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Sample records for evaluate chelator conjugation

  1. Photocatalysts Based on Cobalt-chelating Conjugated Polymers for Hydrogen Evolution from Water

    Energy Technology Data Exchange (ETDEWEB)

    Li, Lianwei; Hadt, Ryan G.; Yao, Shiyu; Lo, Waiyip; Cai, Zhengxu; Wu, Qingliu; Pandit, Bill; Chen, Lin X.; Yu, Luping

    2016-08-09

    Developing photocatalytic systems for water splitting to generate oxygen and hydrogen is one of the biggest chemical challenges in solar energy utilization. In this work, we report the first example of heterogeneous photocatalysts for hydrogen evolution based on in-chain cobalt-chelating conjugated polymers. Four conjugated polymers chelated with earth abundant cobalt ions were synthesized and found to evolve hydrogen photocatalytically from water. These polymers are designed to combine functions of the conjugated backbone as light-harvesting antenna and electron transfer conduit with the in-chain bipyridyl chelated transition metal centers as catalytic active sites. In addition, these polymers are soluble in organic solvents, enabling effective interactions with the substrates as well as detailed characterization. We also found a polymer-dependent optimal cobalt chelating concentration at which the highest photocatalytic hydrogen production (PHP) activity can be achieved.

  2. Conjugates of magnetic nanoparticle-actinide specific chelator for radioactive waste separation.

    Science.gov (United States)

    Kaur, Maninder; Zhang, Huijin; Martin, Leigh; Todd, Terry; Qiang, You

    2013-01-01

    A novel nanotechnology for the separation of radioactive waste that uses magnetic nanoparticles (MNPs) conjugated with actinide specific chelators (MNP-Che) is reviewed with a focus on design and process development. The MNP-Che separation process is an effective way of separating heat generating minor actinides (Np, Am, Cm) from spent nuclear fuel solution to reduce the radiological hazard. It utilizes coated MNPs to selectively adsorb the contaminants onto their surfaces, after which the loaded particles are collected using a magnetic field. The MNP-Che conjugates can be recycled by stripping contaminates into a separate, smaller volume of solution, and then become the final waste form for disposal after reusing number of times. Due to the highly selective chelators, this remediation method could be both simple and versatile while allowing the valuable actinides to be recovered and recycled. Key issues standing in the way of large-scale application are stability of the conjugates and their dispersion in solution to maintain their unique properties, especially large surface area, of MNPs. With substantial research progress made on MNPs and their surface functionalization, as well as development of environmentally benign chelators, this method could become very flexible and cost-effective for recycling used fuel. Finally, the development of this nanotechnology is summarized and its future direction is discussed.

  3. Conjugates of Magnetic Nanoparticle -- Actinide Specific Chelator for Radioactive Waste Separation

    Energy Technology Data Exchange (ETDEWEB)

    Maninder Kaur; Huijin Zhang; Leigh Martin; Terry Todd; You Qiang

    2013-11-01

    A novel nanotechnology for the separation of radioactive waste that uses magnetic nanoparticles (MNPs) conjugated with actinide specific chelators (MNP-Che) is reviewed with a focus on design and process development. The MNP-Che separation process is an effective way of separating heat generating minor actinides (Np, Am, Cm) from spent nuclear fuel solution to reduce the radiological hazard. It utilizes coated MNPs to selectively adsorb the contaminants onto their surfaces, after which the loaded particles are collected using a magnetic field. The MNP-Che conjugates can be recycled by stripping contaminates into a separate, smaller volume of solution, and then become the final waste form for disposal after reusing number of times. Due to the highly selective chelators, this remediation method could be both simple and versatile while allowing the valuable actinides to be recovered and recycled. Key issues standing in the way of large-scale application are stability of the conjugates and their dispersion in solution to maintain their unique properties, especially large surface area, of MNPs. With substantial research progress made on MNPs and their surface functionalization, as well as development of environmentally benign chelators, this method could become very flexible and cost-effective for recycling used fuel. Finally, the development of this nanotechnology is summarized and its future direction is discussed.

  4. Synthesis, structural characterization, and electrochemical studies of nickel porphyrins bearing two peripheral conjugated chelating groups.

    Science.gov (United States)

    Richeter, Sébastien; Jeandon, Christophe; Gisselbrecht, Jean-Paul; Ruppert, Romain; Callot, Henry J

    2007-11-26

    This article describes the synthesis of several new nickel porphyrins bearing peripheral chelating groups conjugated with the macrocyclic pi system. These monomeric nickel porphyrins display quite unusual chromophoric properties, some of them absorbing in the near-infrared region. Extension of the aromatic core of the porphyrin was realized by connecting meso-aryl groups with pyrroles by ketone functionalities. Further functionalizations led to bisenaminoketones or bisenaminothioketones, which are useful building blocks for the elaboration of oligomeric porphyrins linked by metal ions. All new compounds were studied by electrochemistry, some of them showing up to six electron transfers and/or splitting of the first oxidation wave.

  5. Conjugation, immunoreactivity, and immunogenicity of calix[4]arenes; model study to potential calix[4]arene-based Ac3+ chelators

    NARCIS (Netherlands)

    Grote Gansey, Marcel H.B.; Grote gansey, M.H.B.; de Haan, Annemarie S.; Bos, Ebo S.; Verboom, Willem; Reinhoudt, David

    1999-01-01

    For the development of calix[4]arene-based radiotherapeutic agents, the conjugation to biomolecules and immunogenicity in mice of potential 225Ac3+-chelating calix[4]arenes were studied. A calix[4]arene triethyl ester isothiocyanate and a bis(calix[4]arene) hexacarboxylic acid, containing a masked

  6. pi-Conjugated chelating polymers with charged iridium complexes in the backbones: synthesis, characterization, energy transfer, and electrochemical properties.

    Science.gov (United States)

    Liu, Shu-Juan; Zhao, Qiang; Chen, Run-Feng; Deng, Yun; Fan, Qu-Li; Li, Fu-You; Wang, Lian-Hui; Huang, Chun-Hui; Huang, Wei

    2006-05-24

    A series of pi-conjugated chelating polymers with charged iridium (Ir) complexes in the backbones were synthesized by a Suzuki polycondensation reaction, leading to homogeneous polymeric materials that phosphoresce red light. The fluorene and bipyridine (bpy) segments were used as polymer backbones. 5,5'-Dibromobipyridine served as a ligand to form a charged iridium complex monomer with 1-(9'9-dioctylfluorene-2-yl)isoquinoline (Fiq) as the cyclometalated ligand. Chemical and photophysical characterization confirmed that Ir complexes were incorporated into the backbones as one of the repeat units by means of the 5,5'-dibromobipyridine ligand. Chelating polymers showed almost complete energy transfer from the host fluorene segments to the guest Ir complexes in the solid state when the feed ratio was 2 mol %. In the films of the corresponding blend system, however, energy transfer was not complete even when the content of Ir complexes was as high as 16 mol %. Both intra- and intermolecular energy-transfer processes existed in this host-guest system, and the intramolecular energy transfer was a more efficient process. All chelating polymers displayed good thermal stability, redox reversibility, and film formation. These chelating polymers also showed more efficient energy transfer than the corresponding blended system and the mechanism of incorporation of the charged Ir complexes into the pi-conjugated polymer backbones efficiently avoided the intrinsic problems associated with the blend system, thus offering promise in optoelectronic applications.

  7. Spectrophotometric Determination and Removal of Unchelated Europium Ions from Solutions Containing Eu-Diethylenetriaminepentaacetic Acid Chelate-Peptide Conjugates1

    Science.gov (United States)

    Dayan Elshan, N. G. R.; Patek, Renata; Vagner, Josef; Mash, Eugene A.

    2014-01-01

    Europium chelates conjugated with peptide ligands are routinely used as probes for conducting in vitro binding experiments. The presence of unchelated Eu ions in these formulations gives high background luminescence and can lead to poor results in binding assays. In our experience, the reported methods for purification of these probes do not achieve adequate removal of unchelated metal ions in a reliable manner. In this work, a xylenol orange-based assay for the quantification of unchelated metal ions was streamlined and used to determine levels of metal ion contamination, as well as the success of metal ion removal upon attempted purification. We compared the use of Empore™ chelating disks and Chelex® 100 resin for the selective removal of unchelated Eu ions from several Eu-diethylenetriaminepentaacetic acid chelate-peptide conjugates. Both purification methods gave complete and selective removal of the contaminant metal ions. However, Empore™ chelating disks were found to give much higher recoveries of the probes under the conditions utilized. Related to the issue of probe recovery, we also describe a significantly more efficient method for the synthesis of one such probe using Rink amide AM resin in place of Tentagel S resin. PMID:25058927

  8. Spectrophotometric determination and removal of unchelated europium ions from solutions containing Eu-diethylenetriaminepentaacetic acid chelate-peptide conjugates.

    Science.gov (United States)

    Elshan, N G R Dayan; Patek, Renata; Vagner, Josef; Mash, Eugene A

    2014-11-01

    Europium chelates conjugated with peptide ligands are routinely used as probes for conducting in vitro binding experiments. The presence of unchelated Eu ions in these formulations gives high background luminescence and can lead to poor results in binding assays. In our experience, the reported methods for purification of these probes do not achieve adequate removal of unchelated metal ions in a reliable manner. In this work, a xylenol orange-based assay for the quantification of unchelated metal ions was streamlined and used to determine levels of metal ion contamination as well as the success of metal ion removal on attempted purification. We compared the use of Empore chelating disks and Chelex 100 resin for the selective removal of unchelated Eu ions from several Eu-diethylenetriaminepentaacetic acid chelate-peptide conjugates. Both purification methods gave complete and selective removal of the contaminant metal ions. However, Empore chelating disks were found to give much higher recoveries of the probes under the conditions used. Related to the issue of probe recovery, we also describe a significantly more efficient method for the synthesis of one such probe using Rink amide AM resin in place of Tentagel S resin. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Evaluation of macrocyclic hydroxyisophthalamide ligands as chelators for zirconium-89.

    Directory of Open Access Journals (Sweden)

    Nikunj B Bhatt

    Full Text Available The development of bifunctional chelators (BFCs for zirconium-89 immuno-PET applications is an area of active research. Herein we report the synthesis and evaluation of octadentate hydroxyisophthalamide ligands (1 and 2 as zirconium-89 chelators. While both radiometal complexes could be prepared quantitatively and with excellent specific activity, preparation of 89Zr-1 required elevated temperature and an increased reaction time. 89Zr-1 was more stable than 89Zr-2 when challenged in vitro by excess DTPA or serum proteins and in vivo during acute biodistribution studies. Differences in radiometal complex stability arise from structural changes between the two ligand systems, and suggest further ligand optimization is necessary to enhance 89Zr chelation.

  10. HPMA Copolymer–Doxorubicin–Gadolinium Conjugates: Synthesis, Characterization, and in vitro Evaluation

    Science.gov (United States)

    Zarabi, Bahar; Nan, Anjan; Zhuo, Jiachen; Gullapalli, Rao; Ghandehari, Hamidreza

    2009-01-01

    This study describes the synthesis, characterization, and in vitro evaluation of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer–gadolinium (Gd)–doxorubicin (Dox) conjugates. Copolymers of HPMA were derivatized to incorporate side chains for Gd chelation and Dox conjugation. The conjugates were characterized by their side chain contents, T1 relaxivity (r1), stability, and in vitro cytotoxicity. High stability and relaxivity of these conjugates coupled with low toxicity show their potential for monitoring the in vivo fate of HPMA-based drug delivery systems by magnetic resonance imaging techniques. PMID:18484565

  11. Conjugates of Actinide Chelator-Magnetic Nanoparticles for Used Fuel Separation Technology

    Energy Technology Data Exchange (ETDEWEB)

    Qiang, You; Paszczynski, Andrzej; Rao, Linfeng

    2011-10-30

    The actinide separation method using magnetic nanoparticles (MNPs) functionalized with actinide specific chelators utilizes the separation capability of ligand and the ease of magnetic separation. This separation method eliminated the need of large quantity organic solutions used in the liquid-liquid extraction process. The MNPs could also be recycled for repeated separation, thus this separation method greatly reduces the generation of secondary waste compared to traditional liquid extraction technology. The high diffusivity of MNPs and the large surface area also facilitate high efficiency of actinide sorption by the ligands. This method could help in solving the nuclear waste remediation problem.

  12. Design, synthesis and evaluation of novel bifunctional tetrahydroxamate chelators for PET imaging of (89)Zr-labeled antibodies.

