolinium (Gd) was studied. The specific research goals were to test the hypothesis that a linear chelate with macromolecular agents can be used in vitro and in vivo. This work successfully examined the adequacy and viability of the application for this agent in vitro and in vivo. A small animal whole body counter was designed and constructed to allow us to monitor biodistribution and kinetic mechanisms using a radioisotope labeled complex. The procedures of metal labeling, separation and purification have been established from this work. A biodistribution study has been performed using radioisotope induced organ/tissue counting and gamma camera imaging. The ratio of percentage of injected dose per gram organ/tissue for kidney and liver is 3.71 from whole body counter and 3.77 from the gamma camera. The results suggested that retention of Gd (III) is too high and a more kinetically stable chelate should be developed. The pharmacokinetic was evaluated in the whole animal model with the whole body clearance, and a kinetics model was developed. The pharmacokinetic results showed a bi-exponential decay in the animal model with two component excretion constants 1.43e(-5) and 0.0038511, which give half-lives of 3 hours and 33.6 days, respectively. Magnetic resonance imaging of this complex resulted in a 52% contrast enhancement in the rat kidney following the agents' administration in

Radiopharmaceutical chelates and method of external imaging

International Nuclear Information System (INIS)

1976-01-01

The preparation of the following chemicals is described: chelates of technetium-99m, cobalt-57, gallium-67, gallium-68, indium-111 or indium-113m and a substituted iminodiacetic acid or an 8-hydroxyquinoline useful as a radiopharmaceutical external imaging agent. The compounds described are suitable for intravenous injection, have an excellent in vivo stability and are good organ seekers. Tin(II) choride or other tin(II) compounds are used as chelating agents

Chelating agent-assisted electrokinetic removal of cadmium, lead and copper from contaminated soils

International Nuclear Information System (INIS)

Giannis, Apostolos; Nikolaou, Aris; Pentari, Despina; Gidarakos, Evangelos

2009-01-01

An integrated experimental program was conducted to remove Cd, Pb and Cu from contaminated soil. The chelate agents nitrilotriacetic acid (NTA), diethylenetriamine pentaacetic acid (DTPA) and ethyleneglycol tetraacetic acid (EGTA) were used as washing solutions under different pH conditions and concentrations. Results showed that the extraction efficiency for Cd in decreasing order was NTA > EGTA > DTPA, while for Pb and Cu it was DTPA > NTA > EGTA. The use of higher chelate concentrations did not necessarily result in greater extraction efficiency. Electrokinetic remediation was applied by conditioning anolyte-catholyte pH to neutral values in order to avoid any potential alterations to the physicochemical soil properties. The removal efficiency for Cd was 65-95%, for Cu 15-60%, but for Pb was less than 20%. The phytotoxicity of the treated soil showed that the soil samples from the anode section were less phytotoxic than the untreated soil, but the phytotoxicity was increased in the samples from the cathode section. - Cadmium, lead and copper were extracted from contaminated soil by integrated electrokinetic and soil washing studies.

Chelating agent-assisted electrokinetic removal of cadmium, lead and copper from contaminated soils

Energy Technology Data Exchange (ETDEWEB)

Giannis, Apostolos, E-mail: apostolos.giannis@enveng.tuc.g [Laboratory of Toxic and Hazardous Waste Management, Department of Environmental Engineering, Technical University of Crete, Politechnioupolis, Chania 73100 (Greece); Nikolaou, Aris [Laboratory of Toxic and Hazardous Waste Management, Department of Environmental Engineering, Technical University of Crete, Politechnioupolis, Chania 73100 (Greece); Pentari, Despina [Laboratory of Inorganic and Organic Geochemistry and Organic Petrography, Department of Mineral Resources Engineering, Technical University of Crete, Politechnioupolis, Chania 73100 (Greece); Gidarakos, Evangelos, E-mail: gidarako@mred.tuc.g [Laboratory of Toxic and Hazardous Waste Management, Department of Environmental Engineering, Technical University of Crete, Politechnioupolis, Chania 73100 (Greece)

2009-12-15

An integrated experimental program was conducted to remove Cd, Pb and Cu from contaminated soil. The chelate agents nitrilotriacetic acid (NTA), diethylenetriamine pentaacetic acid (DTPA) and ethyleneglycol tetraacetic acid (EGTA) were used as washing solutions under different pH conditions and concentrations. Results showed that the extraction efficiency for Cd in decreasing order was NTA > EGTA > DTPA, while for Pb and Cu it was DTPA > NTA > EGTA. The use of higher chelate concentrations did not necessarily result in greater extraction efficiency. Electrokinetic remediation was applied by conditioning anolyte-catholyte pH to neutral values in order to avoid any potential alterations to the physicochemical soil properties. The removal efficiency for Cd was 65-95%, for Cu 15-60%, but for Pb was less than 20%. The phytotoxicity of the treated soil showed that the soil samples from the anode section were less phytotoxic than the untreated soil, but the phytotoxicity was increased in the samples from the cathode section. - Cadmium, lead and copper were extracted from contaminated soil by integrated electrokinetic and soil washing studies.

Optimized preparation and preliminary evaluation of [64Cu]-DOTA-trastuzumab for targeting ErbB2/Neu expression

International Nuclear Information System (INIS)

Behrooz Alirezapour; Mohammad Javad Rasaee

2013-01-01

Breast cancer radioimmunoscintigraphy targeting HER2/neu expression is a growing field of work in nuclear medicine research. Trastuzumab is a monoclonal antibody that binds with high affinity to HER2/neu, which is over expressed on breast and other tumors. Developing new tracers for the detection of this cancer is of great interest. In this study, trastuzumab was successively labeled with [ 64 Cu]CuCl 2 after conjugation with DOTA-NHS-ester. The conjugate was purified by molecular filtration, the average number of DOTA conjugated per mAb was calculated and total concentration was determined by spectrophotometric method. DOTA-trastuzumab was labeled with 64 Cu produced by 68 Zn(p,αn) 64 Cu nuclear reaction (30 MeV protons at 180 μA). Radiochemical purity, integrity of protein after radiolabeling and immunoreactivity of radiolabeled mAb trastuzumab with HER2/neu antigen and SkBr3 cell line were performed by RIA. In vitro stability of radiolabeled mAb in human serum was determined by thin layer chromatography. In vitro internalization studies were performed with the SkBr3 cell line and the tissue biodistribution of the 64 Cu-DOTA-trastuzumab was evaluated in wild-type rat (90 ± 5.5 μCi, 2, 6, 12, 24 h p.i.). The radioimmunoconjugate was prepared with a radiochemical purity of higher than 96 ± 0.5 % (ITLC) and specific activity as high as 5.3 μCi/μg. The average number of chelators per antibody for the conjugate used in this study was 5.8/1. The sample was showed to have similar patterns of migration in the gel electrophoresis. The 64 Cu-DOTA-trastuzumab showed high immunoreactivity towards HER2/neu antigen and SkBr3 cell line. In vitro stability of the labeled product was found to be more than 94 % in PBS and 82 ± 0.5 % in human serum over 48 h. In vitro internalization studies of the 64 Cu-DOTA-trastuzumab showed that up to 11.5 % of the radioimmunoconjugate internalized after 10 h. The accumulation of the radiolabeled mAb in liver, skin, intestine, lung

Leach studies of chelating agents and influence on radionuclide leaching from simulated LLW/ILW cement waste forms

International Nuclear Information System (INIS)

Vejmelka, P.; Koester, R.; Ferrara, D.; Wacks, M.E.

1990-01-01

Leach studies were performed on cemented waste forms containing sodium nitrate, trace amounts of cesium-137, and cobalt-60, and a chelating agent (ethylene diamine tetraacetic acid (EDTA), nitrilotriacetic acid (NTA), or citric acid). Leaching of the chelates was measured in water and the effect of the chelates on the release of the Cs-137 and Co-60 was studied. The time dependence of the release rate of the chelates is comparable but the chelate concentration in solution and the released fractions are different. EDTA shows the highest release rate followed by NTA and citrate. The release of the non complex forming cesium is not affected by the presence of the chelates. Independent from the strong complex formation of cobalt with EDTA, NTA, and citrate in the alkaline region the cobalt release is also not affected by the presence of the chelates. The high calcium content of the system decreases the stability of the Co complexes in the high pH region (12-13). Experiments were performed to determine the equilibrium concentration of the chelates between liquid and solid phases. The liquid phases were deionized water, saturated sodium chloride, 24 percent magnesium chloride and Q-brine. The equilibrium studies are based on the assumption that in time a stable final condition is to be established in the near field of the waste form in which each compound is at chemical equilibrium between the dissolved and the various solid phases. The total release may be assessed from the concentration in solution and flow rate out of the near field. The fraction of EDTA released from the cement ranged from 0.2 in the Q-brine to 0.5 in the saturated sodium chloride. The concentration of EDSA in solution was dependent on the original amount in the cement sample, but the released fraction was independent of the initial loading. Indicating, EDTA concentration is not affected by solubility limits. 11 refs., 3 figs., 2 tabs

The interplay of T1- and T2-relaxation on T1-weighted MRI of hMSCs induced by Gd-DOTA-peptides.

Science.gov (United States)

Cao, Limin; Li, Binbin; Yi, Peiwei; Zhang, Hailu; Dai, Jianwu; Tan, Bo; Deng, Zongwu

2014-04-01

Three Gd-DOTA-peptide complexes with different peptide sequence are synthesized and used as T1 contrast agent to label human mesenchymal stem cells (hMSCs) for magnetic resonance imaging study. The peptides include a universal cell penetrating peptide TAT, a linear MSC-specific peptide EM7, and a cyclic MSC-specific peptide CC9. A significant difference in labeling efficacy is observed between the Gd-DOTA-peptides as well as a control Dotarem. All Gd-DOTA-peptides as well as Dotarem induce significant increase in T1 relaxation rate which is in favor of T1-weighted MR imaging. Gd-DOTA-CC9 yields the maximum labeling efficacy but poor T1 contrast enhancement. Gd-DOTA-EM7 yields the minimum labeling efficacy but better T1 contrast enhancement. Gd-DOTA-TAT yields a similar labeling efficacy as Gd-DOTA-CC9 and similar T1 contrast enhancement as Gd-DOTA-EM7. The underlying mechanism that governs T1 contrast enhancement effect is discussed. Our results suggest that T1 contrast enhancement induced by Gd-DOTA-peptides depends not only on the introduced cellular Gd content, but more importantly on the effect that Gd-DOTA-peptides exert on the T1-relaxation and T2-relaxation processes/rates. Both T1 and particularly T2 relaxation rate have to be taken into account to interpret T1 contrast enhancement. In addition, the interpretation has to be based on cellular instead of aqueous longitudinal and transverse relaxivities of Gd-DOTA-peptides. Copyright © 2014 Elsevier Ltd. All rights reserved.

Soft-tissue and bone lesions examined with 1.5-T MR imaging and Gd-DOTA

International Nuclear Information System (INIS)

VonSchulthess, G.K.; Kuoni, W.; Wuthrich, R.; Duewell, S.; Thurnher, S.; Marincek, B.

1988-01-01

Fifteen patients with soft-tissue masses or bone lesions underwent 16 MR imaging examinations with gadolinium-DOTA, a new MR contrast agent. T1- and T2-weighted precontrast sequences were obtained. The contrast agent was injected in a concentration of 0.1 mmol/kg without any untoward effects. After contrast examination, one or two T1-weighted sequences were obtained. Contrast medium application improved the distinction between lesion and edema in four of seven cases, between the lesion and central necrosis in seven of eight cases, and between the lesion, and the surrounding tissues in four of 12 cases. In eight of 12 cases, additional structures within the lesion were noted after Gd-DOTA enhancement. Of particular benefit was the use of contrast media to evaluate the vascularization of the lesion (in 12 of 14 cases)

Vascular-targeted photodynamic therapy with BF2-chelated Tetraaryl-Azadipyrromethene agents: a multi-modality molecular imaging approach to therapeutic assessment.

LENUS (Irish Health Repository)

Byrne, A T

2009-11-03

Photodynamic therapy (PDT) is a treatment modality for a range of diseases including cancer. The BF(2)-chelated tetraaryl-azadipyrromethenes (ADPMs) are an emerging class of non-porphyrin PDT agent, which have previously shown excellent photochemical and photophysical properties for therapeutic application. Herein, in vivo efficacy and mechanism of action studies have been completed for the lead agent, ADMP06.

Quantitative property-property relationship (QPPR) approach in predicting flotation efficiency of chelating agents as mineral collectors.

Science.gov (United States)

Natarajan, R; Nirdosh, I; Venuvanalingam, P; Ramalingam, M

2002-07-01

The QPPR approach has been used to model cupferrons as mineral collectors. Separation efficiencies (Es) of these chelating agents have been correlated with property parameters namely, log P, log Koc, substituent-constant sigma, Mullikan and ESP derived charges using multiple regression analysis. Es of substituted-cupferrons in the flotation of a uranium ore could be predicted within experimental error either by log P or log Koc and an electronic parameter. However, when a halo, methoxy or phenyl substituent was in para to the chelating group, experimental Es was greater than the predicted values. Inclusion of a Boolean type indicative parameter improved significantly the predictability power. This approach has been extended to 2-aminothiophenols that were used to float a zinc ore and the correlations were found to be reasonably good.

Synthesis of [64Cu]DOTA-ADIBON3-Ala-PEG28-A20FMDV2 via copper-free click chemistry for PET imaging of integrin αvβ6

International Nuclear Information System (INIS)

Drishty Satpati; Nadine Bauer; Hausner, S.H.

2014-01-01

Catalyst-free click reactions are effective chemical tools for synthesis of radiometal-based radiopharmaceuticals offering advantages towards preparation of non-toxic agents with high specific activity. In the present study the radiotracer [ 64 Cu]DOTA-ADIBON 3 -Ala-PEG 28 -A20FMDV2, [ 64 Cu]3, was synthesized for positron emission tomography imaging of integrin α v β 6 expressing tumors via a strain-promoted click reaction using both a 'pre-click' and 'post-click' approaches. The radiotracer, prepared in >99 % radiochemical yield, was evaluated in vitro (64.6 ± 2.8 % binding to α v β 6 -positive cells vs. v β 6 -negative cells) and in vivo (α v β 6 -positive tumor uptake: 1.52 ± 0.16 % ID/g, 24 h p.i.). While the high initial renal uptake (76.2 ± 10.7 % ID/g at 1 h p.i.) was comparable to a previously reported radiotracer, [ 64 Cu]DOTA-PEG 28 -A20FMDV2, [ 64 Cu]3 showed notably improved renal clearance (11.3 ± 2.5 % ID/g at 24 h p.i.). Thus, the introduction of a chelator-strained alkyne system resulted in improved pharmacokinetics for the present radiotracer, highlighting the attractive prospects of strain-promoted click-based preparations in the construction of radiometalated bioconjugates for targeted molecular imaging and therapy. (author)

Evaluation of (64)Cu-labeled DOTA-D-Phe(1)-Tyr (3)-octreotide ((64)Cu-DOTA-TOC) for imaging somatostatin receptor-expressing tumors.

Science.gov (United States)

Hanaoka, Hirofumi; Tominaga, Hideyuki; Yamada, Keiich; Paudyal, Pramila; Iida, Yasuhiko; Watanabe, Shigeki; Paudyal, Bishnuhari; Higuchi, Tetsuya; Oriuchi, Noboru; Endo, Keigo

2009-08-01

In-111 ((111)In)-labeled octreotide has been clinically used for imaging somatostatin receptor-positive tumors, and radiolabeled octreotide analogs for positron emission tomography (PET) have been developed. Cu-64 ((64)Cu; half-life, 12.7 h) is an attractive radionuclide for PET imaging and is produced with high specific activity using a small biomedical cyclotron. The aim of this study is to produce and fundamentally examine a (64)Cu-labeled octreotide analog, (64)Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-D: -Phe(1)-Tyr(3)-octreotide ((64)Cu-DOTA-TOC). (64)Cu produced using a biomedical cyclotron was reacted with DOTA-TOC for 30 min at 45 degrees C. The stability of (64)Cu-DOTA-TOC was evaluated in vitro (incubated with serum) and in vivo (blood collected after administration) by HPLC analysis. Biodistribution studies were performed in normal mice by administration of mixed solution of (64)Cu-DOTA-TOC and (111)In-DOTA-TOC and somatostatin receptor-positive U87MG tumor-bearing mice by administration of (64)Cu-DOTA-TOC or (64)Cu-1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid-octreotide ((64)Cu-TETA-OC). The tumor was imaged using (64)Cu-DOTA-TOC, (64)Cu-TETA-OC, and FDG with an animal PET scanner. (64)Cu-DOTA-TOC can be produced in amounts sufficient for clinical study with high radiochemical yield. (64)Cu-DOTA-TOC was stable in vitro, but time-dependent transchelation to protein was observed after injection into mice. In biodistribution studies, the radioactivity of (64)Cu was higher than that of (111)In in all organs except kidney. In tumor-bearing mice, (64)Cu-DOTA-TOC showed a high accumulation in the tumor, and the tumor-to-blood ratio reached as high as 8.81 +/- 1.17 at 6 h after administration. (64)Cu-DOTA-TOC showed significantly higher accumulation in the tumor than (64)Cu-TETA-OC. (64)Cu-DOTA-TOC PET showed a very clear image of the tumor, which was comparable to that of (18)F-FDG PET and very similar to that of (64)Cu

Evaluation of 64Cu-labeled DOTA-D-Phe1-Tyr3-octreotide (64Cu-DOTA-TOC) for imaging somatostatin receptor-expressing tumors

International Nuclear Information System (INIS)

Hanaoka, Hirofumi; Tominaga, Hideyuki; Yamada, Keiich

2009-01-01

In-111 ( 111 In)-labeled octreotide has been clinically used for imaging somatostatin receptor-positive tumors, and radiolabeled octreotide analogs for positron emission tomography (PET) have been developed. Cu-64 ( 64 Cu; half-life, 12.7 h) is an attractive radionuclide for PET imaging and is produced with high specific activity using a small biomedical cyclotron. The aim of this study is to produce and fundamentally examine a 64 Cu-labeled octreotide analog, 64 Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-D-Phe 1 -Tyr 3 -octreotide ( 64 Cu-DOTA-TOC). 64 Cu produced using a biomedical cyclotron was reacted with DOTA-TOC for 30 min at 45 deg C. The stability of 64 Cu-DOTA-TOC was evaluated in vitro (incubated with serum) and in vivo (blood collected after administration) by high performance liquid chromatography (HPLC) analysis. Biodistribution studies were performed in normal mice by administration of mixed solution of 64 Cu-DOTA-TOC and 111 In-DOTA-TOC and somatostatin receptor-positive U87MG tumor-bearing mice by administration of 64 Cu-DOTA-TOC or 64 Cu-1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid-octreotide ( 64 Cu-TETA-OC). The tumor was imaged using 64 Cu-DOTA-TOC, 64 Cu-TETA-OC, and fluorodeoxyglucose (FDG) with an animal PET scanner. 64 Cu-DOTA-TOC can be produced in amounts sufficient for clinical study with high radiochemical yield. 64 Cu-DOTA-TOC was stable in vitro, but time-dependent transchelation to protein was observed after injection into mice. In biodistribution studies, the radioactivity of 64 Cu was higher than that of 111 In in all organs except kidney. In tumor-bearing mice, 64 Cu-DOTA-TOC showed a high accumulation in the tumor, and the tumor-to-blood ratio reached as high as 8.81±1.17 at 6 h after administration. 64 Cu-DOTA-TOC showed significantly higher accumulation in the tumor than 64 Cu-TETA-OC. 64 Cu-DOTA-TOC PET showed a very clear image of the tumor, which was comparable to that of 18 F-FDG PET and

Preclinical evaluation of [ 111 In]-DOTA-trastuzumab for clinical trials

Directory of Open Access Journals (Sweden)

Behrouz Alirezapour

2014-01-01

Full Text Available Context: Herceptin and its fragments have been radiolabeled and used in the imaging of human epidermal growth factor receptor 2 (HER2/neu-positive tumors and development of diagnostic kits is of great importance in radiopharmacy. Aims: In this study, 111 In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-trastuzumab ( 111 In-DOTA-trastuzumab was successively prepared and evaluated for ultimate use in the HER2 antigen imaging in oncology. Settings and Design: The conjugate was prepared, labeled and evaluated using in vitro (radioimmunoassay [RIA], enzyme-linked immunosorbent assay (ELISA, stability, binding, internalization/in vivo (bio-distribution, single-photon emission computed tomography [SPECT] experiments. Materials and Methods: 111 In-DOTA-trastuzumab was prepared followed by determination of radiochemical purity (RCP, integrity of protein, immunoreactivity of radiolabeled antibody with HER2/neu antigen (by SkBr3 cell line binding and RIA methods were determined followed by stability tests, internalization studies and the tissue bio-distribution determination in wild-type rats as well as SPECT imaging in SkBr3-bearing mice. Statistical Analysis Used: All values were expressed as mean ± standard deviation (mean ± SD and the data were compared using Student′s t-test. Statistical significance was defined as P 95 ± 0.5%, S.A. 5.3 μCi/μg with the average number of chelators per antibody of 6:1 showing significant immune-reactivity retention using ELISA. In vitro stability was >90% in phosphate buffered saline and 80 ± 0.5% in serum over 48 h. Cell binding was significant (>0.79. In vitro internalization reached up to %12-13 in 10 h. Significant tumor uptake was observed. Conclusions: In vitro and in vivo/SPECT imaging in SkBr3-bearing mice demonstrated that 111 In-DOTA-trastuzumab is a potential compound for molecular imaging of SPECT for diagnosis and follow-up of HER2 expression in oncology.

Biocompatible Polyhydroxyethylaspartamide-based Micelles with Gadolinium for MRI Contrast Agents

Directory of Open Access Journals (Sweden)

Kim Hyo Jeong

2010-01-01

Full Text Available Abstract Biocompatible poly-[N-(2-hydroxyethyl-d,l-aspartamide]-methoxypoly(ethyleneglycol-hexadecylamine (PHEA-mPEG-C16 conjugated with 1,4,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid-gadolinium (DOTA-Gd via ethylenediamine (ED was synthesized as a magnetic resonance imaging (MRI contrast agent. Amphiphilic PHEA-mPEG-C16-ED-DOTA-Gd forms micelle in aqueous solution. All the synthesized materials were characterized by proton nuclear magnetic resonance (1H NMR. Micelle size and shape were examined by dynamic light scattering (DLS and atomic force microscopy (AFM. Micelles with PHEA-mPEG-C16-ED-DOTA-Gd showed higher relaxivities than the commercially available gadolinium contrast agent. Moreover, the signal intensity of a rabbit liver was effectively increased after intravenous injection of PHEA-mPEG-C16-ED-DOTA-Gd.

Comparison of {sup 111}In-DOTA-DPhe{sup 1}-Tyr{sup 3}-octreotide and {sup 111}In-DOTA-lanreotide scintigraphy and dosimetry in patients with neuroendocrine tumours

Energy Technology Data Exchange (ETDEWEB)

Rodrigues, Margarida; Virgolini, Irene [Lainz Hospital, Institute of Nuclear Medicine, Vienna (Austria); University Clinic for Nuclear Medicine, Innsbruck (Austria); Traub-Weidinger, Tatjana [University Clinic for Nuclear Medicine, Innsbruck (Austria); University Hospital, Department of Nuclear Medicine, Vienna (Austria); Li, Shuren [University Hospital, Department of Nuclear Medicine, Vienna (Austria); Ibi, Bettina [Lainz Hospital, Institute of Physics, Vienna (Austria)

2006-05-15

Somatostatin receptor scintigraphy with {sup 111}In-DOTA-DPhe{sup 1}-Tyr{sup 3}-octreotide ({sup 111}In-DOTA-TOC) and {sup 111}In-DOTA-lanreotide ({sup 111}In-DOTA-LAN) has been used for staging of neuroendocrine tumours (NETs). However, the comparative diagnostic value of these radioligands on a lesion basis has not yet been established. The aim of this study was to compare the diagnostic capacity of {sup 111}In-DOTA-TOC and {sup 111}In-DOTA-LAN scintigraphy in patients with NETs, evaluating whether significant differences exist in lesion imaging with these radioligands. Furthermore, dosimetric data were compared. Forty-five patients with NETs were investigated with {sup 111}In-DOTA-TOC and {sup 111}In-DOTA-LAN scintigraphy. Scintigraphic results were compared with those of conventional imaging and/or surgery in each patient, and also {sup 18}F-fluorodeoxyglucose positron emission tomography (FDG-PET) in 20 patients. {sup 111}In-DOTA-TOC and {sup 111}In-DOTA-LAN scintigraphy were true positive in 42/45 (93%) and 39/45 (87%) patients, and imaged 74/91 (81%) and 73/91 (80%) tumour lesions, respectively. {sup 111}In-DOTA-TOC and {sup 111}In-DOTA-LAN detected liver metastases in 21 and 14 patients, mediastinal metastases in seven and 11 patients, and bone metastases in two and seven patients, respectively. These radioligands revealed lesions not seen by conventional imaging in seven and eight patients, respectively, or by {sup 18}F-FDG-PET in eight and seven patients, respectively. The estimated tumour absorbed doses for {sup 90}Y-DOTA-TOC were higher than those for {sup 90}Y-DOTA-LAN in 14 patients, whereas the opposite was true in 12 patients. Both {sup 111}In-DOTA-TOC and {sup 111}In-DOTA-LAN are suitable for imaging tumour lesions in patients with NETs and can detect lesions that may not be seen by conventional imaging and {sup 18}F-FDG-PET. Compared with {sup 111}In-DOTA-LAN, {sup 111}In-DOTA-TOC has a superior diagnostic capacity for liver metastases, but a

Treatment with tandem [{sup 90}Y]DOTA-TATE and [{sup 177}Lu]DOTA-TATE of neuroendocrine tumours refractory to conventional therapy

Energy Technology Data Exchange (ETDEWEB)

Seregni, E.; Maccauro, M.; Chiesa, C.; Pascali, C.; Lorenzoni, A.; Bogni, A.; Coliva, A.; Bombardieri, E. [Fondazione IRCCS Istituto Nazionale Tumori, Nuclear Medicine, Milan (Italy); Mariani, L.; Vullo, S.Lo [Fondazione IRCCS Istituto Nazionale Tumori, Statistics and Biometry Unit, Milan (Italy); Mazzaferro, V. [Fondazione IRCCS Istituto Nazionale Tumori, Surgery and Liver Transplantation, Milan (Italy); De Braud, F.; Buzzoni, R. [Fondazione IRCCS Istituto Nazionale Tumori, Medical Oncology, Milan (Italy); Milione, M. [Fondazione IRCCS Istituto Nazionale Tumori, Pathology Department, Milan (Italy)

2014-02-15

Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues has been demonstrated to be an effective therapeutic option in patients with disseminated neuroendocrine tumours (NET). Treatment with tandem [{sup 90}Y]DOTA-TATE and [{sup 177}Lu]DOTA-TATE may improve the efficacy of PRRT without increasing the toxicity. In a phase II study we evaluated the feasibility of combined PPRT with a high-energy beta emitter ({sup 90}Y) and a medium-energy beta/gamma emitter ({sup 177}Lu) in patients with metastatic NET refractory to conventional therapy. A group of 26 patients with metastatic NET were treated with four therapeutic cycles of alternating [{sup 177}Lu]DOTA-TATE (5.55 GBq) and [{sup 90}Y]DOTA-TATE (2.6 GBq). A dosimetric evaluation was carried out after administration of [{sup 177}Lu]DOTA-TATE to calculate the absorbed doses in healthy organs. The acute and long-term toxicities of repeated treatment were analysed. PRRT efficacy was evaluated according to RECIST. Administration of tandem [{sup 90}Y]DOTA-TATE and [{sup 177}Lu]DOTA-TATE induced objective responses in 42.3 % of patients with metastatic NET with a median progression-free survival longer than 24 months. Of patients with pretreatment carcinoid syndrome, 90 % showed a symptomatic response or a reduction in tumour-associated pain. The cumulative biologically effective doses (BED) were below the toxicity limit in the majority of patients, in the absence of renal function impairment The results of our study indicates that combined [{sup 90}Y]DOTA-TATE and [{sup 177}Lu]DOTA-TATE therapy is a feasible and effective therapeutic option in NET refractory to conventional therapy. Furthermore, the absence of kidney damage and the evaluated cumulative BEDs suggest that increasing the number of tandem administrations is an interesting approach. (orig.)

Gadolinium released by the linear gadolinium-based contrast-agent Gd-DTPA decreases the activity of human epithelial Na+ channels (ENaCs).

Science.gov (United States)

Knoepp, Fenja; Bettmer, Joerg; Fronius, Martin

2017-05-01

Gadolinium-based-contrast-agents (GBCAs) are used for magnetic-resonance-imaging and associated with renal and cardiovascular adverse reactions caused by released Gd 3+ ions. Gd 3+ is also a modulator of mechano-gated ion channels, including the epithelial Na + channel (ENaC) that is expressed in kidney epithelium and the vasculature. ENaC is important for salt-/water homeostasis and blood pressure regulation and a likely target of released Gd 3+ from GBCAs causing the above-mentioned adverse reactions. Therefore this study examined the effect of Gd 3+ and GBCAs on ENaC's activity. Human αβγENaC was expressed in Xenopus laevis oocytes and exposed to Gd 3+ , linear (Gd-DTPA, Magnevist) or cyclic (Dotarem) GBCAs. Transmembrane ion-currents (I M ) were recorded by the two-electrode-voltage-clamp technique and Gd 3+ -release by Gd-DTPA was confirmed by inductively coupled plasma-mass spectrometry. Gd 3+ exerts biphasic effects on ENaC's activity: ≤0.3mmol/l decreased I M which was preventable by DEPC (modifies histidines). Strikingly Gd 3+ ≥0.4mmol/l increased I M and this effect was prevented by cysteine-modifying MTSEA. Linear Gd-DTPA and Magnevist mimicked the effect of ≤0.3mmol/l Gd 3+ , whereas the chelator DTPA showed no effect. Gd 3+ and Gd-DTPA increased the IC 50 for amiloride, but did not affect ENaC's self-inhibition. Interestingly, cyclic Gd-DOTA (Dotarem) increased I M to a similar extent as its chelator DOTA, suggesting that the chelator rather than released Gd 3+ is responsible for this effect. These results confirm Gd 3+ -release from linear Gd-DTPA and indicate that the released Gd 3+ amount is sufficient to interfere with ENaC's activity to provide putative explanations for GBCA-related adverse effects. Copyright © 2017 Elsevier B.V. All rights reserved.

177Lu-DOTA-HH1, a novel anti-CD37 radio-immunoconjugate: a study of toxicity in nude mice.

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Ada H V Repetto-Llamazares

Full Text Available CD37 is an internalizing B-cell antigen expressed on Non-Hodgkin lymphoma (NHL and chronic lymphocytic leukemia cells (CLL. The anti-CD37 monoclonal antibody HH1 was conjugated to the bifunctional chelator p-SCN-Bn-DOTA and labelled with the beta-particle emitting radionuclide 177Lu creating the radio-immunoconjugate (RIC 177Lu-DOTA-HH1 (177Lu-HH1, trade name Betalutin. The present toxicity study was performed prior to initiation of clinical studies with 177Lu-HH1.Nude mice with or without tumor xenografts were treated with 50 to 1000 MBq/kg 177Lu- HH1 and followed for clinical signs of toxicity up to ten months. Acute, life threatening bone marrow toxicity was observed in animals receiving 800 and 1000 MBq/kg 177Lu-HH1. Significant changes in serum concentrations of liver enzymes were evident for treatment with 1000 MBq/kg 177Lu-HH1. Lymphoid depletion, liver necrosis and atrophy, and interstitial cell hyperplasia of the ovaries were also observed for mice in this dose group.177Lu-DOTA-HH1 was well tolerated at dosages about 10 times above those considered relevant for radioimmunotherapy in patients with B-cell derived malignancies.The toxicity profile was as expected for RICs. Our experimental results have paved the way for clinical evaluation of 177Lu-HH1 in NHL patients.

68Ga-autoclabeling of DOTA-TATE and DOTA-NOC

DEFF Research Database (Denmark)

Blom, Elisabeth; Koziorowski, Jacek

2012-01-01

A new method combining (68)Ga-labeling and steam sterilization, here called autoclabeling, has been evaluated for two somatostatin receptor binding tracers used for positron emission tomography (PET) imaging of neuroendocrine tumors; DOTA-TATE and -NOC....

Use of non-hyperaccumulator plant species for the phytoextraction of heavy metals using chelating agents

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Lucas Anjos Souza

2013-08-01

Full Text Available Soil contamination by heavy metals is a challenge faced by many countries, and engineering technologies to solve this problem are expensive and can cause negative impacts on the environment. One way to minimise the levels of heavy metals in the soil is to use plants that can absorb and accumulate heavy metals into harvestable parts, a process called phytoextraction. Typical plant species used in research involving phytoextraction are heavy metal hyperaccumulators, but plants from this group are not good biomass producers and grow more slowly than most species; thus, they have an important role in helping scientists understand the mechanisms involved in accumulating high amounts of heavy metals without developing symptoms or dying. However, because of their slow growth, it is not practical to use these species for phytoextraction. An alternative approach is to use non-hyperaccumulator plants assisted by chelating agents, which may improve the ability of plants to accumulate more heavy metals than they would naturally. Chelating agents can be synthetic or organic acids, and the advantages and disadvantages of their use in improving the phytoextraction potential of non-hyperaccumulator plants are discussed in this article. We hope to draw attention to ways to improve the phytoextraction potential of non-hyperaccumulator plants that produce a large amount of biomass and to stimulate more research on phytoextraction-inducing substances.

Peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors: First comparative results using the somatostatin analogues Lu-177 DOTA-NOC and Lu-177 DOTA-TATE

International Nuclear Information System (INIS)

Wehrmann, C.; Senftleben, S.; Baum, R.P.

2005-01-01

Peptide receptor radionuclide therapy (PRRT) is used in our department since 5 years (approx. 400 applications) for the treatment of patients with metastatic neuroendocrine tumors. Of all known peptides, the somatostatin analogue DOTA-NOC shows in vitro the highest affinity to somatostatin receptors (sstr) 3 and 5 and a very high affinity to sstr 2. We studied the in vivo behaviour of the two peptides DOTA-NOC and DOTA-TATE (highest affinity to sstr 2) by the use of different parameters like tumor and organ uptake, effective half-lifes (kinetics) and mean absorbed organ and tumor doses. We studied 27 patients with metastatic neuroendocrine tumors with high somatostatin expression, as verified prior to treatment by Ga-68 DOTA-NOC receptor PET/CT or somatostatin receptor scintigraphy (Tc-99m EDDA-Hynic TOC or In-111 OctreoScan, planar and SPECT). 22 patients (8M and 14F; aged 619 years) were treated with 2500 6790 MBq Lu-177 DOTA-TATE. Another 5 patients (1M and 4F, aged 6310 years) were treated with 4000 7400 MBq Lu-177 DOTA-NOC. Labelling efficiency and radiochemical purity using Lutetium-177 chloride (obtained from PerkinElmer Life Sciences, USA) were constantly over 99.5%. Whole-body scans (anterior/posterior) were performed at 0.5h, 3h, 24h, 48h, 72h and 96h p.i. ROIs were drawn over the whole-body, organs, and different metastases (mainly in the liver). Blood samples were obtained in 12 patients after therapy with Lu-177 DOTA-TATE over 5 days for calculating the kinetics in blood. The ROI results were used to determine the uptake and effective half-life in different organs (kidney, spleen, liver, bone etc.) and the tumor residence times. By means of geometric mean, and after background correction, the ROI results were also used to calculate the estimated absorbed organ and tumor doses using the OLINDA software. Compared to Lu-177 DOTA-TATE (=100%), the uptake of Lu-177 DOTA-NOC was higher for the whole-body (45%) and for normal tissues (28%), and also in the

Gadolinium(III-DOTA Complex Functionalized with BODIPY as a Potential Bimodal Contrast Agent for MRI and Optical Imaging

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Matthias Ceulemans

2015-11-01

Full Text Available The synthesis and characterization of a novel gadolinium(III DOTA complex functionalized with a boron-dipyrromethene derivative (BODIPY is described. The assembly of the complex relies on azide diazotransfer chemistry in a copper tube flow reactor. The azide thus formed is coupled directly with an alkyne via click chemistry, resulting into a paramagnetic and luminescent gadolinium(III complex. Luminescent data and relaxometric properties of the complex have been evaluated, suggesting the potential applicability of the complexes as a bimodal contrast agent for magnetic resonance and optical imaging. The complex displays a bright emission at 523 nm with an absorption maximum of 507 nm and high quantum yields of up to 83% in water. The proton relaxivity of the complex measured at 310 K and at frequencies of 20 and 60 MHz had the values of 3.9 and 3.6 s−1·mM−1, respectively.

Preparation of therapeutic dose of 177Lu-DOTA-TATE using a novel single vial freeze-dried kit: a comparison with 'in-situ' preparation at hospital radiopharmacy.

Science.gov (United States)

Das, Tapas; Banerjee, Sharmila; Shinto, Ajit; Kamaleshwaran, K K; Sarma, H D

2014-01-01

Patient dose of (177)Lu-DOTA-TATE, used for providing radiotherapeutic treatment to the patients suffering from cancers of neuroendocrine origin, could be prepared at the hospital radiopharmacy either 'in-situ' or by using freezedried kits. The objective of the present work is to formulate and evaluate a single vial freeze-dried DOTA-TATE kit, which is capable of producing up to 7.4 GBq (200 mCi) dose of (177)Lu-DOTA-TATE and to compare the two methodologies presently used for the preparation of the agent. Freeze-dried DOTA-TATE kits, comprising a lyophilized mixture of DOTA-TATE, gentisic acid and ammonium acetate, were prepared and used for the formulation of patient doses of (177)Lu-DOTA-TATE. The kits were subjected to detailed radiochemical evaluation and the shelf-life of the kits was determined. The pharmacokinetic behavior of the agent was studied in normal Wistar rats. These kits were utilized for treating the patients suffering from various types of neuroendocrine cancers. The freeze-dried kits were used for the preparation of up to 7.4 GBq (200 mCi) therapeutic doses of (177)Lu- DOTA-TATE with a radiochemical purity of >99% and were found to have sufficiently long shelf-life. Biological studies carried out in normal Wistar rats exhibited no significant accumulation of activity in any of the vital organs/tissue except in kidneys and non-accumulated activity showed major renal clearance. Clinical studies carried out in cancer patients exhibited accumulation of activity in the cancerous lesions and metastatic sites. The kit was useful for the convenient preparation of therapeutic dose of (177)Lu-DOTA-TATE, suitable for human administration. The use of kit is expected to reduce the batch failure and radiation exposure to the working personnel.

Regeneration of Three-Way Automobile Catalysts using Biodegradable Metal Chelating Agent – S, S-Ethylenediamine Disuccinic Acid (S, S-EDDS)

Science.gov (United States)

Regeneration of the activity of three-way catalytic converters (TWCs) was tested for the first time using a biodegradable metal chelating agent (S, S. Ethylenediamine disuccinic acid (S, S-EDDS). The efficiency of this novel environmentally friendly solvent in removing various c...

Chelating impact assessment of biological ad chemical chelates on metal extraction from contaminated soils

International Nuclear Information System (INIS)

Manwar, S.; Iram, S.

2014-01-01

Soil contamination is the result of uncontrolled waste dumping and poor practices by humans. Of all the pollutants heavy metals are of particular concern due to their atmospheric deposition, leaching capacity and non-biodegradability. Heavy metal containing effluent is discharged into the agricultural fields and water bodies. This results in the accumulation of heavy metals in soil and the crops grown on that soil. Studies have revealed detrimental impacts on soil fertility and the poor health of animals and humans. Phytoextraction is widely researched for remediation of heavy metal contaminated soil. To enhance the effect of phytoextraction heavy metals have to be available to the plants in soluble form. In this study the potential of different chelating agents was assessed in solubilizing the heavy metals making easy for plants to uptake them. For this purpose efficient chemical and biological chelating agent had to be identified. Along with that an optimum dose and application time for chemical chelating agent was determined. Ethylenediamine tetraacetic acid (EDTA), Diethylene triamine pentaacetic acid (DTPA), Nitriloacetic acid (NTA) were applied to the soil, containing Pb, Cr, Cu and Cd, at different concentrations and application time. Aspergillus niger and Aspergillus flavus were incubated in soil for different time periods. In correspondence with findings of the study, Pb and Cr were best solubilized by 5mM EDTA. For Cd and Cu 5mM DTPA carried out efficient chelation. NTA showed relatively inadequate solubilisation, although for Cr it performed equal to EDTA. A. niger and A. flavus instead of solubilizing adsorbed the metals in their biomass. Adsorption was mainly carried out by A. niger. (author)

Selectivity in extraction of copper and indium with chelate extractants

International Nuclear Information System (INIS)

Zivkovic, D.

2003-01-01

Simultaneous extraction of copper and indium with chelate extractants (LIX84 and D2E11PA) was described. Stechiometry of metal-organic complexes examined using the method of equimolar ratios resulted in CuR 2 and InR 3 forms of hydrophobic extracting species. A linear correlation was obtained between logarithm of distribution coefficients and chelate agents and pH, respectively. Selectivity is generally higher with higher concentrations of chelate agents in the organic phase, and is decreased with increase of concentration of hydrogen ions in feeding phase. (Original)

Effects of solvent and chelating agent on synthesis of solid oxide fuel cell perovskite, La0.8Sr0.2CrO3-δ

International Nuclear Information System (INIS)

Lee, Byoung I.; Gupta, Ravindra K.; Whang, Chin M.

2008-01-01

Effects of solvent and chelating agent on synthesis of La 0.8 Sr 0.2 CrO 3-δ perovskite are reported. Samples are synthesized using a solvent (ethylene glycol or 2-methoxyethanol) and a chelating agent (acetylacetone, citric acid or ethylene diamine tetraacetic acid) by polymeric-gel method, and characterized by X-ray diffractometry and Fourier-transform infrared spectroscopy. Citric acid to metal cations molar ratio (Rc) is varied for ethylene glycol-citric acid system. Samples are mainly orthorhombic perovskite. SrCrO 4 is appeared as a secondary phase and found to be the lowest for ethylene glycol-citric acid combination with Rc equal to 7. Crystallographic parameters of perovskite phase are determined and compared with those of LaCrO 3 . A mechanism employing a partial-charge model, chelating effect and solvent-cage effect is proposed to explain the results. Effect of sintering temperature on phase, relative density and morphology of samples prepared using ethylene glycol and citric acid (Rc = 7) is also reported

Gd(III)-DOTA-modified sonosensitive liposomes for ultrasound-triggered release and MR imaging

Science.gov (United States)

Jung, Suk Hyun; Na, Kyunga; Lee, Seul A.; Cho, Sun Hang; Seong, Hasoo; Shin, Byung Cheol

2012-08-01

Ultrasound-sensitive (sonosensitive) liposomes for tumor targeting have been studied in order to increase the antitumor efficacy of drugs and decrease the associated severe side effects. Liposomal contrast agents having Gd(III) are known as a nano-contrast agent system for the efficient and selective delivery of contrast agents into pathological sites. The objective of this study was to prepare Gd(III)-DOTA-modified sonosensitive liposomes (GdSL), which could deliver a model drug, doxorubicin (DOX), to a specific site and, at the same time, be capable of magnetic resonance (MR) imaging. The GdSL was prepared using synthesized Gd(III)-DOTA-1,2-distearoyl- sn-glycero-3-phosphoethanolamine lipid. Sonosensitivity of GdSL to 20-kHz ultrasound induced 33% to 40% of DOX release. The relaxivities ( r 1) of GdSL were 6.6 to 7.8 mM-1 s-1, which were higher than that of MR-bester®. Intracellular uptake properties of GdSL were evaluated according to the intensity of ultrasound. Intracellular uptake of DOX for ultrasound-triggered GdSL was higher than that for non-ultrasound-triggered GdSL. The results of our study suggest that the paramagnetic and sonosensitive liposomes, GdSL, may provide a versatile platform for molecular imaging and targeted drug delivery.

Comparison of tumour and whole body absorbed doses of 177-Lu-DOTA-TATE and Lu-177-DOTA-NOC treatment in the same patient group

International Nuclear Information System (INIS)

Yeyin, N.; Kabasakal, L.; Akyel, R.; Demir, M.; Kanmaz, B.; Ocak, M.; Toklu, T.; Selcuk, N.

2015-01-01

Full text of publication follows. Peptide Receptor Radionuclide Therapy (PRRT) with Lu-177 labelled peptides in patients with neuroendocrine tumours (NETs) aroused great interest. An estimation of actual radiation doses to tumours is very important for therapy planning. There are several radiolabelled peptides, which can be used for PRRT with different biological behaviour. Aim: the aim of the study was to compare the tumour and normal organ absorbed doses in patients who have received Lu-177-DOTA-TATE and Lu-177 DOTA-NOC. Materials and methods: study was composed of 20 patients (M/F: 10/10, mean age: 51.5 ± 14.9) with histologically proven inoperable NETs. All patients received Lu-177-DOTA-NOC treatment 6 to 12 weeks after last Lu-177-DOTA-TATE treatment. Dosimetric calculations were performed using MIRD scheme and lesion doses were calculated using post therapy whole body images obtained at 4, 20, 44, and 68 hours after injection. Tumour volumes were determined from CT images. Thirteen blood samples beginning from time zero to 4 days after injection were obtained for bone marrow and whole body dosimetry. Results: There were 53 lesions in Lu-177-DOTA-TATE post-therapy whole body images and 49 lesions in Lu-177 DOTA-NOC post therapy images. Lesions were selected according to lesion delineation and superimposed lesions were excluded. Mean lesion absorbed dose is calculated to be 47.4 ± 53.4 and 42.9 ± 52.8 Gy per 370 MBq for Lu-177-DOTA-TATE and DOTA-NOC respectively (p>0.5). There were significantly higher absorbed doses for kidney and bone marrow after Lu-177-DOTA-NOC treatment as compared to Lu-177-DOTA-TATE treatment, which were 6.9 ± 2.7 vs 3.9 ± 1.7 (p<0.05) and 0.12 ± 0.0 vs 0.10 ± 0.0 (p<0.05) Gy, respectively. There was not any difference in plasma elimination times between two tracers. On the other hand the whole body absorbed dose was significantly higher after Lu-177-DOTA-NOC treatment, which was 0.24 ± 0.07 vs 0.20 ± 0.06 Gy (p<0

Characterization of the effect of serum and chelating agents on Staphylococcus aureus biofilm formation; chelating agents augment biofilm formation through clumping factor B

Science.gov (United States)

Abraham, Nabil Mathew

Staphylococcus aureus is the causative agent of a diverse array of acute and chronic infections, and some these infections, including infective endocarditis, joint infections, and medical device-associated bloodstream infections, depend upon its capacity to form tenacious biofilms on surfaces. Inserted medical devices such as intravenous catheters, pacemakers, and artificial heart valves save lives, but unfortunately, they can also serve as a substrate on which S. aureus can form a biofilm, attributing S. aureus as a leading cause of medical device-related infections. The major aim of this work was take compounds to which S. aureus would be exposed during infection and to investigate their effects on its capacity to form a biofilm. More specifically, the project investigated the effects of serum, and thereafter of catheter lock solutions on biofilm formation by S. aureus. Pre-coating polystyrene with serum is frequently used as a method to augment biofilm formation. The effect of pre-coating with serum is due to the deposition of extracellular matrix components onto the polystyrene, which are then recognized by MSCRAMMs. We therefore hypothesized that the major component of blood, serum, would induce biofilm formation. Surprisingly, serum actually inhibited biofilm formation. The inhibitory activity was due to a small molecular weight, heat-stable, non-proteinaceous component/s of serum. Serum-mediated inhibition of biofilm formation may represent a previously uncharacterized aspect of host innate immunity that targets the expression of a key bacterial virulence factor: the ability to establish a resistant biofilm. Metal ion chelators like sodium citrate are frequently chosen to lock intravenous catheters because they are regarded as potent inhibitors of bacterial biofilm formation and viability. We found that, while chelating compounds abolished biofilm formation in most strains of S. aureus, they actually augmented the phenotype in a subset of strains. We

Synthesis, radiolabeling and quality control of {sup 111}In-DOTA-bevacizumab for radioimmunoscintigraphy of VEGF receptors

Energy Technology Data Exchange (ETDEWEB)

Khorami-Moghadam, A.; Jalilian, A.R.; Yavari, K.; Alirezapour, B.; Mazidi, M.; Mirzaii, M. [Nuclear Science and Technology Research Institute (NSTRI), Tehran (Iran, Islamic Republic of)

2013-11-01

In this study, bevacizumab was successively labeled with {sup 111}In-InCl{sub 3} after conjugation with DOTA-NHS-ester followed by molecular filtration and determination of the average number ofDOTAconjugated per mAb (6:1) by spectrophotometric method. Radiochemical purity (> 97%, measured by ITLC and HPLC), integrity of protein after radiolabeling (gel electrophoresis) and stability of {sup 111}In-DOTA-Bevacizumab (in final formulation, human serum, liver/kidney homogenates) were determined in 24-72 h as well as biodistribution studies in wild-type rats and human colon cancer (SW-480) bearing mice. The accumulation of the radiolabeled antibody was consistent with the former reported Bevacizumab conjugates. Significant tumor uptake (8%) was observed at 72 h p.i. Tumor/muscle uptake ratios were 2.6 (24 h), 9.74 (48 h) and 25 (72 h). {sup 111}In-DOTA-Bevacizumab was prepared as a SPECT molecular imaging agent for diagnosis and follow-up of vascular endothelial growth factor A (VEGF-A) expression in oncology. (orig.)

Chemical and biological properties of toxic metals and use of chelating agents for the pharmacological treatment of metal poisoning

Energy Technology Data Exchange (ETDEWEB)

Sinicropi, Maria Stefania; Caruso, Anna [University of Calabria, Department of Pharmaceutical Sciences, Rende (Italy); Amantea, Diana [University of Calabria, Department of Pharmacobiology, Rende (Italy); Saturnino, Carmela [University of Salerno, Department of Pharmaceutical Sciences, Fisciano (Italy)

2010-07-15

Exposure to toxic metals is a well-known problem in industrialized countries. Metals interfere with a number of physiological processes, including central nervous system (CNS), haematopoietic, hepatic and renal functions. In the evaluation of the toxicity of a particular metal it is crucial to consider many parameters: chemical forms (elemental, organic or inorganic), binding capability, presence of specific proteins that selectively bind metals, etc. Medical treatment of acute and chronic metal toxicity is provided by chelating agents, namely organic compounds capable of interacting with metal ions to form structures called chelates. The present review attempts to provide updated information about the mechanisms, the cellular targets and the effects of toxic metals. (orig.)

Comments on chelation therapy

International Nuclear Information System (INIS)

Wrenn, M.E.

1981-01-01

The primary purpose of actinide chelation is to decrease the risk from radiation-induced cancer. While occupational exposures in the past have mainly involved low specific activity 239 Pu, future exposures will increasingly involve high specific activity plutonium, americium, and curium - all of which clear more rapidly from the lung. This will tend to shift the cancer risk from lung to bone and liver. Although therapy with Ca- or Zn-DTPA rapidly removes 241 Am from the canine, the sub-human primate, and the human liver, improved methods for removal from bone and lung are needed. DTPA can remove 241 Am more easily from the growing skeleton of a child than from the mature skeleton of an adult. Investigators at Karlsruhe are developing chelation agents for oral administration and are investigating the reduction in local dose to bone resulting from chelation therapy

Evaluation of [64Cu]Cu-DOTA and [64Cu]Cu-CB-TE2A Chelates for Targeted Positron Emission Tomography with an αvβ6-Specific Peptide

Directory of Open Access Journals (Sweden)

Sven H. Hausner

2009-03-01

Full Text Available Significant upregulation of the integrin αvβ6 has been described as a prognostic indicator in several cancers, making it an attractive target for tumor imaging. This study compares variants of a PEGylated αvβ6-targeting peptide, bearing either an [>18F]fluorobenzoyl prosthetic group ([18F]FBA-PEG-A20FMDV2 or different [64Cu]copper chelators (DOTA-PEG-A20FMDV2, CB-TE2A-PEG-A20FMDV2. The compounds were evaluated in vitro by enzyme-linked immunosorbent assay (against the integrin αvβ6 and the closely related integrin αvβ6 and by cell labeling (αvβ6-positive DX3puroβ6/αvβ6-negative DX3puro and in vivo using micro-positron emission tomography in a mouse model bearing paired DX3puroβ6/Dx3puro xenografts. In vitro, all three compounds showed excellent αvβ6-specific binding (50% inhibitory concentration [IC50](αvβ6 = 3 to g nmol/L; IC50(αvβ3 > 10 (μmol/L. In vivo, they displayed comparable, preferential uptake for the αvβ6-expressmg xenograft over the αvβ6-negative control (> 4:1 ratio at 4 hours postinjection. Whereas [64Cu]Cu-DOTA-PEG-A20FMDV2 resulted in increased levels of radioactivity in the liver, [64Cu]Cu-CB-TE2A-PEG-A20FMDV2 did not. Significantly, both 64Cu-labeled tracers showed unexpectedly high and persistent levels of radioactivity in the kidneys (> 40% injected dose/g at 4 and 12 hours postinjection. The findings underscore the potential influence of the prosthetic group on targeted in vivo imaging of clinically relevant markers such as αvβ6. Despite identical targeting peptide moiety and largely equal in vitro behavior, both 64Cu-labeled tracers displayed inferior pharmacokinetics, making them in their present form less suitable candidates than the 18F-labeled tracer for in vivo imaging of αvβ6

A comparison of 111In- or 64Cu-DOTA-trastuzumab Fab fragments for imaging subcutaneous HER2-positive tumor xenografts in athymic mice using microSPECT/CT or microPET/CT

Science.gov (United States)

2011-01-01

radioactivity were observed for 64Cu-DOTA-trastuzumab Fab than 111In-DOTA-trastuzumab Fab. Conclusions We conclude that 111In-DOTA-trastuzumab Fab was more specific than 64Cu-DOTA-trastuzumab Fab for imaging HER2-positive tumors, especially those with low receptor density. This was due to higher levels of circulating radioactivity for 64Cu-DOTA-trastuzumab Fab which disrupted the relationship between HER2 density and T/B ratios. Use of alternative chelators that more stably bind 64Cu may improve the association between T/B ratios and HER2 density for 64Cu-labeled trastuzumab Fab. PMID:22214307

Comparison of sequential planar 177Lu-DOTA-TATE dosimetry scans with 68Ga-DOTA-TATE PET/CT images in patients with metastasized neuroendocrine tumours undergoing peptide receptor radionuclide therapy

International Nuclear Information System (INIS)

Sainz-Esteban, Aurora; Carril, Jose Manuel; Prasad, Vikas; Schuchardt, Christiane; Zachert, Carolin; Baum, Richard P.

2012-01-01

The aim of the study was to compare sequential 177 Lu-DOTA-TATE planar scans ( 177 Lu-DOTA-TATE) in patients with metastasized neuroendocrine tumours (NET) acquired during peptide receptor radionuclide therapy (PRRT) for dosimetry purposes with the pre-therapeutic 68 Ga-DOTA-TATE positron emission tomography (PET)/CT ( 68 Ga-DOTA-TATE) maximum intensity projection (MIP) images obtained in the same patients concerning the sensitivity of the different methods. A total of 44 patients (59 ± 11 years old) with biopsy-proven NET underwent 68 Ga-DOTA-TATE and 177 Lu-DOTA-TATE imaging within 7.9 ± 7.5 days between the two examinations. 177 Lu-DOTA-TATE planar images were acquired at 0.5, 2, 24, 48 and 72 h post-injection; lesions were given a score from 0 to 4 depending on the uptake of the radiopharmaceutical (0 being lowest and 4 highest). The number of tumour lesions which were identified on 177 Lu-DOTA-TATE scans (in relation to the acquisition time after injection of the therapeutic dose as well as with regard to the body region) was compared to those detected on 68 Ga-DOTA-TATE studies obtained before PRRT. A total of 318 lesions were detected; 280 (88%) lesions were concordant. Among the discordant lesions, 29 were 68 Ga-DOTA-TATE positive and 177 Lu-DOTA-TATE negative, whereas 9 were 68 Ga-DOTA-TATE negative and 177 Lu-DOTA-TATE positive. The sensitivity, positive predictive value and accuracy for 177 Lu-DOTA-TATE as compared to 68 Ga-DOTA-TATE were 91, 97 and 88%, respectively. Significantly more lesions were seen on the delayed (72 h) 177 Lu-DOTA-TATE images (91%) as compared to the immediate (30 min) images (68%). The highest concordance was observed for bone metastases (97%) and the lowest for head/neck lesions (75%). Concordant lesions (n = 77; mean size 3.8 cm) were significantly larger than discordant lesions (n = 38; mean size 1.6 cm) (p max ). However, concordant liver lesions with a score from 1 to 3 in the 72-h 177 Lu-DOTA-TATE scan had a lower SUV max

Single vial kit formulation for preparation of PET radiopharmaceutical. 68Ga-DOTA-TOC

International Nuclear Information System (INIS)

Archana Mukherjee; Usha Pandey; Rubel Chakravarty; Ashutosh Dash; Haladhar Dev Sarma

2014-01-01

This paper describes the development of a lyophilized cold kit of DOTA-[Tyr 3 ]-Octreotide (DOTA-TOC) for instant compounding of 68 Ga-DOTA-TOC, suitable for diagnosis of neuroendocrine tumors. The work involved formulation of DOTA-TOC kits, optimization of radiolabeling, quality control of 68 Ga-DOTA-TOC and animal biodistribution studies. The prepared kits enable a reliable method for preparation of 68 Ga-DOTA-TOC of high radiochemical purity and excellent stability. Availability of such kits along with 68 Ge/ 68 Ga generators is expected to stimulate the widespread use of 68 Ga-DOTA-TOC in nuclear medicine practice in developing countries. (author)

Radiolabelled of c-DOTA-RGD and c-DOTA-RGDf with {sup 177}Lu and evaluation in vitro and in vivo stability; Radiomarcado del peptido c-DOTA-RGD y c-DOTA-RGDf con {sup 177}Lu y evaluacion de su estabilidad in vitro e in vivo

Energy Technology Data Exchange (ETDEWEB)

Vilchis J, A.

2010-07-01

Integrin {alpha}v{beta}3 has a critical role in tumor angio genesis and metastasis. Radiolabelled peptides based on the Arg-Gly-Asp (RGD) sequence have been reported as radiopharmaceuticals with high affinity and selectivity for the {alpha}v{beta}3 integrin. The aim of this study was to label c-DOTA-RGD and c-DOTA-RGDf peptides with {sup 177}Lu and to evaluate their in vitro and in vivo stability as potential specific therapeutic radiopharmaceuticals. Labelled was carried out by direct reaction of {sup 177}LuCl{sub 3} with c-DOTA-RGD peptides in 1 M acetate buffer ph 5.5 at 90{sup o} C for 30 min. Radiochemical purity and stability studies were realized by reversed phase HPLC and I TLC-Sg analyses in human serum and saline solution. Biological recognition was performed using MCF7 tumor cells (positive {alpha}v{beta}3) and in athymic mice with induced MCF7 tumors. Molecular mechanics and quantum mechanics calculations were performed to explain experimental results associated with the molecular recognition. {sup 177}Lu-DOTA-RGD and {sup 177}Lu-DOTA-RGDf were obtained with radiochemical purities > 95%, showing adequate in vitro and in vivo stability and specific binding to {open_square}{sub v}{open_square}{sub 3} receptors. (Author)

[Tl(III)(dota)](-): An Extraordinarily Robust Macrocyclic Complex.

Science.gov (United States)

Fodor, Tamás; Bányai, István; Bényei, Attila; Platas-Iglesias, Carlos; Purgel, Mihály; Horváth, Gábor L; Zékány, László; Tircsó, Gyula; Tóth, Imre

2015-06-01

The X-ray structure of {C(NH2)3}[Tl(dota)]·H2O shows that the Tl(3+) ion is deeply buried in the macrocyclic cavity of the dota(4-) ligand (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate) with average Tl-N and Tl-O distances of 2.464 and 2.365 Å, respectively. The metal ion is directly coordinated to the eight donor atoms of the ligand, which results in a twisted square antiprismatic (TSAP') coordination around Tl(3+). A multinuclear (1)H, (13)C, and (205)Tl NMR study combined with DFT calculations confirmed the TSAP' structure of the complex in aqueous solution, which exists as the Λ(λλλλ)/Δ(δδδδ) enantiomeric pair. (205)Tl NMR spectroscopy allowed the protonation constant associated with the protonation of the complex according to [Tl(dota)](-) + H(+) ⇆ [Tl(Hdota)] to be determined, which turned out to be pK(H)Tl(dota) = 1.4 ± 0.1. [Tl(dota)](-) does not react with Br(-), even when using an excess of the anion, but it forms a weak mixed complex with cyanide, [Tl(dota)](-) + CN(-) ⇆ [Tl(dota)(CN)](2-), with an equilibrium constant of Kmix = 6.0 ± 0.8. The dissociation of the [Tl(dota)](-) complex was determined by UV-vis spectrophotometry under acidic conditions using a large excess of Br(-), and it was found to follow proton-assisted kinetics and to take place very slowly (∼10 days), even in 1 M HClO4, with the estimated half-life of the process being in the 10(9) h range at neutral pH. The solution dynamics of [Tl(dota)](-) were investigated using (13)C NMR spectroscopy and DFT calculations. The (13)C NMR spectra recorded at low temperature (272 K) point to C4 symmetry of the complex in solution, which averages to C4v as the temperature increases. This dynamic behavior was attributed to the Λ(λλλλ) ↔ Δ(δδδδ) enantiomerization process, which involves both the inversion of the macrocyclic unit and the rotation of the pendant arms. According to our calculations, the arm-rotation process limits the Λ(λλλλ) ↔ �

Chelation in root canal therapy reconsidered.

Science.gov (United States)

Zehnder, Matthias; Schmidlin, Patrick; Sener, Beatrice; Waltimo, Tuomas

2005-11-01

The aim of this study was to assess interactions of EDTA and citric acid (CA) with sodium hypochlorite (NaOCl), the indispensable endodontic irrigant. Other chelators were simultaneously evaluated as possible alternatives: sodium triphosphate (STP), amino tris methylenephosphonic acid (ATMA), and 1- hydroxyethylidene-1, 1-bisphosphonate (HEBP). Available chlorine was titrated in chelator-NaOCl solutions. All chelators other than HEBP and STP caused an almost complete, immediate loss of available chlorine in solution. Atomic absorbtion spectrometry and SEM evaluation of root canal walls of instrumented teeth indicated that NaOCl had no negative effect on calcium-complexing ability of chelators. STP was too weak a complexing agent to warrant further studies. Finally, CA-, EDTA-, and HEBP-NaOCl mixtures were evaluated for their antimicrobial capacity. Again, EDTA and CA negatively interfered with NaOCl, while HEBP did not.

f-Element Ion Chelation in Highly Basic Media

International Nuclear Information System (INIS)

Paine, R.T.

2000-01-01

A large body of data has been collected over the last fifty years on the chemical behavior of f-element ions. The ions undergo rapid hydrolysis reactions in neutral or basic aqueous solutions that produce poorly understood oxide-hydroxide species; therefore, most of the fundamental f-element solution chemistry has allowed synthetic and separations chemists to rationally design advanced organic chelating ligands useful for highly selective partitioning and separation of f-element ions from complex acidic solution matrices. These ligands and new examples under development allow for the safe use and treatment of solutions containing highly radioactive species. This DOE/EMSP project was undertaken to address the following fundamental objectives: (1) study the chemical speciation of Sr and lanthanide (Ln) ions in basic aqueous media containing classical counter anions found in waste matrices; (2) prepare pyridine N-oxide phosphonates and phosphonic acids that might act as selective chelators for Ln ions in model basic pH waste streams; (3) study the binding of the new chelators toward Ln ions and (4) examine the utility of the chelators as decontamination and dissolution agents under basic solution conditions. The project has been successful in attacking selected aspects of the very difficult problems associated with basic pH solution f-element waste chemistry. In particular, the project has (1) shed additional light on the initial stages of Ln ion sol-gel-precipitate formulation under basic solution conditions; (2) generated new families of pyridine phosphonic acid chelators; (3) characterized the function of the chelators and (4) examined their utility as oxide-hydroxide dissolution agents. These findings have contributed significantly to an improved understanding of the behavior of Ln ions in basic media containing anions found in typical waste sludges as well as to the development of sludge dissolution agents. The new chelating reagents are easily made and could be

Chelating agents related to ethylenediamine bis(2-hydroxyphenyl)acetic acid (EDDHA): synthesis, characterization, and equilibrium studies of the free ligands and their Mg2+, Ca2+, Cu2+, and Fe3+ chelates.

Science.gov (United States)

Yunta, Felipe; García-Marco, Sonia; Lucena, Juan J; Gómez-Gallego, Mar; Alcázar, Roberto; Sierra, Miguel A

2003-08-25

Iron chelates such as ethylenediamine-N,N'-bis(2-hydroxyphenyl)acetic acid (EDDHA) and their analogues are the most efficient soil fertilizers to treat iron chlorosis in plants growing in calcareous soils. EDDHA, EDDH4MA (ethylenediamine-N,N'-bis(2-hydroxy-4-methylphenyl)acetic acid), and EDDCHA (ethylenediamine-N,N'-bis(2-hydroxy-5-carboxyphenyl)acetic acid) are allowed by the European directive, but also EDDHSA (ethylenediamine-N,N'-bis(2-hydroxy-5-sulfonylphenyl)acetic acid) and EDDH5MA (ethylenediamine-N,N'-bis(2-hydroxy-5-methylphenyl)acetic acid) are present in several commercial iron chelates. In this study, these chelating agents as well as p,p-EDDHA (ethylenediamine-N,N'-bis(4-hydroxyphenyl)acetic acid) and EDDMtxA (ethylenediamine-N,N'-bis(2-metoxyphenyl)acetic acid) have been obtained following a new synthetic pathway. Their chemical behavior has been studied to predict the effect of the substituents in the benzene ring on their efficacy as iron fertilizers for soils above pH 7. The purity of the chelating agents has been determined using a novel methodology through spectrophotometric titration at 480 nm with Fe(3+) as titrant to evaluate the inorganic impurities. The protonation constants were determined by both spectrophotometric and potentiometric methods, and Ca(2+) and Mg(2+) stability constants were determined from potentiometric titrations. To establish the Fe(3+) and Cu(2+) stability constants, a new spectrophotometric method has been developed, and the results were compared with those reported in the literature for EDDHA and EDDHMA and their meso- and rac-isomers. pM values have been also determined to provide a comparable basis to establish the relative chelating ability of these ligands. The purity obtained for the ligands is higher than 87% in all cases and is comparable with that obtained by (1)H NMR. No significant differences have been found among ligands when their protonation and stability constants were compared. As expected, no Fe(3

An experimental study on lead removing effect of new chelating agent-FZ-820-4

International Nuclear Information System (INIS)

Feng Jue; Zhang Kangrong; Yin Xieyu; Ji Shaowei

2001-01-01

To evaluate the lead removing effects of F Z-82-4, a new chelating agent, and to compare it with those of DTPA, EDTA, H-73-10 and control group. The experiments are carried out using rats. The Pb-nitrate removing effect of FZ-82-4 was obviously superior to those EDTA, H-73-10 and control group, and equivalent to that of DTPA. According to lead excreting rate of urine in 24 hours. For lead retention rate in bones, liver and kidneys, F Z-82-4 group was lower than control group. The Pb-nitrate removing effect of FZ-82-4 was related to administering time, route and dose

Radiolabelled of c-DOTA-RGD and c-DOTA-RGDf with 177Lu and evaluation in vitro and in vivo stability

International Nuclear Information System (INIS)

Vilchis J, A.

2010-01-01

Integrin αvβ3 has a critical role in tumor angio genesis and metastasis. Radiolabelled peptides based on the Arg-Gly-Asp (RGD) sequence have been reported as radiopharmaceuticals with high affinity and selectivity for the αvβ3 integrin. The aim of this study was to label c-DOTA-RGD and c-DOTA-RGDf peptides with 177 Lu and to evaluate their in vitro and in vivo stability as potential specific therapeutic radiopharmaceuticals. Labelled was carried out by direct reaction of 177 LuCl 3 with c-DOTA-RGD peptides in 1 M acetate buffer ph 5.5 at 90 o C for 30 min. Radiochemical purity and stability studies were realized by reversed phase HPLC and I TLC-Sg analyses in human serum and saline solution. Biological recognition was performed using MCF7 tumor cells (positive αvβ3) and in athymic mice with induced MCF7 tumors. Molecular mechanics and quantum mechanics calculations were performed to explain experimental results associated with the molecular recognition. 177 Lu-DOTA-RGD and 177 Lu-DOTA-RGDf were obtained with radiochemical purities > 95%, showing adequate in vitro and in vivo stability and specific binding to □ v □ 3 receptors. (Author)

(68)Ga-DOTA-peptide: A novel molecular biomarker for nasopharyngeal carcinoma.

Science.gov (United States)

Khor, Lih Kin; Loi, Hoi Yin; Sinha, Arvind Kumar; Tong, Kian Ti; Goh, Boon Cher; Loh, Kwok Seng; Lu, Suat-Jin

2016-04-01

Increased somatostatin receptor (SSTR) expression in patients with undifferentiated nasopharyngeal carcinoma (NPC) has been demonstrated with receptor autoradiography, (111) In-Octreotide scintigraphy, and (68) Ga-DOTA-TOC positron emission tomography (PET)/CT imaging. We sought to compare and correlate the uptake of fluorodeoxyglucose (FDG) and DOTA-NOC in undifferentiated NPC to ascertain the possible role of (68) Ga-DOTA-NOC PET/CT as a new imaging biomarker and to assess whether targeted peptide receptor radionuclide therapy is a feasible treatment option. After obtaining approval from our institutional review board, 4 patients with biopsy proven nonkeratinizing undifferentiated NPC who had just undergone routine staging/restaging (18) F-FDG PET/CT imaging were prospectively and consecutively recruited for (68) Ga-DOTA-NOC PET/CT imaging. Of these 4 patients, 3 were newly diagnosed with untreated NPC, whereas 1 patient was diagnosed with a case of recurrent NPC with previous treatment. These patients subsequently underwent (68) Ga-DOTA-NOC PET/CT within 10 days from the (18) F-FDG PET/CT to ensure lesion comparability. Tracer uptake in tumor lesions were assessed visually and semiquantitatively by measuring maximum standardized uptake values (SUVmax). There were 12 FDG-avid lesions of which 7 showed avid uptake of DOTA-NOC greater than liver uptake, whereas 5 showed low uptake of DOTA-NOC less than liver uptake. Subset analysis of the FDG-avid lesions at the primary and recurrent sites showed that all the FDG-avid primary tumors in the nasopharynx showed avid uptake of DOTA-NOC. On the contrary, the case of recurrent NPC showed avid FDG uptake but low DOTA-NOC uptake. Subset analysis of the suspicious FDG-avid cervical lymph nodes showed that 50% of them demonstrated avid DOTA-NOC uptake greater than liver uptake, whereas the remaining demonstrated low-grade DOTA-NOC uptake less than liver uptake. The 2 subcentimeter cervical lymph nodes that showed low

Biomolecule conjugation strategy using novel water-soluble phosphine-based chelating agents

Science.gov (United States)

Katti, Kattesh V.; Gali, Hariprasad; Volkert, Wynn A.

2004-08-24

This invention describes a novel strategy to produce phosphine-functionalized biomolecules (e.g. peptides or proteins) for potential use in the design and development of site-specific radiopharmaceuticals for diagnosis or therapy of specific cancers. Hydrophilic alkyl phosphines, in general, tend to be oxidatively unstable. Therefore, incorporation of such phosphine functionalities on peptide (and other biomolecule) backbones, without oxidizing the P.sup.III centers, is difficult. In this context this discovery reports on a new technology by which phosphines, in the form of bifunctional chelating agents, can be directly incorporated on biomolecular backbones using manual synthetic or solid phase peptide synthesis methodologies. The superior ligating abilities of phosphine ligands, with various diagnostically (e.g. TC-99m) or therapeutically (e.g. Re186/188, Rh-105, Au-199) useful radiometals, coupled with the findings that the resulting complexes demonstrate high in vivo stability makes this approach useful in the development of radiolabeled biomolecules for applications in the design of tumor-specific radiopharmaceuticals.

Structural characterization of the Actinides (III) and (IV) - DOTA complexes

International Nuclear Information System (INIS)

Audras, Matthieu

2014-01-01

The polyamino-carboxylate anions have been identified as compounds of interest in the operations of actinide separation, in actinide migration in the environment and in human radio-toxicology. The structural characterization of complexes formed between actinides and polyamino-carboxylates ligands is essential for a better understanding of actinide-ligands interactions. Among the polyamino-carboxylate anions, the DOTA ligand (1,4,7,10-tetraaza-cyclododecane tetraacetic acid) is described as a very strong complexing agent of the lanthanides(III), but has been little studied with actinides. The objective of this thesis is to describe the complexes formed between the actinides (III) and (IV) and the DOTA ligand, and compare them with the lanthanide complexes. For this, an approach has been introduced to characterize the complexes by complementary analytical techniques (spectrophotometry, electro-spray ionization mass spectrometry, NMR, EXAFS, electrochemistry), but also by calculations of theoretical chemistry to help the interpretation of the experimental data. The formation of a 1:1 complex is observed with the actinides(III) (plutonium and americium) as for lanthanides(III): rapid formation of intermediate species which evolves slowly towards the formation of a limit complex. Within this complex, the cation is located inside the cavity formed by the ligand. Four nitrogen atoms and four oxygen atoms from the carboxylate functions are involved in the coordination sphere of the cation. However, differences were observed in the bond lengths formed between the cation and the nitrogen atoms (the bonds are somewhat shorter in the case of actinide complexes) as well as the complexation kinetics, which is slightly faster for the actinides(III) than for lanthanide(III) ions of equivalent radius. The same behavior was observed in solution upon complexation of actinides(IV) (uranium, plutonium and neptunium): slow formation of a 1:1 complex (actinide(IV):ligand) in wherein the

Somatostatin-based Radiopeptide Therapy with [177Lu-DOTA]-TOC versus [90Y-DOTA]-TOC in Neuroendocrine Tumors

OpenAIRE

Romer A Seiler D Marincek N Brunner P Koller MT Ng QK Maecke HR Muller-Brand J Rochlitz C B

2014-01-01

PURPOSE: Somatostatin based radiopeptide treatment is generally performed using the ß emitting radionuclides (90)Y or (177)Lu. The present study aimed at comparing benefits and harms of both therapeutic approaches. METHODS: In a comparative cohort study patients with advanced neuroendocrine tumours underwent repeated cycles of [(90)Y DOTA] TOC or [(177)Lu DOTA] TOC until progression of disease or permanent adverse events. Multivariable Cox regression and competing risks regression were emplo...

The effect of macrocyclic chelators on the targeting properties of the 68Ga-labeled gastrin releasing peptide receptor antagonist PEG2-RM26

International Nuclear Information System (INIS)

Varasteh, Zohreh; Mitran, Bogdan; Rosenström, Ulrika; Velikyan, Irina; Rosestedt, Maria; Lindeberg, Gunnar; Sörensen, Jens; Larhed, Mats; Tolmachev, Vladimir; Orlova, Anna

2015-01-01

Introduction: Overexpression of gastrin-releasing peptide receptors (GRPR) has been reported in several cancers. Bombesin (BN) analogs are short peptides with a high affinity for GRPR. Different BN analogs were evaluated for radionuclide imaging and therapy of GRPR-expressing tumors. We have previously investigated an antagonistic analog of BN (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2 , RM26) conjugated to NOTA via a PEG 2 spacer (NOTA-PEG 2 -RM26) labeled with 68 Ga, 111 In and Al 18 F. 68 Ga-labeled NOTA-PEG 2 -RM26 showed high tumor-to-organ ratios. Methods: The influence of different macrocyclic chelators (NOTA, NODAGA, DOTA and DOTAGA) on the targeting properties of 68 Ga-labeled PEG 2 -RM26 was studied in vitro and in vivo. Results: All conjugates were labeled with generator-produced 68 Ga with high yields and demonstrated high stability and specific binding to GRPR. The IC 50 values of nat Ga-X-PEG 2 -RM26 (X = NOTA, DOTA, NODAGA, DOTAGA) were 2.3 ± 0.2, 3.0 ± 0.3, 2.9 ± 0.3 and 10.0 ± 0.6 nM, respectively. The internalization of the conjugates by PC-3 cells was low. However, the DOTA-conjugated analog demonstrated a higher internalization rate compared to other analogs. GRPR-specific uptake was found in receptor-positive normal tissues and PC-3 xenografts for all conjugates. The biodistribution of the conjugates was influenced by the choice of the chelator moiety. Although all radiotracers cleared rapidly from the blood, [ 68 Ga]Ga-NOTA-PEG 2 -RM26 showed significantly lower uptake in lung, muscle and bone compared to the other analogs. The uptake in tumors (5.40 ± 1.04 %ID/g at 2 h p.i.) and the tumor-to-organ ratios (25 ± 3, 157 ± 23 and 39 ± 4 for blood, muscle and bone, respectively) were significantly higher for the NOTA-conjugate than the other analogs. Conclusions: Chelators had a clear influence on the biodistribution and targeting properties of 68 Ga-labeled antagonistic BN analogs. Positively charged [ 68 Ga]Ga-NOTA-PEG 2 -RM26 provided

Preclinical evaluation of multistep targeting of diasialoganglioside GD2 using a IgG-scFv bispecific antibody with high affinity for GD2 and DOTA metal complex

Science.gov (United States)

Cheal, Sarah M.; Xu, Hong; Guo, Hong-fen; Zanzonico, Pat B.; Larson, Steven M.; Cheung, Nai-Kong

2014-01-01

Bispecific antibodies (BsAb) have proven to be useful targeting vectors for pretargeted radioimmunotherapy (PRIT). We sought to overcome key PRIT limitations such as high renal radiation exposure and immunogenicity (e.g. of streptavidin-antibody fusions), to advance clinical translation of this PRIT strategy for diasialoganglioside GD2-positive (GD2(+)) tumors. For this purpose, a IgG-scFv BsAb was engineered using the sequences for the anti-GD2 humanized monoclonal antibody hu3F8 (1) and C825, a murine scFv antibody with high affinity for the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) complexed with beta-particle emitting radiometals such as 177Lu and 90Y (2, 3). A three-step regimen including hu3F8-C825, a dextran-based clearing agent, and p-aminobenzyl-DOTA radiolabeled with 177Lu (as 177Lu-DOTA-Bn; t1/2 = 6.71 days (d)) was optimized in immunocompromised mice carrying subcutaneous (s.c.) human GD2(+) neuroblastoma (NB) xenografts. Absorbed doses for tumor and normal tissues were ∼85 cGy/MBq and ≤3.7 cGy/MBq, respectively, with therapeutic indicies (TI) of 142 for blood and 23 for kidney. A therapy study (n = 5 per group; tumor volume: 240 ± 160 mm3) with three successive PRIT cycles (total 177Lu: ∼33 MBq; tumor dose ∼3400 cGy), revealed complete tumor response in 5/5 animals, with no recurrence up to 28 d post-treatment. Tumor ablation was confirmed histologically in 4/5 mice, and normal organs showed minimal overall toxicities. All non-treated mice required sacrifice within 12 d (>1.0 cm3 tumor volume). We conclude that this novel anti-GD2 PRIT approach has sufficient TI to successfully ablate s.c. GD2(+)–NB in mice while sparing kidney and bone marrow. PMID:24944121

Development of radioinmunoconjugate 90Y-DOTA-nimotuzumab-Fab for therapy of EGFR over expressing tumors

International Nuclear Information System (INIS)

Rodriguez, A. M.; Alonso, L. M.; Gongora, M.; Leyva, R.; Solana, A.