    Science.gov (United States)

    Rousseau, Julie; Zhang, Zhengxing; Dias, Gemma M; Zhang, Chengcheng; Colpo, Nadine; Bénard, François; Lin, Kuo-Shyan

    2017-02-15

    Two compact and symmetrical bifunctional tetrahydroxamate chelators, 1 and 2, were synthesized and evaluated for labeling antibodies with (89)Zr for imaging with positron emission tomography. Using 2,2'-iminodiacetamide as the backbone, four hydroxamate-containing moieties coupled to the diacetamide nitrogen were used for (89)Zr labeling, while a pendant connected to the amino group provided an isothiocyanate group for coupling to the antibody. Both 1- and 2-conjugated Trastuzumab were labeled with (89)Zr efficiently (>90% radiolabeling yield), and their (89)Zr-labeled products maintained comparable immunoreactivity to Trastuzumab. Compared to (89)Zr-labeled deferoxamine-conjugated Trastuzumab, (89)Zr-1- and (89)Zr-2-Trastuzumab showed faster demetalation in mouse plasma, and also displayed higher bone uptake in mice. Despite suboptimal stability of (89)Zr complexes of 1 and 2, our design strategy led to tetrahydroxamate chelators for efficient (89)Zr labeling, and could be potentially modified to provide novel chelators with improved stability. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. 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.

  14. Site-specific conjugation of a lanthanide chelator and its effects on the chemical synthesis and receptor binding affinity of human relaxin-2 hormone

    Energy Technology Data Exchange (ETDEWEB)

    Shabanpoor, Fazel [Florey Neuroscience Institutes, The University of Melbourne, Parkville, VIC 3010 (Australia); School of Chemistry, The University of Melbourne, Parkville, VIC 3010 (Australia); Bathgate, Ross A.D.; Belgi, Alessia [Florey Neuroscience Institutes, The University of Melbourne, Parkville, VIC 3010 (Australia); Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, VIC 3010 (Australia); Chan, Linda J.; Nair, Vinojini B.; Wade, John D. [Florey Neuroscience Institutes, The University of Melbourne, Parkville, VIC 3010 (Australia); School of Chemistry, The University of Melbourne, Parkville, VIC 3010 (Australia); Hossain, Mohammed Akhter, E-mail: akhter.hossain@florey.edu.au [Florey Neuroscience Institutes, The University of Melbourne, Parkville, VIC 3010 (Australia); School of Chemistry, The University of Melbourne, Parkville, VIC 3010 (Australia)

    2012-04-06

    Highlights: Black-Right-Pointing-Pointer A mono-Eu-DTPA conjugated peptide ligand, Eu-DTPA-(A)-H2, has been developed. Black-Right-Pointing-Pointer The choice of a site for incorporation of a chelator is critical. Black-Right-Pointing-Pointer The labeled peptide retains full activity at the RXFP1 receptor. Black-Right-Pointing-Pointer It is markedly cheaper to produce and easier to use than radioactive probes. -- Abstract: Diethylenetriamine pentaacetic acid (DTPA) is a popular chelator agent for enabling the labeling of peptides for their use in structure-activity relationship study and biodistribution analysis. Solid phase peptide synthesis was employed to couple this commercially available chelator at the N-terminus of either the A-chain or B-chain of H2 relaxin. The coupling of the DTPA chelator at the N-terminus of the B-chain and subsequent loading of a lanthanide (europium) ion into the chelator led to a labeled peptide (Eu-DTPA-(B)-H2) in low yield and having very poor water solubility. On the other hand, coupling of the DTPA and loading of Eu at the N-terminus of the A-chain led to a water-soluble peptide (Eu-DTPA-(A)-H2) with a significantly improved final yield. The conjugation of the DTPA chelator at the N-terminus of the A-chain did not have any impact on the secondary structure of the peptide determined by circular dichroism spectroscopy (CD). On the other hand, it was not possible to determine the secondary structure of Eu-DTPA-(B)-H2 because of its insolubility in phosphate buffer. The B-chain labeled peptide Eu-DTPA-(B)-H2 required solubilization in DMSO prior to carrying out binding assays, and showed lower affinity for binding to H2 relaxin receptor, RXFP1, compared to the water-soluble A-chain labeled peptide Eu-DTPA-(A)-H2. The mono-Eu-DTPA labeled A-chain peptide, Eu-DTPA-(A)-H2, thus can be used as a valuable probe to study ligand-receptor interactions of therapeutically important H2 relaxin analogs. Our results show that it is critical to

  15. Evaluation of the chelating effect of methanolic extract of ...

    African Journals Online (AJOL)

    Background: The rate of lead poisoning has decreased in recent years due to increased health control in industries that use this metal. However, it is still a public health problem worldwide. The use of various plants with chelating properties has been a topic of research today. In traditional medicine, it is said that Coriandrum ...

  16. DOTA-Functionalized Polylysine: A High Number of DOTA Chelates Positively Influences the Biodistribution of Enzymatic Conjugated Anti-Tumor Antibody chCE7agl

    OpenAIRE

    Gr?nberg, J?rgen; Jeger, Simone; Sarko, Dikran; Dennler, Patrick; Zimmermann, Kurt; Mier, Walter; Schibli, Roger

    2013-01-01

    Site-specific enzymatic reactions with microbial transglutaminase (mTGase) lead to a homogenous species of immunoconjugates with a defined ligand/antibody ratio. In the present study, we have investigated the influence of different numbers of 1,4,7,10-tetraazacyclododecane-N-N'-N''-N'''-tetraacetic acid (DOTA) chelats coupled to a decalysine backbone on the in vivo behavior of the chimeric monoclonal anti-L1CAM antibody chCE7agl. The enzymatic conjugation of (DOTA)1-decalysine, (DOTA)3-decaly...

  17. Synthesis of new porphyrins with peripheral conjugated chelates and their use for the preparation of porphyrin dimers linked by metal ions.

    Science.gov (United States)

    Richeter, Sébastien; Jeandon, Christophe; Gisselbrecht, Jean-Paul; Graff, Roland; Ruppert, Romain; Callot, Henry J

    2004-01-12

    This article describes the preparation of several new porphyrins bearing chelating peripheral groups fully conjugated with the macrocyclic pi-system. Treatment of a 2-nitro-meso-tetraarylporphyrin with phosphite gave a cyclic enamine, whose formylation gave an enaminoaldehyde. The thio analogue was obtained on treatment with Lawesson's reagent. The same reagent was also used to obtain the isomeric thioenaminoketone chelates. A enaminoketone ligand was prepared from a porphyrinic pyrrolone. All these ligands, as internal nickel complexes, could be metalated with palladium to yield porphyrinic dimers. The dimers obtained from enaminoketones and thioketones show a trans geometry, while in the enaminoaldehyde and -thioaldehyde series the cis isomer is thermodynamically favored. The bathochromic shifts of the electronic spectra of the aldehyde-derived dimers illustrate the strong electronic effect of peripheral metalation and dimerization. However, in the case of the pyrrolone-derived ligand, opposite effects were observed, due to partial reconstitution of the porphyrin chromophore on complexation. As with the dimers derived from enaminoketones, the dimers derived from the new ligands show typical splitting (up to 190 mV) of the electrochemical waves confirming large porphyrin-porphyrin interactions.

  18. DOTA-functionalized polylysine: a high number of DOTA chelates positively influences the biodistribution of enzymatic conjugated anti-tumor antibody chCE7agl.

    Directory of Open Access Journals (Sweden)

    Jürgen Grünberg

    Full Text Available Site-specific enzymatic reactions with microbial transglutaminase (mTGase lead to a homogenous species of immunoconjugates with a defined ligand/antibody ratio. In the present study, we have investigated the influence of different numbers of 1,4,7,10-tetraazacyclododecane-N-N'-N''-N'''-tetraacetic acid (DOTA chelats coupled to a decalysine backbone on the in vivo behavior of the chimeric monoclonal anti-L1CAM antibody chCE7agl. The enzymatic conjugation of (DOTA1-decalysine, (DOTA3-decalysine or (DOTA5-decalysine to the antibody heavy chain (via Gln295/297 gave rise to immunoconjugates containing two, six or ten DOTA moieties respectively. Radiolabeling of the immunoconjugates with (177Lu yielded specific activities of approximately 70 MBq/mg, 400 MBq/mg and 700 MBq/mg with increasing numbers of DOTA chelates. Biodistribution experiments in SKOV3ip human ovarian cancer cell xenografts demonstrated a high and specific accumulation of radioactivity at the tumor site for all antibody derivatives with a maximal tumor accumulation of 43.6±4.3% ID/g at 24 h for chCE7agl-[(DOTA-decalysine]2, 30.6±12.0% ID/g at 24 h for chCE7agl-[(DOTA3-decalysine]2 and 49.9±3.1% ID/g at 48 h for chCE7agl-[(DOTA5-decalysine]2. The rapid elimination from the blood of chCE7agl-[(DOTA-decalysine]2 (1.0±0.1% ID/g at 24 h is associated with a high liver accumulation (23.2±4.6% ID/g at 24 h. This behavior changed depending on the numbers of DOTA moieties coupled to the decalysine peptide with a slower blood clearance (5.1±1.0 (DOTA3 versus 11.7±1.4% ID/g (DOTA5, p<0.005 at 24 h and lower radioactivity levels in the liver (21.4±3.4 (DOTA3 versus 5.8±0.7 (DOTA5, p<0.005 at 24 h. We conclude that the site-specific and stoichiometric uniform conjugation of the highly DOTA-substituted decalysine ((DOTA5-decalysine to an anti-tumor antibody leads to the formation of immunoconjugates with high specific activity and excellent in vivo behavior and is a valuable option for

  19. Evaluation of mutagenic/antimutagenic activity of conjugated linoleic ...

    African Journals Online (AJOL)

    Evaluation of mutagenic/antimutagenic activity of conjugated linoleic acid in mice by micronucleus test. LBD Carvalho-Silva, MDV Oliveira, DT Konichi, MR Maróstica JR, PCB Lollo, J Amaya-Farfán ...

  20. Iron Chelation

    Science.gov (United States)

    Skip to main content Menu Donate Treatments Therapies Iron Chelation Iron chelation therapy is the main treatment ... have iron overload and need treatment. What is iron overload? Iron chelation therapy is used when you ...

  1. The evaluation of chelating agents on cat’s periradicular tissues

    Directory of Open Access Journals (Sweden)

    Razmi H.

    2001-09-01

    Full Text Available "nAbstract: The cleaning and shaping of root canals is one of the most important proccesses in endodontics. In many cases, the physiologic or pathologic proccedures can affect the canals. So, using the instruments and materials, which could be applied in cleaning and shaping of narrow canals is necessary. The aim of this study was the evaluation of Iranian and foreign chelating agents on periradicular tissue of cats. After cleaning and shaping of canals in 18 lower canines of cats, the original RC-Prep and an Iranian chelating agents were placed equally in two groups with 9 teeth in each one. The patency of canals preserved for materials leakage. In 3 lower canines of cats, phosphoric acid was placed as positive controls.3 canine teeth as negative controls had nothing in them. The crowns were sealed and the cats were sacrificed in 1/21/42 days periods after conducting vital perfussions. The teeth samples with their surrounding osseous tissues were gathered and placed in three groups each contained 6 samples. Histologic preparations were done and the tissue reactions to these materials were evaluated by counting the proliferative inflammatory cells. Also the morphometric analysis for these samples was done. The inflammatory reactions of these materials (the original RC-Prep. & the Iranian chelating agent were not statistically different. Both of these materials were different in inducing tissue reactions in comparison with those of positive and negative controls, and these differences were statistically important.

  2. Trilobolide-porphyrin conjugates: on synthesis and biological effects evaluation.

    Science.gov (United States)

    Tomanová, Pavla; Rimpelová, Silvie; Jurášek, Michal; Buděšínský, Miloš; Vejvodová, Lucie; Ruml, Tomáš; Kmoníčková, Eva; Drašar, Pavel B

    2015-05-01

    Trilobolide (Tb), a potent natural counterpart of thapsigargin, is a sesquiterpene lactone of guaianolide type isolated from horse caraway (Laser trilobum, L. Borkh). Tb exerts remarkable pharmacological properties based on irreversible inhibition of sarco/endoplasmic reticulum calcium ATPase (SERCA), thus being of increasing interest for cancer cure. Additionally, another pharmacological activity of Tb, as well as of thapsigargin, was reported in several studies, Tb as being an effective inductor of nitric oxide and cytokine production. These extraordinary biological properties move these molecules in further pre-clinical evaluation. Because of ubiquitous character of SERCA expression, development of specifically targeted bioactive molecules is inevitable. Since it is well known that porphyrins are preferentially taken up by cancer cells, we have designed and synthesized novel Tb-porphyrin conjugates. Copper-catalyzed azide-alkyne cycloaddition was used to link Tb with porphyrin at once. Two model conjugates of Tb and porphyrin were synthesized and properly characterized. Employing naturally occurring fluorescence properties of porphyrins, we investigated the intracellular localization of the conjugates employing fluorescence microscopy in living cells. Intriguingly, the prepared conjugates localized both in mitochondria and lysosomes of HeLa and LNCaP cells. Furthermore, the cytotoxicity of Tb-porphyrin conjugates was assessed in a number of human cancer cell lines and rat peritoneal cells. Likewise in cancer cell lines, viability of rat peritoneal cells was not affected by the tested conjugates. Interestingly, we observed dose-dependent nitric oxide (iNOS) production induced by the tested conjugates. The effect was related to the type of a linker used and the overall size of the molecule. Another potent immunobiological effects are under evaluation. In summary, the results presented here indicate notable immunobiological potential of the prepared Tb conjugates

  3. Gadolinium Nanoparticles Conjugated with Therapeutic Bifunctional Chelate as a Potential T1 Theranostic Magnetic Resonance Imaging Agent.