2015-01-01

Many monoclonal antibodies conjugated with 1,4,7,10-tetraaza cyclododecane-N, N', N'', N'''-tetraacetic acid (DOTA) and radiolabeled with 90 Y, have been used for radioimmunotherapy. As know IgG molecules are heavy proteins with a molecular weight of approximately 150 kDa. Accordingly, intact IgG antibodies may have significant slow kinetics biodistribution and severely limited properties of tissue penetration. Antibody fragments labeled with radio metals could be promising radiopharmaceuticals for imaging and non-invasive therapy due to its high affinity to the tumor, the lack of effector function and rapid pharmacokinetic. In this work, the nimotuzumab Fab fragment was obtained by cleavage with papain in molar excess. After separating the reaction mixture in three steps using affinity, size exclusion and ion exchange chromatography; the Fab fragment showed high values of purity, integrity and identity. The Fab fragment was derivatized with DOTA and labeled with 90 Y. The radioimmunoconjugate with high radiochemical yield was assessed by in vitro stability with an excess of 50mM DTPA. The development of 90 Y-DOTA-Nimotuzumab-Fab radioimmunoconjugate allows to count on as a potential agent for radioimmunotherapy. (Author)

Assessment of toxicity on chelating agent DTPA (diethylenetriaminepentaacetic acid)

International Nuclear Information System (INIS)

Fukuda, Satoshi

1989-01-01

DTPA (diethylenetriaminepentaacetic acid) is a very important chelating agent to decorporate the radionuclides such as plutonium and americium from human body. However, before DTPA will be administered to humans, the toxicity should be clarified. This report described the summary on data of DTPA toxicities obtained from animal experiments and assessment on the safety for humans, based on the results that compared their data among animal species. In short, Ca-DTPA is less toxic than Zn-DTPA when it is injected intravenously, while Zn-DTPA is less toxic than Ca-DTPA when it is administered orally. Both DTPAs acted on the serum calcium metabolism and induced the functional damages of cardiovascular system. Particularly, it is stressed that Zn-DTPA by intravenous injection occurred the heart failure, increases of blood pressure and pulse with hypocalcemia in even normal rats and beagle dogs. Other side effects by both DTPAs were also observed in the intestine, liver, kidney and bone. It is estimated that there are almost no species differences on DTPA toxicity between animals and humans. As a result, it is concluded that DTPA should be used very carefully for humans, with reference to the results obtained from animal experiments. (author) 61 refs

Assessment of toxicity on chelating agent DTPA (diethylenetriaminepentaacetic acid)

Energy Technology Data Exchange (ETDEWEB)

Fukuda, Satoshi (National Inst. of Radiological Sciences, Chiba (Japan))

1989-09-01

DTPA (diethylenetriaminepentaacetic acid) is a very important chelating agent to decorporate the radionuclides such as plutonium and americium from human body. However, before DTPA will be administered to humans, the toxicity should be clarified. This report described the summary on data of DTPA toxicities obtained from animal experiments and assessment on the safety for humans, based on the results that compared their data among animal species. In short, Ca-DTPA is less toxic than Zn-DTPA when it is injected intravenously, while Zn-DTPA is less toxic than Ca-DTPA when it is administered orally. Both DTPAs acted on the serum calcium metabolism and induced the functional damages of cardiovascular system. Particularly, it is stressed that Zn-DTPA by intravenous injection occurred the heart failure, increases of blood pressure and pulse with hypocalcemia in even normal rats and beagle dogs. Other side effects by both DTPAs were also observed in the intestine, liver, kidney and bone. It is estimated that there are almost no species differences on DTPA toxicity between animals and humans. As a result, it is concluded that DTPA should be used very carefully for humans, with reference to the results obtained from animal experiments. (author) 61 refs.

Quantitative Determination of NTA and Other Chelating Agents in Detergents by Potentiometric Titration with Copper Ion Selective Electrode.

Science.gov (United States)

Ito, Sana; Morita, Masaki

2016-01-01

Quantitative analysis of nitrilotriacetate (NTA) in detergents by titration with Cu 2+ solution using a copper ion selective electrode was achieved. This method tolerates a wide range of pH and ingredients in detergents. In addition to NTA, other chelating agents, having relatively lower stability constants toward Cu 2+ , were also qualified with sufficient accuracy by this analytical method for model detergent formulations. The titration process was automated by automatic titrating systems available commercially.

111In-DOTA-dPhe1-Tyr3-octreotide, 111In-DOTA-lanreotide and 67Ga citrate scintigraphy for visualisation of extranodal marginal zone B-cell lymphoma of the MALT type: a comparative study

International Nuclear Information System (INIS)

Li, Shuren; Kurtaran, Amir; Li, Mei; Traub-Weidinger, Tatjana; Kienast, Oskar; Schima, Wolfgang; Angelberger, Peter; Virgolini, Irene; Raderer, Markus; Dudczak, Robert

2003-01-01

Somatostatin receptor (SSTR) scintigraphy and gallium-67 citrate ( 67 Ga) scintigraphy have been used for visualisation of Hodgkin's lymphoma and non-Hodgkin's lymphoma. However, experience with B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type is very limited. The aim of this study was to prospectively compare the 67 Ga scintigraphy results with those obtained by 111 In-DOTA-dPhe 1 -Tyr 3 -octreotide ( 111 In-DOTA-TOCT) and 111 In-DOTA-lanreotide ( 111 In-DOTA-LAN) scintigraphy in patients with proven MALT-type lymphoma. Comparative scintigraphic examinations using 67 Ga, 111 In-DOTA-TOCT and 111 In-DOTA-LAN were performed in 18 patients (11 female and 7 male, median age 64±15 years) with histologically verified MALT-type lymphomas of various origin. Planar and single-photon emission tomography imaging acquisitions were performed after injection of a mean dose of 185±26 MBq 67 Ga and 165±20 MBq 111 In-DOTA-TOCT or 111 In-DOTA-LAN. All scintigraphic results were correlated with other conventional examinations including gastroscopy, colonoscopy, endosonoscopy, ophthalmologic investigation, CT of the thorax and abdomen and bone marrow biopsy. This comparative study showed that 67 Ga scintigraphy found abnormalities in 10 of 16 patients (63%) and detected 18 of 31 clinically involved sites (58%), but was false positive in three patients. 111 In-DOTA-TOCT found abnormalities in 9 of 15 patients (60%) and detected 15 of 27 clinical lesions (56%); it was false positive in two patients. 111 In-DOTA-LAN scintigraphy showed abnormalities in 7 of 11 patients (64%) and found 12 of 22 clinical lesions (55%). False-positive 111 In-DOTA-LAN scan results were found in two patients. For supra-diaphragmatic lesions, 67 Ga scintigraphy detected 12 of 16 sites (75%). 111 In-DOTA-TOCT scintigraphy revealed 7 of 15 lesions (47%). 111 In-DOTA-LAN showed 6 of 12 positive sites (50%). For infra-diaphragmatic involvement, the sensitivities of 67 Ga, 111 In-DOTA

Low-Molecular-Weight Iron Chelates May Be an Alternative to Gadolinium-based Contrast Agents for T1-weighted Contrast-enhanced MR Imaging.

Science.gov (United States)

Boehm-Sturm, Philipp; Haeckel, Akvile; Hauptmann, Ralf; Mueller, Susanne; Kuhl, Christiane K; Schellenberger, Eyk A

2018-02-01

Purpose To synthesize two low-molecular-weight iron chelates and compare their T1 contrast effects with those of a commercial gadolinium-based contrast agent for their applicability in dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging. Materials and Methods The animal experiments were approved by the local ethics committee. Two previously described iron (Fe) chelates of pentetic acid (Fe-DTPA) and of trans-cyclohexane diamine tetraacetic acid (Fe-tCDTA) were synthesized with stability constants several orders of magnitude higher than those of gadolinium-based contrast agents. The T1 contrast effects of the two chelates were compared with those of gadopentetate dimeglumine in blood serum phantoms at 1.5 T, 3 T, and 7 T. For in vivo studies, a human breast cancer cell line (MDA-231) was implanted in five mice per group. The dynamic contrast effects of the chelates were compared by performing DCE MR imaging with intravenous application of Fe-DTPA or Fe-tCDTA on day 1 and DCE MR imaging in the same tumors with gadopentetate dimeglumine on day 2. Quantitative DCE maps were generated with software and were compared by means of a one-tailed Pearson correlation test. Results Relaxivities in serum (0.94 T at room temperature) of Fe-tCDTA (r1 = 2.2 mmol -1 · sec -1 , r2 = 2.5 mmol -1 · sec -1 ) and Fe-DTPA (r1 = 0.9 mmol -1 · sec -1 , r2 = 0.9 mmol -1 · sec -1 ) were approximately twofold and fivefold lower, respectively, compared with those of gadopentetate dimeglumine (r1 = 4.1 mmol -1 · sec -1 , r2 = 4.8 mmol -1 · sec -1 ). Used at moderately higher concentrations, however, iron chelates generated similar contrast effects at T1-weighted MR imaging in vitro in serum, in vivo in blood, and for DCE MR imaging of breast cancer xenografts. The volume transfer constant values for Fe-DTPA and Fe-tCDTA in the same tumors correlated well with those observed for gadopentetate dimeglumine (Fe-tCDTA Pearson R, 0.99; P = .0003; Fe-DTPA Pearson R, 0.97; P

Preparation and quality control of radiometal-DOTARituximab

International Nuclear Information System (INIS)

Jalilian, A.R.; Kamali-dehghan, M.; Moradkhani, S.; Saddadi, F.; Mirsadeghi, L.

2008-01-01

In this work Rituximab has been labeled by Ga-67 using a new one-step method for in-situ preparation of macrocyclic bifunctional chelating agent, N-succinimidyl-1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTANHS). DOTA-NHS was prepared at 25 deg. C using DOTA, Nhydroxy succinimide (NHS) in CH Cl in one step. DOTA- 2 2 Rituximab was obtained by the addition of 1 ml of a Rituximab pharmaceutical solution (5 mg/ml, in phosphate buffer, pH=7.8) to a glass tube pre-coated with DOTA-NHS (0.01-0.1 mg) at 25 deg. C with continuous mild stirring for 15 hours. Radiolabeling was performed at 37 deg. C in 3 hrs using Ga-67 Chlorides or Cu-64 Acetate. Thin layer radiochromatography demonstrated an overall radiochemical purity of 90-95% at optimized conditions (specific activity =30 GBq/mg, labeling efficacy= 82%). The final isotonic radio-metal-DOTA-Rituximab complex was checked by gel electrophoresis for radiolysis. TLC was performed to ensure that only one species was present after filtration through a 0.22 μm filter. Preliminary bio-distribution studies of the Ga-67 immunoconjugate in normal rat model performed to determine complex distribution of the radioimmunoconjugate up to 28hrs by imaging and organ counting after sacrificing the rats. In this study a facile method for incorporation of metal chelating moiety into peptides and antibody structure is presented. (author)

Comparison of sequential planar {sup 177}Lu-DOTA-TATE dosimetry scans with {sup 68}Ga-DOTA-TATE PET/CT images in patients with metastasized neuroendocrine tumours undergoing peptide receptor radionuclide therapy

Energy Technology Data Exchange (ETDEWEB)

Sainz-Esteban, Aurora; Carril, Jose Manuel [Hospital Universitario Marques de Valdecilla, Department of Nuclear Medicine, Santander (Spain); Prasad, Vikas; Schuchardt, Christiane; Zachert, Carolin; Baum, Richard P. [Zentralklinik Bad Berka, Department of Nuclear Medicine and Centre for PET/CT, Bad Berka (Germany)

2012-03-15

The aim of the study was to compare sequential {sup 177}Lu-DOTA-TATE planar scans ({sup 177}Lu-DOTA-TATE) in patients with metastasized neuroendocrine tumours (NET) acquired during peptide receptor radionuclide therapy (PRRT) for dosimetry purposes with the pre-therapeutic {sup 68}Ga-DOTA-TATE positron emission tomography (PET)/CT ({sup 68}Ga-DOTA-TATE) maximum intensity projection (MIP) images obtained in the same patients concerning the sensitivity of the different methods. A total of 44 patients (59 {+-} 11 years old) with biopsy-proven NET underwent {sup 68}Ga-DOTA-TATE and {sup 177}Lu-DOTA-TATE imaging within 7.9 {+-} 7.5 days between the two examinations. {sup 177}Lu-DOTA-TATE planar images were acquired at 0.5, 2, 24, 48 and 72 h post-injection; lesions were given a score from 0 to 4 depending on the uptake of the radiopharmaceutical (0 being lowest and 4 highest). The number of tumour lesions which were identified on {sup 177}Lu-DOTA-TATE scans (in relation to the acquisition time after injection of the therapeutic dose as well as with regard to the body region) was compared to those detected on {sup 68}Ga-DOTA-TATE studies obtained before PRRT. A total of 318 lesions were detected; 280 (88%) lesions were concordant. Among the discordant lesions, 29 were {sup 68}Ga-DOTA-TATE positive and {sup 177}Lu-DOTA-TATE negative, whereas 9 were {sup 68}Ga-DOTA-TATE negative and {sup 177}Lu-DOTA-TATE positive. The sensitivity, positive predictive value and accuracy for {sup 177}Lu-DOTA-TATE as compared to {sup 68}Ga-DOTA-TATE were 91, 97 and 88%, respectively. Significantly more lesions were seen on the delayed (72 h) {sup 177}Lu-DOTA-TATE images (91%) as compared to the immediate (30 min) images (68%). The highest concordance was observed for bone metastases (97%) and the lowest for head/neck lesions (75%). Concordant lesions (n = 77; mean size 3.8 cm) were significantly larger than discordant lesions (n = 38; mean size 1.6 cm) (p < 0.05). No such significance was

Synergy and antagonism between iron chelators and antifungal drugs in Cryptococcus.

Science.gov (United States)

Lai, Yu-Wen; Campbell, Leona T; Wilkins, Marc R; Pang, Chi Nam Ignatius; Chen, Sharon; Carter, Dee A

2016-10-01

Fungal infections remain very difficult to treat, and developing new antifungal drugs is difficult and expensive. Recent approaches therefore seek to augment existing antifungals with synergistic agents that can lower the therapeutic dose, increase efficacy and prevent resistance from developing. Iron limitation can inhibit microbial growth, and iron chelators have been employed to treat fungal infections. In this study, chequerboard testing was used to explore combinations of iron chelators with antifungal agents against pathogenic Cryptococcus spp. with the aim of determining how disruption to iron homeostasis affects antifungal susceptibility. The iron chelators ethylenediaminetetraacetic acid (EDTA), deferoxamine (DFO), deferiprone (DFP), deferasirox (DSX), ciclopirox olamine and lactoferrin (LF) were paired with the antifungal agents amphotericin B (AmB), fluconazole, itraconazole, voriconazole and caspofungin. All chelators except for DFO increased the efficacy of AmB, and significant synergy was seen between AmB and LF for all Cryptococcus strains. Addition of exogenous iron rescued cells from the antifungal effect of LF alone but could not prevent inhibition by AmB + LF, indicating that synergy was not due primarily to iron chelation but to other properties of LF that were potentiated in the presence of AmB. Significant synergy was not seen consistently for other antifungal-chelator combinations, and EDTA, DSX and DFP antagonised the activity of azole drugs in strains of Cryptococcus neoformans var. grubii. This study highlights the range of interactions that can be induced by chelators and indicates that most antifungal drugs are not enhanced by iron limitation in Cryptococcus. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Positron Emission Tomography of (64)Cu-DOTA-Rituximab in a Transgenic Mouse Model Expressing Human CD20 for Clinical Translation to Image NHL

DEFF Research Database (Denmark)

Natarajan, Arutselvan; Gowrishankar, Gayatri; Nielsen, Carsten Haagen

2012-01-01

PURPOSE: This study aims to evaluate (64)Cu-DOTA-rituximab (PETRIT) in a preclinical transgenic mouse model expressing human CD20 for potential clinical translation. PROCEDURES: (64)Cu was chelated to DOTA-rituximab. Multiple radiolabeling, quality assurance, and imaging experiments were performed....... The human CD20 antigen was expressed in B cells of transgenic mice (CD20TM). The mice groups studied were: (a) control (nude mice, n¿=¿3) that received 7.4 MBq/dose, (b) with pre-dose (CD20TM, n¿=¿6) received 2 mg/kg pre-dose of cold rituximab prior to PETRIT of 7.4 MBq/dose, and (c) without pre-dose (CD20......TM, n¿=¿6) PETRIT alone received 7.4 MBq/dose. Small animal PET was used to image mice at various time points (0, 1, 2, 4, 24, 48, and 72 h). The OLINDA/EXM software was used to determine the human equivalent dose for individual organs. RESULTS: PETRIT was obtained with a specific activity of 545...

68Ga/177Lu-labeled DOTA-TATE shows similar imaging and biodistribution in neuroendocrine tumor model.

Science.gov (United States)

Liu, Fei; Zhu, Hua; Yu, Jiangyuan; Han, Xuedi; Xie, Qinghua; Liu, Teli; Xia, Chuanqin; Li, Nan; Yang, Zhi

2017-06-01

Somatostatin receptors are overexpressed in neuroendocrine tumors, whose endogenous ligands are somatostatin. DOTA-TATE is an analogue of somatostatin, which shows high binding affinity to somatostatin receptors. We aim to evaluate the 68 Ga/ 177 Lu-labeling DOTA-TATE kit in neuroendocrine tumor model for molecular imaging and to try human-positron emission tomography/computed tomography imaging of 68 Ga-DOTA-TATE in neuroendocrine tumor patients. DOTA-TATE kits were formulated and radiolabeled with 68 Ga/ 177 Lu for 68 Ga/ 177 Lu-DOTA-TATE (M-DOTA-TATE). In vitro and in vivo stability of 177 Lu-DOTA-TATE were performed. Nude mice bearing human tumors were injected with 68 Ga-DOTA-TATE or 177 Lu-DOTA-TATE for micro-positron emission tomography and micro-single-photon emission computed tomography/computed tomography imaging separately, and clinical positron emission tomography/computed tomography images of 68 Ga-DOTA-TATE were obtained at 1 h post-intravenous injection from patients with neuroendocrine tumors. Micro-positron emission tomography and micro-single-photon emission computed tomography/computed tomography imaging of 68 Ga-DOTA-TATE and 177 Lu-DOTA-TATE both showed clear tumor uptake which could be blocked by excess DOTA-TATE. In addition, 68 Ga-DOTA-TATE-positron emission tomography/computed tomography imaging in neuroendocrine tumor patients could show primary and metastatic lesions. 68 Ga-DOTA-TATE and 177 Lu-DOTA-TATE could accumulate in tumors in animal models, paving the way for better clinical peptide receptor radionuclide therapy for neuroendocrine tumor patients in Asian population.

Production and Quality Control of 177Lu-Dotatate [177Lu-dota- try3]-Octreotate: Clinical Application

International Nuclear Information System (INIS)

Barboza, M.F. de; Herrerias, R.; Souza, A.A. de; Pereira, G.; Pires, J.A.; Fukumori, N.T.O.; Matsuda, M.M.N.; Almeida, E.V.; Mengatti, J.; Belfer, A.J.; Hilario, L.N.

2009-01-01

Introduction: Somatostatin receptors have been identified in different kinds of tumors such as neuroendocrine tumors and tumors of the central nervous system, breast, lung and lymphatic tissue making these receptors potential targets for radionuclide diagnostics and therapy. These observations have served as the biomolecular basis for the clinical use of radiolabeled somatostatin analogues which, at present, are of great interest in nuclear medicine for diagnostic and peptide receptor radionuclide therapy (PRRT) applications. There are only a few treatment modalities for metastasized neuroendocrine gastroenteropancreatic (GEP) tumors. Besides surgery, (chemo)-embolization, chemotherapy, and treatment with somatostatin (SST) analogs, peptide receptor radionuclide therapy (PRRT) offers therapeutic strategy, as the majority of GEP tumors possess somatostatin receptors (SSTRs). Somatostatin analogs featuring a DOTA-chelator can be radiolabeled with the β-emitters radioisotopes, Yttrium-90 ( 90 Y) and Lutetium-177 ( 177 Lu) for PRRT. Analogs frequently used for therapy are: [DOTA-Tyr 3 ]-octreotide and [DOTA-Tyr 3 ]octreotate. In the latter compound, the alcohol threoninol at the C-terminal of the octreotide has been replaced by the natural threonin amino acid. This alteration resulted in an analog: (Tyr 3 -octreotate), which showed increased affinity for sst2, compared to both [Tyr 3 ]-octreotide and [Phe 1 ]octreotide 'in-vitro' and 'in-vivo'. Clinical studies in patients with different SST-positives tumors proved advantages of [ 177 Lu- DOTA-Tr 3 ]-octreate for therapy. PRRT with radiolabeled somatostatin analogs was shown to be effective in patients with SST2-positive-size reduction, improving quality of life and survival. Objective: The aim of this work was to present the production and the quality control of 177 Lu-Tyr 3 ---octreotate, using DOTA (1,4,7,10-tetrazacyclododecane-N,N',N',N''-tetra acetic acid) as chelating agent at the Radiopharmacy Directory, IPEN

Value of 111In-DOTA-lanreotide and 111In-DOTA-DPhe1-Tyr3-octreotide in differentiated thyroid cancer: results of in vitro binding studies and in vivo comparison with 18F-FDG PET

International Nuclear Information System (INIS)

Rodrigues, Margarida; Virgolini, Irene; Traub-Weidinger, Tatjana; Leimer, Maria; Li, Shuren; Dudczak, Robert; Andreae, Fritz; Angelberger, Peter

2005-01-01

Radioiodine-negative thyroid cancer presents diagnostic and therapeutic difficulties, warranting the implementation of new imaging and treatment strategies. The purpose of this study was twofold. First, we investigated in vitro the binding characteristics of 111 In-DOTA-lanreotide ( 111 In-DOTA-LAN) and 111 In-DOTA-DPhe 1 -Tyr 3 -octreotide ( 111 In-DOTA-TOC) to cells derived from differentiated thyroid cancer (DTC). Second, we evaluated the value of somatostatin receptor (SSTR) scintigraphy with these radioligands, as compared with 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET), for the detection of tumour lesions in DTC patients. Binding of 111 In-DOTA-LAN and 111 In-DOTA-TOC to cells isolated from surgically removed thyroid tissue was evaluated in vitro by performing saturation and displacement studies. Eighteen DTC patients with elevated thyroglobulin (12 radioiodine-negative, six radioiodine-positive) were investigated with 111 In-DOTA-LAN, 111 In-DOTA-TOC and 18 F-FDG PET scans. Large numbers of SSTR binding sites for 111 In-DOTA-LAN and 111 In-DOTA-TOC were found on the cells investigated. Both SSTR radioligands exhibited a high binding affinity for these SSTR binding sites. 111 In-DOTA-LAN and 111 In-DOTA-TOC scintigraphy detected 37 and 33 lesions, respectively, in 17 (94%) patients each, whereas 18 F-FDG PET revealed 30 lesions in 15 (83%) patients. Uptake of both SSTR radioligands was found in several radioiodine-negative sites. No striking differences in lesion imaging by 111 In-DOTA-LAN and 111 In-DOTA-TOC were found. In both radioiodine-negative and radioiodine-positive patients, more lesions were SSTR-positive/ 18 F-FDG-negative than were 18 F-FDG-positive/SSTR-negative. Adding a SSTR scan with these radioligands to the diagnostic work-up increases the diagnostic capacity in DTC, and should be considered particularly in radioiodine-negative patients with elevated thyroglobulin levels. (orig.)

Tumour uptake of the radiolabelled somatostatin analogue [DOTA0,TYR3]octreotide is dependent on the peptide amount

International Nuclear Information System (INIS)

Jong, M. de; Breeman, W.A.P.; Bernard, B.F.; Gameren, A. van; Bruin, E. de; Bakker, W.H.; Van der Pluijm, M.E.; Krenning, E.P.; Visser, T.J.; Maecke, H.R.

1999-01-01

Radiolabelled tumour receptor-binding peptides can be used for in vivo scintigraphic imaging. Recently, the somatostatin analogue [Tyr 3 ]octreotide (d-Phe-c(Cys-Tyr-d-Trp-Lys-Thr-Cys)-Thr(ol)) was derivatized with the chelator DOTA (tetra-azacyclododecane-tetra-acetic acid), enabling stable radiolabelling with both the high-energy beta particle-emitter yttrium-90 and the Auger electron-emitter indium-111. The thus produced radiolabelled compounds are promising for peptide receptor radionuclide therapy. Our previous in vitro and in vivo (rat) experiments with these radiolabelled compounds showed favourable binding and biodistribution characteristics with high uptake and retention in the target organs. We also demonstrated receptor-specific, time- and temperature-dependent internalization of radiolabelled [DOTA 0 ,Tyr 3 ]octreotide in somatostatin receptor subtype 2 (sst 2 )-positive rat pancreatic tumour cell lines. In this study we have investigated the effects of differences in the amount of injected peptide on tissue distribution of 111 In-labelled [DOTA 0 ,Tyr 3 ]octreotide in normal, i.e. non-tumour-bearing, and CA20948 tumour-bearing rats. This was done in order to find the amount of peptide at which the highest uptake in target tissues is achieved, and thereby to increase the potential of radionuclide therapy while simultaneously ensuring the lowest possible radiotoxicity in normal organs. Uptake of radiolabelled [DOTA 0 ,Tyr 3 ]octreotide in sst 2 -positive organs showed different bell-shaped functions of the amount of injected peptide, being highest at 0.05 (adrenals), 0.05-0.1 (pituitary and stomach) and 0.25 (pancreas) μg. Uptake in the tumour was highest at 0.5 μg injected peptide. The highest uptake was found at peptide amounts that were lower than those reported for [ 111 In-DTPA 0 ]octreotide (d-Phe-c(Cys-Phe-d-Trp-Lys-Thr-Cys)-Thr(ol), DTPA = diethylene-triamine-penta-acetic acid), consistent with the higher receptor affinity of the first compound

Effect of Chelating Agents on the Stability of Nano-TiO2 Sol Particles for Sol-Gel Coating.

Science.gov (United States)

Maeng, Wan Young; Yoo, Mi

2015-11-01

Agglomeration of sol particles in a titanium alkoxide (tetrabutyl orthotitanate (TBOT), > 97%) solution during the hydrolysis and condensation steps makes the sol solution difficult to use for synthesizing homogeneous sol-gel coating. Here, we have investigated the effect of stabilizing agents (acetic acid and ethyl acetoacetate (EAcAc)) on the agglomeration of Ti alkoxide particles during hydrolysis and condensation in order to determine the optimized conditions for controlling the precipitation of TiO2 particles. The study was conducted at R(AC) ([acetic acid]/[TBOT]) = 0.1-5 and R(EAcAc)([EAcAc]/[TBOT]) = 0.05-0.65. We also studied the effects of a basic catalyst ethanolamine (ETA), water, and HCl on sol stability. The chelating ligands in the precursor sol were analyzed with FT-IR. The coating properties were examined by focused ion beam. The stabilizing agents (acetic acid and EAcAc) significantly influenced the agglomeration and precipitation of TBOT precursor particles during hydrolysis. As R(AC) and R(EAcAc) increased, the agglomeration remarkably decreased. The stability of the sol with acetic acid and EAcAc arises from the coordination of the chelating ligand to TBOT that hinders hydrolysis and condensation. A uniform fine coating (thickness: 30 nm) on stainless steel was obtained by using an optimized sol with R(AC) = 0.5 and R(EAcAc) = 0.65.

Molecular Evolution of the dotA Gene in Legionella pneumophila

OpenAIRE

Ko, Kwan Soo; Hong, Seong Karp; Lee, Hae Kyung; Park, Mi-Yeoun; Kook, Yoon-Hoh

2003-01-01

The molecular evolution of dotA, which is related to the virulence of Legionella pneumophila, was investigated by comparing the sequences of 15 reference strains (serogroups 1 to 15). It was found that dotA has a complex mosaic structure. The whole dotA gene of Legionella pneumophila subsp. pneumophila serogroups 2, 6, and 12 has been transferred from Legionella pneumophila subsp. fraseri. A discrepancy was found between the trees inferred from the nucleotide and deduced amino acid sequences ...

Structural Characterization of Am(III)- and Pu(III)-DOTA Complexes.

Science.gov (United States)

Audras, Matthieu; Berthon, Laurence; Berthon, Claude; Guillaumont, Dominique; Dumas, Thomas; Illy, Marie-Claire; Martin, Nicolas; Zilbermann, Israel; Moiseev, Yulia; Ben-Eliyahu, Yeshayahu; Bettelheim, Armand; Cammelli, Sebastiano; Hennig, Christoph; Moisy, Philippe

2017-10-16

The complexation of 1,4,7,10-tetrazacyclodecane-1,4,7,10-tetraacetic acid (DOTA) ligand with two trivalent actinides (Am 3+ and Pu 3+ ) was investigated by UV-visible spectrophotometry, NMR spectroscopy, and extended X-ray absorption fine structure in conjunction with computational methods. The complexation process of these two cations is similar to what has been previously observed with lanthanides(III) of similar ionic radius. The complexation takes place in different steps and ends with the formation of a (1:1) complex [(An(III)DOTA)(H 2 O)] - , where the cation is bonded to the nitrogen atoms of the ring, the four carboxylate arms, and a water molecule to complete the coordination sphere. The formation of An(III)-DOTA complexes is faster than the Ln(III)-DOTA systems of equivalent ionic radius. Furthermore, it is found that An-N distances are slightly shorter than Ln-N distances. Theoretical calculations showed that the slightly higher affinity of DOTA toward Am over Nd is correlated with slightly enhanced ligand-to-metal charge donation arising from oxygen and nitrogen atoms.

Chelation: Harnessing and Enhancing Heavy Metal Detoxification—A Review

Directory of Open Access Journals (Sweden)

Margaret E. Sears

2013-01-01

Full Text Available Toxic metals such as arsenic, cadmium, lead, and mercury are ubiquitous, have no beneficial role in human homeostasis, and contribute to noncommunicable chronic diseases. While novel drug targets for chronic disease are eagerly sought, potentially helpful agents that aid in detoxification of toxic elements, chelators, have largely been restricted to overt acute poisoning. Chelation, that is multiple coordination bonds between organic molecules and metals, is very common in the body and at the heart of enzymes with a metal cofactor such as copper or zinc. Peptides glutathione and metallothionein chelate both essential and toxic elements as they are sequestered, transported, and excreted. Enhancing natural chelation detoxification pathways, as well as use of pharmaceutical chelators against heavy metals are reviewed. Historical adverse outcomes with chelators, lessons learned in the art of using them, and successes using chelation to ameliorate renal, cardiovascular, and neurological conditions highlight the need for renewed attention to simple, safe, inexpensive interventions that offer potential to stem the tide of debilitating, expensive chronic disease.

Deaths associated with hypocalcemia from chelation therapy--Texas, Pennsylvania, and Oregon, 2003-2005.

Science.gov (United States)

2006-03-03

Chelating agents bind lead in soft tissues and are used in the treatment of lead poisoning to enhance urinary and biliary excretion of lead, thus decreasing total lead levels in the body. During the past 30 years, environmental and dietary exposures to lead have decreased substantially, resulting in a considerable decrease in population blood lead levels (BLLs) and a corresponding decrease in the number of patients requiring chelation therapy. Chelating agents also increase excretion of other heavy metals and minerals, such as zinc and, in certain cases, calcium. This report describes three deaths associated with chelation-therapy--related hypocalcemia that resulted in cardiac arrest. Several drugs are used in the treatment of lead poisoning, including edetate disodium calcium (CaEDTA), dimercaperol (British anti-Lewisite), D-penicillamine, and meso-2,3-dimercaptosuccinic acid (succimer). Health-care providers who are unfamiliar with chelating agents and are considering this treatment for lead poisoning should consult an expert in the chemotherapy of lead poisoning. Hospital pharmacies should evaluate whether continued stocking of Na2EDTA is necessary, given the established risk for hypocalcemia, the availability of less toxic alternatives, and an ongoing safety review by the Food and Drug Administration (FDA). Health-care providers and pharmacists should ensure that Na2EDTA is not administered to children during chelation therapy.

Comparison of effectiveness of four chelating agents in removing incorporated sup 241 Am

Energy Technology Data Exchange (ETDEWEB)

Mingyue, Lun; Yumin, Wang; Zhikang, Wei [Ministry of Nuclear Industry, Taiyuan, SX (China). Inst. of Radiation Protection; and others

1988-02-01

The effectiveness of four chelating agents (Ca-DTPA, Zn-DTPA, quinamic acid and H-73-10) in removing incorporated {sup 241}Am was studied on 200 rats. The results show that Ca-DTPA and Zn-DTPA are more effective than the others. They decreased the {sup 241}Am contents in the rat liver and skeleton down to only about 5 and 10 per cent of the control values, respectively. Quinamic acid has the same effectiveness in reducing the {sup 241}Am contents in the rat skeleton and liver as that of DTPA, but it leads to the cumulation of {sup 241}Am in the kidney, i. e., the {sup 241}Am content in the kidney is even higher than that in control rats. Although H-73-10 can remove {sup 241}Am from the rat organs, it is much less effective than DTPA.

N-Acetyl-Cysteine as Effective and Safe Chelating Agent in Metal-on-Metal Hip-Implanted Patients: Two Cases

Directory of Open Access Journals (Sweden)

Andrea Giampreti

2016-01-01

Full Text Available Systemic toxicity associated with cobalt (Co and chromium (Cr containing metal hip alloy may result in neuropathy, cardiomyopathy, and hypothyroidism. However clinical management concerning chelating therapy is still debated in literature. Here are described two metal-on-metal hip-implanted patients in which N-acetyl-cysteine decreased elevated blood metal levels. A 67-year-old male who underwent Co/Cr hip implant in September 2009 referred to our Poison Control Centre for persisting elevated Co/Cr blood levels (from March 2012 to November 2014. After receiving oral high-dose N-acetyl-cysteine, Co/Cr blood concentrations dropped by 86% and 87% of the prechelation levels, respectively, and persisted at these latter concentrations during the following 6 months of follow-up. An 81-year-old female who underwent Co/Cr hip implant in January 2007 referred to our Centre for detection of high Co and Cr blood levels in June 2012. No hip revision was indicated. After a therapy with oral high-dose N-acetyl-cysteine Co/Cr blood concentrations decreased of 45% and 24% of the prechelation levels. Chelating agents reported in hip-implanted patients (EDTA, DMPS, and BAL are described in few cases. N-acetyl-cysteine may provide chelating sites for metals and in our cases reduced Co and Cr blood levels and resulted well tolerable.

f-Element Ion Chelation in Highly Basic Media - Final Report

International Nuclear Information System (INIS)

Paine, R.T.

2000-01-01

A large body of data has been collected over the last fifty years on the chemical behavior of f-element ions. The ions undergo rapid hydrolysis reactions in neutral or basic aqueous solutions that produce poorly understood oxide-hydroxide species; therefore, most of the fundamental f-element solution chemistry has allowed synthetic and separations chemists to rationally design advanced organic chelating ligands useful for highly selective partitioning and separation of f-element ions from complex acidic solution matrices. These ligands and new examples under development allow for the safe use and treatment of solutions containing highly radioactive species. This DOE/EMSP project was undertaken to address the following fundamental objectives: (1) study the chemical speciation of Sr and lanthanide (Ln) ions in basic aqueous media containing classical counter anions found in waste matrices; (2) prepare pyridine N-oxide phosphonates and phosphonic acids that might act as selective chelator s for Ln ions in model basic pH waste streams; (3) study the binding of the new chelators toward Ln ions and (4) examine the utility of the chelators as decontamination and dissolution agents under basic solution conditions. The project has been successful in attacking selected aspects of the very difficult problems associated with basic pH solution f-element waste chemistry. In particular, the project has (1) shed additional light on the initial stages of Ln ion sol-gel-precipitate formulation under basic solution conditions; (2) generated new families of pyridine phosphonic acid chelators; (3) characterized the function of the chelators and (4) examined their utility as oxide-hydroxide dissolution agents. These findings have contributed significantly to an improved understanding of the behavior of Ln ions in basic media containing anions found in typical waste sludges as well as to the development of sludge dissolution agents. The new chelating reagents are easily made and could be

Mixed and chelated waste test programs with bitumen solidification

International Nuclear Information System (INIS)

Simpson, S.I.; Morris, M.; Vidal, H.

1988-01-01

This paper presents the results of bitumen solidification tests on mixed wastes and chelated wastes. The French Atomic Energy Commission (CEA) performed demonstration tests on radioactive wastes contaminated with chelating agents for Associated Technologies, Inc. (ATI). The chelated wastes were produced and concentrated by Commonwealth Edison Co. as a result of reactor decontamination at Dresden Nuclear Station, Unit 1. Law Engineering in Charlotte, N. C. produced samples and performed tests on simulated heavy metal laden radioactive waste (mixed) to demonstrate the quality of the bituminous product. The simulation is intended to represent waste produced at Oak Ridge National Labs operated by Martin-Marietta

Color stabilization of porcine hemoglobin during spray-drying and powder storage by combining chelating and reducing agents.

Science.gov (United States)

Salvador, P; Toldrà, M; Parés, D; Carretero, C; Saguer, E

2009-10-01

This work focuses on the effects of adding a chelating agent - such as nicotinic acid (NA, 2% w/v) or nicotinamide (Nam, 2.5% w/v) - along with glucose as a reducing agent (G, 10% w/v) to fresh porcine hemoglobin in order to stabilize its red color during spray-drying and powder storage at room temperature. Correlations between the CIELAB color parameters and the relative percentages of the different hemoglobin derivatives (liganded and deliganded ferrohemoglobin, and methemoglobin) were analyzed. The results indicate that, although little effects could be observed for any of the combined treatments on fresh hemoglobin, they were effective against pigment autoxidation during dehydration and subsequent storage. From the results, it can also be concluded that glucose was the main contributor to the color stabilization of the hemoglobin powder, probably due to its high water retention capacity.

Chemistry of bifunctional photoprobes. 3 -- Correlation between the efficiency of CH insertion by photolabile chelating agents and lifetimes of singlet nitrenes by flash photolysis: First example of photochemical attachment of 99mTc-complex with human serum albumin

International Nuclear Information System (INIS)

Pandurangi, R.S.; Lusiak, P.; Kuntz, R.R.; Volkert, W.A.; Rogowski, J.; Platz, M.S.

1998-01-01

Systematic functionalization of perfluoroaryl azides with chelating agents capable of complexing transition metals produces a new class of bifunctional photolabile chelating agents (BFPCAs). The strategy is shield the azide functionality from the electronic and steric influence of the electron-rich metal Pd through ester and amide bridges raised CH insertion efficiency to unprecedented levels (>92%) in a model solvent (cyclohexane). In contrast, perfluoroaryl azides attached to chelating agents via hydrazones show no significant CH insertion in cyclohexane upon photolysis. Measurements of the lifetimes of the singlet nitrenes derived from these agents by flash photolysis techniques correlate well with the efficiency of CH insertion by demonstrating longer lifetimes (10--50 times) for singlet nitrenes derived from azidotetrafluorinated esters and amides compared with the related hydrazones, which failed to yield significant CH insertion. A representative BFPCA 12 is chelated to diagnostic radionuclide 99m Tc and covalently attached to human serum albumin via photochemical activation extending the favorable bimolecular insertion characteristics of BFPCA to tracer level concentrations in buffer conditions. Flash photolysis experiments correlate singlet nitrene lifetimes with the efficiency of intermolecular insertion reactions. This work provides new photo-cross-linking technology, useful in radiodiagnostics and radiotherapy in nuclear medicine

Topology of Legionella pneumophila DotA: an inner membrane protein required for replication in macrophages.

OpenAIRE

Roy, C R; Isberg, R R

1997-01-01

The Legionella pneumophila dotA gene is required for intracellular growth of the bacterium in macrophages. In this study, a structure-function analysis of the DotA protein was conducted to elucidate the role of this protein in L. pneumophila pathogenesis. Translational fusions of dotA to the Escherichia coli phoA and lacZ genes indicated that DotA is an integral cytoplasmic membrane protein with eight membrane-spanning domains. DotA contains two large periplasmic domains of approximately 503 ...

A radiogallium-DOTA-based bivalent peptidic ligand targeting a chemokine receptor, CXCR4, for tumor imaging.

Science.gov (United States)

Sano, Kohei; Masuda, Ryo; Hisada, Hayato; Oishi, Shinya; Shimokawa, Kenta; Ono, Masahiro; Fujii, Nobutaka; Saji, Hideo; Mukai, Takahiro

2014-03-01

We have developed a novel radiogallium (Ga)-DOTA-based bivalent peptidic ligand targeting a chemokine receptor, CXCR4, for tumor imaging. A CXCR4 imaging probe with two CXCR4 antagonists (Ac-TZ14011) on Ga-DOTA core, Ga-DOTA-TZ2, was synthesized, and the affinity and binding to CXCR4 was evaluated in CXCR4 expressing cells in vitro. The affinity of Ga-DOTA-TZ2 for CXCR4 was 20-fold greater than the corresponding monovalent probe, Ga-DOTA-TZ1. (67)Ga-DOTA-TZ2 showed the significantly higher accumulation in CXCR4-expressing tumor cells compared with (67)Ga-DOTA-TZ1, suggesting the bivalent effect enhances its binding to CXCR4. The incorporation of two CXCR4 antagonists to Ga-DOTA could be effective in detecting CXCR4-expressing tumors. Copyright © 2014 Elsevier Ltd. All rights reserved.

[99mTc]Demotate 2 in the detection of sst2-positive tumours: a preclinical comparison with [111In]DOTA-tate

International Nuclear Information System (INIS)

Maina, Theodosia; Nock, Berthold A.; Cordopatis, Paul; Bernard, Bert F.; Breeman, Wout A.P.; Gameren, Arthur van; Berg, Ria van den; Krenning, Eric P.; Jong, Marion de; Reubi, Jean-Claude

2006-01-01

The aim of this study was to evaluate [ 99m Tc]Demotate 2 ([ 99m Tc-N 4 0-1 ,Asp 0 ,Tyr 3 ]octreotate) as a candidate for in vivo imaging of sst 2 -positive tumours and to compare it with [ 111 In]DOTA-tate ([ 111 In-DOTA 0 ,Tyr 3 ]octreotate). Labelling of Demotate 2 with 99m Tc was performed at room temperature using SnCl 2 as reductant in the presence of citrate at alkaline pH. Radiochemical analysis involved ITLC and HPLC methods. Peptide conjugate affinities for sst 2 were determined by receptor autoradiography on rat brain cortex sections using [DOTA 0 , 125 I-Tyr 3 ]octreotate as the radioligand. The affinity profile of Demotate 2 for human sst 1 -sst 5 was studied by receptor autoradiography in cell preparations using the universal somatostatin radioligand [ 125 I][Leu 8 ,(D)Trp 22 ,Tyr 25 ]somatostatin-28. The internalisation rates of [ 99m Tc]Demotate 2 and [ 111 In]DOTA-tate were compared in sst 2 -positive and -negative control cell lines. Biodistribution of radiopeptides was studied in male Lewis rats bearing CA20948 tumours. Peptide conjugates showed selectivity and a high affinity binding for sst 2 (Demotate 2 IC 50 =3.2 nM and DOTA-tate IC 50 =5.4 nM). [ 99m Tc]Demotate 2, like [ 111 In]DOTA-tate, internalised rapidly in all sst 2 -positive cells tested, but not in sst 2 -negative control cells. After injection in CA20948 tumour-bearing rats both radiopeptides showed high and specific uptake in the sst 2 -positive organs and in the implanted tumour and rapid excretion from non-target tissues via the kidneys. [ 99m Tc]Demotate 2, similarly to the known sst 2 -targeting agent [ 111 In]DOTA-tate, showed promising biological qualities for application in the scintigraphy of sst 2 -positive tumours. (orig.)

Are gadolinium contrast agents suitable for gadolinium neutron capture therapy?

Science.gov (United States)

De Stasio, Gelsomina; Rajesh, Deepika; Casalbore, Patrizia; Daniels, Matthew J; Erhardt, Robert J; Frazer, Bradley H; Wiese, Lisa M; Richter, Katherine L; Sonderegger, Brandon R; Gilbert, Benjamin; Schaub, Sebastien; Cannara, Rachel J; Crawford, John F; Gilles, Mary K; Tyliszczak, Tolek; Fowler, John F; Larocca, Luigi M; Howard, Steven P; Mercanti, Delio; Mehta, Minesh P; Pallini, Roberto

2005-06-01

Gadolinium neutron capture therapy (GdNCT) is a potential treatment for malignant tumors based on two steps: (1) injection of a tumor-specific (157)Gd compound; (2) tumor irradiation with thermal neutrons. The GdNC reaction can induce cell death provided that Gd is proximate to DNA. Here, we studied the nuclear uptake of Gd by glioblastoma (GBM) tumor cells after treatment with two Gd compounds commonly used for magnetic resonance imaging, to evaluate their potential as GdNCT agents. Using synchrotron X-ray spectromicroscopy, we analyzed the Gd distribution at the subcellular level in: (1) human cultured GBM cells exposed to Gd-DTPA or Gd-DOTA for 0-72 hours; (2) intracerebrally implanted C6 glioma tumors in rats injected with one or two doses of Gd-DOTA, and (3) tumor samples from GBM patients injected with Gd-DTPA. In cell cultures, Gd-DTPA and Gd-DOTA were found in 84% and 56% of the cell nuclei, respectively. In rat tumors, Gd penetrated the nuclei of 47% and 85% of the tumor cells, after single and double injection of Gd-DOTA, respectively. In contrast, in human GBM tumors 6.1% of the cell nuclei contained Gd-DTPA. Efficacy of Gd-DTPA and Gd-DOTA as GdNCT agents is predicted to be low, due to the insufficient number of tumor cell nuclei incorporating Gd. Although multiple administration schedules in vivo might induce Gd penetration into more tumor cell nuclei, a search for new Gd compounds with higher nuclear affinity is warranted before planning GdNCT in animal models or clinical trials.

Chelation studies involving decontamination of light lanthanides by polyaminopolycarboxylic

International Nuclear Information System (INIS)

Hassan, N.E.H.

1985-01-01

The present thesis constitutes chelation studies involving decontamination of light lanthanides, cobalt , and uranium with 2,2-bis-acryloyliminomethylene- acid (BAETA) using the spectrophotometric method. the work carried out aimed to clear up the effectiveness of BAETA as a decontaminating agent for radioactive nuclides from human body . the thesis includes a general introduction , outlines the aim of work and contains three main chapters . the results of the work are discussed at the end of the thesis. the first chapter deals with a comprehensive survey of the relevant literature. this includes the metabolism and toxicity of cerium, uranium, cobalt and Ln +3 elements, general methodologies of internal decontamination, choice and effectiveness of chelating agents

Breaking the Barrier to Slow Water Exchange Rates for Optimal Magnetic Resonance Detection of paraCEST Agents.

Science.gov (United States)

Fernando, W Shirangi; Martins, André F; Zhao, Piyu; Wu, Yunkou; Kiefer, Garry E; Platas-Iglesias, Carlos; Sherry, A Dean

2016-03-21

EuDOTA-tetraamide complexes as paraCEST agents offer an attractive platform for designing biological sensors and responsive agents. The early versions of these agents showed low sensitivity at temperature and power levels suitable for in vivo applications partly due to non-optimal water exchange rates. Here we report two new EuDOTA derivatives having glutamyl-phosphonate side arms that display the slowest water exchange rates of any other paraCEST agent reported so far. The advantages of such systems are demonstrated experimentally both in vitro and in vivo and DFT calculations were performed to help understand the physical-chemical reasons for this interesting behavior.

Tumor Targeting via Sialic Acid: [68Ga]DOTA-en-pba as a New Tool for Molecular Imaging of Cancer with PET.

Science.gov (United States)

Tsoukalas, Charalambos; Geninatti-Crich, Simonetta; Gaitanis, Anastasios; Tsotakos, Theodoros; Paravatou-Petsotas, Maria; Aime, Silvio; Jiménez-Juárez, Rogelio; Anagnostopoulos, Constantinos D; Djanashvili, Kristina; Bouziotis, Penelope

2018-02-20

The aim of this study was to demonstrate the potential of Ga-68-labeled macrocycle (DOTA-en-pba) conjugated with phenylboronic vector for tumor recognition by positron emission tomography (PET), based on targeting of the overexpressed sialic acid (Sia). The imaging reporter DOTA-en-pba was synthesized and labeled with Ga-68 at high efficiency. Cell binding assay on Mel-C and B16-F10 melanoma cells was used to evaluate melanin production and Sia overexpression to determine the best model for demonstrating the capability of [ 68 Ga]DOTA-en-pba to recognize tumors. The in vivo PET imaging was done with B16-F10 tumor-bearing SCID mice injected with [ 68 Ga]DOTA-en-pba intravenously. Tumor, blood, and urine metabolites were assessed to evaluate the presence of a targeting agent. The affinity of [ 68 Ga]DOTA-en-pba to Sia was demonstrated on B16-F10 melanoma cells, after the production of melanin as well as Sia overexpression was proved to be up to four times higher in this cell line compared to that in Mel-C cells. Biodistribution studies in B16-F10 tumor-bearing SCID mice showed blood clearance at the time points studied, while uptake in the tumor peaked at 60 min post-injection (6.36 ± 2.41 % ID/g). The acquired PET images were in accordance with the ex vivo biodistribution results. Metabolite assessment on tumor, blood, and urine samples showed that [ 68 Ga]DOTA-en-pba remains unmetabolized up to at least 60 min post-injection. Our work is the first attempt for in vivo imaging of cancer by targeting overexpression of sialic acid on cancer cells with a radiotracer in PET.

Radiopharmaceutical chelates and method of external imaging

International Nuclear Information System (INIS)

Loberg, M.D.; Callery, P.S.; Cooper, M.

1977-01-01

A chelate of technetium-99m, cobalt-57, gallium-67, gallium-68, indium-111 or indium-113m and a substituted iminodiacetic acid or an 8-hydroxyquinoline useful as a radiopharmaceutical external imaging agent. The invention also includes preparative methods therefor

New method for studying the efficiency of chelating agents of the polyamine acid series for internal decontamination; Methode nouvelle d'etude de l'efficacite des chelateurs de la serie des acides polyamines pour la decontamination interne

Energy Technology Data Exchange (ETDEWEB)

Lafuma, J; Nenot, J C; Morin, M [Commissariat a l' Energie Atomique, Fontenay-aux-Roses (France). Centre d' Etudes Nucleaires

1968-07-01

We followed the biological fate of a complex formed on one side with either a rare earth (cerium-144) or a transuranium element (plutonium-239), and on the other side with a chelating agent of the polyamino acid series (EDTA, BAETA, DTPA, TTHA). This method allowed to study: 1 - the in vivo stability of the various complexes and to compare them; 2 - the stability of the complexes as a function of the isotope - chelating agent weight relationships; 3 - the metabolism of the chelating agents resulting in stable complexes, i. e. DTPA and TTHA mainly. This simple method brought out the higher efficiency, of DTPA in chelating rare earths and plutonium and for therapeutic purposes. (authors) [French] La methode consiste a suivre le devenir biologique d'un complexe forme d'une part avec une terre rare (cerium 144) ou un transuranien (plutonium 239) et d'autre part avec un chelateur de la serie des acides polyamines (EDTA, BAETA, DTPA, TTHA). Elle permet d'etudier: 1 - la stabilite in vivo des differents complexes, de les comparer; 2 - la stabilite des complexes en fonction des rapports ponderaux isotope - chelateurs; 3 - le metabolisme des chelateurs formant des complexes stables, essentiellement DTPA et TTHA. Cette methode simple degage la suprematie du DTPA en ce qui concerne la chelation des terres rares et du plutonium, et son utilisation a des fins therapeutiques. (auteurs)

{sup 111}In-DOTA-dPhe{sup 1}-Tyr{sup 3}-octreotide, {sup 111}In-DOTA-lanreotide and {sup 67}Ga citrate scintigraphy for visualisation of extranodal marginal zone B-cell lymphoma of the MALT type: a comparative study

Energy Technology Data Exchange (ETDEWEB)

Li, Shuren; Kurtaran, Amir; Li, Mei; Traub-Weidinger, Tatjana; Kienast, Oskar [Department of Nuclear Medicine, University of Vienna, Waehringer Guertel 18-20, 1090, Vienna (Austria); Schima, Wolfgang [Department of Nuclear Medicine, University of Vienna, Waehringer Guertel 18-20, 1090, Vienna (Austria); Department of Radiodiagnostics, University of Vienna (Austria); Angelberger, Peter [Research Center Seibersdorf (Austria); Virgolini, Irene [Institute for Nuclear Medicine, Vienna Hospital Lainz (Austria); Ludwig-Boltzman Institute for Nuclear Medicine, Vienna (Austria); Raderer, Markus [Department of Internal Medicine I, Division of Oncology, University of Vienna (Austria); Dudczak, Robert [Department of Nuclear Medicine, University of Vienna, Waehringer Guertel 18-20, 1090, Vienna (Austria)

2003-08-01

Somatostatin receptor (SSTR) scintigraphy and gallium-67 citrate ({sup 67}Ga) scintigraphy have been used for visualisation of Hodgkin's lymphoma and non-Hodgkin's lymphoma. However, experience with B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type is very limited. The aim of this study was to prospectively compare the {sup 67}Ga scintigraphy results with those obtained by {sup 111}In-DOTA-dPhe{sup 1}-Tyr{sup 3}-octreotide ({sup 111}In-DOTA-TOCT) and {sup 111}In-DOTA-lanreotide ({sup 111}In-DOTA-LAN) scintigraphy in patients with proven MALT-type lymphoma. Comparative scintigraphic examinations using {sup 67}Ga, {sup 111}In-DOTA-TOCT and {sup 111}In-DOTA-LAN were performed in 18 patients (11 female and 7 male, median age 64{+-}15 years) with histologically verified MALT-type lymphomas of various origin. Planar and single-photon emission tomography imaging acquisitions were performed after injection of a mean dose of 185{+-}26 MBq {sup 67}Ga and 165{+-}20 MBq {sup 111}In-DOTA-TOCT or {sup 111}In-DOTA-LAN. All scintigraphic results were correlated with other conventional examinations including gastroscopy, colonoscopy, endosonoscopy, ophthalmologic investigation, CT of the thorax and abdomen and bone marrow biopsy. This comparative study showed that {sup 67}Ga scintigraphy found abnormalities in 10 of 16 patients (63%) and detected 18 of 31 clinically involved sites (58%), but was false positive in three patients. {sup 111}In-DOTA-TOCT found abnormalities in 9 of 15 patients (60%) and detected 15 of 27 clinical lesions (56%); it was false positive in two patients. {sup 111}In-DOTA-LAN scintigraphy showed abnormalities in 7 of 11 patients (64%) and found 12 of 22 clinical lesions (55%). False-positive {sup 111}In-DOTA-LAN scan results were found in two patients. For supra-diaphragmatic lesions, {sup 67}Ga scintigraphy detected 12 of 16 sites (75%). {sup 111}In-DOTA-TOCT scintigraphy revealed 7 of 15 lesions (47%). {sup 111}In-DOTA

44Sc-DOTA-BN[2-14]NH2 in comparison to 68Ga-DOTA-BN[2-14]NH2 in pre-clinical investigation. Is 44Sc a potential radionuclide for PET?

International Nuclear Information System (INIS)

Koumarianou, E.; Loktionova, N.S.; Fellner, M.; Roesch, F.; Thews, O.; Pawlak, D.; Archimandritis, S.C.; Mikolajczak, R.

2012-01-01

Aim: In the present study we demonstrate the in vitro and in vivo comparison of the 44 Sc and 68 Ga labeled DOTA-BN[2-14]NH 2 . 44 Sc is a positron emitter with a half life of 3.92 h. Hence it could be used for PET imaging with ligands requiring longer observation time than in the case of 68 Ga. Methods: The binding affinity of nat Sc-DOTA-BN[2-14]NH 2 and nat Ga-DOTA-BN[2-14]NH 2 to GRP receptors was studied in competition to [ 125 I-Tyr 4 ]-Bombesin in the human prostate cancer cell line PC-3. A preliminary biodistribution in normal rats was performed, while first microPET images were assessed in male Copenhagen rats bearing the androgen-independent Dunning R-3327-AT-1 prostate cancer tumor. Results: The affinity to GRP receptors in the PC-3 cell line was higher for nat Ga-DOTA-BN[2-14]NH 2 (IC 50 (nM)=0.85±0.06) than that of nat Sc-DOTA-BN[2-14]NH 2 (IC 50 (nM)=6.49±0.13). The internalization rate of 68 Ga labeled DOTA-BN[2-14]NH 2 was slower than that of 44 Sc, but their final internalization percents were comparable. 68 Ga-DOTA-BN[2-14]NH 2 was externalized faster than 44 Sc-DOTA-BN[2-14]NH 2 . The biodistribution of 44 Sc-DOTA-BN[2-14]NH 2 and 68 Ga-DOTA-BN[2-14]NH 2 in normal rats revealed a higher uptake in target organs and tissues of the first one while both excreted mainly through urinary tract. In microPET images both tracers were accumulated in the tumor with similar uptake patterns. Conclusions: Despite the differences in the receptor affinity both the 68 Ga- and the 44 Sc-labeled DOTA-BN[2-14]NH 2 tracers showed comparable distribution and similar time constants of uptake and elimination. Moreover no differences in tumor accumulation (neither in the overall uptake nor in the dynamics) were observed from the microPet imaging. From that perspective the use of either 44 Sc or 68 Ga for detecting tumors with GRP receptors is equivalent. - Highlights: ► In vitro and in vivo evaluation of 44 Sc- and 68 Ga-DOTA-BN[2-14]NH 2 in reference to published

Comparison and systematic optimization of synthetic protocols for DOTA-hydrazide generation

NARCIS (Netherlands)

Fuge, F.; Weiler, M.; Gaetjens, J.; Lammers, Twan Gerardus Gertudis Maria

2013-01-01

DOTA-based organometallic complexes are extensively used in functional and molecular imaging studies, as well as in radioimmunotherapy. DOTA forms thermodynamically stable and kinetically inert complexes with various different diagnostic and therapeutic metals, such as gadolinium, gallium, yttrium

Simple method for quantification of gadolinium magnetic resonance imaging contrast agents using ESR spectroscopy.

Science.gov (United States)

Takeshita, Keizo; Kinoshita, Shota; Okazaki, Shoko

2012-01-01

To develop an estimation method of gadolinium magnetic resonance imaging (MRI) contrast agents, the effect of concentration of Gd compounds on the ESR spectrum of nitroxyl radical was examined. A solution of either 4-oxo-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPONE) or 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPOL) was mixed with a solution of Gd compound and the ESR spectrum was recorded. Increased concentration of gadolinium-diethylenetriamine pentaacetic acid chelate (Gd-DTPA), an MRI contrast agent, increased the peak-to-peak line widths of ESR spectra of the nitroxyl radicals, in accordance with a decrease of their signal heights. A linear relationship was observed between concentration of Gd-DTPA and line width of ESR signal, up to approximately 50 mmol/L Gd-DTPA, with a high correlation coefficient. Response of TEMPONE was 1.4-times higher than that of TEMPOL as evaluated from the slopes of the lines. The response was slightly different among Gd compounds; the slopes of calibration curves for acua[N,N-bis[2-[(carboxymethyl)[(methylcarbamoyl)methyl]amino]ethyl]glycinato(3-)]gadolinium hydrate (Gd-DTPA-BMA) (6.22 μT·L/mmol) and gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid chelate (Gd-DOTA) (6.62 μT·L/mmol) were steeper than the slope for Gd-DTPA (5.45 μT·L/mmol), whereas the slope for gadolinium chloride (4.94 μT·L/mmol) was less steep than that for Gd-DTPA. This method is simple to apply. The results indicate that this method is useful for rough estimation of the concentration of Gd contrast agents if calibration is carried out with each standard compound. It was also found that the plot of the reciprocal square root of signal height against concentrations of contrast agents could be useful for the estimation if a constant volume of sample solution is taken and measured at the same position in the ESR cavity every time.

64Cu-DOTA-trastuzumab PET imaging in patients with HER2-positive breast cancer.

Science.gov (United States)

Tamura, Kenji; Kurihara, Hiroaki; Yonemori, Kan; Tsuda, Hitoshi; Suzuki, Junko; Kono, Yuzuru; Honda, Natsuki; Kodaira, Makoto; Yamamoto, Harukaze; Yunokawa, Mayu; Shimizu, Chikako; Hasegawa, Koki; Kanayama, Yousuke; Nozaki, Satoshi; Kinoshita, Takayuki; Wada, Yasuhiro; Tazawa, Shusaku; Takahashi, Kazuhiro; Watanabe, Yasuyoshi; Fujiwara, Yasuhiro

2013-11-01

The purpose of this study was to determine the safety, distribution, internal dosimetry, and initial human epidermal growth factor receptor 2 (HER2)-positive tumor images of (64)Cu-DOTA-trastuzumab in humans. PET was performed on 6 patients with primary or metastatic HER2-positive breast cancer at 1, 24, and 48 h after injection of approximately 130 MBq of the probe (64)Cu-DOTA-trastuzumab. Radioactivity data were collected from the blood, urine, and normal-tissue samples of these 6 patients, and the multiorgan biodistribution and internal dosimetry of the probe were evaluated. Safety data were collected for all the patients after the administration of (64)Cu-DOTA-trastuzumab and during the 1-wk follow-up period. According to our results, the best timing for the assessment of (64)Cu-DOTA-trastuzumab uptake by the tumor was 48 h after injection. Radiation exposure during (64)Cu-DOTA-trastuzumab PET was equivalent to that during conventional (18)F-FDG PET. The radioactivity in the blood was high, but uptake of (64)Cu-DOTA-trastuzumab in normal tissues was low. In 2 patients, (64)Cu-DOTA-trastuzumab PET showed brain metastases, indicative of blood-brain barrier disruptions. In 3 patients, (64)Cu-DOTA-trastuzumab PET imaging also revealed primary breast tumors at the lesion sites initially identified by CT. The findings of this study indicated that (64)Cu-DOTA-trastuzumab PET is feasible for the identification of HER2-positive lesions in patients with primary and metastatic breast cancer. The dosimetry and pharmacologic safety results were acceptable at the dose required for adequate PET imaging.

44Sc-DOTA-BN[2-14]NH2 in comparison to 68Ga-DOTA-BN[2-14]NH2 in pre-clinical investigation. Is 44Sc a potential radionuclide for PET?

Science.gov (United States)

Koumarianou, E; Loktionova, N S; Fellner, M; Roesch, F; Thews, O; Pawlak, D; Archimandritis, S C; Mikolajczak, R

2012-12-01

In the present study we demonstrate the in vitro and in vivo comparison of the (44)Sc and (68)Ga labeled DOTA-BN[2-14]NH(2). (44)Sc is a positron emitter with a half life of 3.92 h. Hence it could be used for PET imaging with ligands requiring longer observation time than in the case of (68)Ga. The binding affinity of (nat)Sc-DOTA-BN[2-14]NH(2) and (nat)Ga-DOTA-BN[2-14]NH(2) to GRP receptors was studied in competition to [(125)I-Tyr(4)]-Bombesin in the human prostate cancer cell line PC-3. A preliminary biodistribution in normal rats was performed, while first microPET images were assessed in male Copenhagen rats bearing the androgen-independent Dunning R-3327-AT-1 prostate cancer tumor. The affinity to GRP receptors in the PC-3 cell line was higher for (nat)Ga-DOTA-BN[2-14]NH(2) (IC(50)(nM)=0.85 ± 0.06) than that of (nat)Sc-DOTA-BN[2-14]NH(2) (IC(50) (nM)=6.49 ± 0.13). The internalization rate of (68)Ga labeled DOTA-BN[2-14]NH(2) was slower than that of (44)Sc, but their final internalization percents were comparable. (68)Ga-DOTA-BN[2-14]NH(2) was externalized faster than (44)Sc-DOTA-BN[2-14]NH(2). The biodistribution of (44)Sc-DOTA-BN[2-14]NH(2) and (68)Ga-DOTA-BN[2-14]NH(2) in normal rats revealed a higher uptake in target organs and tissues of the first one while both excreted mainly through urinary tract. In microPET images both tracers were accumulated in the tumor with similar uptake patterns. Despite the differences in the receptor affinity both the (68)Ga- and the (44)Sc-labeled DOTA-BN[2-14]NH(2) tracers showed comparable distribution and similar time constants of uptake and elimination. Moreover no differences in tumor accumulation (neither in the overall uptake nor in the dynamics) were observed from the microPet imaging. From that perspective the use of either (44)Sc or (68)Ga for detecting tumors with GRP receptors is equivalent. Copyright © 2012 Elsevier Ltd. All rights reserved.

Radiolabeling parameters of 177Lu-DOTA-RITUXIMAB

International Nuclear Information System (INIS)

Massicano, Adriana V.F.; Alcarde, Lais F.; Oliveira, Ricardo S.; Mengatti, Jair; Araujo, Elaine B. de

2013-01-01

Cancer treatment using radioimmunotherapy (RIT) has been the focus of much research in the last two decades. In RIT, a radioisotope is coupled to a monoclonal antibody (mAb) to form a tumor-specific target agent to improve the cytocidal effect of the mAbs. RIT allows the systemic delivery of radiation to disease target by mAbs while sparing normal tissues. Rituximab® (Mabthera - Roche) is a chimeric mouse-human monoclonal antibody; it selectively binds with high affinity to the CD20 antigen, a hydrophobic transmembrane protein, which is expressed on B-lymphocytes and in more than 90% of B cell non-Hodgkin's lymphomas (NHL). The conjugation and radiolabeling process involve special conditions of pH and temperature, long processes of manipulation and mixing. All this process can damage the antibody structure and compromise its clinical application. Therefore, these parameters must be largely studied. The aim of this work was to evaluate the best radiolabeling conditions of DOTA-rituximab. Briefly, 10 mg of antibody previously purified by ultrafiltration device was conjugated with DOTA-NHS-ester (Macrocyclics) in 50 fold molar excess. The reaction was conducted for 1 hour in phosphate buffer pH 8.0 and gently mixing at room temperature, remaining for 24 hours under refrigeration. The immunoconjugated was purified by size exclusion column and ultrafiltration device. The radiolabeled parameters studied were: immunoconjugated mass, activity of 177 LuCl 3 , reaction time, temperature and pH. The radiochemical purity of the preparations was determined using analysis by thin layer chromatography (TLC-SG plates). The best studied condition presented radiochemical purity above 95% and the integrity of antibody was preserved. (author)

Localization of Hidden Insulinomas with ⁶⁸Ga-DOTA-Exendin-4 PET/CT: A Pilot Study.

Science.gov (United States)

Antwi, Kwadwo; Fani, Melpomeni; Nicolas, Guillaume; Rottenburger, Christof; Heye, Tobias; Reubi, Jean Claude; Gloor, Beat; Christ, Emanuel; Wild, Damian

2015-07-01

(111)In-DOTA-exendin-4 SPECT/CT has been shown to be highly efficient in the detection of insulinomas. We aimed at determining whether novel PET/CT imaging with [Nle(14),Lys(40)(Ahx-DOTA-(68)Ga)NH2]exendin-4 ((68)Ga-DOTA-exendin-4) is feasible and sensitive in detecting benign insulinomas. (68)Ga-DOTA-exendin-4 PET/CT and (111)In-DOTA-exendin-4 SPECT/CT were performed in a randomized cross-over order on 5 patients with endogenous hyperinsulinemic hypoglycemia. The gold standard for comparison was the histologic diagnosis after surgery. In 4 patients histologic diagnosis confirmed a benign insulinoma, whereas one patient refused surgery despite a positive (68)Ga-DOTA-exendin-4 PET/CT scan. In 4 of 5 patients, previously performed conventional imaging (CT or MR imaging) was not able to localize the insulinoma. (68)Ga-DOTA-exendin-4 PET/CT correctly identified the insulinoma in 4 of 4 patients, whereas (111)In-DOTA-exendin-4 SPECT/CT correctly identified the insulinoma in only 2 of 4 patients. These preliminary data suggest that the use of (68)Ga-DOTA-exendin-4 PET/CT in detecting hidden insulinomas is feasible. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Photo-Fenton treatment of saccharin in a solar pilot compound parabolic collector: Use of olive mill wastewater as iron chelating agent, preliminary results.

Science.gov (United States)

Davididou, K; Chatzisymeon, E; Perez-Estrada, L; Oller, I; Malato, S

2018-03-14

The aim of this work was to investigate the treatment of the artificial sweetener saccharin (SAC) in a solar compound parabolic collector pilot plant by means of the photo-Fenton process at pH 2.8. Olive mill wastewater (OMW) was used as iron chelating agent to avoid acidification of water at pH 2.8. For comparative purposes, Ethylenediamine-N, N-disuccinic acid (EDDS), a well-studied iron chelator, was also employed at circumneutral pH. Degradation products formed along treatment were identified by LC-QTOF-MS analysis. Their degradation was associated with toxicity removal, evaluated by monitoring changes in the bioluminescence of Vibrio fischeri bacteria. Results showed that conventional photo-Fenton at pH 2.8 could easily degrade SAC and its intermediates yielding k, apparent reaction rate constant, in the range of 0.64-0.82 L kJ -1 , as well as, eliminate effluent's chronic toxicity. Both OMW and EDDS formed iron-complexes able to catalyse H 2 O 2 decomposition and generate HO. OMW yielded lower SAC oxidation rates (k = 0.05-0.1 L kJ -1 ) than EDDS (k = 2.21-7.88 L kJ -1 ) possibly due to its higher TOC contribution. However, the degradation rates were improved (k = 0.13 L kJ -1 ) by increasing OMW dilution in the reactant mixture. All in all, encouraging results were obtained by using OMW as iron chelating agent, thus rendering this approach promising towards the increase of process sustainability. Copyright © 2018 Elsevier B.V. All rights reserved.

Quantitative structure-property relationship (correlation analysis) of phosphonic acid-based chelates in design of MRI contrast agent.

Science.gov (United States)

Tiwari, Anjani K; Ojha, Himanshu; Kaul, Ankur; Dutta, Anupama; Srivastava, Pooja; Shukla, Gauri; Srivastava, Rakesh; Mishra, Anil K

2009-07-01

Nuclear magnetic resonance imaging is a very useful tool in modern medical diagnostics, especially when gadolinium (III)-based contrast agents are administered to the patient with the aim of increasing the image contrast between normal and diseased tissues. With the use of soft modelling techniques such as quantitative structure-activity relationship/quantitative structure-property relationship after a suitable description of their molecular structure, we have studied a series of phosphonic acid for designing new MRI contrast agent. Quantitative structure-property relationship studies with multiple linear regression analysis were applied to find correlation between different calculated molecular descriptors of the phosphonic acid-based chelating agent and their stability constants. The final quantitative structure-property relationship mathematical models were found as--quantitative structure-property relationship Model for phosphonic acid series (Model 1)--log K(ML) = {5.00243(+/-0.7102)}- MR {0.0263(+/-0.540)}n = 12 l r l = 0.942 s = 0.183 F = 99.165 quantitative structure-property relationship Model for phosphonic acid series (Model 2)--log K(ML) = {5.06280(+/-0.3418)}- MR {0.0252(+/- .198)}n = 12 l r l = 0.956 s = 0.186 F = 99.256.

Country report: Italy (Chinol). Pre-clinical evaluation of a new biotin-DOTA conjugate labeled with 90Y for application in pretargeting clinical protocols

International Nuclear Information System (INIS)

Chinol, Marco

2010-01-01

In the attempt to improve the therapeutic efficacy of radiolabeled mAbs in cancer radioimmunotherapy, various studies have examined the concept of tumor pretargeting. The so called three-step pretargeting technique, employing the avidin–biotin system, was applied in phase I-II clinical trials showing low toxicity and therapeutic efficacy. The final step of the pretargeting protocols consists in the systemic injection of radiolabeled biotin. The worldwide recognized “successful association” is between 90 Y and the tetraazamacrocycle DOTA chelator chemically bound to biotin. Improvements in the structure of the biotin-DOTA conjugate have been reported by our group following a novel approach which simplified the synthetic pattern by reducing the amide group to a methylene group, thus transforming the amide into a secondary amine without affecting the length of the biotin side arm. Preliminary in-vitro experiments, previously published by our group, indicated the potential of the new conjugate. Based on our previous experience with avidin-based pre-targeting followed 90 Y-DOTA-biotin in the locoregional treatment of peritoneal carcinomatosis and malignant glioma suggested that similar radionuclide therapy might be worth investigating as a partial replacement of external beam radiotherapy in breast cancer. We have developed IART® the Intra-operative Avidination for Radionuclide Therapy that relies on the avidin-biotin binding system. In fact, the “avidination” of the anatomical area of the tumor with native avidin, directly injected by the surgeon into and around the tumor bed, provides a target for the radiolabeled biotin intravenously (iv) injected one day later. In order to optimize the overall strategy, further efforts were needed to optimize the use of the labeled new biotin conjugate and to elucidate its chemical and biological properties. In the first 18 months of this CRP, the pre-clinical evaluation of this new reduced biotinamidohexylamine-DOTA

Self-assembled polymeric chelate nanoparticles as potential theranostic agents

Czech Academy of Sciences Publication Activity Database

Škodová, Michaela; Černoch, Peter; Štěpánek, Petr; Chánová, Eliška; Kučka, Jan; Kálalová, Zuzana; Kaňková, Dana; Hrubý, Martin

2012-01-01

Roč. 13, č. 18 (2012), s. 4244-4250 ISSN 1439-4235 R&D Projects: GA ČR GPP207/10/P054; GA ČR GA202/09/2078; GA ČR GAP304/12/0950 Institutional research plan: CEZ:AV0Z40500505 Institutional support: RVO:61389013 Keywords : chelate s * nanoparticles * polymers Subject RIV: CD - Macromolecular Chemistry Impact factor: 3.349, year: 2012

The use of chelating agents in the remediation of metal-contaminated soils: A review

Energy Technology Data Exchange (ETDEWEB)

Lestan, Domen [Agronomy Department, Centre for Soil and Environmental Science, Biotechnical Faculty, University of Ljubljana, Jamnikarjeva 101, 1000 Ljubljana (Slovenia); Luo Chunling [Department of Civil and Structural Engineering, Hong Kong Polytechnic University, Hung Hom, Kowloon (Hong Kong); Li Xiangdong [Department of Civil and Structural Engineering, Hong Kong Polytechnic University, Hung Hom, Kowloon (Hong Kong)], E-mail: cexdli@polyu.edu.hk

2008-05-15

This paper reviews current remediation technologies that use chelating agents for the mobilization and removal of potentially toxic metals from contaminated soils. These processes can be done in situ as enhanced phytoextraction, chelant enhanced electrokinetic extraction and soil flushing, or ex situ as the extraction of soil slurry and soil heap/column leaching. Current proposals on how to treat and recycle waste washing solutions after soil is washed are discussed. The major controlling factors in phytoextraction and possible strategies for reducing the leaching of metals associated with the application of chelants are also reviewed. Finally, the possible impact of abiotic and biotic soil factors on the toxicity of metals left after the washing of soil and enhanced phytoextraction are briefly addressed. - The use of synthetic chelants for soil washing and enhanced phytoextraction by plants has been well studied for the remediation of metal-contaminated soils in the last two decades.

The use of chelating agents in the remediation of metal-contaminated soils: A review

International Nuclear Information System (INIS)

Lestan, Domen; Luo Chunling; Li Xiangdong

2008-01-01

This paper reviews current remediation technologies that use chelating agents for the mobilization and removal of potentially toxic metals from contaminated soils. These processes can be done in situ as enhanced phytoextraction, chelant enhanced electrokinetic extraction and soil flushing, or ex situ as the extraction of soil slurry and soil heap/column leaching. Current proposals on how to treat and recycle waste washing solutions after soil is washed are discussed. The major controlling factors in phytoextraction and possible strategies for reducing the leaching of metals associated with the application of chelants are also reviewed. Finally, the possible impact of abiotic and biotic soil factors on the toxicity of metals left after the washing of soil and enhanced phytoextraction are briefly addressed. - The use of synthetic chelants for soil washing and enhanced phytoextraction by plants has been well studied for the remediation of metal-contaminated soils in the last two decades

Simultaneous Determination of Chelating Agents by Ion-Suppression and Ion-Pair Chromatography in Wastewater

International Nuclear Information System (INIS)

Dodi, Alain; Bouscarel, Maelle

2008-01-01

This article describes two methods for analysing chelating agents found in nuclear waste. First, ion-suppression chromatography using an anion exchange stationary phase and mobile phase consisting of a nitric acid solution and pure water gradient. UV detection was performed at 330 nm after the reaction with a post-column reagent composed of iron nitrate in perchloric acid. Secondly, ion-pair chromatography with a mobile phase consisting of a mixture of nitric acid, tetra-butyl-ammonium hydrogeno-sulphate, tetra-butyl-ammonium hydroxide and iron chloride. A reversed-phase material was used as a stationary phase and detection was performed by direct measurement of the UV absorption at 260 nm. The quantification limits were lower for ion-pair chromatography than for ion-suppression chromatography. Both methods were easy to implement and allow a multi-element separation in less than 30 min with low detection limits. (authors)

Simultaneous Determination of Chelating Agents by Ion-Suppression and Ion-Pair Chromatography in Wastewater

Energy Technology Data Exchange (ETDEWEB)

Dodi, Alain; Bouscarel, Maelle [Commissariat a l' energie atomique - C.E.A, Centre d' Etude de Cadarache, Laboratoire d' Analyses Radiochimiques et Chimiques, St Paul lez Durance (France)

2008-07-01

This article describes two methods for analysing chelating agents found in nuclear waste. First, ion-suppression chromatography using an anion exchange stationary phase and mobile phase consisting of a nitric acid solution and pure water gradient. UV detection was performed at 330 nm after the reaction with a post-column reagent composed of iron nitrate in perchloric acid. Secondly, ion-pair chromatography with a mobile phase consisting of a mixture of nitric acid, tetra-butyl-ammonium hydrogeno-sulphate, tetra-butyl-ammonium hydroxide and iron chloride. A reversed-phase material was used as a stationary phase and detection was performed by direct measurement of the UV absorption at 260 nm. The quantification limits were lower for ion-pair chromatography than for ion-suppression chromatography. Both methods were easy to implement and allow a multi-element separation in less than 30 min with low detection limits. (authors)

Neuroendocrine tumor imaging with 68Ga-DOTA-NOC: physiologic and benign variants.