    Science.gov (United States)

    Kang, Min-Kyoung; Lee, Gang Ho; Jung, Ki-Hye; Jung, Jae-Chang; Kim, Hee-Kyung; Kim, Yeon-Hee; Lee, Jongmin; Ryeom, Hun-Kyu; Kim, Tae-Jeong; Chang, Yongmin

    2016-05-01

    This work is directed toward the synthesis of two types of gadolinium oxide nanoparticles (Gd-oxide NPs), abbreviated as Gd@SiO2-DO3A and Gd@SiO2-DO2A-BTA, with diameters of 50-60 nm. The synthesis involves sequential coating of Gd-oxide NPs with tetraethyl orthosilicate (TEOS) and (3-aminopropyl) triethoxysilane (APTES), followed by functionalization of the aminopropylsilane group with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid conjugates of benzothiazoles (DO3A-BTA). Gd@SiO2-DO3A and Gd@SiO2-DO2A-BTA exhibit high water solubility and colloidal stability. The r1 relaxivities of both Gd@SiO2-DO3A and Gd@SiO2-DO2A-BTA are higher than those of the corresponding low-molecular-weight magnetic resonance imaging contrast agents (MRI CAs), and their r2/r1 ratios are close to 1, indicating that both can be used as potential T1 MRI CAs. Biodistribution studies demonstrated that Gd@SiO2-DO2A-BTA was excreted via both hepatobiliary and renal pathways. Gd@SiO2-DO2A-BTA exhibits a strong intracellular uptake property in a series of tumor cell lines, and has significant anticancer characteristics against cell lines such as SK-HEP-1, MDA-MB-231, HeLa, and Hep-3B.

  4. Evaluation of mutagenic/antimutagenic activity of conjugated linoleic ...

    African Journals Online (AJOL)

    Jane

    2011-10-12

    Oct 12, 2011 ... exposure to clastogenic and/or aneugenic agents. (Ramírez, 1999). Thus, after determining the fatty acid profile of the CLA and placebo (safflower oil), the objective of this study was to evaluate the effects of mutagenic and antimutagenic effects of conjugated linoleic acid on bone-marrow cell of.

  5. Evaluation of extractants and chelating resins in polishing actinide-contaminated waste streams

    Energy Technology Data Exchange (ETDEWEB)

    Schreiber, S.B.; Dunn, S.L.; Yarbro, S.L.

    1991-06-01

    At the Los Alamos National Laboratory Plutonium Facility, anion exchange is used for recovering plutonium from nitric acid solutions. Although this approach recovers >99%, the trace amounts of plutonium and other actinides remaining in the effluent require additional processing. We are doing research to develop a secondary unit operation that can directly polish the effluent so that actinide levels are reduced to below the maximum allowed for facility discharge. We selected solvent extraction, the only unit operation that can meet the stringent process requirements imposed; several carbonyl and phosphoryl extractants were evaluated and their performance characterized. We also investigated various engineering approaches for solvent extraction; the most promising was a chelating resin loaded with extractant. Our research now focuses on the synthesis of malonamides, and our goal is to bond these extractants to a resin matrix. 7 refs., 12 figs., 1 tab.

  6. A comparative evaluation of the chelators H4octapa and CHX-A″-DTPA with the therapeutic radiometal 90Y☆

    Science.gov (United States)

    Price, Eric W.; Edwards, Kimberly J.; Carnazza, Kathryn E.; Carlin, Sean D.; Zeglis, Brian M.; Adam, Michael J.; Orvig, Chris; Lewis, Jason S.

    2016-01-01

    Objectives To compare the radiolabeling performance, stability, and practical efficacy of the chelators CHX-A″-DTPA and H4octapa with the therapeutic radiometal 90Y. Methods The bifunctional chelators p-SCN-Bn-H4octapa and p-SCN-Bn-CHX-A″-DTPA were conjugated to the HER2-targeting antibody trastuzumab. The resulting immunoconjugates were radiolabeled with 90Y to compare radiolabeling efficiency, in vitro and in vivo stability, and in vivo performance in a murine model of ovarian cancer. Results High radiochemical yields (>95%) were obtained with 90Y-CHX-A′-DTPA-trastuzumab and 90Y-octapa-trastuzumab after 15 min at room temperature. Both 90Y-CHX-A″-DTPA-trastuzumab and 90Y-octapa-trastuzumab exhibited excellent in vitro and in vivo stability. Furthermore, the radioimmunoconjugates displayed high tumoral uptake values (42.3 ± 4.0%ID/g for 90Y-CHX-A″-DTPA-trastuzumab and 30.1 ± 7.4%ID/g for 90Y-octapa-trastuzumab at 72 h post-injection) in mice bearing HER2-expressing SKOV3 ovarian cancer xenografts. Finally, 90Y radioimmunotherapy studies performed in tumor-bearing mice demonstrated that 90Y-CHX-A″-DTPA-trastuzumab and 90Y-octapa-trastuzumab are equally effective therapeutic agents, as treatment with both radioimmunoconjugates yielded substantially decreased tumor growth compared to controls. Conclusions Ultimately, this work demonstrates that the acyclic chelators CHX-A″-DTPA and H4octapa have comparable radiolabeling, stability, and in vivo performance, making them both suitable choices for applications requiring 90Y. PMID:27419360

  7. Conjugation effects on antibody-drug conjugates: evaluation of interaction kinetics in real time on living cells.

    Science.gov (United States)

    Bondza, Sina; Stenberg, Jonas; Nestor, Marika; Andersson, Karl; Björkelund, Hanna

    2014-11-03

    Antibody-drug conjugates (ADC) have shown promising effects in cancer therapy by combining the target specificity of an antibody with the toxicity of a chemotherapeutic drug. As the number of therapeutic antibodies is significantly larger than those used as ADCs, there is unused potential for more effective therapies. However, the conjugation of an additional molecule to an antibody may affect the interaction with its target, altering association rate, dissociation rate, or both. Any changes of the binding kinetics can have subsequent effects on the efficacy of the ADCs, thus the kinetics are important to monitor during ADC development and production. This paper describes a method for the analysis of conjugation effects on antibody binding to its antigen, using the instrument LigandTracer and a fluorescent monovalent anti-IgG binder denoted FIBA, which did not affect the interaction. All measurements were done in real time using living cells which naturally expressed the antigens. With this method the binding profiles of different conjugations of the therapeutic anti-EGFR antibody cetuximab and the anti-CD44v6 antibody fragment AbD15171 were evaluated and compared. Even comparatively small modifications of cetuximab altered the interaction with the epidermal growth factor receptor (EGFR). In contrast, no impact on the AbD15171-CD44v6 interaction was observed upon conjugation. This illustrates the importance to study the binding profile for each ADC combination, as it is difficult to draw any general conclusion about conjugation effects. The modification of interaction kinetics through conjugation opens up new possibilities when optimizing an antibody or an ADC, since the conjugations can be used to create a binding profile more apt for a specific clinical need.

  8. Preparation and evaluation of APTES-PEG coated iron oxide nanoparticles conjugated to rhenium-188 labeled rituximab.

    Science.gov (United States)

    Azadbakht, Bakhtiar; Afarideh, Hossein; Ghannadi-Maragheh, Mohammad; Bahrami-Samani, Ali; Asgari, Mehdi

    2017-05-01

    Radioimmuno-conjugated (Rhenium-188 labeled Rituximab), 3-aminopropyltriethoxysilane (APTES)-polyethylene glycol (PEG) coated iron oxide nanoparticles were synthesized and then characterized. Therapeutic effect and targeting efficacy of complex were evaluated in CD20 express B cell lines and tumor bearing Balb/c mice respectively. To reach these purposes, superparamagnetic iron oxide nanoparticles (SPIONs) were synthesized using coprecipitation method and then their surface was treated with APTES for increasing retention time of SPIONs in blood circulation and amine group creation. In the next step, N-hydroxysuccinimide (NHS) ester of polyethylene glycol maleimide (NHS-PEG-Mal) was conjugated to the APTES-treated SPIONs. After radiolabeling of Rituximab antibody with Rhenium-188 (T1/2=16.9h) using synthesized N2S4 chelator, it was attached to the APTES-PEG-MAL-SPIONs surface through thiol-maleimide coupling reaction. In vitro evaluation of the (188)ReN2S4-Rituximab-SPION-complex thus obtained revealed that at 24 and 48h post-treatment effective cancer cell killing had been achieved. Bio-distribution study in tumor bearing mice showed capability of this complex for targeted cancer therapy. Active and passive tumor targeting strategies were applied through incorporated anti-CD20 (Rituximab) antibody and also enhanced permeability and retention (EPR) effect of solid tumors for nanoparticles respectively. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. The use of iron chelators in biocidal compositions: evaluation of patent, WO2014059417A1.

    Science.gov (United States)

    Sahni, Sumit; Krishan, Sukriti; Palanimuthu, Duraippandi; Richardson, Des R

    2015-03-01

    Anti-microbial-potentiating compositions, containing one or more anti-microbial agents and an iron chelator, are claimed in the patent application. Different combinations of anti-microbial agents with various classes of iron chelators are claimed. The use of such formulations enhances the biocidal activity of the anti-microbial agents. The compositions can be used for a number of applications, such as preservatives, personal care formulations, water-based paints, household cleaning products, and so on. These compositions have therapeutic use in the treatment of acne where they have been shown to markedly potentiate the effect of anti-microbial agents. They also have possible use in wound-healing products.

  10. Synthesis of Copper-Chelates Derived from Amino Acids and Evaluation of Their Efficacy as Copper Source and Growth Stimulator for Lactuca sativa in Nutrient Solution Culture.

    Science.gov (United States)

    Kaewchangwat, Narongpol; Dueansawang, Sattawat; Tumcharern, Gamolwan; Suttisintong, Khomson

    2017-11-15

    Five tetradentate ligands were synthesized from l-amino acids and utilized for the synthesis of Cu(II)-chelates 1-5. The efficacy of Cu(II)-chelates as copper (Cu) source and growth stimulator in hydroponic cultivation was evaluated with Lactuca sativa. Their stability test was performed at pH 4-10. The results suggested that Cu(II)-chelate 3 is the most pH tolerant complex. Levels of Cu, Zn, and Fe accumulated in plants supplied with Cu(II)-chelates were compared with those supplied with CuSO 4 at the same Cu concentration of 8.0 μM. The results showed that Cu(II)-chelate 3 significantly enhanced Cu, Zn, and Fe content in shoot by 35, 15, and 48%, respectively. Application of Cu(II)-chelate 3 also improved plant dry matter yield by 54%. According to the results, Cu(II)-chelate 3 demonstrated the highest stimulating effect on plant growth and plant mineral accumulation so that it can be used as an alternative to CuSO 4 for supplying Cu in nutrient solutions and enhancing the plant growth.

  11. Preclinical Evaluation of MEDI0641, a Pyrrolobenzodiazepine-Conjugated Antibody-Drug Conjugate Targeting 5T4.

    Science.gov (United States)

    Harper, Jay; Lloyd, Christopher; Dimasi, Nazzareno; Toader, Dorin; Marwood, Rose; Lewis, Leeanne; Bannister, David; Jovanovic, Jelena; Fleming, Ryan; D'Hooge, Francois; Mao, Shenlan; Marrero, Allison M; Korade, Martin; Strout, Patrick; Xu, Linda; Chen, Cui; Wetzel, Leslie; Breen, Shannon; van Vlerken-Ysla, Lilian; Jalla, Sanjoo; Rebelatto, Marlon; Zhong, Haihong; Hurt, Elaine M; Hinrichs, Mary Jane; Huang, Keven; Howard, Philip W; Tice, David A; Hollingsworth, Robert E; Herbst, Ronald; Kamal, Adeela

    2017-08-01

    Antibody-drug conjugates (ADC) are used to selectively deliver cytotoxic agents to tumors and have the potential for increased clinical benefit to cancer patients. 5T4 is an oncofetal antigen overexpressed on the cell surface in many carcinomas on both bulk tumor cells as well as cancer stem cells (CSC), has very limited normal tissue expression, and can internalize when bound by an antibody. An anti-5T4 antibody was identified and optimized for efficient binding and internalization in a target-specific manner, and engineered cysteines were incorporated into the molecule for site-specific conjugation. ADCs targeting 5T4 were constructed by site-specifically conjugating the antibody with payloads that possess different mechanisms of action, either a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer or a microtubule-destabilizing tubulysin, so that each ADC had a drug:antibody ratio of 2. The resulting ADCs demonstrated significant target-dependent activity in vitro and in vivo; however, the ADC conjugated with a PBD payload (5T4-PBD) elicited more durable antitumor responses in vivo than the tubulysin conjugate in xenograft models. Likewise, the 5T4-PBD more potently inhibited the growth of 5T4-positive CSCs in vivo, which likely contributed to its superior antitumor activity. Given that the 5T4-PBD possessed both potent antitumor activity as well as anti-CSC activity, and thus could potentially target bulk tumor cells and CSCs in target-positive indications, it was further evaluated in non-GLP rat toxicology studies that demonstrated excellent in vivo stability with an acceptable safety profile. Taken together, these preclinical data support further development of 5T4-PBD, also known as MEDI0641, against 5T4(+) cancer indications. Mol Cancer Ther; 16(8); 1576-87. ©2017 AACR. ©2017 American Association for Cancer Research.

  12. "Evaluation Of compliance To Iron Chelation Therapy With Defe-Roxamine In Patients With Major Thalassemia In Iran In 2004 "

    Directory of Open Access Journals (Sweden)

    M. Izadyar

    2006-06-01

    Full Text Available Background and Aim: With the introduction of long term subcutaneous administration of Deferoxamine there has been a decline in the morbidity and mortality of transfusion-dependent beta thalassemia patients. But parenteral iron chelation therapy is still a burden and a major reason for unsatisfactory compliance and places an additional psychological burden on the patients. There are some factors contributing to low compliance in these patients. To evaluate compliance to Deferoxamine and barriers of non adherence and assessment the prevalence of depression and it’s association with compliance. Materials and Methods: 205 patients with major thalassemia in children medical center older than 6 years old were included. They were classified in 3 groups by compliance index (CI: No. of days of treatment per one month/No. of treatment days prescribed by physician. CI>75 % was considered good ,CI< 50-75%: moderate,CI<50%:weak and 3d group the patients without compliance. For assessment of depression: Beck Depression questionnaires were given to the patients older than 18 years old and Children Depression Inventories (CDI“kovacs” were given to the rest Results: Of 205 patients (110 females (54% and 95 males (46%, 13.3% were non compliant, 14% had poor compliance, 62.7% had good compliance. Females were more compliant than males (P=0.034. Compliance improved in older age groups meaningfully (P=0.037. There was negative association between compliance and serum ferritin level (P=0.02. 22% of children and 12% of Adults had severe depression according to the questionnaires. There was no association between compliance and depression. The most prevalent problem rgarding Desferal injection was local reactions in injection site (83%. Conclusion: As oral chelation therapies are not used routinely, more investigations regarding the noncompliance must be considered; and this method of chelation therapy must be encouraged. Compliance is a multifactorial problem

  13. Evaluation of 99mTc-Labeled Cyclic RGD Dimers: Impact of Cyclic RGD Peptides and 99mTc Chelates on Biological Properties

    Science.gov (United States)

    Zhou, Yang; Kim, Young-Seung; Lu, Xin; Liu, Shuang

    2012-01-01

    The main objective of this study is to explore the impact of cyclic RGD peptides and 99mTc chelates on biological properties of 99mTc radiotracers. Cyclic RGD peptide conjugates, HYNIC-K(NIC)-RGD2 (HYNIC = 6-hydrazinonicotinyl; RGD2 = E[c(RGDfK)]2 and NIC = nicotinyl) HYNIC-K(NIC)-3G-RGD2 (3G-RGD2 = Gly-Gly-Gly-E[Gly-Gly-Gly-c(RGDfK)]2), and HYNIC-K(NIC)-3P-RGD2 (3P-RGD2 = PEG4-E[PEG4-c(RGDfK)]2), were prepared. Macrocyclic 99mTc complexes [99mTc(HYNIC-K(NIC)-RGD2)(tricine)] (1), [99mTc(HYNIC-K(NIC)-3G-RGD2)(tricine)] (2) and [99mTc(HYNIC-K(NIC)-3P-RGD2)(tricine)] (3) were evaluated for their biodistribution and tumor-targeting capability in athymic nude mice bearing MDA-MB-435 human breast tumor xenografts. It was found that 1, 2 and 3 could be prepared with high specific activity (~111GBq/3mol). All three 99mTc radiotracers have two major isomers, which show almost identical uptake in tumors and normal organs. Replacing the bulky and highly charged [99mTc(HYNIC)(tricine)(TPPTS)] (TPPTS = trisodium triphenylphosphine-3,3′,3″-trisulfonate) with a smaller [99mTc(HYNIC-K(NIC))(tricine)] resulted in less uptake in the kidneys and lungs for 3. Surprisingly, all three 99mTc radiotracers shared a similar tumor uptake (1: 5.73 ± 0.40 %ID/g; 2: 5.24 ± 1.09 %ID/g; and 3: 4.94 ± 1.71 %ID/g) at 60 min p.i. The metabolic stability of 99mTc radiotracers depends on cyclic RGD peptides (3P-RGD2 > 3G-RGD2 ~ RGD2) and 99mTc chelates ([99mTc(HYNIC)(tricine)(TPPTS)] > [99mTc(HYNIC-K(NIC))(tricine)]). Immunohistochemical studies revealed a linear relationship between the αvβ3 expression levels and tumor uptake or tumor/muscle ratios of 3, suggesting that 3 is useful for monitoring the tumor αvβ3 expression. Complex 3 is a very attractive radiotracer for detection of integrin αvβ3 –positive tumors. PMID:22369387

  14. Evaluation of 99mTc-labeled cyclic RGD dimers: impact of cyclic RGD peptides and 99mTc chelates on biological properties.

    Science.gov (United States)

    Zhou, Yang; Kim, Young-Seung; Lu, Xin; Liu, Shuang

    2012-03-21

    The main objective of this study is to explore the impact of cyclic RGD peptides and (99m)Tc chelates on biological properties of (99m)Tc radiotracers. Cyclic RGD peptide conjugates, HYNIC-K(NIC)-RGD(2) (HYNIC = 6-hydrazinonicotinyl; RGD(2) = E[c(RGDfK)](2) and NIC = nicotinyl), HYNIC-K(NIC)-3G-RGD(2) (3G-RGD(2) = Gly-Gly-Gly-E[Gly-Gly-Gly-c(RGDfK)](2)), and HYNIC-K(NIC)-3P-RGD(2) (3P-RGD(2) = PEG(4)-E[PEG(4)-c(RGDfK)](2)), were prepared. Macrocyclic (99m)Tc complexes [(99m)Tc(HYNIC-K(NIC)-RGD(2))(tricine)] (1), [(99m)Tc(HYNIC-K(NIC)-3G-RGD(2))(tricine)] (2), and [(99m)Tc(HYNIC-K(NIC)-3P-RGD(2))(tricine)] (3) were evaluated for their biodistribution and tumor-targeting capability in athymic nude mice bearing MDA-MB-435 human breast tumor xenografts. It was found that 1, 2, and 3 could be prepared with high specific activity (∼111 GBq/μmol). All three (99m)Tc radiotracers have two major isomers, which show almost identical uptake in tumors and normal organs. Replacing the bulky and highly charged [(99m)Tc(HYNIC)(tricine)(TPPTS)] (TPPTS = trisodium triphenylphosphine-3,3',3″-trisulfonate) with a smaller [(99m)Tc(HYNIC-K(NIC))(tricine)] resulted in less uptake in the kidneys and lungs for 3. Surprisingly, all three (99m)Tc radiotracers shared a similar tumor uptake (1, 5.73 ± 0.40%ID/g; 2, 5.24 ± 1.09%ID/g; and 3, 4.94 ± 1.71%ID/g) at 60 min p.i. The metabolic stability of (99m)Tc radiotracers depends on cyclic RGD peptides (3P-RGD(2) > 3G-RGD(2) ∼ RGD(2)) and (99m)Tc chelates ([(99m)Tc(HYNIC)(tricine)(TPPTS)] > [(99m)Tc(HYNIC-K(NIC))(tricine)]). Immunohistochemical studies revealed a linear relationship between the α(v)β(3) expression levels and tumor uptake or tumor/muscle ratios of 3, suggesting that 3 is useful for monitoring the tumor α(v)β(3) expression. Complex 3 is a very attractive radiotracer for detection of integrin α(v)β(3)-positive tumors.

  15. 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.

  16. In Vitro Structural and Functional Evaluation of Gold Nanoparticles Conjugated Antibiotics

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    Dasgupta Anjan

    2007-01-01

    Full Text Available AbstractBactericidal efficacy of gold nanoparticles conjugated with ampicillin, streptomycin and kanamycin were evaluated. Gold nanoparticles (Gnps were conjugated with the antibiotics during the synthesis of nanoparticles utilizing the combined reducing property of antibiotics and sodium borohydride. The conjugation of nanoparticles was confirmed by dynamic light scattering (DLS and electron microscopic (EM studies. Such Gnps conjugated antibiotics showed greater bactericidal activity in standard agar well diffusion assay. The minimal inhibitory concentration (MIC values of all the three antibiotics along with their Gnps conjugated forms were determined in three bacterial strains,Escherichia coli DH5α,Micrococcus luteusandStaphylococcus aureus. Among them, streptomycin and kanamycin showed significant reduction in MIC values in their Gnps conjugated form whereas; Gnps conjugated ampicillin showed slight decrement in the MIC value compared to its free form. On the other hand, all of them showed more heat stability in their Gnps conjugated forms. Thus, our findings indicated that Gnps conjugated antibiotics are more efficient and might have significant therapeutic implications.

  17. Rhenium and Technetium-oxo Complexes with Thioamide Derivatives of Pyridylhydrazine Bifunctional Chelators Conjugated to the Tumour Targeting Peptides Octreotate and Cyclic-RGDfK.

    Science.gov (United States)

    North, Andrea J; Karas, John A; Ma, Michelle T; Blower, Philip J; Ackermann, Uwe; White, Jonathan M; Donnelly, Paul S

    2017-08-21

    This research aimed to develop new tumor targeted theranostic agents taking advantage of the similarities in coordination chemistry between technetium and rhenium. A γ-emitting radioactive isotope of technetium is commonly used in diagnostic imaging, and there are two β(-) emitting radioactive isotopes of rhenium that have the potential to be of use in radiotherapy. Variants of the 6-hydrazinonicotinamide (HYNIC) bifunctional ligands have been prepared by appending thioamide functional groups to 6-hydrazinonicotinamide to form pyridylthiosemicarbazide ligands (SHYNIC). The new bidentate ligands were conjugated to the tumor targeting peptides Tyr(3)-octreotate and cyclic-RGD. The new ligands and conjugates were used to prepare well-defined {M═O}(3+) complexes (where M = (99m)Tc or (nat)Re or (188)Re) that feature two targeting peptides attached to the single metal ion. These new SHYNIC ligands are capable of forming well-defined rhenium and technetium complexes and offer the possibility of using the (99m)Tc imaging and (188/186)Re therapeutic matched pairs.

  18. Production of the natural iron chelator deferriferrichrysin from Aspergillus oryzae and evaluation as a novel food-grade antioxidant.

    Science.gov (United States)

    Todokoro, Takehiko; Fukuda, Katsuharu; Matsumura, Kengo; Irie, Motoko; Hata, Yoji

    2016-07-01

    Deferriferrichrysin (Dfcy) is a siderophore found in foods fermented by Aspergillus oryzae and is a promising candidate for an antioxidant food additive because of its high binding constant toward iron. However, the Dfcy concentration is typically low in foods and cultures. We optimised culture conditions to improve Dfcy production to 2800 mg L(-1) from 22.5 mg L(-1) under typical conditions. Then, we evaluated the potential of Dfcy as a food additive by measuring its safety, stability, and antioxidant activity. Dfcy was sufficiently stable that over 90% remained after pasteurisation at 63 °C for 30 min at pH 3-11, or after sterilisation at 120 °C for 4 min at pH 4-6. Dfcy showed high antioxidant activity in an oil-in-water model, where inhibition of lipid oxidation was measured by peroxide value (PV) and thiobarbituric acid reactive substances (TBARS) assays. Dfcy decreased PV and TBARS by 83% and 75%, respectively. Antioxidant activity of Dfcy was equal to or higher than that of the synthetic chelator EDTA. Our study provides the first practical method for production of Dfcy. Dfcy can be a novel food-grade antioxidant and the first natural alternative to the synthesised iron chelator EDTA. © 2015 Society of Chemical Industry. © 2015 Society of Chemical Industry.

  19. USE OF TWO DIGESTION METHODS IN THE EVALUATION OF CHROMIUM CONTENT IN CATTLE'S MEAT SUPPLEMENTED WITH CHROMIUM CHELATES

    Directory of Open Access Journals (Sweden)

    R. L. T. de Andrade

    2015-06-01

    Full Text Available The present study aimed to analyze the chromium content in beef using two digestion methods. There were used samples from 24 18-month-old male cattle, and twelve of them were supplemented and twelve were not supplemented with chromium chelate. These samples were evaluated by atomic absorption spectroscopy, previously submitted to digestion method using nitric acid (65% with hydrogen peroxide (35% and to digestion method, using solution of nitric perchloric acid in the proportion 3:1. Immediately after the slaughter, the carcasses were sent to sanitary maturation. After 24 hours, samples between 12th and 13th rib in the muscle Longissimus Thoracis were taken. For evaluation, it was used completely randomized design (Die and analysis of variance (ANOVA at 5% of significance level. The results didn't evidenced any significant difference (p>0,05 between the (cromo content, regardless the supplementation. The same happened with the digestion methods used.