Science.gov (United States)

Kagna, Olga; Pirmisashvili, Natalia; Tshori, Sagi; Freedman, Nanette; Israel, Ora; Krausz, Yodphat

2014-12-01

Imaging with (68)Ga-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotide analogs has become an important modality in patients with neuroendocrine tumors (NETs). In addition to high uptake in NET lesions, prominent physiologic radiotracer activity has been reported in the pituitary gland, pancreas, adrenal glands, liver, and spleen, and faint activity has been reported in the thyroid and gastrointestinal tract. This article describes previously unknown sites of 68Ga-DOTA-1-NaI3-octreotide (NOC) uptake unrelated to NETs. One hundred eighty-two patients (96 female and 86 male patients; age range, 4-89 years) with documented (n=156) or suspected (n=26) NETs underwent 207 68Ga-DOTA-NOC PET/CT studies. Studies were retrospectively reviewed for the presence, intensity, and localization of foci of increased uptake that were further correlated with findings on additional imaging studies and clinical follow-up for a period of 4-32 months. Uptake of 68Ga-DOTA-NOC not identified as NET or known physiologic activity was detected in 297 sites with confirmation in 149 of 207 studies (72%). The most common location of non-NET-related 68Ga-DOTA-NOC-avid sites was in small lymph nodes, followed by prostate, uterus, breasts, lungs, brown fat, musculoskeletal system, and other sites, including oropharynx, pineal body, thymus, aortic plaque, genitalia, surgical bed, and subcutaneous granuloma. Intensity of uptake in non-NET-related 68Ga-DOTA-NOC-avid sites ranged in maximum standardized uptake value from 0.8 to 10.5. Previously unreported benign sites of 68Ga-DOTA-NOC uptake were found in the majority of studies, suggesting the presence of somatostatin receptors in physiologic variants or processes with no evidence of tumor. Knowledge of increased tracer uptake in non-NET-related sites is important for accurate interpretation and for avoiding potential pitfalls of 68Ga-DOTA-NOC PET/CT.

New method for studying the efficiency of chelating agents of the polyamine acid series for internal decontamination; Methode nouvelle d'etude de l'efficacite des chelateurs de la serie des acides polyamines pour la decontamination interne

Energy Technology Data Exchange (ETDEWEB)

Lafuma, J.; Nenot, J.C.; Morin, M. [Commissariat a l' Energie Atomique, Fontenay-aux-Roses (France). Centre d' Etudes Nucleaires

1968-07-01

We followed the biological fate of a complex formed on one side with either a rare earth (cerium-144) or a transuranium element (plutonium-239), and on the other side with a chelating agent of the polyamino acid series (EDTA, BAETA, DTPA, TTHA). This method allowed to study: 1 - the in vivo stability of the various complexes and to compare them; 2 - the stability of the complexes as a function of the isotope - chelating agent weight relationships; 3 - the metabolism of the chelating agents resulting in stable complexes, i. e. DTPA and TTHA mainly. This simple method brought out the higher efficiency, of DTPA in chelating rare earths and plutonium and for therapeutic purposes. (authors) [French] La methode consiste a suivre le devenir biologique d'un complexe forme d'une part avec une terre rare (cerium 144) ou un transuranien (plutonium 239) et d'autre part avec un chelateur de la serie des acides polyamines (EDTA, BAETA, DTPA, TTHA). Elle permet d'etudier: 1 - la stabilite in vivo des differents complexes, de les comparer; 2 - la stabilite des complexes en fonction des rapports ponderaux isotope - chelateurs; 3 - le metabolisme des chelateurs formant des complexes stables, essentiellement DTPA et TTHA. Cette methode simple degage la suprematie du DTPA en ce qui concerne la chelation des terres rares et du plutonium, et son utilisation a des fins therapeutiques. (auteurs)

Value of {sup 111}In-DOTA-lanreotide and {sup 111}In-DOTA-DPhe{sup 1}-Tyr{sup 3}-octreotide in differentiated thyroid cancer: results of in vitro binding studies and in vivo comparison with {sup 18}F-FDG PET

Energy Technology Data Exchange (ETDEWEB)

Rodrigues, Margarida; Virgolini, Irene [Lainz Hospital, Institute of Nuclear Medicine, Vienna (Austria); University Clinic for Nuclear Medicine, Innsbruck (Austria); Traub-Weidinger, Tatjana [University Clinic for Nuclear Medicine, Innsbruck (Austria); University Hospital, Department of Nuclear Medicine, Vienna (Austria); Leimer, Maria; Li, Shuren; Dudczak, Robert [University Hospital, Department of Nuclear Medicine, Vienna (Austria); Andreae, Fritz [University Clinic for Nuclear Medicine, Innsbruck (Austria); Angelberger, Peter [Austrian Research Center, Department of Radiochemistry, Seibersdorf (Austria)

2005-10-01

Radioiodine-negative thyroid cancer presents diagnostic and therapeutic difficulties, warranting the implementation of new imaging and treatment strategies. The purpose of this study was twofold. First, we investigated in vitro the binding characteristics of {sup 111}In-DOTA-lanreotide ({sup 111}In-DOTA-LAN) and {sup 111}In-DOTA-DPhe{sup 1}-Tyr{sup 3}-octreotide ({sup 111}In-DOTA-TOC) to cells derived from differentiated thyroid cancer (DTC). Second, we evaluated the value of somatostatin receptor (SSTR) scintigraphy with these radioligands, as compared with {sup 18}F-fluorodeoxyglucose (FDG) positron emission tomography (PET), for the detection of tumour lesions in DTC patients. Binding of {sup 111}In-DOTA-LAN and {sup 111}In-DOTA-TOC to cells isolated from surgically removed thyroid tissue was evaluated in vitro by performing saturation and displacement studies. Eighteen DTC patients with elevated thyroglobulin (12 radioiodine-negative, six radioiodine-positive) were investigated with {sup 111}In-DOTA-LAN, {sup 111}In-DOTA-TOC and {sup 18}F-FDG PET scans. Large numbers of SSTR binding sites for {sup 111}In-DOTA-LAN and {sup 111}In-DOTA-TOC were found on the cells investigated. Both SSTR radioligands exhibited a high binding affinity for these SSTR binding sites. {sup 111}In-DOTA-LAN and {sup 111}In-DOTA-TOC scintigraphy detected 37 and 33 lesions, respectively, in 17 (94%) patients each, whereas {sup 18}F-FDG PET revealed 30 lesions in 15 (83%) patients. Uptake of both SSTR radioligands was found in several radioiodine-negative sites. No striking differences in lesion imaging by {sup 111}In-DOTA-LAN and {sup 111}In-DOTA-TOC were found. In both radioiodine-negative and radioiodine-positive patients, more lesions were SSTR-positive/{sup 18}F-FDG-negative than were {sup 18}F-FDG-positive/SSTR-negative. Adding a SSTR scan with these radioligands to the diagnostic work-up increases the diagnostic capacity in DTC, and should be considered particularly in radioiodine

Gallium-68-DOTA-albumin as a PET blood-pool marker: experimental evaluation in vivo

International Nuclear Information System (INIS)

Hoffend, Johannes; Mier, Walter; Schuhmacher, Jochen; Schmidt, Kerstin; Dimitrakopoulou-Strauss, Antonia; Strauss, Ludwig G.; Eisenhut, Michael; Kinscherf, Ralf; Haberkorn, Uwe

2005-01-01

Investigations into tumor angiogenesis and antiangiogenic treatment have renewed interest in tumor perfusion. To image tumor blood-pool by PET, suitable tracers are not generally available. In this experimental study, we characterized a 68 Ga-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) conjugate of rat serum albumin ( 68 Ga-DOTA-RSA) in vivo using a generator-produced isotope. Biodistribution was determined in ACI rats after intravenous administration of 3-6 MBq of 68 Ga-DOTA-RSA. Three ACI rats were imaged over 1 h by dynamic PET after intravenous administration of 15-25 MBq of 68 Ga-DOTA-RSA while the blood-pool activity was recorded simultaneously in a closed extracorporeal loop (ECL) between the carotid artery and the jugular vein. Time-activity curves (TACs) were obtained from volume of interest (VOI) analysis and from the ECL data. Stability and metabolites in plasma and urine were analyzed by size exclusion HPLC (SE-HPLC) 1 h after intravenous injection of 67 Ga-DOTA-RSA. Blood radioactivity decreased by 10% and 18% from 10 to 60 min p.i. by biodistribution and PET or ECL, respectively. Tissue sampling between 10 and 60 min p.i. showed slight increases in the uptake of spleen, myocardium, kidney and skeletal muscle while hepatic accretion remained unchanged. Total urinary excretion after 60 min amounted to 9% of the injected dose. HPLC demonstrated a single urinary metabolite corresponding in size to gallium-labeled DOTA. 68 Ga-DOTA-RSA is a blood-pool tracer whose physical and biological half-life is well suited for PET. Our findings support clinical imaging using 68 Ga-DOTA-labeled human serum albumin (HSA). The generator-produced label makes 68 Ga-DOTA-labeled albumin continuously available even to centers lacking an in-house cyclotron

MR study of acute myocardial infarction with injection of Gd-DOTA (Fifteen patients)

International Nuclear Information System (INIS)

Richoz, B.; Delcour, C.; Depelchin, P.; Lenaers, A.; Jacquemin, C.; Gusella, P.; Struyven, J.; Richoz, B.

1990-01-01

We studied 15 patients 4 to 8 days after myocardial infarction by using ECG gated MR before and after administration of 0.2 mmol/kg Gd-DOTA. The diagnosis in each patient was confirmed by electrocardiographic criteria, elevated levels of fractionated creatine kinase (CK) isoenzyme, thallium scintigraphy, ventriculography and coronarography. T1-weighted, spin-echo images, were obtained before and immediately after injection of Gd-DOTA and were repeated 15 min later. The site of infarction was visualized in 10 patients as an area of high signal intensity after the injection of Gd-DOTA. Contrast between normal and infarcted myocardium was greatest 15 min after injection. Three patients were excluded because of failure to acquire adequate MR studies. In 2 other patients, the infarct were not detected. Before injection of Gd-DOTA, only 2 infarcts were detected. These results suggest that Gd-DOTA can improve MR visualization and detection of acute myocardial infarction [fr

Lutetium-177 complexation of DOTA and DTPA in the presence of competing metals

International Nuclear Information System (INIS)

Watanabe, Satoshi; Ishioka, Noriko S.; Hashimoto, Kazuyuki

2013-01-01

177 Lu complexation of DOTA and DTPA is investigated by the addition of Ca(II), Fe(II) and Zn(II). The 177 Lu complexation yield of DTPA was higher than that of DOTA in the presence of Ca(II), Fe(II) and Zn(II). Therefore, it was found that the 177 Lu complexation of DTPA was more advantageous compared with DOTA in the presence of competing metals, Ca, Fe and Zn. (author)

Country report: Italy (Chinol). Pre-clinical evaluation of a new biotin-DOTA conjugate labeled with {sup 90}Y for application in pretargeting clinical protocols

Energy Technology Data Exchange (ETDEWEB)

Chinol, Marco

2010-07-01

In the attempt to improve the therapeutic efficacy of radiolabeled mAbs in cancer radioimmunotherapy, various studies have examined the concept of tumor pretargeting. The so called three-step pretargeting technique, employing the avidin–biotin system, was applied in phase I-II clinical trials showing low toxicity and therapeutic efficacy. The final step of the pretargeting protocols consists in the systemic injection of radiolabeled biotin. The worldwide recognized “successful association” is between {sup 90}Y and the tetraazamacrocycle DOTA chelator chemically bound to biotin. Improvements in the structure of the biotin-DOTA conjugate have been reported by our group following a novel approach which simplified the synthetic pattern by reducing the amide group to a methylene group, thus transforming the amide into a secondary amine without affecting the length of the biotin side arm. Preliminary in-vitro experiments, previously published by our group, indicated the potential of the new conjugate. Based on our previous experience with avidin-based pre-targeting followed {sup 90}Y-DOTA-biotin in the locoregional treatment of peritoneal carcinomatosis and malignant glioma suggested that similar radionuclide therapy might be worth investigating as a partial replacement of external beam radiotherapy in breast cancer. We have developed IART® the Intra-operative Avidination for Radionuclide Therapy that relies on the avidin-biotin binding system. In fact, the “avidination” of the anatomical area of the tumor with native avidin, directly injected by the surgeon into and around the tumor bed, provides a target for the radiolabeled biotin intravenously (iv) injected one day later. In order to optimize the overall strategy, further efforts were needed to optimize the use of the labeled new biotin conjugate and to elucidate its chemical and biological properties. In the first 18 months of this CRP, the pre-clinical evaluation of this new reduced biotinamidohexylamine-DOTA

Evaluation of (68)Ga- and (177)Lu-DOTA-PEG4-LLP2A for VLA-4-Targeted PET Imaging and Treatment of Metastatic Melanoma.

Science.gov (United States)

Beaino, Wissam; Nedrow, Jessie R; Anderson, Carolyn J

2015-06-01

Malignant melanoma is a highly aggressive cancer, and the incidence of this disease is increasing worldwide at an alarming rate. Despite advances in the treatment of melanoma, patients with metastatic disease still have a poor prognosis and low survival rate. New strategies, including targeted radiotherapy, would provide options for patients who become resistant to therapies such as BRAF inhibitors. Very late antigen-4 (VLA-4) is expressed on melanoma tumor cells in higher levels in more aggressive and metastatic disease and may provide an ideal target for drug delivery and targeted radiotherapy. In this study, we evaluated (177)Lu- and (68)Ga-labeled DOTA-PEG4-LLP2A as a VLA-4-targeted radiotherapeutic with a companion PET agent for diagnosis and monitoring metastatic melanoma treatment. DOTA-PEG4-LLP2A was synthesized by solid-phase synthesis. The affinity of (177)Lu- and (68)Ga-labeled DOTA-PEG4-LLP2A to VLA-4 was determined in B16F10 melanoma cells by saturation binding and competitive binding assays, respectively. Biodistribution of the LLP2A conjugates was determined in C57BL/6 mice bearing B16F10 subcutaneous tumors, while PET/CT imaging was performed in subcutaneous and metastatic models. (177)Lu-DOTA-PEG4-LLP2A showed high affinity to VLA-4 with a Kd of 4.1 ± 1.5 nM and demonstrated significant accumulation in the B16F10 melanoma tumor after 4 h (31.5 ± 7.8%ID/g). The tumor/blood ratio of (177)Lu-DOTA-PEG4-LLP2A was highest at 24 h (185 ± 26). PET imaging of metastatic melanoma with (68)Ga-DOTA-PEG4-LLP2A showed high uptake in sites of metastases and correlated with bioluminescence imaging of the tumors. These data demonstrate that (177)Lu-DOTA-PEG4-LLP2A has potential as a targeted therapeutic for treating melanoma as well as other VLA-4-expressing tumors. In addition, (68)Ga-DOTA-PEG4-LLP2A is a readily translatable companion PET tracer for imaging of metastatic melanoma.

MULTIDENTATE TEREPHTHALAMIDATE AND HYDROXYPYRIDONATE LIGANDS: TOWARDS NEW ORALLY ACTIVE CHELATORS

Energy Technology Data Exchange (ETDEWEB)

Abergel, Rebecca J.; Raymond, Kenneth N.

2011-07-13

The limitations of current therapies for the treatment of iron overload or radioisotope contamination have stimulated efforts to develop new orally bioavailable iron and actinide chelators. Siderophore-inspired tetradentate, hexadentate and octadentate terephthalamidate and hydroxypyridonate ligands were evaluated in vivo as selective and efficacious iron or actinide chelating agents, with several metal loading and ligand assessment procedures, using {sup 59}Fe, {sup 238}Pu, and {sup 241}Am as radioactive tracers. The compounds presented in this study were compared to commercially available therapeutic sequestering agents [deferoxamine (DFO) for iron and diethylenetriaminepentaacetic acid (DPTA) for actinides] and are unrivaled in terms of affinity, selectivity and decorporation efficacy, which attests to the fact that high metal affinity may overcome the low bioavailability properties commonly associated to multidenticity.

68Ga-DOTA-RGD peptide: biodistribution and binding into atherosclerotic plaques in mice

International Nuclear Information System (INIS)

Haukkala, Johanna; Laitinen, Iina; Luoto, Pauliina; Knuuti, Juhani; Iveson, Peter; Wilson, Ian; Karlsen, Hege; Cuthbertson, Alan; Laine, Jukka; Leppaenen, Pia; Ylae-Herttula, Seppo; Roivainen, Anne

2009-01-01

Increased expression of αvβ3/αvβ5 integrin is involved in angiogenesis and the inflammatory process in atherosclerotic plaques. The novel 68 Ga-DOTA-RGD peptide binds with high affinity to αvβ3/αvβ5 integrin. The aim of this study was to investigate the uptake of the 68 Ga-DOTA-RGD peptide in atherosclerotic plaques. Uptake of intravenously administered 68 Ga-DOTA-RGD peptide was studied ex vivo in excised tissue samples and aortic sections of LDLR -/- ApoB 100/100 atherosclerotic mice. The uptake of the tracer in aortic cryosections was examined by using digital autoradiography. Subsequently, the autoradiographs were combined with histological and immunohistological analysis of the sections. DOTA-RGD peptide was successfully labelled with the generator-produced 68 Ga. The tracer had reasonably good specific radioactivity (8.7 ± 1.1 GBq/μmol) and was quite stable in vivo. According to ex vivo biodistribution results, 68 Ga-DOTA-RGD was cleared rapidly from the blood circulation and excreted through the kidneys to the urine with high radioactivity in the intestine, lungs, spleen and liver. Autoradiography results showed significantly higher uptake of 68 Ga-DOTA-RGD peptide in the atherosclerotic plaques compared to healthy vessel wall (mean ratio ± SD 1.4 ± 0.1, p = 0.0004). We observed that 68 Ga-DOTA-RGD is accumulated into the plaques of atherosclerotic mice. However, this data only shows the feasibility of the approach, while the clinical significance still remains to be proven. Further studies are warranted to assess the uptake of this tracer into human atherosclerotic plaques. (orig.)

Chelation therapy in intoxications with mercury, lead and copper

DEFF Research Database (Denmark)

Cao, yang; Skaug, Marit Aralt; Andersen, Ole

2015-01-01

In the present review we provide an update of the appropriate use of chelating agents in the treatment of intoxications with compounds of mercury, lead and copper. The relatively new chelators meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercapto-propanesulphonate (DMPS) can effectively...... mobilize deposits of mercury as well as of lead into the urine. These drugs can be administered orally and have relatively low toxicity compared to the classical antidote dimercaptopropanol (BAL). d-Penicillamine has been widely used in copper overload, although 2,3-dimercaptosuccinic acid...

Heavy metal displacement in chelate-irrigated soil during phytoremediation

Science.gov (United States)

Madrid, F.; Liphadzi, M. S.; Kirkham, M. B.

2003-03-01

Heavy metals in wastewater sewage sludge (biosolids), applied to land, contaminate soils. Phytoremediation, the use of plants to clean up toxic heavy metals, might remove them. Chelating agents are added to soil to solubilize the metals for enhanced phytoextraction. Yet no studies follow the displacement and leaching of heavy metals in soil with and without roots following solubilization with chelates. The objective of this work was to determine the mobility of heavy metals in biosolids applied to the surface of soil columns (76 cm long; 17 cm diam.) with or without plants (barley; Hordeum vulgare L.). Three weeks after barley was planted, all columns were irrigated with the disodium salt of the chelating agent, EDTA (ethylenediamine tetraacetic acid) (0.5 g/kg soil). Drainage water, soil, and plants were analyzed for heavy metals (Cd, Cu, Fe, Mn, Ni, Pb, Zn). Total concentrations of the heavy metals in all columns at the end of the experiment generally were lower in the top 30 cm of soil with EDTA than without EDTA. The chelate increased concentrations of heavy metals in shoots. With or without plants, the EDTA mobilized Cd, Fe, Mn, Ni, Pb, and Zn, which leached to drainage water. Drainage water from columns without EDTA had concentrations of these heavy metals below detection limits. Only Cu did not leach in the presence of EDTA. Even though roots retarded the movement of Cd, Fe, Mn, Ni, Pb, and Zn through the EDTA-treated soil from 1 d (Cd) to 5 d (Fe), the drainage water from columns with EDTA had concentrations of Cd, Fe, Mn, and Pb that exceeded drinking water standards by 1.3, 500, 620, and 8.6 times, respectively. Because the chelate rendered Cd, Fe, Mn, Ni, Pb, and Zn mobile, it is suggested that the theory for leaching of soluble salts, put forward by Nielsen and associates in 1965, could be applied to control movement of the heavy metals for maximum uptake during chelate-assisted phytoremediation.

An assessment tumor targeting ability of 177Lu labeled cyclic CCK analogue peptide by binding with cholecystokinin receptor

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Eun-Ha Cho

2016-07-01

Full Text Available The cholecystokinin (CCK receptor is known as a receptor that is overexpressed in many human tumors. The present study was designed to investigate the targeting ability of cyclic CCK analogue in AR42J pancreatic cells. The CCK analogues, DOTA-K(glucose-Gly-Trp-Nle-Asp-Phe (DOTA-glucose-CCK and DOTA-Nle-cyclo(Glu-Trp-Nle-Asp-Phe-Lys-NH2 (DOTA-[Nle]-cCCK, were synthesized and radiolabeled with 177Lu, and competitive binding was evaluated. The binding appearance of synthesized peptide with AR42J cells was evaluated by confocal microscopy. And bio-distribution was performed in AR42J xenografted mice. Synthesized peptides were prepared by a solid phase synthesis method, and their purity was over 98%. DOTA is the chelating agent for 177Lu-labeling, in which the peptides were radiolabeled with 177Lu by a high radiolabeling yield. A competitive displacement of 125I-CCK8 on the AR42J cells revealed that the 50% inhibitory concentration value (IC50 was 12.3 nM of DOTA-glucose-CCK and 1.7 nM of DOTA-[Nle]-cCCK. Radio-labeled peptides were accumulated in AR42J tumor in vivo, and %ID/g of the tumor was 0.4 and 0.9 at 2 h p.i. It was concluded that 177Lu-DOTA-[Nle]-cCCK has higher binding affinity than 177Lu-DOTA-glucose-CCK and can be a potential candidate as a targeting modality for a CCK receptor over-expressing tumors.

The experimental study on protective effects and mechanisms of chelating agents of catechols amino carboxylic acid for radiation injury induced by actimides(Th-234)

International Nuclear Information System (INIS)

Chen, H. H.; Luo, M. C.; Sun, M. Z.; Hu, Y. X.; Wang, Y. H.; Jin, M. Y.; Cheng, W. Y.

2002-01-01

The decorporative efficacy and antioxidative action of prompt and delayed consecutive administration of catecholicpolyaminopolycarboxylate ligands, 7601 and 9501 for radiothorium in mice were investigated. DTPA and Vitamin E were used as positive controls. The competitive abilities of 7601 and 9501 to mobilize the thorium with BSA were studied. Their inhibition effects on superoxide anionas radicals were measured with electron spin resonance. The results showed that 7601 and 9501 are able to effectively prevent the internal radiation injury induced radiothorium, attributing to their double functions of pronounced removal effectiveness and antioxidative action. Their protective effects were better than DTPA and Vitamin E. The mechanisms of protective effects of 7601 and 9501 for internal radiation injury was close related to competitive ability of chelating agent to chelate the thorium with BSA and oxygen free radical scavenging activities

Radiolabeling parameters of {sup 177}Lu-DOTA-RITUXIMAB

Energy Technology Data Exchange (ETDEWEB)

Massicano, Adriana V.F.; Alcarde, Lais F.; Oliveira, Ricardo S.; Mengatti, Jair; Araujo, Elaine B. de, E-mail: adriana.avfernandes@gmail.com [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

2013-07-01

Cancer treatment using radioimmunotherapy (RIT) has been the focus of much research in the last two decades. In RIT, a radioisotope is coupled to a monoclonal antibody (mAb) to form a tumor-specific target agent to improve the cytocidal effect of the mAbs. RIT allows the systemic delivery of radiation to disease target by mAbs while sparing normal tissues. Rituximab® (Mabthera - Roche) is a chimeric mouse-human monoclonal antibody; it selectively binds with high affinity to the CD20 antigen, a hydrophobic transmembrane protein, which is expressed on B-lymphocytes and in more than 90% of B cell non-Hodgkin's lymphomas (NHL). The conjugation and radiolabeling process involve special conditions of pH and temperature, long processes of manipulation and mixing. All this process can damage the antibody structure and compromise its clinical application. Therefore, these parameters must be largely studied. The aim of this work was to evaluate the best radiolabeling conditions of DOTA-rituximab. Briefly, 10 mg of antibody previously purified by ultrafiltration device was conjugated with DOTA-NHS-ester (Macrocyclics) in 50 fold molar excess. The reaction was conducted for 1 hour in phosphate buffer pH 8.0 and gently mixing at room temperature, remaining for 24 hours under refrigeration. The immunoconjugated was purified by size exclusion column and ultrafiltration device. The radiolabeled parameters studied were: immunoconjugated mass, activity of {sup 177}LuCl{sub 3}, reaction time, temperature and pH. The radiochemical purity of the preparations was determined using analysis by thin layer chromatography (TLC-SG plates). The best studied condition presented radiochemical purity above 95% and the integrity of antibody was preserved. (author)

Labeling of DOTA-conjugated HPMA-based polymers with trivalent metallic radionuclides for molecular imaging.

Science.gov (United States)

Eppard, Elisabeth; de la Fuente, Ana; Mohr, Nicole; Allmeroth, Mareli; Zentel, Rudolf; Miederer, Matthias; Pektor, Stefanie; Rösch, Frank

2018-02-27

In this work, the in vitro and in vivo stabilities and the pharmacology of HPMA-made homopolymers were studied by means of radiometal-labeled derivatives. Aiming to identify the fewer amount and the optimal DOTA-linker structure that provides quantitative labeling yields, diverse DOTA-linker systems were conjugated in different amounts to HPMA homopolymers to coordinate trivalent radiometals Me(III)* = gallium-68, scandium-44, and lutetium-177. Short linkers and as low as 1.6% DOTA were enough to obtain labeling yields > 90%. Alkoxy linkers generally exhibited lower labeling yields than alkane analogues despite of similar chain length and DOTA incorporation rate. High stability of the radiolabel in all examined solutions was observed for all conjugates. Labeling with scandium-44 allowed for in vivo PET imaging and ex vivo measurements of organ distribution for up to 24 h. This study confirms the principle applicability of DOTA-HPMA conjugates for labeling with different trivalent metallic radionuclides allowing for diagnosis and therapy.

[{sup 177}Lu]DOTA-anti-CD20: Labeling and pre-clinical studies

Energy Technology Data Exchange (ETDEWEB)

Audicio, Paola F., E-mail: paudicio@cin.edu.u [Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la Republica, Mataojo 2055, 11400 Montevideo (Uruguay); Castellano, Gustavo, E-mail: gcas@famaf.unc.edu.a [FaMAF, Universidad Nacional de Cordoba, Ciudad Universitaria, 5016 Cordoba (Argentina); Tassano, Marcos R.; Rezzano, Maria E.; Fernandez, Marcelo [Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la Republica, Mataojo 2055, 11400 Montevideo (Uruguay); Riva, Eloisa [Clinica Hematologica ' Prof. Dra. L. Diaz' , Hospital de Clinicas. Av. Italia. sn, Montevideo (Uruguay); Robles, Ana; Cabral, Pablo; Balter, Henia; Oliver, Patricia [Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la Republica, Mataojo 2055, 11400 Montevideo (Uruguay)

2011-07-15

Anti-CD20 (Rituximab), a specific chimeric monoclonal antibody used in CD20-positive Non-Hodgkin's Lymphoma, was conjugated to a bifunctional quelate (DOTA) and radiolabeled with {sup 177}Lu through a simple method. [{sup 177}Lu]-DOTA-anti-CD20 was obtained with a radiochemical purity higher than 97%, and showed good chemical and biological stability, maintaining its biospecificity to CD20 antigens. Monte Carlo simulation showed high doses deposited on a spheroid tumor mass model. This method seems to be an appropriate alternative for the production of [{sup 177}Lu]-DOTA-anti-CD20 as therapeutic radiopharmaceutical.

Correlation of Somatostatin Receptor-2 Expression with Gallium-68-DOTA-TATE Uptake in Neuroblastoma Xenograft Models

OpenAIRE

Zhang, Libo; Vines, Douglass C.; Scollard, Deborah A.; McKee, Trevor; Komal, Teesha; Ganguly, Milan; Do, Trevor; Wu, Bing; Alexander, Natasha; Vali, Reza; Shammas, Amer; Besanger, Travis; Baruchel, Sylvain

2017-01-01

Peptide-receptor imaging and therapy with radiolabeled somatostatin analogs such as 68Ga-DOTA-TATE and 177Lu-DOTA-TATE have become an effective treatment option for SSTR-positive neuroendocrine tumors. The purpose of this study was to evaluate the correlation of somatostatin receptor-2 (SSTR2) expression with 68Ga-DOTA-TATE uptake and 177Lu-DOTA-TATE therapy in neuroblastoma (NB) xenograft models. We demonstrated variable SSTR2 expression profiles in eight NB cell lines. From micro-PET imagin...

Development of a new radiolabel (lead-203) and new chelating agents for labeling monoclonal anntibodies for imaging

International Nuclear Information System (INIS)

Srivastava, S.C.; Mease, R.C.; Meinken, G.E.; Mausner, L.F.; Steplewski, Z.

1988-01-01

High liver uptake and slow body clearance presently limit the usefulness of 111 In labeled antibodies for tumor imaging. We have investigated 203 Pb as an alternate and better antibody label. The DTPA and cyclohexyl EDTA (CDTA) conjugates of an anticolon carcinoma antibody, 17-1A were labeled (bicyclic anhydride method) with 203 Pb and 111 In with 60 and 90% labeling yields, respectively. The biodistribution of 203 Pb-17-1A conjugates was compared with the corresponding 111 In-labeled preparations and with 203 Pb-DTPA, 203 Pb-nitrate and nonrelevant antibody controls in normal and human tumor (SW948) xenografted nude mice at 24, and 96 hr. Lead-203-labeled CDTA and DTPA antibody conjugates gave similar in vivo distributions. Even though the lead bound to these chelate-antibody conjugates was more labile in serum and in vivo, compared to indium, it cleared much faster from the liver and the whole body. A new series of chelating agents based on the incorporation of a trans-1,2- diaminocyclohexane moiety into the carbon backbone of polyaminocarboxylates is being synthesized. These are expected to provide stronger complexing ability for lead and produce greater in vivo stability. These ligands are also expected to be superior to EDTA and DTPA for labeling antibodies with other radiometals, including indium. 32 refs., 3 tabs

Dosimetry of 64Cu-DOTA-AE105, a PET tracer for uPAR imaging

International Nuclear Information System (INIS)

Persson, Morten; El Ali, Henrik H.; Binderup, Tina; Pfeifer, Andreas; Madsen, Jacob; Rasmussen, Palle; Kjaer, Andreas

2014-01-01

64 Cu-DOTA-AE105 is a novel positron emission tomography (PET) tracer specific to the human urokinase-type plasminogen activator receptor (uPAR). In preparation of using this tracer in humans, as a new promising method to distinguish between indolent and aggressive cancers, we have performed PET studies in mice to evaluate the in vivo biodistribution and estimate human dosimetry of 64 Cu-DOTA-AE105. Methods: Five mice received iv tail injection of 64 Cu-DOTA-AE105 and were PET/CT scanned 1, 4.5 and 22 h post injection. Volume-of-interest (VOI) were manually drawn on the following organs: heart, lung, liver, kidney, spleen, intestine, muscle, bone and bladder. The activity concentrations in the mentioned organs [%ID/g] were used for the dosimetry calculation. The %ID/g of each organ at 1, 4.5 and 22 h was scaled to human value based on a difference between organ and body weights. The scaled values were then exported to OLINDA software for computation of the human absorbed doses. The residence times as well as effective dose equivalent for male and female could be obtained for each organ. To validate this approach, of human projection using mouse data, five mice received iv tail injection of another 64 Cu-DOTA peptide-based tracer, 64 Cu-DOTA-TATE, and underwent same procedure as just described. The human dosimetry estimates were then compared with observed human dosimetry estimate recently found in a first-in-man study using 64 Cu-DOTA-TATE. Results: Human estimates of 64 Cu-DOTA-AE105 revealed the heart wall to receive the highest dose (0.0918 mSv/MBq) followed by the liver (0.0815 mSv/MBq), All other organs/tissue were estimated to receive doses in the range of 0.02–0.04 mSv/MBq. The mean effective whole-body dose of 64 Cu-DOTA-AE105 was estimated to be 0.0317 mSv/MBq. Relatively good correlation between human predicted and observed dosimetry estimates for 64 Cu-DOTA-TATE was found. Importantly, the effective whole body dose was predicted with very high

Dosimetry of 64Cu-DOTA-AE105, a PET tracer for uPAR imaging.

Science.gov (United States)

Persson, Morten; El Ali, Henrik H; Binderup, Tina; Pfeifer, Andreas; Madsen, Jacob; Rasmussen, Palle; Kjaer, Andreas

2014-03-01

(64)Cu-DOTA-AE105 is a novel positron emission tomography (PET) tracer specific to the human urokinase-type plasminogen activator receptor (uPAR). In preparation of using this tracer in humans, as a new promising method to distinguish between indolent and aggressive cancers, we have performed PET studies in mice to evaluate the in vivo biodistribution and estimate human dosimetry of (64)Cu-DOTA-AE105. Five mice received iv tail injection of (64)Cu-DOTA-AE105 and were PET/CT scanned 1, 4.5 and 22 h post injection. Volume-of-interest (VOI) were manually drawn on the following organs: heart, lung, liver, kidney, spleen, intestine, muscle, bone and bladder. The activity concentrations in the mentioned organs [%ID/g] were used for the dosimetry calculation. The %ID/g of each organ at 1, 4.5 and 22 h was scaled to human value based on a difference between organ and body weights. The scaled values were then exported to OLINDA software for computation of the human absorbed doses. The residence times as well as effective dose equivalent for male and female could be obtained for each organ. To validate this approach, of human projection using mouse data, five mice received iv tail injection of another (64)Cu-DOTA peptide-based tracer, (64)Cu-DOTA-TATE, and underwent same procedure as just described. The human dosimetry estimates were then compared with observed human dosimetry estimate recently found in a first-in-man study using (64)Cu-DOTA-TATE. Human estimates of (64)Cu-DOTA-AE105 revealed the heart wall to receive the highest dose (0.0918 mSv/MBq) followed by the liver (0.0815 mSv/MBq), All other organs/tissue were estimated to receive doses in the range of 0.02-0.04 mSv/MBq. The mean effective whole-body dose of (64)Cu-DOTA-AE105 was estimated to be 0.0317 mSv/MBq. Relatively good correlation between human predicted and observed dosimetry estimates for (64)Cu-DOTA-TATE was found. Importantly, the effective whole body dose was predicted with very high precision

{sup 68}Ga labelling strategies for nanodimensional and polymeric systems for the positron-emission topmography; {sup 68}Ga-Markierungsstrategien fuer nanodimensionale und polymere Systeme fuer die Positronen-Emissions-Tomographie

Energy Technology Data Exchange (ETDEWEB)

Stockhofe, Katharina

2016-10-15

Positron Emission Tomography (PET) is a non-invasive imaging technique that depicts metabolic processes in the body. With PET it becomes possible to get detailed information about the pharmacokinetics of polymeric and nanodimensional drug delivery systems, in a very elegant way. Therefore, it is absolutely necessary to have a reliable and robust technique to introduce the radioactive nuclide. In the presented work the positron emitting {sup 68}Ga was attached to homopolymers, various inorganic nanoparticles and core-crosslinked polymermicelles via different strategies. One of the used techniques was stain promoted alkyne azide cycloaddition (SPAAC), for which the presence of a strained alkyne and an azide is required. The conditions for this reactions are very mild. To have suitable chelating agents for ligation via SPAAC, the chelators DOTA, NODA-GA and DATA were functionalized with either an azide or a strained cycloalkyne. The derivatized chelators were radiolabeled with {sup 68}Ga, {sup 44}Sc and {sup 177}Lu and showed excellent complexation of the respective metal ions. The azide-functionalized chelators showed very good stabilities after complexation of the metal ions, in contrast to the Dibenzylcyclooctyne (DBCO)-derivatized ones. The reason lies here in the lipophilic character of the DBCO, as well as in sterical hindrances. Polysarcosine homopolymers carrying either an azide or a DBCO as one of their terminal groups were radiolabeled via SPAAC with the chelators described above. The focus was to investigate the radiochemical yields after and before the clickreaction with the particular chelator has taken place. Those reactions are called ''direct'' and ''indirect'' radiolabeling. Due to the very mild conditions the indirect strategy is a good and elegant alternative to the direct one. NODA-GA-TEG-azide and DOTA-TEG-azide both showed very good results for the direct and the indirect radiolabeling strategy. Polymer

Tumor targeting using {sup 67}Ga-DOTA-Bz-folate - investigations of methods to improve the tissue distribution of radiofolates

Energy Technology Data Exchange (ETDEWEB)

Mueller, Cristina, E-mail: cristina.mueller@psi.ch [Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI (Switzerland); Vlahov, Iontcho R.; Santhapuram, Hari Krishna R.; Leamon, Christopher P. [Endocyte Inc., West Lafayette, IN 47906 (United States); Schibli, Roger [Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI (Switzerland); Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich (Switzerland)

2011-07-15

Introduction: Use of folic acid radioconjugates for folate receptor (FR) targeting is a promising strategy for imaging purposes as well as for potential therapy of cancer and inflammatory diseases due to the frequent FR overexpression found on cancer cells and activated macrophages. Herein, we report on preclinical results using a novel DOTA-Bz-EDA-folate conjugate radiolabeled with [{sup 67}Ga]-gallium. Methods: DOTA-Bz-EDA-folate was prepared by conjugation of ethylenediamine-({gamma})-folate with 2-(p-isothiocyanobenzyl)-DOTA. Radiolabeling was carried out with {sup 67}GaCl{sub 3} according to standard procedures. Biodistribution studies of the tracer were performed in mice bearing FR-positive KB tumor xenografts. The effects on radiofolate biodistribution with coadministered renal uptake-blocking amino acids, diuretic agents, antifolates as well as different routes of administration were likewise investigated. Supportive imaging studies were performed using a small-animal single photon emission computed tomography (SPECT)/CT scanner. Results: {sup 67}Ga-DOTA-Bz-EDA-folate showed a high and specific accumulation in tumors (6.30%{+-}0.75% ID/g, 1 h pi and 6.08%{+-}0.89% ID/g, 4 h pi). Nonspecific radioactivity uptake in nontargeted tissues was negligible, but significant accumulation was found in FR-positive kidneys, which resulted in unfavorably low tumor-to-kidney ratios (<0.1). Coadministered amino acids or diuretics did not effectively reduce renal accumulation; in contrast, predosed pemetrexed did significantly reduce kidney uptake (<29% of control values). The SPECT/CT studies confirmed the excellent tumor-to-background contrast of {sup 67}Ga-radiofolate and the favorable reduction in kidney uptake (with improved imaging quality) resulting from pemetrexed administration. Conclusion: Conventional methods to reduce kidney uptake of radiofolates fail. However, the novel {sup 67}Ga-radiolabeled DOTA-Bz-EDA-folate can effectively be used to image FR

New biodegradable organic-soluble chelating agents for simultaneous removal of heavy metals and organic pollutants from contaminated media

International Nuclear Information System (INIS)

Ullmann, Amos; Brauner, Neima; Vazana, Shlomi; Katz, Zhanna; Goikhman, Roman; Seemann, Boaz; Marom, Hanit; Gozin, Michael

2013-01-01

Highlights: • New soil remediation process using phase transition of partially miscible solvents. • Design and synthesis of new bio-degradable, organic soluble chelating agents. • Feasibility tests of the process on authentically polluted sediments and sludge. • Simultaneous removal of toxic metals and organic pollutants was demonstrated. -- Abstract: Advanced biodegradable and non-toxic organic chelators, which are soluble in organic media, were synthesized on the basis of the S,S-ethylenediamine-disuccinate (S,S-EDDS) ligand. The modifications suggested in this work include attachment of a lipophilic hydrocarbon chain (“tail”) to one or both nitrogen atoms of the S,S-EDDS. The new ligands were designed and evaluated for application in the Sediments Remediation Phase Transition Extraction (SR-PTE) process. This novel process is being developed for the simultaneous removal of both heavy metals and organic pollutants from contaminated soils, sediments or sludge. The new chelators were designed to bind various target metal ions, to promote extraction of these ions into organic solvents. Several variations of attached tails were synthesized and tested. The results for one of them, N,N′-bis-dodecyl-S,S-EDDS (C24-EDDS), showed that the metal-ligand complexes are concentrated in the organic-rich phase in the Phase Transition Extraction process (more than 80%). Preliminary applications of the SR-PTE process with the C24-EDDS ligand were conducted also on actually contaminated sludge (field samples). The extraction of five toxic metals, namely, Cd, Cu, Ni, Pb and Zn was examined. In general, the extraction performance of the new ligand was not less than that of S,S-EDDS when a sufficient ligand-to-extracted ion ratio (about 4:1 was applied

New biodegradable organic-soluble chelating agents for simultaneous removal of heavy metals and organic pollutants from contaminated media

Energy Technology Data Exchange (ETDEWEB)

Ullmann, Amos, E-mail: Ullmann@eng.tau.ac.il [Faculty of Engineering, School of Mechanical Engineering, Tel Aviv University, Tel Aviv 69978 (Israel); Brauner, Neima; Vazana, Shlomi; Katz, Zhanna [Faculty of Engineering, School of Mechanical Engineering, Tel Aviv University, Tel Aviv 69978 (Israel); Goikhman, Roman [The Hebrew University of Jerusalem, The Robert H. Smith, Faculty of Agriculture, Food and Environment, Rehovot (Israel); Seemann, Boaz; Marom, Hanit [School of Chemistry, Faculty of Exact Sciences, Tel Aviv University, Tel Aviv 69978 (Israel); Gozin, Michael, E-mail: cogozin@gmail.com [School of Chemistry, Faculty of Exact Sciences, Tel Aviv University, Tel Aviv 69978 (Israel)

2013-09-15

Highlights: • New soil remediation process using phase transition of partially miscible solvents. • Design and synthesis of new bio-degradable, organic soluble chelating agents. • Feasibility tests of the process on authentically polluted sediments and sludge. • Simultaneous removal of toxic metals and organic pollutants was demonstrated. -- Abstract: Advanced biodegradable and non-toxic organic chelators, which are soluble in organic media, were synthesized on the basis of the S,S-ethylenediamine-disuccinate (S,S-EDDS) ligand. The modifications suggested in this work include attachment of a lipophilic hydrocarbon chain (“tail”) to one or both nitrogen atoms of the S,S-EDDS. The new ligands were designed and evaluated for application in the Sediments Remediation Phase Transition Extraction (SR-PTE) process. This novel process is being developed for the simultaneous removal of both heavy metals and organic pollutants from contaminated soils, sediments or sludge. The new chelators were designed to bind various target metal ions, to promote extraction of these ions into organic solvents. Several variations of attached tails were synthesized and tested. The results for one of them, N,N′-bis-dodecyl-S,S-EDDS (C24-EDDS), showed that the metal-ligand complexes are concentrated in the organic-rich phase in the Phase Transition Extraction process (more than 80%). Preliminary applications of the SR-PTE process with the C24-EDDS ligand were conducted also on actually contaminated sludge (field samples). The extraction of five toxic metals, namely, Cd, Cu, Ni, Pb and Zn was examined. In general, the extraction performance of the new ligand was not less than that of S,S-EDDS when a sufficient ligand-to-extracted ion ratio (about 4:1 was applied.

Thermodynamic and kinetic study of scandium(III) complexes of DTPA and DOTA: a step toward scandium radiopharmaceuticals.

Science.gov (United States)

Pniok, Miroslav; Kubíček, Vojtěch; Havlíčková, Jana; Kotek, Jan; Sabatie-Gogová, Andrea; Plutnar, Jan; Huclier-Markai, Sandrine; Hermann, Petr

2014-06-23

Diethylenetriamine-N,N,N',N'',N''-pentaacetic acid (DTPA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) scandium(III) complexes were investigated in the solution and solid state. Three (45)Sc NMR spectroscopic references suitable for aqueous solutions were suggested: 0.1 M Sc(ClO4)3 in 1 M aq. HClO4 (δSc =0.0 ppm), 0.1 M ScCl3 in 1 M aq. HCl (δSc =1.75 ppm) and 0.01 M [Sc(ox)4](5-) (ox(2-) = oxalato) in 1 M aq. K2C2O4 (δSc =8.31 ppm). In solution, [Sc(dtpa)](2-) complex (δSc = 83 ppm, Δν = 770 Hz) has a rather symmetric ligand field unlike highly unsymmetrical donor atom arrangement in [Sc(dota)](-) anion (δSc = 100 ppm, Δν = 4300 Hz). The solid-state structure of K8[Sc2(ox)7]⋅13 H2O contains two [Sc(ox)3](3-) units bridged by twice "side-on" coordinated oxalate anion with Sc(3+) ion in a dodecahedral O8 arrangement. Structures of [Sc(dtpa)](2-) and [Sc(dota)](-) in [(Hguanidine)]2[Sc(dtpa)]⋅3 H2O and K[Sc(dota)][H6 dota]Cl2⋅4 H2O, respectively, are analogous to those of trivalent lanthanide complexes with the same ligands. The [Sc(dota)](-) unit exhibits twisted square-antiprismatic arrangement without an axial ligand (TSA' isomer) and [Sc(dota)](-) and (H6 dota)(2+) units are bridged by a K(+) cation. A surprisingly high value of the last DOTA dissociation constant (pKa =12.9) was determined by potentiometry and confirmed by using NMR spectroscopy. Stability constants of scandium(III) complexes (log KScL 27.43 and 30.79 for DTPA and DOTA, respectively) were determined from potentiometric and (45)Sc NMR spectroscopic data. Both complexes are fully formed even below pH 2. Complexation of DOTA with the Sc(3+) ion is much faster than with trivalent lanthanides. Proton-assisted decomplexation of the [Sc(dota)](-) complex (τ1/2 =45 h; 1 M aq. HCl, 25 °C) is much slower than that for [Ln(dota)](-) complexes. Therefore, DOTA and its derivatives seem to be very suitable ligands for scandium

Dosimetry of 64Cu-DOTA-AE105, a PET tracer for uPAR imaging

DEFF Research Database (Denmark)

Persson, Morten; El Ali, Henrik H.; Binderup, Tina

2014-01-01

64Cu-DOTA-AE105 is a novel positron emission tomography (PET) tracer specific to the human urokinase-type plasminogen activator receptor (uPAR). In preparation of using this tracer in humans, as a new promising method to distinguish between indolent and aggressive cancers, we have performed PET...... studies in mice to evaluate the in vivo biodistribution and estimate human dosimetry of 64Cu-DOTA-AE105. MethodsFive mice received iv tail injection of 64Cu-DOTA-AE105 and were PET/CT scanned 1, 4.5 and 22h post injection. Volume-of-interest (VOI) were manually drawn on the following organs: heart, lung......Favorable dosimetry estimates together with previously reported uPAR PET data fully support human testing of 64Cu-DOTA-AE105....

Selective chelation-supercritical fluid extraction of metal ions from waste materials

International Nuclear Information System (INIS)

Wai, C.N.; Laintz, K.E.; Yonker, C.R.

1993-01-01

The removal of toxic organics, metals, and radioisotopes from solids or liquids is a major concern in the treatment of industrial and nuclear wastes. For this reason, developing methods for selective separation of toxic metals and radioactive materials from solutions of complex matrix is an important problem in environmental research. Recent developments indicate supercritical fluids are good solvents for organic compounds. Many gases become supercritical fluids under moderate temperatures and pressures. For example, the critical temperature and pressure of carbon dioxide are 31 degrees C and 73 atm, respectively. The high diffusivity, low viscosity, and T-P dependence of solvent strength are some attractive properties of supercritical fluid extraction (SFE). Since CO 2 offers the additional benefits of stability and non-toxicity, the SFE technique avoids generation of organic liquid waste and exposure of personnel to toxic solvents. While direct extraction of metal ions by supercritical fluids is highly inefficient, these ions when complexed with organic ligands become quite soluble in supercritical fluids. Specific ligands can be used to achieve selective extraction of metal ions in this process. After SFE, the fluid phase can be depressurized for precipitation of the metal chelates and recycled. The ligand can also be regenerated for repeated use. The success of this selective chelation-supercritical fluid extraction (SC-SFE) process depends on a number of factors including the efficiencies of the selective chelating agents, solubilities of metal chelates in supercritical fluids, rate of extraction, ease of regeneration of the ligands, etc. In this report, the authors present recent results on the studies of the solubilities of metal chelates in supercritical CO 2 , experimental ions from aqueous solution, and the development of selective chelating agents (ionizable crown ethers) for the extraction of lanthanides and actinides

Gadolinium retention after administration of contrast agents based on linear chelators and the recommendations of the European Medicines Agency

International Nuclear Information System (INIS)

Dekkers, Ilona A.; Roos, Rick; Molen, Aart J. van der

2018-01-01

The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) earlier this year recommended to suspend some marketing authorisations for Gadolinium Containing Contrast Agents (GCCAs) based on linear chelators due to the potential risk of gadolinium retention in the human body. These recommendations have recently been re-evaluated by EMA's Committee for Medicinal Products for Human Use (CHMP), and confirmed the final opinion of the European Medicines Agency. This editorial provides an overview of the available GCCAs and summarises the recent evidence of gadolinium retention. Moreover, a critical appraisal of the strengths and limitations of the scientific evidence currently available on gadolinium retention is given. (orig.)

Neodymium-140 DOTA-LM3

DEFF Research Database (Denmark)

Severin, Gregory; Kristensen, Lotte K.; Nielsen, Carsten H.

2017-01-01

analogue, DOTA-LM3 (1,4,7,10- tetraazacyclododecane, 1,4,7- tri acetic acid, 10- acetamide N - p-Cl-Phecyclo(D-Cys-Tyr-d-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH2) and injected into H727 xenograft bearing mice. Comparative pre- and post-mortem PET imaging at 16 h postinjection was used to quantify......140Nd (t1/2 = 3.4 days), owing to its short-lived positron emitting daughter 140Pr (t1/2 = 3.4 min), has promise as an in vivo generator for positron emission tomography (PET). However, the electron capture decay of 140Nd is chemically disruptive to macrocycle-based radiolabeling, meaning...... the in vivo redistribution of 140Pr following 140Nd decay. The somatostatin receptor-positive pancreas exhibited the highest tissue accumulation of 140Nd-DOTA-LM3 (13% ID/g at 16 h) coupled with the largest observed redistribution rate, where 56 ± 7% (n = 4, mean ± SD) of the in situ produced 140Pr washed out...

{sup 68}Ga-DOTA-RGD peptide: biodistribution and binding into atherosclerotic plaques in mice

Energy Technology Data Exchange (ETDEWEB)

Haukkala, Johanna; Laitinen, Iina; Luoto, Pauliina; Knuuti, Juhani [University of Turku, Turku PET Centre, Turku (Finland); Iveson, Peter; Wilson, Ian [Medical Diagnostics, GE Healthcare Biosciences, London (United Kingdom); Karlsen, Hege; Cuthbertson, Alan [GE Healthcare MDx Research, Oslo (Norway); Laine, Jukka [Turku University Hospital, Department of Pathology, Turku (Finland); Leppaenen, Pia; Ylae-Herttula, Seppo [University of Kuopio, A.I. Virtanen Institute, Kuopio (Finland); Roivainen, Anne [University of Turku, Turku PET Centre, Turku (Finland); University of Turku, Turku Centre for Disease Modelling, Turku (Finland)

2009-12-15

Increased expression of {alpha}v{beta}3/{alpha}v{beta}5 integrin is involved in angiogenesis and the inflammatory process in atherosclerotic plaques. The novel {sup 68}Ga-DOTA-RGD peptide binds with high affinity to {alpha}v{beta}3/{alpha}v{beta}5 integrin. The aim of this study was to investigate the uptake of the {sup 68}Ga-DOTA-RGD peptide in atherosclerotic plaques. Uptake of intravenously administered {sup 68}Ga-DOTA-RGD peptide was studied ex vivo in excised tissue samples and aortic sections of LDLR{sup -/-}ApoB{sup 100/100} atherosclerotic mice. The uptake of the tracer in aortic cryosections was examined by using digital autoradiography. Subsequently, the autoradiographs were combined with histological and immunohistological analysis of the sections. DOTA-RGD peptide was successfully labelled with the generator-produced {sup 68}Ga. The tracer had reasonably good specific radioactivity (8.7 {+-} 1.1 GBq/{mu}mol) and was quite stable in vivo. According to ex vivo biodistribution results, {sup 68}Ga-DOTA-RGD was cleared rapidly from the blood circulation and excreted through the kidneys to the urine with high radioactivity in the intestine, lungs, spleen and liver. Autoradiography results showed significantly higher uptake of {sup 68}Ga-DOTA-RGD peptide in the atherosclerotic plaques compared to healthy vessel wall (mean ratio {+-} SD 1.4 {+-} 0.1, p = 0.0004). We observed that {sup 68}Ga-DOTA-RGD is accumulated into the plaques of atherosclerotic mice. However, this data only shows the feasibility of the approach, while the clinical significance still remains to be proven. Further studies are warranted to assess the uptake of this tracer into human atherosclerotic plaques. (orig.)

In vitro and in vivo evaluation of potential aluminum chelators.

Science.gov (United States)

Graff, L; Muller, G; Burnel, D

1995-10-01

The potential for aluminium (Al) chelation by different compounds was determined using 2 in vitro techniques. The formation of stable complexes with Al in an aqueous solution was evaluated using pulse polarography. This technique allowed the influence of temperature and calcium (Ca) to be studied for each compound. Certain compounds (EDDHA, HAES, citric acid and HBED) showed great chelation in the absence of Ca2+ at a temperature of 37 +/- 1 C. An ultrafiltration technique combined with Al determination by atomic emission spectroscopy allowed the efficiency of different substances to complex Al that were previously bound to serum proteins to be estimated. The kinetics of chelation and minimum efficient concentration have been determined for all products studied. EDDHA had chelation potential similar to DFO. The real efficacies of the compounds were studied in vivo to compare the effectiveness of repeated administrations of the best chelating agents (EDDHA, DFO, HAES and tartaric acid) on the distribution and excretion of Al after repeated i.p. administrations to rats. Intraperitoneal EDDHA significantly increased urinary metal (Al, Ca, Cu, Fe and Zn) excretion. These excretions may be correlated to a renal toxic potential property.

68Ga-DOTA0-Tyr3-octreotide positron emission tomography in nasopharyngeal carcinoma

International Nuclear Information System (INIS)

Schartinger, Volker H.; Dudas, Jozsef; Url, Christoph; Riechelmann, Herbert; Reinold, Susanne; Virgolini, Irene J.; Kroiss, Alexander; Uprimny, Christian

2015-01-01

PET/CT with 68 Ga-labelled [DOTA 0 ,Tyr 3 ]-octreotide ( 68 Ga-DOTA-TOC PET/CT) is a routinely used imaging modality for neuroendocrine tumours expressing somatostatin receptors (SSTR). Recent studies have shown SSTR expression in head and neck squamous cell carcinoma, albeit lower than in highly differentiated neuroendocrine tumours. We sought to determine whether nasopharyngeal carcinoma (NPC) positive for Epstein-Barr virus (EBV), a rare subtype of head and neck cancer, shows increased 68 Ga-DOTA-TOC uptake indicating expression of SSTR. Five patients with untreated, histologically proven EBV-positive NPC were referred for 68 Ga-DOTA-TOC PET/CT. Tracer uptake in tumour lesions was assessed visually and semiquantitatively measuring maximum standardized uptake values (SUVmax) and tumour to background ratios. Increased tumour-specific uptake was detected in all five patients with a median SUVmax of 10.6 (range 3.6 - 17.1) in the primary tumour and 13.2 (range 6.1 - 14.5) in cervical lymph node metastases. 68 Ga-DOTA-TOC PET/CT demonstrated tracer uptake in EBV-positive NPC comparable to that in highly differentiated neuroendocrine tumours. This observation is consistent with increased SSTR expression in EBV-positive NPC and may open new diagnostic and therapeutic windows in NPC. (orig.)

(68)Ga-DOTA (0)-Tyr (3)-octreotide positron emission tomography in nasopharyngeal carcinoma.

Science.gov (United States)

Schartinger, Volker H; Dudás, József; Url, Christoph; Reinold, Susanne; Virgolini, Irene J; Kroiss, Alexander; Riechelmann, Herbert; Uprimny, Christian

2015-01-01

PET/CT with (68)Ga-labelled [DOTA(0),Tyr(3)]-octreotide ((68)Ga-DOTA-TOC PET/CT) is a routinely used imaging modality for neuroendocrine tumours expressing somatostatin receptors (SSTR). Recent studies have shown SSTR expression in head and neck squamous cell carcinoma, albeit lower than in highly differentiated neuroendocrine tumours. We sought to determine whether nasopharyngeal carcinoma (NPC) positive for Epstein-Barr virus (EBV), a rare subtype of head and neck cancer, shows increased (68)Ga-DOTA-TOC uptake indicating expression of SSTR. Five patients with untreated, histologically proven EBV-positive NPC were referred for (68)Ga-DOTA-TOC PET/CT. Tracer uptake in tumour lesions was assessed visually and semiquantitatively measuring maximum standardized uptake values (SUVmax) and tumour to background ratios. Increased tumour-specific uptake was detected in all five patients with a median SUVmax of 10.6 (range 3.6 - 17.1) in the primary tumour and 13.2 (range 6.1 - 14.5) in cervical lymph node metastases. (68)Ga-DOTA-TOC PET/CT demonstrated tracer uptake in EBV-positive NPC comparable to that in highly differentiated neuroendocrine tumours. This observation is consistent with increased SSTR expression in EBV-positive NPC and may open new diagnostic and therapeutic windows in NPC.

Preparation of Ga-68-NOTA as a renal PET agent and feasibility tests in mice

International Nuclear Information System (INIS)

Lee, Ji Youn; Jeong, Jae Min; Kim, Young Ju; Jeong, Hyuk-Jin; Lee, Yun-Sang; Lee, Dong Soo

2014-01-01

Introduction: Positron emission tomography (PET) may provide more accurate quantification of kidney function such as glomerular filtration rate (GFR) than gamma imaging. The purpose of these experiments was to prepare and evaluate Ga-68 complexes as potential PET agents for measurement of GFR. Methods: We labeled EDTA, DTPA, DOTA, and NOTA with Ga-68 obtained from a Ge-68/Ga-68-generator and measured the binding to serum and red blood cells. Biodistribution study was performed in male BALB/c mice after intravenous injection together with Cr-51-EDTA as the standard for glomerular filtration rate (GFR) measurement. Animal-PET study was performed using BALB/c mice. Results: All the tested chelating agents except DTPA showed quantitative labeling yields (> 99%). Among them, Ga-68-NOTA showed consistently low binding to both human and mouse RBC and serum protein. Biodistribution study showed no significant difference between Ga-68-NOTA and Cr-51-EDTA groups by one-way analysis of variance (ANOVA) (p > 0.05). Furthermore, the GFR values obtained by Ga-68-NOTA and Cr-51-EDTA were almost same (0.26 ± 0.04 and 0.25 ± 0.04 mL/min, respectively). Animal-PET study showed almost the same GFR (0.25 mL/min) with the values obtained by biodistribution study. Conclusion: We proved that an easy-to-prepare agent Ga-68-NOTA is ideal for renal PET as well as for GFR measurement

Optimization of isolation of cellulose from orange peel using sodium hydroxide and chelating agents.

Science.gov (United States)

Bicu, Ioan; Mustata, Fanica

2013-10-15

Response surface methodology was used to optimize cellulose recovery from orange peel using sodium hydroxide (NaOH) as isolation reagent, and to minimize its ash content using ethylenediaminetetraacetic acid (EDTA) as chelating agent. The independent variables were NaOH charge, EDTA charge and cooking time. Other two constant parameters were cooking temperature (98 °C) and liquid-to-solid ratio (7.5). The dependent variables were cellulose yield and ash content. A second-order polynomial model was used for plotting response surfaces and for determining optimum cooking conditions. The analysis of coefficient values for independent variables in the regression equation showed that NaOH and EDTA charges were major factors influencing the cellulose yield and ash content, respectively. Optimum conditions were defined by: NaOH charge 38.2%, EDTA charge 9.56%, and cooking time 317 min. The predicted cellulose yield was 24.06% and ash content 0.69%. A good agreement between the experimental values and the predicted was observed. Copyright © 2013 Elsevier Ltd. All rights reserved.

Preclinical Evaluation of 68Ga-DOTA-Minigastrin for the Detection of Cholecystokinin-2/Gastrin Receptor–Positive Tumors

Science.gov (United States)

Brom, Maarten; Joosten, Lieke; Laverman, Peter; Oyen, Wim J.G.; Béhé, Martin; Gotthardt, Martin; Boerman, Otto C.

2011-01-01

In comparison to somatostatin receptor scintigraphy, gastrin receptor scintigraphy using 111In-DTPA-minigastrin (MG0) showed added value in diagnosing neuroendocrine tumors. We investigated whether the 68Ga-labeled gastrin analogue DOTA-MG0 is suited for positron emission tomography (PET), which could improve image quality. Targeting of cholecystokinin-2 (CCK2)/gastrin receptor–positive tumor cells with DOTA-MG0 labeled with either 111In or 68Ga in vitro was investigated using the AR42J rat tumor cell line. Biodistribution was examined in BALB/c nude mice with a subcutaneous AR42J tumor. In vivo PET imaging was performed using a preclinical PET–computed tomographic scanner. DOTA-MG0 showed high receptor affinity in vitro. Biodistribution studies revealed high tumor uptake of 68Ga-DOTA-MG0: 4.4 ± 1.3 %ID/g at 1 hour postinjection. Coadministration of an excess unlabeled peptide blocked the tumor uptake (0.7 ± 0.1 %ID/g), indicating CCK2/gastrin receptor–mediated uptake (p = .0005). The biodistribution of 68Ga-DOTA-MG0 was similar to that of 111In-DOTA-MG0. Subcutaneous and intraperitoneal tumors were clearly visualized by small-animal PET imaging with 5 MBq 68Ga-DOTA-MG0. 111In- and 68Ga-labeled DOTA-MG0 specifically accumulate in CCK2/gastrin receptor–positive AR42J tumors with similar biodistribution apart from the kidneys. AR42J tumors were clearly visualized by microPET. Therefore, 68Ga-DOTA-MG0 is a promising tracer for PET imaging of CCK2/gastrin receptor–positive tumors in humans. PMID:21439259

Preclinical Evaluation of 68Ga-DOTA-Minigastrin for the Detection of Cholecystokinin-2/Gastrin Receptor-Positive Tumors

Directory of Open Access Journals (Sweden)

Maarten Brom

2011-03-01

Full Text Available In comparison to somatostatin receptor scintigraphy, gastrin receptor scintigraphy using 111In-DTPA-minigastrin (MG0 showed added value in diagnosing neuroendocrine tumors. We investigated whether the 68Ga-labeled gastrin analogue DOTA-MG0 is suited for positron emission tomography (PET, which could improve image quality. Targeting of cholecystokinin-2 (CCK2/gastrin receptor-positive tumor cells with DOTA-MG0 labeled with either 111In or 68Ga in vitro was investigated using the AR42J rat tumor cell line. Biodistribution was examined in BALB/c nude mice with a subcutaneous AR42J tumor. In vivo PET imaging was performed using a preclinical PET-computed tomographic scanner. DOTA-MG0 showed high receptor affinity in vitro. Biodistribution studies revealed high tumor uptake of 68Ga-DOTA-MG0: 4.4 ± 1.3 %ID/g at 1 hour postinjection. Coadministration of an excess unlabeled peptide blocked the tumor uptake (0.7 ± 0.1 %ID/g, indicating CCK2/gastrin receptor-mediated uptake (p = .0005. The biodistribution of 68Ga-DOTA-MG0 was similar to that of 111In-DOTA-MG0. Subcutaneous and intraperitoneal tumors were clearly visualized by small-animal PET imaging with 5 MBq 68Ga-DOTA-MG0. 111In- and 68Ga-labeled DOTA-MG0 specifically accumulate in CCK2/gastrin receptor-positive AR42J tumors with similar biodistribution apart from the kidneys. AR42J tumors were clearly visualized by microPET. Therefore, 68Ga-DOTA-MG0 is a promising tracer for PET imaging of CCK2/gastrin receptor-positive tumors in humans.

Improved PET Imaging of uPAR expression using new Cu-64-labeled cross-bridged peptide ligands

DEFF Research Database (Denmark)

Persson, Morten; Hosseini, Masood; Madsen, Jacob

2013-01-01

The correlation between uPAR expression, cancer cell invasion and metastases is now well-established and has prompted the development of a number of uPAR PET imaging agents, which could potentially identify cancer patients with invasive and metastatic lesions. In the present study, we synthesized......, the more stable of the new uPAR PET tracers, (64)Cu-CB-TE2A-PA-AE105, exhibits a significantly reduced liver uptake compared to (64)Cu-DOTA-AE105 as well as (64)Cu-CB-TE2A-AE105, (p...... and characterized two new cross-bridged (64)Cu-labeled peptide conjugates for PET imaging of uPAR and performed a head-to-head comparison with the corresponding and more conventionally used DOTA conjugate. Based on in-source laser-induced reduction of chelated Cu(II) to Cu(I), we now demonstrate the following...... ranking with respect to the chemical inertness of their complexed Cu ions: DOTA-AE105 95%) were achieved in all cases by incubation at 95ºC. In vivo, they display identical tumor uptake after 1h, but differ significantly after 22 hrs, where the DOTA-AE105 uptake remains surprisingly high. Importantly...

Preparation and biological evaluation of 111In-, 177Lu- and 90Y-labeled DOTA analogues conjugated to B72.3

International Nuclear Information System (INIS)

Mohsin, Huma; Fitzsimmons, Jonathan; Shelton, Tiffani; Hoffman, Timothy J.; Cutler, Cathy S.; Lewis, Michael R.; Athey, Phillip S.; Gulyas, Gyongyi; Kiefer, Garry E.; Frank, R. Keith; Simon, Jaime; Lever, Susan Z.; Jurisson, Silvia S.

2007-01-01

Three 1,4,7,10-tetraazacyclododecane-N,N',N '' ,N '' '-tetraacetic acid (DOTA) analogues were evaluated for relative in vivo stability when radiolabeled with 111 In, 90 Y and 177 Lu and conjugated to the monoclonal antibody B72.3. The DOTA analogues evaluated were 'NHS-DOTA' [N-hydroxysuccinimdyl (NHS) group activating one carboxylate], 'Arm-DOTA' (also known as MeO-DOTA; with a p-NCS, o-MeO-benzyl moiety on the methylene group of one acetic acid arm) and 'Back-DOTA' (with a p-NCS-benzyl moiety on a backbone methylene group of the macrocycle). The B72.3 was conjugated to the DOTA analogues to increase the retention time of the radioloabeled conjugates in vivo in mice. The serum stability of the various radiometalated DOTA conjugates showed them to have good stability out to 168 h (all >95% except 111 In-NHS-DOTA-B72.3, which was 91% stable). Hydroxyapatite stability for the 111 In and 177 Lu DOTA-conjugates was >95% at 168 h, while the 90 Y DOTA-conjugates were somewhat less stable (between 90% and 95% at 168 h). The biodistribution studies of the radiometalated DOTA-conjugates showed that no significant differences were observed for the 111 In and 177 Lu analogues; however, the 90 Y analogues showed lower stabilities, as evidenced by their increased bone uptake relative to the other two [2-20% injected dose per gram (% ID/g) for 90 Y and 2-8% ID/g for 111 In and 177 Lu]. The lower stability of the 90 Y analogues could be due to the higher beta energy of 90 Y and/or to the larger ionic radius of Y 3+ . Based on the bone uptake observed, the 177 Lu-NHS-DOTA-B72.3 had slightly lower stability than the 177 Lu-Arm-DOTA-B72.3 and 177 Lu-Back-DOTA-B72.3, but not significantly at all time points. For 90 Y, the analogue showing the lowest stability based on bone uptake was 90 Y-Arm-DOTA-B72.3, perhaps because of the metal's larger ionic radius and potential steric interactions minimizing effective complexation. The 111 In analogues all showed similar biological

A smart T(1)-weighted MRI contrast agent for uranyl cations based on a DNAzyme-gadolinium conjugate.

Science.gov (United States)

Xu, Weichen; Xing, Hang; Lu, Yi

2013-11-07

Rational design of smart MRI contrast agents with high specificity for metal ions remains a challenge. Here, we report a general strategy for the design of smart MRI contrast agents for detecting metal ions based on conjugation of a DNAzyme with a gadolinium complex. The 39E DNAzyme, which has high selectivity for UO2(2+), was conjugated to Gd(III)-DOTA and streptavidin. The binding of UO2(2+) to its 39E DNAzyme resulted in the dissociation of Gd(III)-DOTA from the large streptavidin, leading to a decrease of the T1 correlation time, and a change in the MRI signal.

Exploring the radiosynthesis and in vitro characteristics of [68 Ga]Ga-DOTA-Siglec-9.

Science.gov (United States)

Jensen, Svend B; Käkelä, Meeri; Jødal, Lars; Moisio, Olli; Alstrup, Aage K O; Jalkanen, Sirpa; Roivainen, Anne

2017-07-01

Vascular adhesion protein 1 is a leukocyte homing-associated glycoprotein, which upon inflammation rapidly translocates from intracellular sources to the endothelial cell surface. It has been discovered that the cyclic peptide residues 283-297 of sialic acid-binding IgG-like lectin 9 (Siglec-9) "CARLSLSWRGLTLCPSK" bind to vascular adhesion protein 1 and hence makes the radioactive analogues of this compound ([ 68 Ga]Ga-DOTA-Siglec-9) interesting as a noninvasive visualizing marker of inflammation. Three different approaches to the radiosynthesis of [ 68 Ga]Ga-DOTA-Siglec-9 are presented and compared with previously published methods. A simple, robust radiosynthesis of [ 68 Ga]Ga-DOTA-Siglec-9 with a yield of 62% (non decay-corrected) was identified, and it had a radiochemical purity >98% and a specific radioactivity of 35 MBq/nmol. Furthermore, the protein binding and stability of [ 68 Ga]Ga-DOTA-Siglec-9 were analyzed in vitro in mouse, rat, rabbit, pig, and human plasma and compared with in vivo pig results. The plasma in vitro protein binding of [ 68 Ga]Ga-DOTA-Siglec-9 was the lowest in the pig followed by rabbit, human, rat, and mouse. It was considerably higher in the in vivo pig experiments. The in vivo stability in pigs was lower than the in vitro stability. Despite considerable species differences, the observed characteristics of [ 68 Ga]Ga-DOTA-Siglec-9 are suitable as a positron emission tomography tracer. Copyright © 2017 John Wiley & Sons, Ltd.

3,4,5-trihydroxybenzoic acid as chelating agent

International Nuclear Information System (INIS)

Agrawal, M.D.; Bhandari, C.S.; Dixit, M.K.; Sogani, N.C.

1976-01-01

Stability constants of praseodymium chelates of 3,4,5-trihydroxy sodium benzoate are determined by using Bjerrum-Calvin pH titration techniques at constant ionic strength 0.1M-sodium perchlorate and at 28+-0.1 0 C. Values calculated by different methods are in good agreement. The study reveals that during complexation only one proton of the ligand molecule is replaced by the metal and oxygen of adjacent phenolic group acts as a coordinating atom. IR and NMR spectral studies of the ligand reveal that one of the OH groups (in meta position to carboxylic group) remains free while two other phenolic groups are involved in intramolecular hydrogen bonding. One water molecule is found attached in crystalline gallic acid. (author)

Effect of Surface Modification by Chelating Agents on Fischer- Tropsch Performance of Co/SiO{sub 2} Catalysts

Energy Technology Data Exchange (ETDEWEB)

Bambal, Ashish S.; Kugler, Edwin L.; Gardner, Todd H.; Dadyburjor, Dady B.

2013-11-14

The silica support of a Co-based catalyst for Fischer-Tropsch (FT) synthesis was modified by the chelating agents (CAs) nitrilotriacetic acid (NTA) and ethylenediaminetetraacetic acid (EDTA). After the modification, characterization of the fresh and spent catalysts show reduced crystallite sizes, a better-dispersed Co₃O₄ phase on the calcined samples, and increased metal dispersions for the reduced samples. The CA-modified catalysts display higher CO conversions, product yields, reaction rates and rate constants. The improved FT performance of CA-modified catalysts is attributed to the formation of stable complexes with Co. The superior performance of the EDTA-modified catalyst in comparison to the NTA-modified catalyst is due to the higher affinity of the former for complex formation with Co ions.

Chemical exchange saturation transfer (CEST) properties of albumin-binding and gold nanoparticle-bound Eu (III) chelates

Science.gov (United States)

Melendez, Milleo Dalmacio

CEST agents derived from paramagnetic complexes, commonly referred to as PARACEST agents represent a new class of MRI contrast agents that respond to biological information such as pH, temperature, redox, and metabolite levels. In this work, CEST properties of two novel PARACEST agents were investigated upon binding to human serum albumin (HSA) and conjugation to gold nanoparticles (Au NPs). CEST properties of [EuDOTA(O-Et-Tyr)4] -when bound to HSA was studied to address the effect of proteins on CEST. The interaction of this Eu3+ complex to HSA was investigated by performing fluorescent probe displacement studies and it was found to bind HSA at two different binding pockets, the normal warfarin and dansyl glycine binding sites. The lipophilic pendant arms and the negative charge of this complex contribute to the favorable protein binding. However, the CEST signal was reduced 2-fold upon binding to HSA. The exchangeable protons on HSA provide a large proton pool that can exchange with the bound H 2O, competing for the exchange between bulk and bound water. Au NPs coated with [EuDOTA(CAM)4]3+ were prepared using the Brust method and characterized by measuring the CEST properties. The water residence lifetime for the Au-Eu NP conjugates increased 2-fold compared to the free Eu3+ complex presumably, as a result of the formation of hindered structure between the particle and the Eu3+ complex. Sensitivity enhancement in CEST was achieved by slowing down water exchange and increasing the number of exchangeable groups on the agent using Au-Eu NP conjugates. The CEST properties of small molecule PARACEST agents were shown to vary depending on the platform used in assembling larger adducts.

High clinical and morphologic response using 90Y-DOTA-octreotate sequenced with 177Lu-DOTA-octreotate induction peptide receptor chemoradionuclide therapy (PRCRT) for bulky neuroendocrine tumours.

Science.gov (United States)

Kong, Grace; Callahan, Jason; Hofman, Michael S; Pattison, David A; Akhurst, Tim; Michael, Michael; Eu, Peter; Hicks, Rodney J

2017-03-01

Bulky disease is an adverse prognostic factor for 177 Lu-DOTA-octreotate ( 177 Lu-DOTATATE) peptide receptor radionuclide therapy (PRRT). 90 Y-DOTA-octreotate ( 90 Y-DOTATATE) has theoretical advantages in this setting but may less effectively treat co-existent smaller deposits and have higher toxicity than 177 Lu-DOTATATE. The aim of this study was to assess the efficacy and safety of using these agents sequentially. We reviewed patients (pts) with at least one lesion of a transaxial diameter >4 cm who completed 1-2 cycles of 90 Y-DOTATATE followed by 2-3 cycles of 177 Lu-DOTATATE, with treatment empirically adapted to disease size and burden in individual patients. Data collected included morphological and molecular imaging response, toxicity, and progression-free and overall survival. Twenty-six pts (17 men; aged 27-74 years) received a median cumulative activity of 6.5 GBq 90 Y-DOTATATE, and 21 GBq 177 Lu-DOTATATE. All but one received radiosensitising chemotherapy. Adverse prognostic factors included ENETS grade 2 or 3 in 58 %, and FDG-avid disease in 73 %. Nineteen pts treated for progressive disease had stabilisation (37 %) or regression on CT (42 % partial response, 21 % minor response), with a mean 59 % (8-99 %) reduction in disease burden. All seven pts treated for uncontrolled symptoms reported improvement during PRRT with 4/7 having complete symptom resolution at 3 months. Eight patients had grade 3/4 lymphopaenia, and two patients grade 3/4 thrombocytopaenia without significant hepatic or renal toxicity. Median survival was not reached after a median follow-up of 35 months. Median progression-free survival was 33 months. PRCRT with 90 Y -DOTATATE followed by 177 Lu-DOTATATE in individualised regimens achieved high clinical and morphological response in patients with bulky tumours. Despite lack of a control arm, the efficacy of this treatment approach appears higher than reported results with either agent used alone or other approved

Coupling fast water exchange to slow molecular tumbling in Gd3+ chelates: why faster is not always better.