  20. Antibodies conjugated with new highly luminescent Eu3+ and Tb3+ chelates as markers for time resolved immunoassays. Application to simultaneous determination of clenbuterol and free cortisol in horse urine.

    Science.gov (United States)

    Bacigalupo, M A; Meroni, G; Secundo, F; Scalera, C; Quici, S

    2009-12-15

    Highly luminescent Eu(3+) and Tb(3+) complexes of 10-[4-(3-isothiocyanatopropoxy)benzoylmethyl]-1,4,7,10-tetraazacyclododecane-1,4,7 triacetic acid Eu(3+) is a subset of 1 and Tb(3+) is a subset of 1 were conjugated with a goat anti-rabbit IgG and a rabbit anti-mouse IgG, respectively, and applied as markers in a time resolved immunoassay for simultaneous quantitative determination of anabolic compounds clenbuterol (CL) and hydrocortisone (HC). The assay was performed in horse urine, using a monoclonal antibody specific to CL and a rabbit polyclonal antibody specific to the free HC. These lanthanide chelates are very stable and highly luminescent in aqueous solution and allowed to reach 10 microg L(-1) and 40 microg L(-1) sensitivities for CL and for HC, respectively. Application to the horse urine, that is a very complex matrix, has a considerable interest in the control of illegal use of these compounds.

  1. Cytotoxicity of cis-platinum(II) conjugate models. The effect of chelating arms and leaving groups on cytotoxicity: a quantitative structure-activity relationship approach.

    Science.gov (United States)

    Monti, Elena; Gariboldi, Marzia; Maiocchi, Alessandro; Marengo, Emilio; Cassino, Claudio; Gabano, Elisabetta; Osella, Domenico

    2005-02-10

    Thirteen newly synthesized or resynthesized diamine-platinum(II) complexes were characterized, and their cytotoxic activities (IC50) were tested on parental and resistant ovarian cancer cell lines. They represent models of conjugates between biologically active vectors and cytotoxic Pt(II) moieties within the "drug targeting and delivery strategy". Three drugs, routinely employed in the clinical treatment of cancer, namely, cisplatin, carboplatin, and oxaliplatin, were also included in the study as controls. The quantitative structure-activity relationship approach provides simple regression models able to predict log(1/IC50) of diamine-platinum(II) complexes on both parental and resistant ovarian cancer cell lines. The 16 complexes were characterized using 197 molecular descriptors, after which the best regression models relating a subset of these descriptors to the log(1/IC50) in the two cancer cell lines were calculated. Models with four variables proved to be endowed with very good predictive ability Q2(LMO-50%) > or = 85.6%, making it possible to discard 50% of the molecules from the test set following for cross-validation procedure. A four-variable regression model also proved effective in predicting the resistance index RI, Q2(LMO-50%) = 84.4%.

  2. Economic evaluation of pneumococcal conjugate vaccination in The Gambia

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    Kim Sun-Young

    2010-09-01

    Full Text Available Abstract Background Gambia is the second GAVI support-eligible country to introduce the 7-valent pneumococcal conjugate vaccine (PCV7, but a country-specific cost-effectiveness analysis of the vaccine is not available. Our objective was to assess the potential impact of PCVs of different valences in The Gambia. Methods We synthesized the best available epidemiological and cost data using a state-transition model to simulate the natural histories of various pneumococcal diseases. For the base-case, we estimated incremental cost (in 2005 US dollars per disability-adjusted life year (DALY averted under routine vaccination using PCV9 compared to no vaccination. We extended the base-case results for PCV9 to estimate the cost-effectiveness of PCV7, PCV10, and PCV13, each compared to no vaccination. To explore parameter uncertainty, we performed both deterministic and probabilistic sensitivity analyses. We also explored the impact of vaccine efficacy waning, herd immunity, and serotype replacement, as a part of the uncertainty analyses, by assuming alternative scenarios and extrapolating empirical results from different settings. Results Assuming 90% coverage, a program using a 9-valent PCV (PCV9 would prevent approximately 630 hospitalizations, 40 deaths, and 1000 DALYs, over the first 5 years of life of a birth cohort. Under base-case assumptions ($3.5 per vaccine, compared to no intervention, a PCV9 vaccination program would cost $670 per DALY averted in The Gambia. The corresponding values for PCV7, PCV10, and PCV13 were $910, $670, and $570 per DALY averted, respectively. Sensitivity analyses that explored the implications of the uncertain key parameters showed that model outcomes were most sensitive to vaccine price per dose, discount rate, case-fatality rate of primary endpoint pneumonia, and vaccine efficacy against primary endpoint pneumonia. Conclusions Based on the information available now, infant PCV vaccination would be expected to reduce

  3. Synthesis and biological evaluation of hybrid acridine-HSP90 ligand conjugates as telomerase inhibitors.

    Science.gov (United States)

    Roe, S; Gunaratnam, M; Spiteri, C; Sharma, P; Alharthy, R D; Neidle, S; Moses, J E

    2015-08-21

    The synthesis and biological evaluation of a series of bifunctional acridine-HSP90 inhibitor ligands as telomerase inhibitors is herein described. Four hybrid acridine-HSP90 inhibitor conjugates were prepared using a click-chemistry approach, and subsequently shown to display comparable results to the established telomerase inhibitor BRACO-19 in the TRAP-LIG telomerase assay. The conjugates also demonstrated significant cyctotoxity against a number of cancer cell lines, in the sub-μM range.

  4. Metal chelate surfactants. Kinzoku chelate kaimen kasseizai

    Energy Technology Data Exchange (ETDEWEB)

    Maeda, S. (Kagoshima Univ., Kagoshima (Japan). Faculty of Engineering); Takeshita, T. (Sendai Polytechnic College, Kagoshima (Japan))

    1990-10-20

    The chelating agent which forms soluble metal chelates by combining with metal ions and masks metal irons, is one of builder added in order to improve the efficiency of surface activity. This report reviews the compounds having chelating ligands and surface activity. Hydrophobic groups have been introduced into the chelate ligands such as ethylenediamine, polyethylene-polyimines, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), aminophosphonic acids, and 2-salicylic acid. Carbon- and nitrogen-substitution products or ester- and amide-derivatives of EDTA and DTPA were found to form metal chelates and have excellent surface activities. Some of them were applied to additives for coatings, coal slurry fuels and anti-tumor drugs. 32 refs., 29 figs.

  5. 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

  6. TSPO Ligand-Methotrexate Prodrug Conjugates: Design, Synthesis, and Biological Evaluation

    Directory of Open Access Journals (Sweden)

    Valentino Laquintana

    2016-06-01

    Full Text Available The 18-kDa translocator protein (TSPO is a potential mitochondrial target for drug delivery to tumors overexpressing TSPO, including brain cancers, and selective TSPO ligands have been successfully used to selectively deliver drugs into the target. Methotrexate (MTX is an anticancer drug of choice for the treatment of several cancers, but its permeability through the blood brain barrier (BBB is poor, making it unsuitable for the treatment of brain tumors. Therefore, in this study, MTX was selected to achieve two TSPO ligand-MTX conjugates (TSPO ligand α-MTX and TSPO ligand γ-MTX, potentially useful for the treatment of TSPO-rich cancers, including brain tumors. In this work, we have presented the synthesis, the physicochemical characterizations, as well as the in vitro stabilities of the new TSPO ligand-MTX conjugates. The binding affinity for TSPO and the selectivity versus central-type benzodiazepine receptor (CBR was also investigated. The cytotoxicity of prepared conjugates was evaluated on MTX-sensitive human and rat glioma cell lines overexpressing TSPO. The estimated coefficients of lipophilicity and the stability studies of the conjugates confirm that the synthesized molecules are stable enough in buffer solution at pH 7.4, as well in physiological medium, and show an increased lipophilicity compared to the MTX, compatible with a likely ability to cross the blood brain barrier. The latter feature of two TSPO ligand-MTX conjugates was also confirmed by in vitro permeability studies conducted on Madin-Darby canine kidney cells transfected with the human MDR1 gene (MDCK-MDR1 monolayers. TSPO ligand-MTX conjugates have shown to possess a high binding affinity for TSPO, with IC50 values ranging from 7.2 to 40.3 nM, and exhibited marked toxicity against glioma cells overexpressing TSPO, in comparison with the parent drug MTX.

  7. Mercury exposure: evaluation and intervention the inappropriate use of chelating agents in the diagnosis and treatment of putative mercury poisoning.

    Science.gov (United States)

    Risher, John F; Amler, Sherlita N

    2005-08-01

    Public awareness of the potential for mercury to cause health problems has increased dramatically in the last 15 years. It is now widely recognized that significant exposure to all forms of mercury (elemental/metallic and both inorganic and organic compounds) can result in a variety of adverse health effects, including neurological, renal, respiratory, immune, dermatologic, reproductive, and developmental sequellae. And while the various media have made the general population cognizant of the need to avoid unnecessary exposure to this naturally occurring element, there has also evolved a growing tendency to attribute unexplainable neurologic, as well as other, signs and symptoms to mercury, whether or not significant exposure to mercury has actually occurred. For the physician, making a diagnosis of mercury intoxication can be difficult, because many of the clinical signs and symptoms of mercury exposure can also be attributed to any number of causes, including undiagnosed neurological diseases, pharmacotherapy, vitamin or mineral deficiencies, and psychological stress. The physician must be able to recognize the clinical manifestations of mercury intoxication, and understand the importance of biological markers in making a definitive diagnosis of mercury poisoning. In a desire to treat the patient complaining of symptoms similar to some that can be caused by mercury, a growing number of physicians, particularly those in alternative medicine fields, result to chelation to "rid" the body of the mercury, believed to be the cause of the ailments. And although the use of chelation is increasing, controlled studies showing that this procedure actually improves outcome are lacking. If chelation therapy is considered to be indicated, the attending physician should communicate the risks of chelation to the patient before beginning treatment with metal-chelating drugs.

  8. Synthesis and initial in vitro biological evaluation of two new zinc-chelating compounds: comparison with TPEN and PAC-1.

    Science.gov (United States)

    Strand, O Alexander H; Aziz, Gulzeb; Ali, Sidra Farzand; Paulsen, Ragnhild E; Hansen, Trond Vidar; Rongved, Pål

    2013-09-01

    The lipophilic, cell-penetrating zinc chelator N,N,N',N',-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN, 1) and the zinc chelating procaspase-activating compound PAC-1 (2) both have been reported to induce apoptosis in various cell types. The relationship between apoptosis-inducing ability and zinc affinity (Kd), have been investigated with two new model compounds, ZnA-DPA (3) and ZnA-Pyr (4), and compared to that of TPEN and PAC-1. The zinc-chelating o-hydroxybenzylidene moiety in PAC-1 was replaced with a 2,2'-dipicoylamine (DPA) unit (ZnA-DPA, 3) and a 4-pyridoxyl unit (ZnA-Pyr, 4), rendering an order of zinc affinity TPEN>ZnA-Pyr>ZnA-DPA>PAC-1. The compounds were incubated with the rat pheochromocytoma cell line PC12 and cell death was measured in combination with ZnSO4, a caspase-3 inhibitor, or a ROS scavenger. The model compounds ZnA-DPA (3) and ZnA-Pyr (4) induced cell death at higher concentrations as compared to PAC-1 and TPEN, reflecting differences in lipophilicity and thereby cell-penetrating ability. Addition of ZnSO4 reduced cell death induced by ZnA-Pyr (4) more than for ZnA-DPA (3). The ability to induce cell death could be reversed for all compounds using a caspase-3-inhibitor, and most so for TPEN (1) and ZnA-Pyr (4). Reactive oxygen species (ROS), as monitored using dihydro-rhodamine (DHR), were involved in cell death induced by all compounds. These results indicate that the Zn-chelators ZnA-DPA (3) and ZnA-Pyr (4) exercise their apoptosis-inducing effect by mechanisms similar to TPEN (1) and PAC-1 (2), by chelation of zinc, caspase-3 activation, and ROS production. Copyright © 2013. Published by Elsevier Ltd.