Science.gov (United States)

Avedano, Stefano; Botta, Mauro; Haigh, Julian S; Longo, Dario L; Woods, Mark

2013-08-05

The influence of dynamics on solution state structure is a widely overlooked consideration in chemistry. Variations in Gd(3+) chelate hydration with changing coordination geometry and dissociative water exchange kinetics substantially impact the effectiveness (or relaxivity) of monohydrated Gd(3+) chelates as T1-shortening contrast agents for MRI. Theory shows that relaxivity is highly dependent upon the Gd(3+)-water proton distance (rGdH), and yet this distance is almost never considered as a variable in assessing the relaxivity of a Gd(3+) chelate as a potential contrast agent. The consequence of this omission can be seen when considering the relaxivity of isomeric Gd(3+) chelates that exhibit different dissociative water exchange kinetics. The results described herein show that the relaxivity of a chelate with "optimal" dissociative water exchange kinetics is actually lower than that of an isomeric chelate with "suboptimal" dissociative water exchange. When the rate of molecular tumbling of these chelates is slowed, an approach that has long been understood to increase relaxivity, the observed difference in relaxivity is increased with the more rapidly exchanging ("optimal") chelate exhibiting lower relaxivity than the "suboptimally" exchanging isomer. The difference between the chelates arises from a non-field-dependent parameter: either the hydration number (q) or rGdH. For solution state Gd(3+) chelates, changes in the values of q and rGdH are indistinguishable. These parametric expressions simply describe the hydration state of the chelate--i.e., the number and position of closely associating water molecules. The hydration state (q/rGdH(6)) of a chelate is intrinsically linked to its dissociative water exchange rate kex, and the interrelation of these parameters must be considered when examining the relaxivity of Gd(3+) chelates. The data presented herein indicate that the changes in the hydration parameter (q/rGdH(6)) associated with changing dissociative

Effect of DOTA position on melanoma targeting and pharmacokinetic properties of 111In-labeled lactam bridge-cyclized alpha-melanocyte stimulating hormone peptide.

Science.gov (United States)

Guo, Haixun; Yang, Jianquan; Gallazzi, Fabio; Prossnitz, Eric R; Sklar, Larry A; Miao, Yubin

2009-11-01

The purpose of this study was to examine the effect of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) position on melanoma targeting and pharmacokinetics of radiolabeled lactam bridge-cyclized alpha-melanocyte stimulating hormone (alpha-MSH) peptide. A novel lactam bridge-cyclized alpha-MSH peptide, Ac-GluGlu-CycMSH[DOTA] {Ac-Glu-Glu-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Lys(DOTA)]}, was synthesized using standard 9-fluorenylmethyloxycarbonyl (Fmoc) chemistry. DOTA was directly attached to the alpha-amino group of Lys in the cyclic ring, while the N-terminus of the peptide was acetylated to generate Ac-GluGlu-CycMSH[DOTA]. The MC1 receptor binding affinity of Ac-GluGlu-CycMSH[DOTA] was determined in B16/F1 melanoma cells. Melanoma targeting and pharmacokinetic properties of Ac-GluGlu-CycMSH[DOTA]-111In were determined in B16/F1 melanoma-bearing C57 mice and compared to that of 111In-DOTA-Gly-Glu-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Asp] (111In-DOTA-GlyGlu-CycMSH; DOTA was coupled to the N-terminus of the peptide). Ac-GluGlu-CycMSH[DOTA] displayed 0.6 nM MC1 receptor binding affinity in B16/F1 cells. Ac-GluGlu-CycMSH[DOTA]-111In was readily prepared with greater than 95% radiolabeling yield. Ac-GluGlu-CycMSH[DOTA]-111In exhibited high tumor uptake (11.42 +/- 2.20% ID/g 2 h postinjection) and prolonged tumor retention (9.42 +/- 2.41% ID/g 4 h postinjection) in B16/F1 melanoma-bearing C57 mice. The uptake values for nontarget organs were generally low (<1.3% ID/g) except for the kidneys 2, 4, and 24 h postinjection. DOTA position exhibited profound effect on melanoma targeting and pharmacokinetic properties of Ac-GluGlu-CycMSH[DOTA]-111In, providing a new insight into the design of lactam bridge-cyclized peptide for melanoma imaging and therapy.

Bimodal MR-PET agent for quantitative pH imaging

Science.gov (United States)

Frullano, Luca; Catana, Ciprian; Benner, Thomas; Sherry, A. Dean; Caravan, Peter

2010-01-01

Activatable or “smart” magnetic resonance contrast agents have relaxivities that depend on environmental factors such as pH or enzymatic activity, but the MR signal depends on relaxivity and agent concentration – two unknowns. A bimodal approach, incorporating a positron emitter, solves this problem. Simultaneous positron emission tomography (PET) and MR imaging with the biomodal, pH-responsive MR-PET agent GdDOTA-4AMP-F allows direct determination of both concentration (PET) and T1 (MRI), and hence pH. PMID:20191650

Combinational chelation therapy abrogates lead-induced neurodegeneration in rats

International Nuclear Information System (INIS)

Pachauri, Vidhu; Saxena, Geetu; Mehta, Ashish; Mishra, Deepshikha; Flora, Swaran J.S.

2009-01-01

Lead, a ubiquitous and potent neurotoxicant causes oxidative stress which leads to numerous neurobehavioral and physiological alterations. The ability of lead to bind sulfhydryl groups or compete with calcium could be one of the reasons for its debilitating effects. In the present study, we addressed: i) if chelation therapy could circumvent the altered oxidative stress and prevent neuronal apoptosis in chronic lead-intoxicated rats, ii) whether chelation therapy could reverse biochemical and behavioral changes, and iii) if mono or combinational therapy with captopril (an antioxidant) and thiol chelating agents (DMSA/MiADMSA) is more effective than individual thiol chelator in lead-exposed rats. Results indicated that lead caused a significant increase in reactive oxygen species, nitric oxide, and intracellular free calcium levels along with altered behavioral abnormalities in locomotor activity, exploratory behavior, learning, and memory that were supported by changes in neurotransmitter levels. A fall in membrane potential, release of cytochrome c, and DNA damage indicated mitochondrial-dependent apoptosis. Most of these alterations showed significant recovery following combined therapy with captopril with MiADMSA and to a smaller extend with captopril + DMSA over monotherapy with these chelators. It could be concluded from our present results that co-administration of a potent antioxidant (like captopril) might be a better treatment protocol than monotherapy to counter lead-induced oxidative stress. The major highlight of the work is an interesting experimental evidence of the efficacy of combinational therapy using an antioxidant with a thiol chelator in reversing neurological dystrophy caused due to chronic lead exposure in rats.

Development of new folate-based PET radiotracers: preclinical evaluation of 68Ga-DOTA-folate conjugates

International Nuclear Information System (INIS)

Fani, Melpomeni; Maecke, Helmut R.; Wang, Xuejuan; Nicolas, Guillaume; Medina, Christelle; Raynal, Isabelle; Port, Marc

2011-01-01

A number of 111 In- and 99m Tc-folate-based tracers have been evaluated as diagnostic agents for imaging folate receptor (FR)-positive tumours. A 68 Ga-folate-based radiopharmaceutical would be of great interest, combining the advantages of PET technology and the availability of 68 Ga from a generator. The aim of the study was to develop a new 68 Ga-folate-based PET radiotracer. Two new DOTA-folate conjugates, named P3026 and P1254, were synthesized using the 1,2-diaminoethane and 3-{2-[2-(3-amino-propoxy)-ethoxy]-ethoxy}-propylamine as a spacer, respectively. Both conjugates were labelled with 67/68 Ga. Binding affinity, internalization and externalization studies were performed using the FR-positive KB cell line. Biodistribution and PET/CT imaging studies were performed in nude mice, on a folate-deficient diet, bearing KB and HT1080 (FR-negative) tumours, concurrently. The new radiotracers were evaluated comparatively to the reference molecule 111 In-DTPA-folate ( 111 In-P3139). The K d values of 67/68 Ga-P3026 (4.65 ± 0.82 nM) and 67/68 Ga-P1254 (4.27 ± 0.42 nM) showed high affinity for the FR. The internalization rate followed the order 67/68 Ga-P3026 > 67/68 Ga-P1254 > 111 In-P3139, while almost double cellular retention was found for 67/68 Ga-P3026 and 67/68 Ga-P1254, compared to 111 In-P3139. The biodistribution data of 67/68 Ga-DOTA-folates showed high and receptor-mediated uptake on the FR-positive tumours and kidneys, with no significant differences compared to 111 In-P3139. PET/CT images, performed with 68 Ga-P3026, showed high uptake in the kidneys and clear visualization of the FR-positive tumours. The DOTA-folate conjugates can be efficiently labelled with 68 Ga in labelling yields and specific activities which allow clinical application. The characteristics of the 67/68 Ga-DOTA-folates are comparable to 111 In-DTPA-folate, which has already been used in clinical trials, showing that the new conjugates are promising candidates as PET radiotracers

The attachment of metal-chelating groups to proteins: tagging of albumin by diazonium coupling and use of the products as radiopharmaceuticals

International Nuclear Information System (INIS)

Leung, C.S.H.; Meares, C.F.; Goodwin, D.A.

1978-01-01

The ability to attach firmly chelated metal ions or powerful chelating agents to sites on biological molecules can enhance the utility of a number of physical techniques now used in the study of biological systems. A 'bifunctional' chelating agent, containing both an EDTA group and a diazonium group, has been prepared and coupled to human serum albumin. The extent of labeling under various conditions and the amino-acid sidechains labeled have been investigated. The reaction of protein-bound chelating groups with added metal ions has been studied, with the finding that only about 40-50% of these groups are available to bind metal ions. Proteolysis of the products leads to recovery of full metal-binding capacity. Properties of the products in vivo are discussed. (author)

XAS studies of the effectiveness of iron chelating treatments of Mary Rose timbers

International Nuclear Information System (INIS)

Berko, A; Schofield, E J; Chadwick, A V; Smith, A D; Jones, A M; Mosselmans, J F W

2009-01-01

The oxidation of sulfur in marine archaeological timbers under museum storage conditions is a recently identified problem, particularly for major artefacts such as historic ships excavated from the seabed. Recent work on the Vasa has stressed the role of iron in catalysing the oxidative degradation of the wood cellulose and the polyethylene glycols used to restore mechanical integrity to the timbers. In developing new treatment protocols for the long term preservation of Henry VIII of England's flagship, the Mary Rose, we are investigating the potential of chelating agents to neutralise and remove the iron products from the ships timbers. We have explored the use of aqueous solutions of chelating agents of calcium phytate, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA) and ammonium citrate to extract the iron compounds. All of these solutions exhibit some level of iron removal; however the key is to find the most effective concentration at pH of around 7 of the reagent solution, to minimise the treatment time and find the most cost-effective treatment for the whole of the Mary Rose hull. Fe K-edge XAFS data from samples of Mary Rose timbers, before and after treatment by the chelating agents mentioned has been collected. The data collected provide valuable insights into the effectiveness of the treatment solutions.

Polyaminoquinoline iron chelators for vectorization of antiproliferative agents: design, synthesis, and validation.

Science.gov (United States)

Corcé, Vincent; Morin, Emmanuelle; Guihéneuf, Solène; Renault, Eric; Renaud, Stéphanie; Cannie, Isabelle; Tripier, Raphaël; Lima, Luís M P; Julienne, Karine; Gouin, Sébastien G; Loréal, Olivier; Deniaud, David; Gaboriau, François

2012-09-19

Iron chelation in tumoral cells has been reported as potentially useful during antitumoral treatment. Our aim was to develop new polyaminoquinoline iron chelators targeting tumoral cells. For this purpose, we designed, synthesized, and evaluated the biological activity of a new generation of iron chelators, which we named Quilamines, based on an 8-hydroxyquinoline (8-HQ) scaffold linked to linear polyamine vectors. These were designed to target tumor cells expressing an overactive polyamine transport system (PTS). A set of Quilamines bearing variable polyamine chains was designed and assessed for their ability to interact with iron. Quilamines were also screened for their cytostatic/cytotoxic effects and their selective uptake by the PTS in the CHO cell line. Our results show that both the 8-HQ moiety and the polyamine part participate in the iron coordination. HQ1-44, the most promising Quilamine identified, presents a homospermidine moiety and was shown to be highly taken up by the PTS and to display an efficient antiproliferative activity that occurred in the micromolar range. In addition, cytotoxicity was only observed at concentrations higher than 100 μM. We also demonstrated the high complexation capacity of HQ1-44 with iron while much weaker complexes were formed with other cations, indicative of a high selectivity. We applied the density functional theory to study the binding energy and the electronic structure of prototypical iron(III)-Quilamine complexes. On the basis of these calculations, Quilamine HQ1-44 is a strong tridentate ligand for iron(III) especially in the form of a 1:2 complex.

Solubilidade, fracionamento e fitoextração de metais pesados após aplicação de agentes quelantes Solubility, phytoextraction and fractionation of heavy metals as a function of chelating agents applied to soil

Directory of Open Access Journals (Sweden)

Évio Eduardo Chaves de Melo

2006-12-01

Full Text Available A baixa biodegrabilidade de quelantes sintéticos usados para induzir a fitoextração resulta em alto risco ambiental pela possibilidade de lixiviação de metais pesados. Agentes quelantes naturais, mais rapidamente degradados no solo, podem ser uma alternativa para os quelantes sintéticos. O objetivo deste trabalho foi comparar a performance de ácidos orgânicos naturais (gálico, cítrico e oxálico com ácidos sintéticos (EDTA, DTPA e NTA na fitoextração induzida de metais. O solo foi contaminado com 500, 300 e 200 mg kg-1 de Pb, Zn e Cu, respectivamente, e cultivado com milho (Zea mays e mucuna preta (Stizolobium aterrimum. Os agentes quelantes, na dose de 10 mmol kg-1, foram aplicados no solo sete dias antes da coleta das plantas. Amostras do solo foram submetidas à extração com CaCl2 e fracionamento. Os teores dos metais na solução do solo foram também determinados. Os quelantes sintéticos EDTA, DTPA e NTA foram eficientes na solubilização dos metais pesados no solo. Dentre os ácidos orgânicos naturais, apenas o ácido cítrico foi eficiente na solubilização dos metais nas primeiras vinte e quatro horas após a sua aplicação. A distribuição dos metais entre as frações apresentou a seguinte ordem: Pb: matéria orgânica (MO > óxido de Fe amorfo (OxFeA > trocável (Tr > óxido de Fe cristalino (OxFeC; Cu: MO > Tr > OxFeC > OxFeA; e Zn: MO > Tr > OxFeC > OxFeA. De modo geral, a adição dos quelantes sintéticos provocou aumento nos teores trocáveis de Pb e Cu e redução nos teores de Pb, Cu e Zn nas frações óxidos de Fe amorfo e cristalino. O extrator CaCl2 0,01 mol L-1 pode ser utilizado para predição da concentração de Pb, Cu e Zn na solução do solo.The low biodegradability of synthetic chelating agents used for phytoextraction poses a great environmental risk due to the potential for metal leaching. Natural chelating agents can be an alternative to synthetic chelates due to their rapid biodegrability

DOTA-TATE peptides labelling with Lutetium 177: Preliminary study

International Nuclear Information System (INIS)

Aliaga, Eleazar; Robles, Anita; Ramos, Bertha; Martinez, Flor

2014-01-01

he peptide DOTA-TATE was labeled with lutetium 177 according to the methodology provided under the regional project RLA/6/074, sponsored by the IAEA. The labeling was done in 0.26 M gentisic acid solution in 0.8 M sodium acetate buffer, pH 5, at 100 °C for 30 minutes in a dry heating block. The radiochemical purity was assessed by thin layer chromatography, using ITLC SG strips and a mixture of 0.15 M ammonium acetate - methanol (1:1) as solvent. The radiolabeled peptide 177 Lu-DOTA-TATE reached a radiochemical purity of 98 % with a specific activity of 2,8 mCi/µg of peptide. (authors).

Synthesis and photocatalytic application of TiO{sub 2} nanoparticles immobilized on polyacrylonitrile nanofibers using EDTA chelating agents

Energy Technology Data Exchange (ETDEWEB)

Chaúque, Eutilério F.C., E-mail: efchauque@gmail.com [Department of Applied Chemistry, University of Johannesburg, Doornfontein, 2028, Johannesburg (South Africa); Adelodun, Adedeji A., E-mail: aadelodun@uj.ac.za [Department of Applied Chemistry, University of Johannesburg, Doornfontein, 2028, Johannesburg (South Africa); Dlamini, Langelihle N., E-mail: lndlamini@uj.ac.za [Department of Applied Chemistry, University of Johannesburg, Doornfontein, 2028, Johannesburg (South Africa); Greyling, Corinne J., E-mail: GreylingC@cput.ac.za [Technology Station in Clothing and Textiles, Cape Peninsula University of Technology, Symphony Way, Belville, 7535 (South Africa); Ray, Sekhar C., E-mail: raysc@unisa.ac.za [Department of Physics, University of South Africa, Florida, 1710, Johannesburg (South Africa); Ngila, J. Catherine, E-mail: jcngila@uj.ac.za [Department of Applied Chemistry, University of Johannesburg, Doornfontein, 2028, Johannesburg (South Africa)

2017-05-01

The photocatalytic properties of TiO{sub 2} nanoparticles (TNPs) have been widely demonstrated in the literature. Here, we report the chemical attachment of TNPs to the surface of polyacrylonitrile nanofibers (PNFs) using the ethylenediaminetetraacetic acid (EDTA) and ethylenediamine (EDA) as the chelating agents. The composite nanofibers were prepared through the chelation of Ti{sup 4+} ions with surface carboxylic and amine groups followed by self-growth of TiO{sub 2} nanoparticles on the surface of modified PNFs during the incubation process. The fabricated composite nanofibers were stabilized at 240 °C in a tube furnace under N{sub 2} gas. The heat treatment served to simultaneously crystallize the TNPs and enhance robustness of PNFs as cyclization reactions and the cross-linking of adjacent nitrile groups (–C=N−C=N–) usually takes place at temperatures above 200 °C. Characterization techniques included X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier transform infrared (FT-IR), Raman spectroscopy and Brunauer-Emmett-Teller (BET) technique. The chemical impregnation of EDTA-EDA on the surface of PNFs resulted in slight increase in the average nanofiber's diameter. The anatase TiO{sub 2} nanoparticles with average 9.4 nm particle size prepared in situ were immobilized on the surface of pre-functionalized PNFs. The fabricated composite nanofibers were applied in the photocatalytic degradation of methyl orange (MO) in synthetic aqueous solutions. The as-prepared composite nanofibers were reused for five (5) cycles without considerable decline in the MO removal efficiency (i.e. >98% of initial performance). - Highlights: • Electrospun polyacrylonitrile nanofibers (PNFs) were chemically modified with EDTA. • The TiO{sub 2}-EDTA-EDA-PNFs composites were prepared through chelation of Ti{sup 4+} ions. • Composites were calcined for simultaneous crystallization and chemical stability. • Ti

Phase II trial of yttrium-90-DOTA-biotin pretargeted by NR-LU-10 antibody/streptavidin in patients with metastatic colon cancer

International Nuclear Information System (INIS)

Knox, S J.; Goris, M L.; Tempero, M.; Weiden, P L.; Gentner, L.; Breitz, H.; Adams, G. P.; Axworthy, D.; Gaffigan, S.; Bryan, K.; Fisher, Darrell R.; Colcher, D; Horak, I D.; Weiner, L M.

1999-01-01

A Phase II study of yttrium-90-tetra-azacyclododecanetetra-acetic acid-biotin (Y-90-DOTA-biotin) pretargeted by NR-LU-10 antibody/streptavidin (SA) was performed. The primary objectives of the study were to evaluate the efficacy and safety of this therapy in patients with metastatic colon cancer. Twenty-five patients were treated with a single dose of 110 mCi/m 2 (mean administered dose, 106.5-10.3 mCi/m 2 ) of Y-90-DOTA-biotin. There were three components of the therapy. Patients first received NR-LU-10/SA on day 1. A clearing agent (biotin-galactose-human serum albumin) was administered 48 h after the NR-LU-10/SA to remove residual circulating unbound NR-LU-10/SA. Lastly, 24 h after administration of clearing agent, patients received biotin-DOTA-labeled with 110 mCi/m 2 Y-90. All three components of the therapy were administered i.v. Both hematological and nonhematological toxicities were observed. Diarrhea was the most frequent grade 4 nonhematological toxicity (16%; with 16% grade 3 diarrhea). Hematological toxicity was less severe with 8% grade 3 and 8% grade 4 neutropenia and 8% grade 3 and 16% grade 4 thrombocytopenia. The overall response rate was 8%. Two partial responders had freedom from progression of 16 weeks. Four patients (16%) had stable disease with freedom from progression of 10-20 weeks. Despite the relatively disappointing results of this study in terms of therapeutic efficacy and toxicity, proof of principle was obtained for the pretargeting approach. In addition, valuable new information was obtained about normal tissue tolerance to low-dose-rate irradiation that will help to provide useful guidelines for future study designs

Multicenter comparison of 18F-FDG and 68Ga-DOTA-peptide PET/CT for pulmonary carcinoid.

Science.gov (United States)

Lococo, Filippo; Perotti, Germano; Cardillo, Giuseppe; De Waure, Chiara; Filice, Angelina; Graziano, Paolo; Rossi, Giulio; Sgarbi, Giorgio; Stefanelli, Antonella; Giordano, Alessandro; Granone, Pierluigi; Rindi, Guido; Versari, Annibale; Rufini, Vittoria

2015-03-01

The aims of this study were to retrospectively evaluate and compare the detection rate (DR) of 68Ga-DOTA-peptide and 18F-FDG PET/CT in the preoperative workup of patients with pulmonary carcinoid (PC) and to assess the utility of various functional indices obtained with the 2 tracers in predicting the histological characterization of PC, that is, typical versus atypical. Thirty-three consecutive patients with confirmed PC referred for 18F-FDG and 68Ga-DOTA-peptide PET/CT in 2 centers between January 2009 and April 2013 were included. The semiquantitative evaluation included the SUV max, the SUV of the tumor relative to the maximal liver uptake for 18F-FDG (SUV T/L) or the maximal spleen uptake for 68Ga-DOTA-peptides (SUV T/S), the ratio between SUV max of 68Ga-DOTA-peptides PET/CT, and the SUV max of 18F-FDG PET/CT (SUV max ratio). Histology was used as reference standard. Definitive diagnosis consisted of 23 typical carcinoids (TCs) and 10 atypical carcinoids. 18F-FDG PET/CT was positive in 18 cases and negative in 15 (55% DR). 68Ga-DOTA-peptide PET/CT was positive in 26 cases and negative in 7 (79% DR). In the subgroup analysis, 68Ga-DOTA-peptide PET/CT was superior in detecting TC (91% DR; P DOTA-peptide PET/CT findings. In the subgroup analysis, the SUV max ratio seems to be the most accurate index in predicting TC. Both methods should be performed when PC is suspected or when the histological subtype is undefined.

[Decorporation agents for internal radioactive contamination].

Science.gov (United States)

Ohmachi, Yasushi

2015-01-01

When radionuclides are accidentally ingested or inhaled, blood circulation or tissue/organ deposition of the radionuclides causes systemic or local radiation effects. In such cases, decorporation therapy is used to reduce the health risks due to their intake. Decorporation therapy includes reduction and/or inhibition of absorption from the gastrointestinal tract, isotopic dilution, and the use of diuretics, adsorbents, and chelating agents. For example, penicillamine is recommended as a chelating agent for copper contamination, and diethylene triamine pentaacetic acid is approved for the treatment of internal contamination with plutonium. During chelation therapy, the removal effect of the drugs should be monitored using a whole-body counter and/or bioassay. Some authorities, such as the National Council on Radiation Protection and Measurements and International Atomic Energy Agency, have reported recommended decorporation agents for each radionuclide. However, few drugs are approved by the US Food and Drug Administration, and many are off-label-use agents. Because many decontamination agents are drugs that have been available for a long time and have limited efficacy, the development of new, higher-efficacy drugs has been carried out mainly in the USA and France. In this article, in addition to an outline of decorporation agents for internal radioactive contamination, an outline of our research on decorporation agents for actinide (uranium and plutonium) contamination and for radio-cesium contamination is also presented.

Genotoxic evaluation of [DOTA,Tyr3]octreotate labeled with 131I and 177Lu in human peripheral lymphocytes in vitro by micronucleus assay

International Nuclear Information System (INIS)

Suzauki, Miriam Fussae; Silva, Marcia Augusta da; Caldeira Filho, Jose de Souza; Colturato, Maria Tereza; Araujo, Elaine Bortoleti de; Bartolini, Paolo; Okazaki, Kayo

2005-01-01

The radiolabeled receptor-binding peptides have being used for cancer diagnosis and therapy. The octreotate, a somatostatin analogue peptide, bound to various tumors expressing sst receptors (thyroid, pancreas, prostrate, melanoma and lymphomas). The amount and the type of receptors for somatostatin influence the tissue uptake. The [DOTA, Tyr 3 ]octreotate has been used because of its high affinity to somatostatin subtype receptors sstr 2 and sstr 5 . The pharmacokinetic study showed that the blood clearance is rapid and only 9% of the intravenous injected activity remains in human blood after one hour. The aim of this study was to evaluate the cytogenetic effect of radiolabeled [DOTA, Tyr 3 ]octreotate in blood cells in vitro, using the cytokinesis-block micronucleus (MN) assay. This technique allows evaluating the mutagenic effects of both endogenous and exogenous agents at chromosome level. Blood samples of healthy donors were collected in heparinized syringes and exposed to different activities of [DOTA, Tyr 3 ]octreotate labeled with with 131 I (n=3) and 177 Lu (n=3), where radioactive concentration ranged from 600 to 5600 kBq/mL, corresponding to an injected activity of 3.1 to 28.9 GBq in a reference man of 70 kg weight. 131 I and 177 Lu are beta- and gamma-emitters. After one-hour exposition to radiopharmaceuticals at 37 deg C, the cells were washed with culture medium for removing the non internalised octreotate and cultivated for 72 hours, according to criteria adopted by the IAEA. The results showed a positive correlation between radioactive concentrations (X) and the frequency of binucleated cells with micronuclei (Y) (P 131 I-DOTA, Tyr 3 ]octreotate was Y = (1.634 ± 0.236) + (0.912 ± 0.137) 10 -3 X and for [ 177 Lu-DOTA, Tyr 3 ]octreotate was Y = (1.715 ± 0.342) + (0.743 ± 0.135) 10 -3 X. The non labeled molecule, [DOTA, Tyr 3 ]octreotate, has no influence in the induction of cytogenetic damage. The micronucleus assay with rat pancreatic tumor cells

Development and biological studies of ¹⁷⁷Lu-DOTA-rituximab for the treatment of Non-Hodgkin's lymphoma.

Science.gov (United States)

Massicano, Adriana V F; Pujatti, Priscilla B; Alcarde, Lais F; Suzuki, Miriam F; Spencer, Patrick J; Araújo, Elaine B

2016-01-01

The optimization of DOTA-NHS-ester conjugation to Rituximab using different Ab:DOTA molar ratios (1:10, 1:20, 1:50 and 1:100) was studied. High radiochemical yield, in vitro stability and immunoreactive fraction were obtained for the Rituximab conjugated at 1:50 molar ratio, resulting in the incorporation of an average number of 4.9 ± 1.1 DOTA per Rituximab molecule. Labeling with 177Lu was performed in high specific activity with great in vitro stability. Biodistribution in healthy and xenographed mice showed tumor uptake and high in vivo stability as evidenced by low uptake in bone. The properties of 177Lu-DOTA-Rituximab prepared from DOTA-NHS-ester suggest the potential for the application of the 177Lu-labeled antibody in preliminary clinical studies.

Chelating capture and magnetic removal of non-magnetic heavy metal substances from soil

Science.gov (United States)

Fan, Liren; Song, Jiqing; Bai, Wenbo; Wang, Shengping; Zeng, Ming; Li, Xiaoming; Zhou, Yang; Li, Haifeng; Lu, Haiwei

2016-02-01

A soil remediation method based on magnetic beneficiation is reported. A new magnetic solid chelator powder, FS@IDA (core-shell Fe3O4@SiO2 nanoparticles coated with iminodiacetic acid chelators), was used as a reactive magnetic carrier to selectively capture non-magnetic heavy metals in soil by chelation and removal by magnetic separation. FS@IDA was prepared via inorganic-organic and organic synthesis reactions that generated chelating groups on the surface of magnetic, multi-core, core-shell Fe3O4@SiO2 (FS) nanoparticles. These reactions used a silane coupling agent and sodium chloroacetate. The results show that FS@IDA could chelate the heavy metal component of Cd, Zn, Pb, Cu and Ni carbonates, lead sulfate and lead chloride in water-insoluble salt systems. The resulting FS@IDA-Cd and FS@IDA-Pb chelates could be magnetically separated, resulting in removal rates of approximately 84.9% and 72.2% for Cd and Pb, respectively. FS@IDA could not remove the residual heavy metals and those bound to organic matter in the soil. FS@IDA did not significantly alter the chemical composition of the soil, and it allowed for fast chelating capture, simple magnetic separation and facilitated heavy metal elution. FS@IDA could also be easily prepared and reprocessed.

Exploring the radiosynthesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9

DEFF Research Database (Denmark)

Jensen, Svend Borup; Käkelä, Meeri; Jødal, Lars

2017-01-01

(Siglec-9) "CARLSLSWRGLTLCPSK" bind to VAP-1 and hence makes the radioactive analogues of this compound ([68 Ga]Ga-DOTA-Siglec-9) interesting as a non-invasive visualizing marker of inflammation. Three different approaches to the radiosynthesis of [68 Ga]Ga-DOTA-Siglec-9 are presented and compared...

Ga-68-DOTA-TATE PET/CT for discrimination of tumors of the optic pathway.

Science.gov (United States)

Klingenstein, Annemarie; Haug, Alexander R; Miller, Christina; Hintschich, Christoph

2015-02-01

Symptomatic tumors of the optic nerve pathway may endanger vision. They are difficult to classify by imaging alone and biopsy may damage visual function. Tumor pathology influences treatment decision and a diagnostic tool with a high sensitivity and specificity would therefore be invaluable. We hypothesized that Ga-68-DOTA-TATE PET/CT may help in discriminating optic nerve tumors as uptake of somatostatin is elevated in meningiomas. Ga-68-DOTA-TATE PET/CT was used to examine 13 patients with ambiguous, symptomatic lesions of the optic pathway for treatment planning. The presence or absence of meningioma was validated by histopathology or supplementary diagnostic work-up. Ga-68-DOTA-TATE PET/CT identified 10 meningiomas (en plaque = 1, optic nerve sheath = 4, sphenoidal = 5) correctly via increased SSTR (somatostatin receptor) expression (mean SUVmax (maximum standardized uptake value) = 14.3 ± 15.4). 3 tumors did not show elevated Ga-68-DOTA-TATE uptake (SUVmax = 2.1 ± 1.0). Subsumizing all clinical-radiological follow-up tools available, these lesions were classified as an intracerebral metastasis of an advanced gastric carcinoma, histologically proven inflammatory collagenous connective tissue and presumed leukemic infiltration of a newly diagnosed chronic lymphocytic leukemia. In this case series, Ga-68-DOTA-TATE PET/CT demonstrated both a sensitivity and specificity of 100%. Yet, the golden standard of histopathology was only available in a subset of patients included. Ga-68-DOTA-TATE PET/CT proved to be a valuable diagnostic tool for the correct classification of equivocal, symptomatic tumors of the anterior optic pathway requiring therapy. PET/CT results influenced therapy decision essentially in all cases.

Radioimmunotherapy: Development of an effective approach

International Nuclear Information System (INIS)

DeNardo, S.J.

1991-01-01

We plan to extend our success in treating B cell malignancies with 131 I labeled Lym-1 by a major effort in therapy with 67 Cu Lym-1. Yttrium-90 labeled by a macrocycle, DOTA will be studied in patients as a continuation of the 111 In-BAD (DOTA) Lym-1 studies. Excellent images and pharmacokinetics of the 111 In-BAD(DOTA)-Lym-1 studies. Lymphomas and related diseases represent a special case for radioimmunotherapy because of their documented radiosensitivity and immunodeficiency, and thus offer a unique opportunity to conduct therapeutic feasibility studies in a responsive human model. Using marine and chimeric L6 and other MoAb to breast cancer, we have applied the strategies that were developed in taking Lym-1 antibody from the bench to the patient. We have examined a number of monoclonal antibodies for treatment of breast cancer and chose chimeric L6 for prototype studies because of certain characteristics. The chemistry of attachment of conjugates to antibodies and their impact on immunological targeting biological activities (cytotoxicity), metabolic fate, and therapeutic index will continue to be a major strength and function of this program. This grant has supported the conception, synthesis, and development of the first macrocylic, bifunctional chelating agent TETA (6-p-nitrobenzyl-1,4,8,11-tetraazatetradecane-N,N',N double-prime, N'double-prime-tetraacetic acid and its derivatives, including Lym-1-2IT-BAT), for use in Cu-67-based radioimmunodiagnosis and therapy. This work has led to the further development of several new macrocylic bifunctional chelating agents for copper, indium, yttrium and other metals. In addition, successful Cu-67 labelings of Lym-1-2IT-BAT for human radiopharmaceutical have shown patient pharmacokinetics of 67 Cu-BAT(TETA)-Lym-1 with promising therapeutic dosimetry

Characterizing the magnetic susceptibility tensor of lanthanide-containing polymethylated-DOTA complexes

Energy Technology Data Exchange (ETDEWEB)

Strickland, Madeleine [National Institutes of Health, Laboratory of Molecular Biophysics, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute (United States); Schwieters, Charles D. [National Institutes of Health, Office of Intramural Research, Center for Information Technology (United States); Göbl, Christoph [Technische Universität München, Department of Chemistry (Germany); Opina, Ana C. L. [National Institutes of Health, Imaging Probe Development Center, National Heart, Lung, and Blood Institute (United States); Strub, Marie-Paule [National Institutes of Health, Laboratory of Molecular Biophysics, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute (United States); Swenson, Rolf E.; Vasalatiy, Olga [National Institutes of Health, Imaging Probe Development Center, National Heart, Lung, and Blood Institute (United States); Tjandra, Nico, E-mail: tjandran@nhlbi.nih.gov [National Institutes of Health, Laboratory of Molecular Biophysics, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute (United States)

2016-10-15

Lanthanide complexes based on the DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) cage are commonly used as phase contrast agents in magnetic resonance imaging, but can also be utilized in structural NMR applications due to their ability to induce either paramagnetic relaxation enhancement or a pseudocontact shift (PCS) depending on the choice of the lanthanide. The size and sign of the PCS for any given atom is determined by its coordinates relative to the metal center, and the characteristics of the lanthanide’s magnetic susceptibility tensor. Using a polymethylated DOTA tag (Ln-M8-SPy) conjugated to ubiquitin, we calculated the position of the metal center and characterized the susceptibility tensor for a number of lanthanides (dysprosium, thulium, and ytterbium) under a range of pH and temperature conditions. We found that there was a difference in temperature sensitivity for each of the complexes studied, which depended on the size of the lanthanide ion as well as the isomeric state of the cage. Using {sup 17}O-NMR, we confirmed that the temperature sensitivity of the compounds was enhanced by the presence of an apically bound water molecule. Since amide-containing lanthanide complexes are known to be pH sensitive and can be used as probes of physiological pH, we also investigated the effect of pH on the Ln-M8-SPy susceptibility tensor, but we found that the changes in this pH range (5.0–7.4) were not significant.

Characterizing the magnetic susceptibility tensor of lanthanide-containing polymethylated-DOTA complexes

International Nuclear Information System (INIS)

Strickland, Madeleine; Schwieters, Charles D.; Göbl, Christoph; Opina, Ana C. L.; Strub, Marie-Paule; Swenson, Rolf E.; Vasalatiy, Olga; Tjandra, Nico

2016-01-01

Lanthanide complexes based on the DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) cage are commonly used as phase contrast agents in magnetic resonance imaging, but can also be utilized in structural NMR applications due to their ability to induce either paramagnetic relaxation enhancement or a pseudocontact shift (PCS) depending on the choice of the lanthanide. The size and sign of the PCS for any given atom is determined by its coordinates relative to the metal center, and the characteristics of the lanthanide’s magnetic susceptibility tensor. Using a polymethylated DOTA tag (Ln-M8-SPy) conjugated to ubiquitin, we calculated the position of the metal center and characterized the susceptibility tensor for a number of lanthanides (dysprosium, thulium, and ytterbium) under a range of pH and temperature conditions. We found that there was a difference in temperature sensitivity for each of the complexes studied, which depended on the size of the lanthanide ion as well as the isomeric state of the cage. Using "1"7O-NMR, we confirmed that the temperature sensitivity of the compounds was enhanced by the presence of an apically bound water molecule. Since amide-containing lanthanide complexes are known to be pH sensitive and can be used as probes of physiological pH, we also investigated the effect of pH on the Ln-M8-SPy susceptibility tensor, but we found that the changes in this pH range (5.0–7.4) were not significant.

High clinical and morphologic response using {sup 90}Y-DOTA-octreotate sequenced with {sup 177}Lu-DOTA-octreotate induction peptide receptor chemoradionuclide therapy (PRCRT) for bulky neuroendocrine tumours

Energy Technology Data Exchange (ETDEWEB)

Kong, Grace; Callahan, Jason; Pattison, David A.; Akhurst, Tim; Eu, Peter [Peter MacCallum Cancer Centre, Centre for Cancer Imaging, Melbourne, VIC (Australia); Hofman, Michael S. [Peter MacCallum Cancer Centre, Centre for Cancer Imaging, Melbourne, VIC (Australia); The University of Melbourne, Department of Medicine, Parkville (Australia); Michael, Michael [Peter MacCallum Cancer Centre, Division of Cancer Medicine, Neuroendocrine Tumour Unit, Melbourne, VIC (Australia); The University of Melbourne, The Sir Peter MacCallum Department of Oncology, Parkville (Australia); Hicks, Rodney J. [Peter MacCallum Cancer Centre, Centre for Cancer Imaging, Melbourne, VIC (Australia); The University of Melbourne, The Sir Peter MacCallum Department of Oncology, Parkville (Australia)

2017-03-15

Bulky disease is an adverse prognostic factor for {sup 177}Lu-DOTA-octreotate ({sup 177}Lu-DOTATATE) peptide receptor radionuclide therapy (PRRT). {sup 90}Y-DOTA-octreotate ({sup 90}Y-DOTATATE) has theoretical advantages in this setting but may less effectively treat co-existent smaller deposits and have higher toxicity than {sup 177}Lu-DOTATATE. The aim of this study was to assess the efficacy and safety of using these agents sequentially. We reviewed patients (pts) with at least one lesion of a transaxial diameter >4 cm who completed 1-2 cycles of {sup 90}Y-DOTATATE followed by 2-3 cycles of {sup 177}Lu-DOTATATE, with treatment empirically adapted to disease size and burden in individual patients. Data collected included morphological and molecular imaging response, toxicity, and progression-free and overall survival. Twenty-six pts (17 men; aged 27-74 years) received a median cumulative activity of 6.5 GBq {sup 90}Y-DOTATATE, and 21 GBq {sup 177}Lu-DOTATATE. All but one received radiosensitising chemotherapy. Adverse prognostic factors included ENETS grade 2 or 3 in 58 %, and FDG-avid disease in 73 %. Nineteen pts treated for progressive disease had stabilisation (37 %) or regression on CT (42 % partial response, 21 % minor response), with a mean 59 % (8-99 %) reduction in disease burden. All seven pts treated for uncontrolled symptoms reported improvement during PRRT with 4/7 having complete symptom resolution at 3 months. Eight patients had grade 3/4 lymphopaenia, and two patients grade 3/4 thrombocytopaenia without significant hepatic or renal toxicity. Median survival was not reached after a median follow-up of 35 months. Median progression-free survival was 33 months. PRCRT with {sup 90}Y -DOTATATE followed by {sup 177}Lu-DOTATATE in individualised regimens achieved high clinical and morphological response in patients with bulky tumours. Despite lack of a control arm, the efficacy of this treatment approach appears higher than reported results with either

Bioinspired Interfacial Chelating-like Reinforcement Strategy toward Mechanically Enhanced Lamellar Materials.