  9. Critical evaluation of equilibrium constants involving 8-hydroxyquinoline and its metal chelates critical evaluation of equilibrium constants in solution : part b : equilibrium constants of liquid-liquid distribution systems

    CERN Document Server

    Stary, J

    1979-01-01

    Critical Evaluation of Equilibrium Constants Involving 8-Hydroxyquinoline and Its Metal Chelates presents and evaluates the published data on the solubility, dissociation, and liquid-liquid distribution of oxine and its metal chelates to recommend the most reliable numerical data. This book explores the dissociation constants of oxine in aqueous solutions.Organized into four chapters, this book begins with an overview of the characteristics of 8-hydroxyquinoline (oxine). This text then examines the total solubility of oxine in aqueous solution at different pH values. Other chapters consider th

  10. Synthesis and evaluation of radiolabeled, folic acid-PEG conjugated, amino silane coated magnetic nanoparticles in tumor bearing Balb/C mice

    Directory of Open Access Journals (Sweden)

    Razjouyan Javad

    2015-07-01

    Full Text Available To design a potent agent for positron emission tomography/magnetic resonance imaging (PET/MRI imaging and targeted magnetic hyperthermia-radioisotope cancer therapy radiolabeled surface modified superparamagnetic iron oxide nanoparticles (SPIONs were used as nanocarriers. Folic acid was conjugated for increasing selective cellular binding and internalization through receptor-mediated endocytosis. SPIONs were synthesized by the thermal decomposition of tris (acetylacetonato iron (III to achieve narrow and uniform nanoparticles. To increase the biocompatibility of SPIONs, they were coated with (3-aminopropyl triethoxysilane (APTES, and then conjugated with synthesized folic acid-polyethylene glycol (FA-PEG through amine group of (3-aminopropyl triethoxysilane. Finally, the particles were labeled with 64Cu (t1/2 = 12.7 h using 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono (N-hydroxy succinimide ester DOTA-NHS chelator. After the characterization of SPIONs, their cellular internalization was evaluated in folate receptor (FR overexpressing KB (established from a HeLa cell contamination and mouse fibroblast cell (MFB lines. Eventually, active and passive targeting effects of complex were assessed in KB tumor-bearing Balb/C mice through biodistribution studies. Synthesized bare SPIONs had low toxicity effect on healthy cells, but surface modification increased their biocompatibility. Moreover, KB cells viability was reduced when using folate conjugated SPIONs due to FR-mediated endocytosis, while having little effect on healthy cells (MFB. Moreover, this radiotracer had tolerable in vivo characteristics and tumor uptake. In the receptor blocked case, tumor uptake was decreased, indicating FR-specific uptake in tumor tissue while enhanced permeability and retention effect was major mechanism for tumor uptake.

  11. Ru(II) carbazole thiosemicarbazone complexes with four membered chelate ring: Synthesis, molecular structures and evaluation of biological activities.

    Science.gov (United States)

    Kumar, Ramasamy Raj; Ramesh, Rengan; Małecki, Jan Grzegorz

    2016-12-01

    Formation of ruthenium(II) complexes of the type [RuH(CO)(PPh3)2(L)] (where L=N-Substituted 9-ethyl carbazole thiosemicarbazone ligands) has been described from the reactions of [RuHCl(CO)(PPh3)3] and substituted carbazole thiosemicarbazones in 1:1 equivalent respectively. The composition of the complexes was established by elemental analysis, IR, NMR (1H ,13C and 31P) and UV-visible spectral methods. The solid state molecular structure of the ligands (L1-L3) and one of the complexes have been analysed by single-crystal X-ray studies, and found that the ruthenium(II) complexes possess a pseudo-octahedral geometry. The thiosemicarbazone ligand is coordinated to ruthenium as a monoanionic bidendate N,S-donor forming a four-membered chelate ring with a bite angle of 64.47(5)°. The stability of the complexes in aqueous medium was confirmed by UV-visible and ESI-Mass spectral studies. The DNA binding interactions of the complexes with Calf thymus DNA have been investigated by absorption, emission, elctrochemical, circular dichromism and viscosity measurements revealed that the complexes could interact with DNA via intercalation. Further, their protein binding ability was monitored by the quenching of tryptophan emission using bovine serum albumin (BSA) as a model protein. The alterations in the secondary structure of BSA by the complexes were confirmed with synchronous and three-dimensional fluorescence spectral studies. The ability of complexes to cleave BSA varies from 3>2>1 in the presence of activator like H2O2, as revealed from SDS-PAGE is consistent with their strong hydrophobic interaction with the protein. Free-radical scavenging ability of all the complexes were also carried out against a panel of radicals such as DPPH, NO, OH, O2- and reducing power assay under in vitro experimental conditions. The potential of complexes to act as anticancer agents is thoroughly examined on human cervical cancer cell line HeLa, Osteosarcoma cell line MG-63 and a normal mouse

  12. 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.

  13. Quinolidene-rhodanine conjugates: Facile synthesis and biological evaluation.

    Science.gov (United States)

    Subhedar, Dnyaneshwar D; Shaikh, Mubarak H; Shingate, Bapurao B; Nawale, Laxman; Sarkar, Dhiman; Khedkar, Vijay M; Kalam Khan, Firoz A; Sangshetti, Jaiprakash N

    2017-01-05

    A series of rhodanine incorporated quinoline derivatives were efficiently synthesized using reusable DBU acetate as ionic liquid and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Ra (MTB) (ATCC 25177) and Mycobacterium bovis BCG (ATCC 35743) both in active and dormant state. Compounds 3e, 3f, 3g, 3h and 3i exhibited very good antitubercular activity. The active compounds were studied for cytotoxicity against HUVEC, THP-1, macrophages, A549, PANC-1 and HeLa cell lines using modified MTT assay and were found to be noncytotoxic. Inactivity of all these compounds against Gram positive and Gram negative bacteria indicates their specificity towards the MTB. Further, the synthesized compounds have been screened for their in vitro antifungal activity. In addition, the molecular docking studies revealed the binding modes of these compounds in active site of Zmp1 enzyme, which in turn helped to establish a structural basis of inhibition of mycobacteria. The results of present study clearly indicate the identification of some novel, selective and specific inhibitors against MTB that can be explored further for potential antitubercular drug. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  14. Iron Binding and Iron Removal Efficiency of Desferrioxamine Based Polymeric Iron Chelators: Influence of Molecular Size and Chelator Density.

    Science.gov (United States)

    Hamilton, Jasmine L; Ul-Haq, Muhammad Imran; Creagh, A Louise; Haynes, Charles A; Kizhakkedathu, Jayachandran N

    2017-03-01

    Desferrioxamine (DFO) is a clinically approved, high affinity iron chelator used for the treatment of iron overload. Due to its short half-life and toxicity, DFO is administered for 8-12 h per day, 5-7 d per week. In this manuscript, the influence of molecular properties of hyperbranched polyglycerol (HPG)-DFO conjugates on their iron binding by isothermal titration calorimetry, iron removal efficiency from ferritin in presence and absence of a low molecular weight (MW) iron chelator, and protection against iron mediated oxidation of proteins is reported. The iron binding properties of HPG-DFO are slightly altered with size and DFO density of conjugates. The lower MW conjugate shows greater iron removal efficiency at room temperature, however, the efficacy of high MW conjugates increases at physiological temperature. The iron removal from ferritin by HPG-DFO conjugates increases significantly in presence of a low MW chelator, suggesting the potential of combination therapy. The molecular properties of the polymer scaffold also have influence on the prevention of iron mediated oxidation of proteins by the conjugates. The results therefore help to define the iron binding thermodynamics of HPG-DFO and their dependence on MW, and can be extended to improve the general understanding of polymeric chelator-iron interactions in situ. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. In vitro and in vivo evaluation of cysteine and site specific conjugated herceptin antibody-drug conjugates.

    Directory of Open Access Journals (Sweden)

    Dowdy Jackson

    Full Text Available Antibody drug conjugates (ADCs are monoclonal antibodies designed to deliver a cytotoxic drug selectively to antigen expressing cells. Several components of an ADC including the selection of the antibody, the linker, the cytotoxic drug payload and the site of attachment used to attach the drug to the antibody are critical to the activity and development of the ADC. The cytotoxic drugs or payloads used to make ADCs are typically conjugated to the antibody through cysteine or lysine residues. This results in ADCs that have a heterogeneous number of drugs per antibody. The number of drugs per antibody commonly referred to as the drug to antibody ratio (DAR, can vary between 0 and 8 drugs for a IgG1 antibody. Antibodies with 0 drugs are ineffective and compete with the ADC for binding to the antigen expressing cells. Antibodies with 8 drugs per antibody have reduced in vivo stability, which may contribute to non target related toxicities. In these studies we incorporated a non-natural amino acid, para acetyl phenylalanine, at two unique sites within an antibody against Her2/neu. We covalently attached a cytotoxic drug to these sites to form an ADC which contains two drugs per antibody. We report the results from the first direct preclinical comparison of a site specific non-natural amino acid anti-Her2 ADC and a cysteine conjugated anti-Her2 ADC. We report that the site specific non-natural amino acid anti-Her2 ADCs have superior in vitro serum stability and preclinical toxicology profile in rats as compared to the cysteine conjugated anti-Her2 ADCs. We also demonstrate that the site specific non-natural amino acid anti-Her2 ADCs maintain their in vitro potency and in vivo efficacy against Her2 expressing human tumor cell lines. Our data suggests that site specific non-natural amino acid ADCs may have a superior therapeutic window than cysteine conjugated ADCs.

  16. Evaluation of Immunogenicity of Yersinia enterocolitica O:8 Oligopolysaccaride-DiphtheriaeToxoide Conjugate in Mice

    Directory of Open Access Journals (Sweden)

    SM Rezavian

    2015-06-01

    Full Text Available Background & objectives: Yersiniosis is created by Yersinia enterocolitica O:8 and causes problems in the world especialy in cold and mild countries. The purpose of this study is to evaluate the immunogenicity of Yersinia enterocolitica O:8 oligopolysaccaride (OPS conjugate to diphtheria toxoid (DT as a vaccine candidate.   Methods : After cultivation of bacteria, the LPS were isolated by modified hot phenol method. Then dialysis and concentration were done and the OPS were extracted by acetic acid 2%. To conjugate with diphtheria toxoid, ADH was used as a spacer molecule and EDAC as a linker. Conjugate was purified by gel filtration. Then 4 groups of female BALB/c mice were selected (15 mice in each group. Injection was performed intraperitoneally in three doses with two weeks interval. Then serum samples were collected and antibody response against OPS was measured by indirect ELISA method for detection of total IgG, IgA, IgM, IgG1, IgG2a, IgG2b and IgG3.   Results: After second and third doses, OPS-DT recieved group showed significant increase in all types of antibodies titer in anti-OPS in comparison to group that recived nonconjugated OPS. The increase in titer of antibodies was as: OPS-DT>OPS>DT. A remarkable increase was shown in total IgG and IgM titers (with total amount of 3204 and 670, respectively. In IgG1 subclass the amount was 920 and in other subclasses of IgG (IgG3, IgG2a and IgG2b the amounts were 910, 110, and 99, respectively.   Conclusion: The results shows that OPS of Yersinia enterocolitica O:8 increases the anti-OPS antibodies in the form of conjugate with diphtheria toxoid and could be considered as an appropriate vaccine candidate.

  17. [64Cu]-Labelled Trastuzumab: Optimisation of Labelling by DOTA and NODAGA Conjugation and Initial Evaluation in Mice

    DEFF Research Database (Denmark)

    Schjøth-Eskesen, Christina; Nielsen, Carsten Haagen; Heissel, Søren

    2015-01-01

    ,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...... [(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......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...

  18. Cyclotron Production of High–Specific Activity 55Co and In Vivo Evaluation of the Stability of 55Co Metal-Chelate-Peptide Complexes

    Directory of Open Access Journals (Sweden)

    Tara Mastren

    2015-10-01

    Full Text Available This work describes the production of high–specific activity 55Co and the evaluation of the stability of 55Co-metal-chelate-peptide complexes in vivo. 55Co was produced via the 58Ni(p,α55Co reaction and purified using anion exchange chromatography with an average recovery of 92% and an average specific activity of 1.96 GBq/μmol. 55Co-DO3A and 55Co-NO2A peptide complexes were radiolabeled at 3.7 MBq/μg and injected into HCT-116 tumor xenografted mice. Positron emission tomography (PET and biodistribution studies were performed at 24 and 48 hours postinjection and compared to those of 55CoCl2. Both 55Co-metal-chelate complexes demonstrated good in vivo stability by reducing the radiotracers’ uptake in the liver by sixfold at 24 hours with ˜ 1% ID/g and at 48 hours with ˜ 0.5% ID/g and reducing uptake in the heart by fourfold at 24 hours with ˜ 0.7% ID/g and sevenfold at 48 hours with ˜ 0.35% ID/g. These results support the use of 55Co as a promising new radiotracer for PET imaging of cancer and other diseases.

  19. Cyclotron production of high specific activity 55Co and in vivo evaluation of the stability of 55Co metal-chelate-peptide complexes

    Science.gov (United States)

    Mastren, Tara; Marquez, Bernadette V.; Sultan, Deborah E.; Bollinger, Elizabeth; Eisenbeis, Paul; Voller, Tom; Lapi, Suzanne E.

    2016-01-01

    This work describes the production of high-specific activity 55Co and the evaluation of the stability of 55Co-metal-chelate-peptide complexes in vivo. 55Co was produced via the 58Ni(p,α)55Co reaction and purified using anion exchange chromatography with an average recovery of 92% and an average specific activity of 1.96GBq/µmol. 55Co-DO3A and 55Co-NO2A peptide complexes were radiolabelled at 3.7MBq/µg and injected into HCT-116 tumor xenografted mice. PET imaging and biodistribution studies were performed at 24 and 48 hours post injection and compared with that of 55CoCl2. Both 55Co-metal-chelate complexes demonstrated good in vivo stability by reducing the radiotracers’ uptake in the liver by 6-fold at 24 with ~1% ID/g and at 48 hours with ~0.5% ID/g, and reducing uptake in the heart by 4-fold at 24 hours with ~0.7% ID/g and 7-fold at 48 hours with ~0.35% ID/g. These results support the use of 55Co as a promising new radiotracer for Positron Emission Tomography (PET) imaging of cancer and other diseases. PMID:26505224

  20. 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 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...

  1. Synthesis and biological evaluation of 2-benzoylpyridine thiosemicarbazones in a dimeric system: structure-activity relationship studies on their anti-proliferative and iron chelation efficacy.

    Science.gov (United States)

    Lukmantara, Adeline Y; Kalinowski, Danuta S; Kumar, Naresh; Richardson, Des R

    2014-12-01

    Thiosemicarbazone chelators represent an exciting class of biologically active compounds that show great potential as anti-tumor agents. Our previous studies demonstrated the potent anti-tumor activity of the 2'-benzoylpyridine thiosemicarbazone series. While extensive studies have been performed on monomeric thiosemicarbazone compounds, dimeric thiosemicarbazone chelators have received comparatively less attention. Thus, it was of interest to investigate the anti-proliferative activity and iron chelation efficacy of dimeric thiosemicarbazones. Two classes of dimeric thiosemicarbazones were designed and synthesized. The first class consisted of two benzoylpyridine-based thiosemicarbazone units connected via a hexane or dodecane alkyl bridge, while the second class of dimer consisted of two thiosemicarbazones attached to a 2,6-dibenzoylpyridine core. These dimeric ligands demonstrated greater anti-proliferative activity than the clinically used iron chelator, desferrioxamine. This study highlights the importance of optimal lipophilicity as a factor influencing the cytotoxicity and iron chelation efficacy of these chelators. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Chelating polymeric membranes

    KAUST Repository

    Peinemann, Klaus-Viktor

    2015-01-22

    The present application offers a solution to the current problems associated with recovery and recycling of precious metals from scrap material, discard articles, and other items comprising one or more precious metals. The solution is premised on a 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.

  3. Synthesis, characterization and in vitro cytotoxicity evaluation of polyamidoamine conjugate containing pamidronate and platinum drug

    CSIR Research Space (South Africa)

    Ndamase, AS

    2018-02-01

    Full Text Available Bisphosphonates have been found to be effective when combined with anticancer drugs for chemotherapy. In this paper, pamidronate and platinum complexes were conjugated to linear poly(amidoamine)s (PAMAM) to improve the drug efficacy. The conjugates...

  4. Synthesis and evaluation of novel bifunctional chelating agents based on 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid for radiolabeling proteins

    Energy Technology Data Exchange (ETDEWEB)

    Chappell, L.L.; Ma, D.; Milenic, D.E.; Garmestani, K.; Venditto, V.; Beitzel, M.P.; Brechbiel, M.W. E-mail: martinwb@mail.nih.gov

    2003-08-01

    Detailed synthesis of the bifunctional chelating agents 2-methyl-6-(p-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10 -tetraacetic acid (1B4M-DOTA) and 2-(p-isothiocyanatobenzyl)-5, 6-cyclohexano-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetate (CHX-DOTA) are reported. These chelating agents were compared to 2-(p-isothiocyanatobenzyl)-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (C-DOTA) and 1, 4, 7, 10-Tetraaza-N-(1-carboxy-3-(4-nitrophenyl)propyl)-N', N'', N'''-tris(acetic acid) cyclododecane (PA-DOTA) as their {sup 177}Lu radiolabeled conjugates with Herceptin{sup TM}. In vitro stability of the immunoconjugates radiolabeled with {sup 177}Lu was assessed by serum stability studies. The in vivo stability of the radiolabeled immunoconjugates and their targeting characteristics were determined by biodistribution studies in LS-174T xenograft tumor-bearing mice. Relative radiolabeling rates and efficiencies were determined for all four immunoconjugates. Insertion of the 1B4M moiety into the DOTA backbone increases radiometal chelation rate and provides complex stability comparable to C-DOTA and PA-DOTA while the CHX-DOTA appears to not form as stable a {sup 177}Lu complex while exhibiting a substantial increase in formation rate. The 1B4M-DOTAmay have potential for radioimmunotherapy applications. Published by Elsevier Inc. All rights reserved.

  5. 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.

  6. NHS-MAS{sub 3}: a bifunctional chelator alternative to NHS-MAG{sub 3}

    Energy Technology Data Exchange (ETDEWEB)

    Chang, F.; Qu, T.; Rusckowski, M.; Hnatowich, D.J

    1999-04-01

    This laboratory uses an N-hydroxysuccinimide derivative of S-acetylmercaptoacetyltriglycine (NHS-MAG{sub 3}) to conjugate amines for subsequent labeling with {sup 99m}Tc. However, the synthesis from triglycerine is general and not restricted to this tripeptide. We had earlier selected a small number of alternative tripeptides and synthesized the corresponding NHS derivatives. Each was then evaluated in a search for bifunctional chelators with properties superior to NHS-MAG{sub 3}, such as lower serum protein binding or improved stability to cysteine challenge. Based on these preliminary results, NHS-S-acetylmercaptoacetyltriserine (NHS-MAS{sub 3}) was selected for further investigation. We have now conjugated this bifunctional chelator to biocytin and to an amine-derivatized peptide nucleic acid (PNA). Both carriers were also conjugated with NHS-MAG{sub 3} under identical conditions and all were labeled with {sup 99m}Tc at neutral pH and at boiling temperature while the conjugated PNAs were radiolabelled at neutral pH and at room temperature. Regardless of the chelator, reverse phase HPLC radiochromatograms of the labeled biotins and PNAs after purification showed a single peak. However, by size exclusion HPLC, the radiochromatograms always showed several peaks even after purification, but the MAS{sub 3} radiochromatograms were less complicated. For biotin and PNA both, radiolabeling via MAS{sub 3} showed improved {sup 99m}Tc stability in 37 deg. C serum and in cysteine solution. The four preparations were administered to mice implanted in one thigh with avidin beads (biotins) or complementary PNA beads (PNAs). At 5 h post-administration, no significant differences were observed in the targeting of PNA beads between the two chelators, however the target thigh/normal thigh ratio was significantly higher for MAS{sub 3}-biotin compared to MAG{sub 3}-biotin. We conclude that labeling biocytin and amine-derivatized PNA with NHS-MAS{sub 3} compared to NHS-MAG{sub 3

  7. Fluorescent Europium Chelate Stain

    Science.gov (United States)

    Scaff, W. L.; Dyer, D. L.; Mori, K.

    1969-01-01

    The europium chelate of 4,4,4-trifluoro-1-(2-thienyl)-1,3-butanedione (thenoyl-trifluoroacetone; TTA) is firmly bound to microorganisms. It fluoresces brightly at 613 nm with activation at 340 nm. Cells may be stained with 10−3m chelate in 50% ethyl alcohol, followed by washing with 50% ethyl alcohol. Equal or better stains are produced with 10−3m aqueous europium salt, water wash, and 10−2m aqueous TTA. A noncomplexing buffer should be used to maintain the pH at 6.5 to 6.8. Images PMID:4181107

  8. Easy and Efficient 111Indium Labeling of Long-Term Stored DTPA Conjugated Protein

    DEFF Research Database (Denmark)

    Nalla, Amarnadh; Buch, Inge; Hesse, Birger

    2011-01-01

    The labelling efficiency of long-term stored DTPA-conjugates has not been reported previously even though DTPA has been in extensive use as metal chelator in the development of radiopharmaceuticals and contrast agents. DTPA is often used as a bifunctional chelating agent conjugated to tumor targe...

  9. 1H-1,2,3-triazole tethered isatin-ferrocene conjugates: Synthesis and in vitro antimalarial evaluation.

    Science.gov (United States)

    Kumar, Kewal; Pradines, Bruno; Madamet, Marilyn; Amalvict, Rémy; Benoit, Nicolas; Kumar, Vipan

    2014-11-24

    1H-1,2,3-triazole tethered isatin-ferrocene conjugates were synthesized and evaluated for their antiplasmodial activities against chloroquine-susceptible (3D7) and chloroquine-resistant (W2) strains of Plasmodium falciparum. The conjugates 5f and 5h with an optimum combination of electron-withdrawing halogen substituent at C-5 position of isatin ring and a propyl chain, introduced as linker, proved to be most potent and non-cytotoxic among the series with IC50 values of 3.76 and 4.58 μM against 3D7 and W2 strains, respectively. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  10. Design, synthesis and biological evaluation of ciprofloxacin tethered bis-1,2,3-triazole conjugates as potent antibacterial agents.

    Science.gov (United States)

    Kant, Rama; Singh, Vishal; Nath, Gopal; Awasthi, Satish Kumar; Agarwal, Alka

    2016-11-29

    A series of new bis-1,2,3-triazole linked ciprofloxacin conjugates was designed, synthesized and evaluated in vitro antibacterial activity against a panel of clinically relevant bacteria. A significant part of the compounds displayed enhanced activity against both Gram-positive and Gram-negative species of bacteria as compared to the parent drug. Additionally, negligible toxicity profile of compounds indicates that they may act a good antibiotic in future. Despite relatively small number of synthesized conjugates, it was possible to observe important dependences between their structure and activity. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  11. Rational Design of Nucleoside–Bile Acid Conjugates Incorporating a Triazole Moiety for Anticancer Evaluation and SAR Exploration

    OpenAIRE

    Maria Luisa Navacchia; Elena Marchesi; Lara Mari; Nicola Chinaglia; Eleonora Gallerani; Riccardo Gavioli; Massimo Luigi Capobianco; Daniela Perrone

    2017-01-01

    Herein we report a study on the synthesis and biological evaluation of a library of nucleoside-bile acid conjugates prepared by combining 2′-deoxyadenosine, 2′-deoxyguanosine, 2′-deoxyuridine as well as adenosine and guanosine derivatives with cheno-, urso-, nor-cheno-, nor-urso- and taurourso-desoxycholic acid derivatives by means of the click reaction. The new nucleoside-bile acid conjugates incorporating a triazole moiety were tested in vitro against leukemic K562 and HCT116 colon carcinom...

  12. Synthesis and evaluation of anticancer activity in cells of novel stoichiometric pegylated fullerene-doxorubicin conjugates.

    Science.gov (United States)

    Magoulas, George E; Bantzi, Marina; Messari, Danai; Voulgari, Efstathia; Gialeli, Chrisostomi; Barbouri, Despoina; Giannis, Athanassios; Karamanos, Nikos K; Papaioannou, Dionissios; Avgoustakis, Konstantinos

    2015-05-01

    To synthesize pegylated stoichiometrically and structurally well-defined conjugates of fullerene (C60) with doxorubicin (DOX) and investigate their antiproliferative effect against cancer cell lines. Stoichiometric (1:1 and 1:2) pegylated conjugates of C60 with DOX were synthesized using the Prato reaction to create fulleropyrrolidines equipped with a carboxyl function for anchoring a polyethylene glycol (PEG) moiety and either a hydroxyl group for attaching one molecule of DOX or a terminal alkyne group for attaching two molecules of DOX through a click reaction. In both conjugates, the DOX moieties are held through a urethane-type bond. Drug release was studied in phosphate buffer (PBS, pH 7.4) and MCF-7 cancer cells lysate. The uptake of the conjugates by MCF-7 cancer cells and their intracellular localization were studied with fluorescence microscopy. The antiproliferative activity of the conjugates was investigated using the WST-1 test. One or two DOX molecules were anchored on pegylated C60 particles to form DOX-C60-PEG conjugates. Drug liberation from the conjugates was significantly accelerated in the presence of tumor cell lysate compared to PBS. The conjugates could be internalized by MCF-7 cells. DOX from the conjugates exhibited much delayed, compared to free DOX, localization in the nucleus and antiproliferative activity. Pegylated DOX-C60 conjugates (1:1) and (2:1) with well-defined structure were successfully synthesized and found to exhibit comparable, but with a delayed onset, antiproliferative activity with free DOX against MCF-7 cancer cells. The results obtained justify further investigation of the potential of these conjugates as anticancer nanomedicines.

  13. 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...

  14. Synthesis and evaluation of a well-defined HPMA copolymer-dexamethasone conjugate for effective treatment of rheumatoid arthritis.