Science.gov (United States)

Chen, Ke; Zhang, Shuhao; Li, Anran; Tang, Xuke; Li, Lidong; Guo, Lin

2018-05-22

Many biological organisms usually derived from the ordered assembly of heterogeneous, hierarchical inorganic/organic constituents exhibit outstanding mechanical integration, but have proven to be difficult to produce the combination of excellent mechanical properties, such as strength, toughness, and light weight, by merely mimicking their component and structural characteristics. Herein, inspired by biologically strong chelating interactions of phytic acid (PA) or IP6 in many biomaterials, we present a biologically interfacial chelating-like reinforcement (BICR) strategy for fabrication of a highly dense ordered "brick-and-mortar" microstructure by incorporating tiny amounts of a natural chelating agent ( e. g., PA) into the interface or the interlamination of a material ( e. g., graphene oxide (GO)), which shows joint improvement in hardness (∼41.0%), strength (∼124.1%), maximum Young's modulus (∼134.7%), and toughness (∼118.5%) in the natural environment. Besides, for different composite matrix systems and artificial chelating agents, the BICR strategy has been proven successful for greatly enhancing their mechanical properties, which is superior to many previous reinforcing approaches. This point can be mainly attributed to the stronger noncovalent cross-linking interactions such as dense hydrogen bonds between the richer phosphate (hydroxyl) groups on its cyclohexanehexol ring and active sites of GO, giving rise to the larger energy dissipation at its hybrid interfaces. It is also simple and environmentally friendly for further scale-up fabrication and can be readily extended to other material systems, which opens an advanced reinforcement route to construct structural materials with high mechanical performance in an efficient way for practical applications.

Antibacterial and antibiofilm effects of iron chelators against Prevotella intermedia.

Science.gov (United States)

Moon, Ji-Hoi; Kim, Cheul; Lee, Hee-Su; Kim, Sung-Woon; Lee, Jin-Yong

2013-09-01

Prevotella intermedia, a major periodontopathogen, has been shown to be resistant to many antibiotics. In the present study, we examined the effect of the FDA-approved iron chelators deferoxamine (DFO) and deferasirox (DFRA) against planktonic and biofilm cells of P. intermedia in order to evaluate the possibility of using these iron chelators as alternative control agents against P. intermedia. DFRA showed strong antimicrobial activity (MIC and MBC values of 0.16 mg ml(-1)) against planktonic P. intermedia. At subMICs, DFRA partially inhibited the bacterial growth and considerably prolonged the bacterial doubling time. DFO was unable to completely inhibit the bacterial growth in the concentration range tested and was not bactericidal. Crystal violet binding assay for the assessment of biofilm formation by P. intermedia showed that DFRA significantly decreased the biofilm-forming activity as well as the biofilm formation, while DFO was less effective. DFRA was chosen for further study. In the ATP-bioluminescent assay, which reflects viable cell counts, subMICs of DFRA significantly decreased the bioactivity of biofilms in a concentration-dependent manner. Under the scanning electron microscope, P. intermedia cells in DFRA-treated biofilm were significantly elongated compared to those in untreated biofilm. Further experiments are necessary to show that iron chelators may be used as a therapeutic agent for periodontal disease.

Diagnostic performance and impact on patient management of 68Ga-DOTA-TOC PET/CT for detecting osteomalacia-associated tumours.

Science.gov (United States)

Paquet, Marie; Gauthé, Mathieu; Zhang Yin, Jules; Nataf, Valérie; Bélissant, Ophélie; Orcel, Philippe; Roux, Christian; Talbot, Jean-Noël; Montravers, Françoise

2018-03-12

Oncogenic osteomalacia is an endocrine disorder induced by small benign tumours (TIO) producing excessive fibroblast growth factor-23 (FGF23). The only way of curing oncogenic osteomalacia is surgical resection of the culprit TIO, which is extremely difficult to detect using conventional imaging modalities due to its small size and variable location in the body. Since TIO frequently overexpress somatostatin receptors, a clinical utility of SPECT or PET with radiolabelled somatostatin analogues has been reported. Among them, 68 Ga-DOTA-TOC has recently been granted a marketing authorization, facilitating its routine application. We report here the results of the first series evaluating the diagnostic performance of 68 Ga-DOTA-TOC PET/CT in detecting TIO and its impact on patient management. 68 Ga-DOTA-TOC PET/CT and clinical and imaging data from 15 patients with clinical and biochemical signs of oncogenic osteomalacia were retrospectively reviewed. The 68 Ga-DOTA-TOC PET/CT findings were compared with the results of post-surgical pathology and clinical and biochemical follow-up. 68 Ga-DOTA-TOC PET/CT resulted in the detection of one focus suspicious for TIO in nine of 15 patients (60%), and a tumour was surgically removed in eight. Post-operative pathology confirmed a TIO in those eight patients whose symptoms diminished promptly and biochemical anomalies resolved. 68 Ga-DOTA-TOC PET/CT sensitivity, specificity and accuracy were 73%, 67% and 71%, respectively. 68 Ga-DOTA-TOC PET/CT findings affected patient management in 67% of cases. In particular, 68 Ga-DOTA-TOC PET/CT was able to detect the TIO with a negative or a false-positive result of a previous 111 In-pentetreotide SPECT/CT in 5/8 patients (63%) or a previous FDG PET/CT in 7/11 patients (64%). No close relationship was found between the positivity of 68 Ga-DOTA-TOC PET/CT and the serum level of a biochemical marker. However, a true-positive result of 68 Ga-DOTA-TOC PET/CT was obtained in only one patient

Mixed ligand chelate therapy for plutonium and toxic metals from energy power production. Final report, April 15, 1977-October 14, 1980

International Nuclear Information System (INIS)

Schubert, J.

1980-01-01

The results of experiments are summarized on the ability of combinations of chelating agents to modify the genotoxicity or tissue distributions. The mutagenicities of Cr and of chelating agents were determined. The metals described in the report are Pu(IV), Cd(II), Cr(III), and Cr(VI). Accurate measurements were made of the ability of CaNa 2 EDTA, CaNa 3 DTPA, and DMPS to reduce mortality in mice given doses (i.p.) of CdCl 2 well above the 100% lethal level. The efficacy in terms of the mmoles/kg needed to reduce the mortality was: DTPA > EDTA > DMPS. The combination of DTPA + DMPS proved most promising though little evidence for mixed complex formation was noted. Potentiometric titration studies the case of Pu(IV) a few combinations proved effective, but only when given shortly after Pu administration and then only in the liver but not the skeleton. It is recommended that metabolically stable chelating agents be used in combinations, especially for those combinations which may form very stable mixed ligand chelates

Demetalation of Fe, Mn, and Cu chelates and complexes: application to the NMR analysis of micronutrient fertilizers.

Science.gov (United States)

López-Rayo, Sandra; Lucena, Juan J; Laghi, Luca; Cremonini, Mauro A

2011-12-28

The application of nuclear magnetic resonance (NMR) for the quality control of fertilizers based on Fe(3+), Mn(2+), and Cu(2+) chelates and complexes is precluded by the strong paramagnetism of metals. Recently, a method based on the use of ferrocyanide has been described to remove iron from commercial iron chelates based on the o,o-EDDHA [ethylenediamine-N,N'bis(2-hydroxyphenylacetic)acid] chelating agent for their analysis and quantification by NMR. The present work extended that procedure to other paramagnetic ions, manganese and copper, and other chelating, EDTA (ethylenediaminetetraacetic acid), IDHA [N-(1,2-dicarboxyethyl)-d,l-aspartic acid], and complexing agents, gluconate and heptagluconate. Results showed that the removal of the paramagnetic ions was complete, allowing us to obtain (1)H NMR spectra characterized by narrow peaks. The quantification of the ligands by NMR and high-performance liquid chromatography showed that their complete recovery was granted. The NMR analysis enabled detection and quantification of unknown impurities without the need of pure compounds as internal standards.

68Ga-DOTA-NGR as a novel molecular probe for APN-positive tumor imaging using MicroPET.

Science.gov (United States)

Zhang, Jun; Lu, Xiaoli; Wan, Nan; Hua, Zichun; Wang, Zizheng; Huang, Hongbo; Yang, Min; Wang, Feng

2014-03-01

Aminopeptidase N (APN) is selectively expressed on many tumors and the endothelium of tumor neovasculature, and may serve as a promising target for cancer diagnosis and therapy. Asparagine-glycine-arginine (NGR) peptides have been shown to bind specifically to the APN receptor and have served as vehicles for the delivery of various therapeutic drugs in previous studies. The purpose of this study was to synthesize and evaluate the efficacy of a (68)Ga-labeled NGR peptide as a new molecular probe that binds to APN. NGR peptide was conjugated with 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA) and labeled with (68)Ga at 95°C for 10 min. In vitro uptake and binding analysis was performed with A549 and MDA-MB231 cells. Biodistribution of (68)Ga-DOTA-NGR was determined in normal mice by dissection method. (68)Ga-DOTA-NGR PET was performed in A549 and MDA-MB231 xenografts, and included dynamic and static imaging. APN expression in tumors and new vasculatures was analyzed by immunohistochemistry. The radiochemical purity of (68)Ga-DOTA-NGR was 98.0% ± 1.4% with a specific activity of about 17.49 MBq/nmol. The uptake of (68)Ga-DOTA-NGR in A549 cells increased with longer incubation times, and could be blocked by cold DOTA-NGR, while no specific uptake was found in MDA-MB231 cells. In vivo biodistribution studies showed that (68)Ga-DOTA-NGR was mainly excreted from the kidney, and rapidly cleared from blood and nonspecific organs. MicroPET imaging showed that high focal accumulation had occurred in the tumor site at 1 h post-injection (pi) in A549 tumor xenografts. A significant reduction of tumor uptake was observed following coinjection with a blocking dose of DOTA-NGR, whereas only mild uptake was found in MDA-MB231 tumor xenografts. Tumor uptake, measured as the tumor/lung ratio, increased with time peaking at 12.58 ± 1.26 at 1.5 h pi. Immunohistochemical staining confirmed that APN was overexpressed on A549 cells and neovasculature. (68)Ga-DOTA

Biodegradable gadolinium-chelated cationic poly(urethane amide) copolymers for gene transfection and magnetic resonance imaging

Energy Technology Data Exchange (ETDEWEB)

Gao, Xiaolong [Department of Radiology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065 (China); Wang, Gangmin [Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040 (China); Shi, Ting [The Institute for Translational Nanomedicine, Shanghai East Hospital, Institute for Biomedical Engineering and Nanoscience, Tongji University School of Medicine, Shanghai 200092 (China); Shao, Zhihong [Department of Radiology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065 (China); Zhao, Peng; Shi, Donglu [The Institute for Translational Nanomedicine, Shanghai East Hospital, Institute for Biomedical Engineering and Nanoscience, Tongji University School of Medicine, Shanghai 200092 (China); Ren, Jie [Institute of Nano and Biopolymeric Materials, School of Materials Science and Engineering, Tongji University, 4800 Caoan Road, Shanghai 201804 (China); Lin, Chao, E-mail: chaolin@tongji.edu.cn [The Institute for Translational Nanomedicine, Shanghai East Hospital, Institute for Biomedical Engineering and Nanoscience, Tongji University School of Medicine, Shanghai 200092 (China); Wang, Peijun, E-mail: tjpjwang@sina.com [Department of Radiology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065 (China)

2016-08-01

Theranostic nano-polyplexes containing gene and imaging agents hold a great promise for tumor diagnosis and therapy. In this work, we develop a group of new gadolinium (Gd)-chelated cationic poly(urethane amide)s for gene delivery and T{sub 1}-weighted magnetic resonance (MR) imaging. Cationic poly(urethane amide)s (denoted as CPUAs) having multiple disulfide bonds, urethane and amide linkages were synthesized by stepwise polycondensation reaction between 1,4-bis(3-aminopropyl)piperazine and a mixture of di(4-nitrophenyl)-2, 2′-dithiodiethanocarbonate (DTDE-PNC) and diethylenetriaminepentaacetic acid (DTPA) dianhydride at varied molar ratios. Then, Gd-chelated CPUAs (denoted as GdCPUAs) were produced by chelating Gd(III) ions with DTPA residues of CPUAs. These GdCPUAs could condense gene into nanosized and positively-charged polyplexes in a physiological condition and, however, liberated gene in an intracellular reductive environment. In vitro transfection experiments revealed that the GdCPUA at a DTDE-PNC/DTPA residue molar ratio of 85/15 induced the highest transfection efficiency in different cancer cells. This efficiency was higher than that yielded with 25 kDa branched polyethylenimine as a positive control. GdCPUAs and their polyplexes exhibited low cytotoxicity when an optimal transfection activity was detected. Moreover, GdCPUAs may serve as contrast agents for T{sub 1}-weighted magnetic resonance imaging. The results of this work indicate that biodegradable Gd-chelated cationic poly(urethane amide) copolymers have high potential for tumor theranostics. - Highlights: • Novel cationic gadolinium-chelated poly(urethane amide)s (GdCPUAs) are prepared. • GdCPUAs can induce a high transfection efficacy in different cancer cells. • GdCPUAs reveal good cyto-compatibility against cancer cells. • GdCPUAs may be applied as T{sub 1}-contrast agents for magnetic resonance imaging. • GdCPUAs hold high potential for cancer theranostics.

Biodegradable gadolinium-chelated cationic poly(urethane amide) copolymers for gene transfection and magnetic resonance imaging

International Nuclear Information System (INIS)

Gao, Xiaolong; Wang, Gangmin; Shi, Ting; Shao, Zhihong; Zhao, Peng; Shi, Donglu; Ren, Jie; Lin, Chao; Wang, Peijun

2016-01-01

Theranostic nano-polyplexes containing gene and imaging agents hold a great promise for tumor diagnosis and therapy. In this work, we develop a group of new gadolinium (Gd)-chelated cationic poly(urethane amide)s for gene delivery and T 1 -weighted magnetic resonance (MR) imaging. Cationic poly(urethane amide)s (denoted as CPUAs) having multiple disulfide bonds, urethane and amide linkages were synthesized by stepwise polycondensation reaction between 1,4-bis(3-aminopropyl)piperazine and a mixture of di(4-nitrophenyl)-2, 2′-dithiodiethanocarbonate (DTDE-PNC) and diethylenetriaminepentaacetic acid (DTPA) dianhydride at varied molar ratios. Then, Gd-chelated CPUAs (denoted as GdCPUAs) were produced by chelating Gd(III) ions with DTPA residues of CPUAs. These GdCPUAs could condense gene into nanosized and positively-charged polyplexes in a physiological condition and, however, liberated gene in an intracellular reductive environment. In vitro transfection experiments revealed that the GdCPUA at a DTDE-PNC/DTPA residue molar ratio of 85/15 induced the highest transfection efficiency in different cancer cells. This efficiency was higher than that yielded with 25 kDa branched polyethylenimine as a positive control. GdCPUAs and their polyplexes exhibited low cytotoxicity when an optimal transfection activity was detected. Moreover, GdCPUAs may serve as contrast agents for T 1 -weighted magnetic resonance imaging. The results of this work indicate that biodegradable Gd-chelated cationic poly(urethane amide) copolymers have high potential for tumor theranostics. - Highlights: • Novel cationic gadolinium-chelated poly(urethane amide)s (GdCPUAs) are prepared. • GdCPUAs can induce a high transfection efficacy in different cancer cells. • GdCPUAs reveal good cyto-compatibility against cancer cells. • GdCPUAs may be applied as T 1 -contrast agents for magnetic resonance imaging. • GdCPUAs hold high potential for cancer theranostics.

Synthesis of novel bifunctional chelators and their use in preparing monoclonal antibody conjugates for tumor targeting

International Nuclear Information System (INIS)

Westerberg, D.A.; Carney, P.L.; Rogers, P.E.; Kline, S.J.; Johnson, D.K.

1989-01-01

Bifunctional derivatives of the chelating agents ethylenediaminetetraacetic acid and diethylenetriaminepentaacetic acid, in which a p-isothiocyanatobenzyl moiety is attached at the methylene carbon atom of one carboxymethyl arm, was synthesized by reductive alkylation of the relevant polyamine with (p-nitrophenyl)pyruvic acid followed by carboxymethylation, reduction of the nitro group, and reaction with thiophosgene. The resulting isothiocyanate derivatives reacted with monoclonal antibody B72.3 to give antibody-chelator conjugates containing 3 mol of chelator per mole of immunoglobulin, without significant loss of immunological activity. Such conjugates, labeled with the radioisotopic metal indium-111, selectively bound a human colorectal carcinoma implanted in nude mice when given intravenously. Uptake into normal tissues was comparable to or lower than that reported for analogous conjugates with known bifunctional chelators. It is concluded that substitution with a protein reactive group at this position in polyaminopolycarboxylate chelators does not alter the chelating properties of these molecules to a sufficient extent to adversely affect biodistribution and thus provides a general method for the synthesis of such chelators

STUDIES REGARDING THE CHELATE-INDUCED HYPERACCUMULATION OF CU AND FE USING LOLIUM PERENNE SPECIES IN MINING AREAS

Directory of Open Access Journals (Sweden)

ANCA-DIANA PRICOP

2009-05-01

Full Text Available The plant capacity to absorb high amounts of metal for a short period of time is the major factor that influences the efficiency of phytoextraction. The hyperaccumulating plants uptake high amounts in their tissues correlated to the metal concentrations in soil. Chelating agents have the capacity to induce the metal accumulation in biomass. They increase metal bioavailability for plants by releasing the metal in accessible forms. The present study emphasizes that in the case of EDTA use, the obtained biomass is smaller compared to the other variants, showing a lower tolerance to this chelating agent of Lolium perenne species. Cu and Fe phytoextraction by Lolium perenne species is higher in the case of EDTA use. Cu bioaccumulation has higher values in variants with compost-sterile mixture ratio of 1:4 in comparison with Fe. In the case of the best compost-sterile mixture ratio of 1:3 the highest biomass is obtained in all the variants, biosolids’ effect being stronger compared to the chelating agent.

Intraindividual, randomized comparison of the macrocyclic contrast agents gadobutrol and gadoterate meglumine in breast magnetic resonance imaging

Energy Technology Data Exchange (ETDEWEB)

Fallenberg, Eva M.; Renz, Diane M.; Hamm, Bernd [Charite - Universitaetsmedizin Berlin, Campus Virchow-Klinikum, Department of Radiology, Berlin (Germany); Karle, Bettina [Clinic of Radiation Therapy, Helios Clinics, Berlin (Germany); Schwenke, Carsten [SCOSSIS Statistical Consulting, Berlin (Germany); Ingod-Heppner, Barbara [Charite Universitaetsmedizin, Campus Charite Mitte, Institute of Pathology, Berlin (Germany); Reles, Angela [Charite Universitaetsmedizin, Charite-Partner-Practice, Interdisciplinary Breast Center, Berlin (Germany); Engelken, Florian J. [Charite - Universitaetsmedizin Berlin, Charite Campus Mitte, Department of Radiology, Berlin (Germany); Huppertz, Alexander; Taupitz, Matthias [Charite - Universitaetsmedizin Berlin, Campus Benjamin Franklin, Department of Radiology, Berlin (Germany)

2014-09-25

To compare intraindividually two macrocyclic contrast agents - gadobutrol and gadoterate meglumine (Gd-DOTA) - for dynamic and quantitative assessment of relative enhancement (RE) in benign and malignant breast lesions. This was an ethically approved, prospective, single-centre, randomized, crossover study in 52 women with suspected breast lesions referred for magnetic resonance imaging (MRI). Each patient underwent one examination with gadobutrol and one with Gd-DOTA (0.1 mmol/kg BW) on a 1.5 T system 1 - 7 days apart. Dynamic, T1-weighted, 3D gradient echo sequences were acquired under identical conditions. Quantitative evaluation with at least three regions of interest (ROI) per lesion was performed. Primary endpoint was RE during the initial postcontrast phase after the first and second dynamic acquisition, and peak RE. All lesions were histologically proven; differences between the examinations were evaluated. Forty-five patients with a total of 11 benign and 34 malignant lesions were assessed. Mean RE was significantly higher for gadobutrol than Gd-DOTA (p < 0.0001). Gadobutrol showed significantly less washout (64.4 %) than Gd-DOTA (75.4 %) in malignant lesions (p = 0.048) Gadobutrol has higher RE values compared with Gd-DOTA, whereas Gd-DOTA shows more marked washout in malignant lesions. This might improve the detection of breast lesions and influence the specificity of breast MRI-imaging. (orig.)

⁶⁸Ga-DOTA-TOC-PET/CT detects heart metastases from ileal neuroendocrine tumors.

Science.gov (United States)

Calissendorff, Jan; Sundin, Anders; Falhammar, Henrik

2014-09-01

Metastases from ileal neuroendocrine tumors (NETs) to the myocardium are rare and generally seen in patients with widespread metastatic NET disease. The objectives of this investigation were to describe the frequency of intracardiac metastases in ileal NET patients examined by (68)Ga-DOTA-TOC-PET/CT and to describe the cases in detail. All (68)Ga-DOTA-TOC-PET/CT examinations performed at the Karolinska University Hospital since 2010 until April 2012 were reviewed. In all, 128 out of 337 examinations were in patients with ileal NETs. Four patients had seven myocardiac metastases, yielding a frequency of 4.3 % in patients with ileal NETs. One patient had cardiac surgery while three were treated with somatostatin analogs. The cardiac metastases did not affect the patients' activity of daily life. (68)Ga-DOTA-TOC-PET/CT is an established imaging modality in identifying cardiac metastases in ileal NETs. Prospective studies are needed to confirm the true clinical value of (68)Ga-DOTA-TOC-PET/CT in detecting cardiac metastases in both ileal and non-ileal NETs.

Complexation studies with 90Y from a novel 90Sr-90Y generator

International Nuclear Information System (INIS)

Venkatesh, M.; Pandey, U.; Banerjee, S.; Samuel, G.; Pillai, M.R.A.; Dhami, P.S.; Kannan, R.; Achuthan, P.V.; Chitnis, R.R.; Gopalakrishnan, V.; Ramanujam, A.

2001-01-01

Some features of a novel 90 Sr- 90 Y generator which employs supported liquid membrane (SLM) to separate carrier-free 90 Y from 90 Sr present in the high level waste of the spent fuel of reactor are described. After ascertaining the purity of 90 Y particularly with respect to 90 Sr breakthrough, its complexation was studied with a few oxo/aza donor ligands, such as DTPA, EDTMP, DOTA, TETA and a cyclic phosphonate, CTMP. These studies were primarily carried out to adjudge the quality of the 90 Y obtained from a novel 90 Sr- 90 Y generator and ascertain its usability for labelling biomolecules such as antibodies and peptides. The DOTA complexes are most stable at 37 C in human serum; they appear to be ideal bifunctional chelating agent for use in radioimmunotherapy with 90 Y. (orig.)

Copper chelators: chemical properties and bio-medical applications.

Science.gov (United States)

Tegoni, M; Valensin, D; Toso, L; Remelli, M

2014-01-01

Copper is present in different concentrations and chemical forms throughout the earth crust, surface and deep water and even, in trace amounts, in the atmosphere itself. Copper is one of the first metals used by humans, the first artifacts dating back 10,000 years ago. Currently, the world production of refined copper exceeds 16,000 tons/year. Copper is a micro-element essential to life, principally for its red-ox properties that make it a necessary cofactor for many enzymes, like cytochrome-c oxidase and superoxide dismutase. In some animal species (e.g. octopus, snails, spiders, oysters) copper-hemocyanins also act as carriers of oxygen instead of hemoglobin. However, these red-ox properties also make the pair Cu(+)/Cu(2+) a formidable catalyst for the formation of reactive oxygen species, when copper is present in excess in the body or in tissues. The treatment of choice in cases of copper overloading or intoxication is the chelation therapy. Different molecules are already in clinical use as chelators or under study or clinical trial. It is worth noting that chelation therapy has also been suggested to treat some neurodegenerative diseases or cardiovascular disorders. In this review, after a brief description of the homeostasis and some cases of dyshomeostasis of copper, the main (used or potential) chelators are described; their properties in solution, even in relation to the presence of metal or ligand competitors, under physiological conditions, are discussed. The legislation of the most important Western countries, regarding both the use of chelating agents and the limits of copper in foods, drugs and cosmetics, is also outlined.

Characterization of antibody-chelator conjugates: Determination of chelator content by terbium fluorescence titration

Energy Technology Data Exchange (ETDEWEB)

Brandt, K.D.; Schnobrich, K.E.; Johnson, D.K. (Abbott Laboratories, Department 90M, Abbott Park, IL (United States))

1991-01-01

Fluorescence titrations were performed by adding varying mole ratios of terbium(III) to antibody conjugates formed by benzyl isothiocyanate derivatives of three different polyaminopolycarboxylate chelators (NTA, EDTA, and DTPA) and the results compared to values for average chelator content obtained by cobalt-57 binding assays. For two different murine monoclonal antibodies, the average chelator content obtained by terbium fluorescence titration correlated closely with that measured by the cobalt-57 binding assay. It is concluded that lanthanide fluorescence titrations provide a useful alternative to radiometal binding assays for the determination of chelator content in protein-chelator conjugates.

Characterization of antibody-chelator conjugates: Determination of chelator content by terbium fluorescence titration

International Nuclear Information System (INIS)

Brandt, K.D.; Schnobrich, K.E.; Johnson, D.K.

1991-01-01

Fluorescence titrations were performed by adding varying mole ratios of terbium(III) to antibody conjugates formed by benzyl isothiocyanate derivatives of three different polyaminopolycarboxylate chelators (NTA, EDTA, and DTPA) and the results compared to values for average chelator content obtained by cobalt-57 binding assays. For two different murine monoclonal antibodies, the average chelator content obtained by terbium fluorescence titration correlated closely with that measured by the cobalt-57 binding assay. It is concluded that lanthanide fluorescence titrations provide a useful alternative to radiometal binding assays for the determination of chelator content in protein-chelator conjugates

REVIEW ARTICLE:Future of Lead Chelation – Distribution and Treatment

Directory of Open Access Journals (Sweden)

Venkatesh Thuppil

2012-01-01

Full Text Available Lead is the major environmental toxin resulting in the ill health and deleterious effect on almost all organs in the human body in a slow and effective manner. The best treatment for lead poisoning is chelation therapy which is next only to prevention. The authors describe the disruption of homeostasis of the human body by lead in various tissues like blood, bones, liver, kidneys and brain; and the ability of lead to enter the cell using calcium channels and calcium receptors like Ca++ dependant K+ ion channels, transient receptor potential channels, T-tubules, calmodulin receptors, inositol trisphosphate receptors and ryanodine receptors. We report a few novel chelating agents like ionophores, decadentate ligands, picolinate ligands, octadentate ligand, allicin, thiamine, that show good potential for being used in chelation therapy. Future of leadpoisoning is a challenge to all and it needs to be meticulously studies to have an economic and health approach.

Chelate chase of radiopharmaceuticals reversibly bound to monoclonal antibodies improves dosimetry

International Nuclear Information System (INIS)

Goodwin, D.A.; Smith, S.I.; Meares, C.F.; David, G.S.; McTigue, M.; Finston, R.A.

1986-01-01

One hundred micrograms of monoclonal antibody (MoAb) CHA 255 with a binding constant Kb of 4 x 10 9 was complexed with indium-111 labeled BLEDTA II, GLEDTA IV, benzyl EDTA, and an EDTA conjugate of Fab. The 24-hour tumor and organ distribution in BALB/c mice bearing KHJJ tumors was studied for each compound alone, the antibody complex, and 3 hours following a chelate chase of the antibody complex. Whole-body biological half-life was measured for 7 days with and without a chelate chase for each antibody complex. The 24-hour whole-body counts dropped 20-60% within 3 hours of administering the chelate chase. Blood concentration fell over 89% within 3 hours of administering the chase and there was a decrease in concentration in all organs, except the kidneys, of 10 to 85%. Theoretical equivalent human doses were calculated from the 24-hour organ concentrations, effective half-life, and MIRD 11 S values (absorbed dose per cumulated activity). Liver and spleen were the target organs, with the dose ranging from 0.50 to 3.91 rads per millicurie. The reduction in organ radiation dose varied up to 95% following the chelate chase. Rapid selective renal clearance of chelate labeled radiopharmaceuticals by competitive inhibition (chelate chase) of their reversible binding to monoclonal antibodies, greatly improves the radiation dosimetry of tumor imaging agents. 28 references, 5 figures, 5 tables

Comparison of 68Ga-DOTA-Siglec-9 and 18F-Fluorodeoxyribose-Siglec-9: Inflammation Imaging and Radiation Dosimetry.

Science.gov (United States)

Virtanen, Helena; Silvola, Johanna M U; Autio, Anu; Li, Xiang-Guo; Liljenbäck, Heidi; Hellberg, Sanna; Siitonen, Riikka; Ståhle, Mia; Käkelä, Meeri; Airaksinen, Anu J; Helariutta, Kerttuli; Tolvanen, Tuula; Veres, Tibor Z; Saraste, Antti; Knuuti, Juhani; Jalkanen, Sirpa; Roivainen, Anne

2017-01-01

Sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) is a ligand of inflammation-inducible vascular adhesion protein-1 (VAP-1). We compared 68 Ga-DOTA- and 18 F-fluorodeoxyribose- (FDR-) labeled Siglec-9 motif peptides for PET imaging of inflammation. Methods . Firstly, we examined 68 Ga-DOTA-Siglec-9 and 18 F-FDR-Siglec-9 in rats with skin/muscle inflammation. We then studied 18 F-FDR-Siglec-9 for the detection of inflamed atherosclerotic plaques in mice and compared it with previous 68 Ga-DOTA-Siglec-9 results. Lastly, we estimated human radiation dosimetry from the rat data. Results . In rats, 68 Ga-DOTA-Siglec-9 (SUV, 0.88 ± 0.087) and 18 F-FDR-Siglec-9 (SUV, 0.77 ± 0.22) showed comparable ( P = 0.29) imaging of inflammation. In atherosclerotic mice, 18 F-FDR-Siglec-9 detected inflamed plaques with a target-to-background ratio (1.6 ± 0.078) similar to previously tested 68 Ga-DOTA-Siglec-9 ( P = 0.35). Human effective dose estimates for 68 Ga-DOTA-Siglec-9 and 18 F-FDR-Siglec-9 were 0.024 and 0.022 mSv/MBq, respectively. Conclusion . Both tracers are suitable for PET imaging of inflammation. The easier production and lower cost of 68 Ga-DOTA-Siglec-9 present advantages over 18 F-FDR-Siglec-9, indicating it as a primary choice for clinical studies.

Effects of iron(III)chelates on the solubility of heavy metals in calcareous soils

Energy Technology Data Exchange (ETDEWEB)

Ylivainio, Kari, E-mail: kari.ylivainio@mtt.f [Department of Applied Chemistry and Microbiology, FIN-00014 University of Helsinki (Finland)

2010-10-15

In this study I evaluated the effects of complexing agents on the solubility of heavy metals in an incubation experiment up to 56 days when complexing agents were applied as Fe-chelates (Fe-EDDS(S,S), Fe-EDDS(mix), Fe-EDTA and Fe-EDDHA) on calcareous soils at a level sufficient to correct Fe chlorosis (0.1 mmol kg{sup -1}). Of these ligands, EDDHA was the most efficient in keeping Fe in water-soluble form, and EDDS increased the solubility of Cu and Zn most, and only EDTA increased the solubility of Cd and Pb. EDTA increased the solubility of Ni steadily during the incubation period, equalling about 5-8% of the added EDTA concentration. [S,S]-EDDS was biodegraded within 56 days, whereas EDDS(mix) was less biodegradable. Ni-chelates were the most recalcitrant against biodegradation. The study shows that even a moderate input of chelates to soil increases the solubility of toxic heavy metals and their risk of leaching. - When correcting Fe chlorosis Fe-EDDS causes lower environmental concern than Fe-EDTA.

Effects of iron(III)chelates on the solubility of heavy metals in calcareous soils

International Nuclear Information System (INIS)

Ylivainio, Kari

2010-01-01

In this study I evaluated the effects of complexing agents on the solubility of heavy metals in an incubation experiment up to 56 days when complexing agents were applied as Fe-chelates (Fe-EDDS(S,S), Fe-EDDS(mix), Fe-EDTA and Fe-EDDHA) on calcareous soils at a level sufficient to correct Fe chlorosis (0.1 mmol kg -1 ). Of these ligands, EDDHA was the most efficient in keeping Fe in water-soluble form, and EDDS increased the solubility of Cu and Zn most, and only EDTA increased the solubility of Cd and Pb. EDTA increased the solubility of Ni steadily during the incubation period, equalling about 5-8% of the added EDTA concentration. [S,S]-EDDS was biodegraded within 56 days, whereas EDDS(mix) was less biodegradable. Ni-chelates were the most recalcitrant against biodegradation. The study shows that even a moderate input of chelates to soil increases the solubility of toxic heavy metals and their risk of leaching. - When correcting Fe chlorosis Fe-EDDS causes lower environmental concern than Fe-EDTA.

Effects of iron(III)chelates on the solubility of heavy metals in calcareous soils.

Science.gov (United States)

Ylivainio, Kari

2010-10-01

In this study I evaluated the effects of complexing agents on the solubility of heavy metals in an incubation experiment up to 56 days when complexing agents were applied as Fe-chelates (Fe-EDDS(S,S), Fe-EDDS(mix), Fe-EDTA and Fe-EDDHA) on calcareous soils at a level sufficient to correct Fe chlorosis (0.1 mmol kg(-1)). Of these ligands, EDDHA was the most efficient in keeping Fe in water-soluble form, and EDDS increased the solubility of Cu and Zn most, and only EDTA increased the solubility of Cd and Pb. EDTA increased the solubility of Ni steadily during the incubation period, equalling about 5-8% of the added EDTA concentration. [S,S]-EDDS was biodegraded within 56 days, whereas EDDS(mix) was less biodegradable. Ni-chelates were the most recalcitrant against biodegradation. The study shows that even a moderate input of chelates to soil increases the solubility of toxic heavy metals and their risk of leaching. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Chelating polymeric membranes

KAUST Repository

Peinemann, Klaus-Viktor; Villalobos Vazquez de la Parra, Luis Francisco; Hilke, Roland

2015-01-01

microporous chelating polymeric membrane. Embodiments include, but are not limited to, microporous chelating polymeric membranes, device comprising the membranes, and methods of using and making the same.

Investigation on the influence of metal ion impurities on the complexation behavior of generator produced {sup 90}Y with bifunctional chelators

Energy Technology Data Exchange (ETDEWEB)

Pandey, Usha; Gamre, Naresh; Dash, Ashutosh [Isotope Applications and Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai (India)

2014-05-01

The {sup 90}Sr/ {sup 90}Y generator is the exclusive source of 'no carrier added' {sup 90}Y for targeted therapy. However, the concomitant presence of trace metals diminishes the complexation of {sup 90}Y with bifunctional chelators (BFCs). A systematic investigation was performed to evaluate the influence of trace metals on the complexation of {sup 90}Y (from an electrochemical generator) with BFCs such as p-SCN-Bn-PCTA, p-SCN-Bn-DTPA and p-SCN-Bn-DOTA. Our study indicates that while p-SCN-Bn-DTPA was least affected by most of the trace metals studied, p-SCN-Bn-PCTA was most sensitive to their presence and hence could be the ligand of choice for assessing the chemical purity of generator derived {sup 90}Y. (author)

In Vitro Cytotoxicity of Low-Dose-Rate Radioimmunotherapy by the Alpha-Emitting Radioimmunoconjugate Thorium-227-DOTA-Rituximab

International Nuclear Information System (INIS)

Dahle, Jostein; Krogh, Cecilie; Melhus, Katrine B.; Borrebaek, Jorgen; Larsen, Roy H.; Kvinnsland, Yngve

2009-01-01

Purpose: To determine whether the low-dose-rate α-particle-emitting radioimmunoconjugate 227 Th-1,4,7,10-p-isothiocyanato-benzyl-tetraazacyclododecane-1,4,7, 10-tetraacetic acid (DOTA)-rituximab can be used to inactivate lymphoma cells growing as single cells and small colonies. Methods and Materials: CD20-positive lymphoma cell lines were treated with 227 Th-DOTA-rituximab for 1-5 weeks. To simulate the in vivo situation with continuous but decreasing supply of radioimmunoconjugates from the blood pool, the cells were not washed after incubation with 227 Th-DOTA-rituximab, but half of the medium was replaced with fresh medium, and cell concentration and cell-bound activity were determined every other day after start of incubation. A microdosimetric model was established to estimate the average number of hits in the nucleus for different localizations of activity. Results: There was a specific targeted effect on cell growth of the 227 Th-DOTA-rituximab treatment. Although the cells were not washed after incubation with 227 Th-DOTA-rituximab, the average contribution of activity in the medium to the mean dose was only 6%, whereas the average contribution from activity on the cells' own surface was 78%. The mean dose rates after incubation with 800 Bq/mL 227 Th-DOTA-rituximab varied from 0.01 to 0.03 cGy/min. The average delay in growing from 10 5 to 10 7 cells/mL was 15 days when the cells were treated with a mean absorbed radiation dose of 2 Gy α-particle radiation from 227 Th-DOTA-rituximab, whereas it was 11 days when the cells were irradiated with 6 Gy of X-radiation. The relative biologic effect of the treatment was estimated to be 2.9-3.4. Conclusions: The low-dose-rate radioimmunoconjugate 227 Th-DOTA-rituximab is suitable for inactivation of single lymphoma cells and small colonies of lymphoma cells.

Quantitative Gd-DOTA uptake from cerebrospinal fluid into rat brain using 3D VFA-SPGR at 9.4T.

Science.gov (United States)

Lee, Hedok; Mortensen, Kristian; Sanggaard, Simon; Koch, Palle; Brunner, Hans; Quistorff, Bjørn; Nedergaard, Maiken; Benveniste, Helene

2018-03-01

We propose a quantitative technique to assess solute uptake into the brain parenchyma based on dynamic contrast-enhanced MRI (DCE-MRI). With this approach, a small molecular weight paramagnetic contrast agent (Gd-DOTA) is infused in the cerebral spinal fluid (CSF) and whole brain gadolinium concentration maps are derived. We implemented a 3D variable flip angle spoiled gradient echo (VFA-SPGR) longitudinal relaxation time (T1) technique, the accuracy of which was cross-validated by way of inversion recovery rapid acquisition with relaxation enhancement (IR-RARE) using phantoms. Normal Wistar rats underwent Gd-DOTA infusion into CSF via the cisterna magna and continuous MRI for approximately 130 min using T1-weighted imaging. Dynamic Gd-DOTA concentration maps were calculated and parenchymal uptake was estimated. In the phantom study, T1 discrepancies between the VFA-SPGR and IR-RARE sequences were approximately 6% with a transmit coil inhomogeneity correction. In the in vivo study, contrast transport profiles indicated maximal parenchymal retention of approximately 19% relative to the total amount delivered into the cisterna magna. Imaging strategies for accurate 3D contrast concentration mapping at 9.4T were developed and whole brain dynamic concentration maps were derived to study solute transport via the glymphatic system. The newly developed approach will enable future quantitative studies of the glymphatic system in health and disease states. Magn Reson Med 79:1568-1578, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.