    Science.gov (United States)

    Liu, Xin-Ming; Quan, Ling-Dong; Tian, Jun; Alnouti, Yazen; Fu, Kai; Thiele, Geoffrey M; Wang, Dong

    2008-12-01

    To develop a pH-sensitive dexamethasone (Dex)-containing N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugate with well-defined structure for the improved treatment of rheumatoid arthritis (RA). A new pH-sensitive Dex-containing monomer (MA-Gly-Gly-NHN=Dex) was synthesized and copolymerized with HPMA using reversible addition-fragmentation transfer (RAFT) polymerization. The structure of the resulting HPMA copolymer-Dex conjugate (P-Dex) was analyzed and its therapeutic efficacy was evaluated on adjuvant-induced arthritis (AIA) rats. P-Dex was synthesized with controllable molecular weight and polydispersity index (PDI). The Dex content can be controlled by the feed-in ratio of MA-Gly-Gly-NHN=Dex. The P-Dex used for in vitro and in vivo evaluation has a average molecular weight (M (w)) of 34 kDa and a PDI of 1.34. The in vitro drug-release studies showed that the Dex release from the conjugate was triggered by low pH. Clinical measurements, endpoint bone mineral density (BMD) test and histology grading from the in vivo evaluation all suggest that newly synthesized P-Dex has strong and long-lasting anti-inflammatory and joint protection effects. A HPMA copolymer-dexamethasone conjugate with a well-defined structure has been synthesized and proved to be an effective anti-arthritis therapy. It may have a unique clinical application in the treatment of rheumatoid arthritis.

  15. [(68)Ga]FSC-(RGD)3 a trimeric RGD peptide for imaging αvβ3 integrin expression based on a novel siderophore derived chelating scaffold-synthesis and evaluation.

    Science.gov (United States)

    Knetsch, Peter A; Zhai, Chuangyan; Rangger, Christine; Blatzer, Michael; Haas, Hubertus; Kaeopookum, Piriya; Haubner, Roland; Decristoforo, Clemens

    2015-02-01

    Over the last years Gallium-68 ((68)Ga) has received tremendous attention for labeling of radiopharmaceuticals for positron emission tomography (PET). (68)Ga labeling of biomolecules is currently based on bifunctional chelators containing aminocarboxylates (mainly DOTA and NOTA). We have recently shown that cyclic peptide siderophores have very good complexing properties for (68)Ga resulting in high specific activities and excellent metabolic stabilities, in particular triacetylfusarinine-C (TAFC). We postulated, that, starting from its deacetylated form (Fusarinine-C (FSC)) trimeric bioconjugates are directly accessible to develop novel targeting peptide based (68)Ga labeled radiopharmaceuticals. As proof of principle we report on the synthesis and (68)Ga-radiolabeling of a trimeric FSC-RGD conjugate, [(68)Ga]FSC-(RGD)3, targeting αvβ3 integrin, which is highly expressed during tumor-induced angiogenesis. Synthesis of the RGD peptide was carried out applying solid phase peptide synthesis (SPPS), followed by the coupling to the siderophore [Fe]FSC via in situ activation using HATU/HOAt and DIPEA. Subsequent demetalation allowed radiolabeling of FSC-(RGD)3 with (68)Ga. The radiolabeling procedure was optimized regarding peptide amount, reaction time, temperature as well buffer systems. For in vitro evaluation partition coefficient, protein binding, serum stability, αvβ3 integrin binding affinity, and tumor cell uptake were determined. For in vitro tests as well as for the biodistribution studies αvβ3 positive human melanoma M21 and αvβ3 negative M21-L cells were used. [(68)Ga]FSC-(RGD)3 was prepared with high radiochemical yield (>98%). Distribution coefficient was -3.6 revealing a hydrophilic character, and an IC50 value of 1.8±0.6 nM was determined indicating a high binding affinity for αvβ3 integrin. [(68)Ga]FSC-(RGD)3 was stable in PBS (pH7.4), FeCl3- and DTPA-solution as well as in fresh human serum at 37°C for 2hours. Biodistribution assay

  16. Development and Evaluation of a Fluorescent Antibody-Drug Conjugate for Molecular Imaging and Targeted Therapy of Pancreatic Cancer.

    Directory of Open Access Journals (Sweden)

    Steve Knutson

    Full Text Available Antibodies are widely available and cost-effective research tools in life science, and antibody conjugates are now extensively used for targeted therapy, immunohistochemical staining, or in vivo diagnostic imaging of cancer. Significant advances in site-specific antibody labeling technologies have enabled the production of highly characterized and homogenous conjugates for biomedical purposes, and some recent studies have utilized site-specific labeling to synthesize bifunctional antibody conjugates with both imaging and drug delivery properties. While these advances are important for the clinical safety and efficacy of such biologics, these techniques can also be difficult, expensive, and time-consuming. Furthermore, antibody-drug conjugates (ADCs used for tumor treatment generally remain distinct from conjugates used for diagnosis. Thus, there exists a need to develop simple dual-labeling methods for efficient therapeutic and diagnostic evaluation of antibody conjugates in pre-clinical model systems. Here, we present a rapid and simple method utilizing commercially available reagents for synthesizing a dual-labeled fluorescent ADC. Further, we demonstrate the fluorescent ADC's utility for simultaneous targeted therapy and molecular imaging of cancer both in vitro and in vivo. Employing non-site-specific, amine-reactive chemistry, our novel biopharmaceutical theranostic is a monoclonal antibody specific for a carcinoembryonic antigen (CEA biomarker conjugated to both paclitaxel and a near-infrared (NIR, polyethylene glycol modified (PEGylated fluorophore (DyLight™ 680-4xPEG. Using in vitro systems, we demonstrate that this fluorescent ADC selectively binds a CEA-positive pancreatic cancer cell line (BxPC-3 in immunofluorescent staining and flow cytometry, exhibits efficient internalization kinetics, and is cytotoxic. Model studies using a xenograft of BxPC-3 cells in athymic mice also show the fluorescent ADC's efficacy in detecting tumors in

  17. Novel Selective Estrogen Receptor Ligand Conjugates Incorporating Endoxifen-Combretastatin and Cyclofenil-Combretastatin Hybrid Scaffolds: Synthesis and Biochemical Evaluation

    Directory of Open Access Journals (Sweden)

    Patrick M. Kelly

    2017-08-01

    Full Text Available Nuclear receptors such as the estrogen receptors (ERα and ERβ modulate the effects of the estrogen hormones and are important targets for design of innovative chemotherapeutic agents for diseases such as breast cancer and osteoporosis. Conjugate and bifunctional compounds which incorporate an ER ligand offer a useful method of delivering cytotoxic drugs to tissue sites such as breast cancers which express ERs. A series of novel conjugate molecules incorporating both the ER ligands endoxifen and cyclofenil-endoxifen hybrids covalently linked to the antimitotic and tubulin targeting agent combretastatin A-4 were synthesised and evaluated as ER ligands. A number of these compounds demonstrated pro-apoptotic effects, with potent antiproliferative activity in ER-positive MCF-7 breast cancer cell lines and low cytotoxicity. These conjugates displayed binding affinity towards ERα and ERβ isoforms at nanomolar concentrations e.g., the cyclofenil-amide compound 13e is a promising lead compound of a clinically relevant ER conjugate with IC50 in MCF-7 cells of 187 nM, and binding affinity to ERα (IC50 = 19 nM and ERβ (IC50 = 229 nM while the endoxifen conjugate 16b demonstrates antiproliferative activity in MCF-7 cells (IC50 = 5.7 nM and binding affinity to ERα (IC50 = 15 nM and ERβ (IC50 = 115 nM. The ER binding effects are rationalised in a molecular modelling study in which the disruption of the ER helix-12 in the presence of compounds 11e, 13e and 16b is presented These conjugate compounds have potential application for further development as antineoplastic agents in the treatment of ER positive breast cancers.

  18. Evaluation of two conjugate gradient based algorithms for quantitation in cardiac SPECT imaging

    Energy Technology Data Exchange (ETDEWEB)

    Sire, P.; Grangeat, P.; Iovleff, S.; Mallon, L.A. [LETI CEA - Technologies Avancees, Grenoble (France)

    1996-12-31

    Correction attenuation in SPECT is a very important issue in cardiac imaging. In this paper we evaluate two conjugate gradient (CG) based algorithms to reconstruct an attenuation compensated emission map. The first algorithm is a classic preconditioned CG approach, the second one uses the minimal residual (MR) algorithm. We discuss the emission reconstruction problem and the difficulty to get a good uniformity within the reconstructed cardiac wall. An evaluation on numerical and real phantoms shows that the point spread function (PSF) of the system strongly affects the uniformity. Thus, two essential improvements are made. First, the response of the reconstruction procedure is made isotropic by replacing the classic 1D apodized ramp reconstruction filter with a 2D filter. Second, to improve the spatial resolution, we apply a PSF deconvolution to the projections. A threshold parameter is used to prevent the deconvolution from amplifying high-frequency noise. Stabilization is also achieved by incorporating into the reconstruction algorithms a regularization, which is made spatially adaptive to preserve high contrast within the heart while smoothing the rest of the image. Results obtained on numerical and anatomic phantoms show that the proposed algorithms lead to fast, stabilized and more accurate attenuation compensation.

  19. In vivo pharmacological evaluation of a lactose-conjugated luteinizing hormone releasing hormone analogue.

    Science.gov (United States)

    Moradi, Shayli Varasteh; Varamini, Pegah; Steyn, Frederik; Toth, Istvan

    2015-11-10

    In the current study, the efficacy and pharmacokinetic profile of lactose-conjugated luteinizing hormone releasing hormone (LHRH) was examined following oral administration in male rats. A rapid and sensitive liquid chromatography/mass spectrometry technique was developed and applied for measuring the concentration of lactose[Q(1)][w(6)]LHRH (compound 1) in rat plasma in order to allow measurement of pharmacokinetic parameters. LH release was evaluated using a sandwich ELISA. Maximum serum concentration (Cmax = 0.11 μg/ml) was reached at 2h (Tmax) following oral administration of the compound at 10mg/kg. The half-life was determined to be 2.6h. The absolute bioavailability of the orally administered compound was found to be 14%, which was a remarkable improvement compared to zero-to-low oral bioavailability of the native peptide. Compound 1 was effective in stimulating LH release at 20mg/kg after oral administration. The method was validated at a linear range of 0.01-20.0 μg/ml and a correlation coefficient of r(2) ≥ 0.999. The accuracy and precision values showed the reliability and reproducibility of the method for evaluation of the pharmacokinetic parameters. These findings showed that the lactose derivative of LHRH has a therapeutic potential to be further developed as an orally active therapeutics for the treatment of hormone-dependent diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Synthesis and biological evaluation of novel conjugates of camptothecin and 5-flurouracil as cytotoxic agents

    OpenAIRE

    Yang, Liu; Zhao,Chun-Yan; Liu, Ying-Qian

    2011-01-01

    A series of novel conjugates of camptothecin and 5-fluorouracil were first synthesized and their cytotoxic activities against two human tumor cell lines (SGC-7901 and A-549) as well as in vitro pharmacokinetic determination of lactone stability were studied. Among these compounds, most tested conjugates showed comparable or superior cytotoxic activities to 2, but less potent compared with 1. Particularly, conjugates 10b and 10d were highly active against A-549 with IC50 values of 0.45 and 0.3...

  1. Evaluation of the kinetics of beta-elimination reactions of selenocysteine Se-conjugates in human renal cytosol : possible implications for the use as kidney selective prodrugs

    NARCIS (Netherlands)

    Rooseboom, M; Vermeulen, N P; Andreadou, I; Commandeur, J N

    This study was performed to evaluate whether selenocysteine Se-conjugates are substrates for human cysteine conjugate beta-lyase enzymes. By testing kidney cytosols of three different humans, we studied interindividual differences in beta-lyase enzymes in humans. A series of 22 selenocysteine

  2. Synthesis and evaluation of intercalating somatostatin receptor binding peptide conjugates for endoradiotherapy

    National Research Council Canada - National Science Library

    Graham, Keith; Wang, Qin; Garcia Boy, Regine; Eisenhut, Michael; Haberkorn, Uwe; Mier, Walter

    2007-01-01

    .... In order to exploit the cytotoxic potential of intercalator-Auger-emitter conjugates, bis-benzimidazole dyes, Hoechst 33258 and 33342, were linked to a somatostatin receptor affine carrier peptide...

  3. Design, synthesis, and biological evaluation of theranostic vitamin-linker-taxoid conjugates.

    Science.gov (United States)

    Vineberg, Jacob G; Wang, Tao; Zuniga, Edison S; Ojima, Iwao

    2015-03-12

    Novel tumor-targeting theranostic conjugates 1 and 2, bearing either a fluorine-labeled prosthetic as a potential (18)F-PET radiotracer (1) or a fluorescence probe (2) for internalization studies in vitro, were designed and synthesized. We confirmed efficient internalization of 2 in biotin-receptor positive (BR+) cancer cells via receptor-mediated endocytosis (RME) based on flow cytometry and confocal fluorescence microscopy (CFM) analyses, which exhibited very high specificity to BR+ cancer cells. The potency and cancer-cell selectivity of 1 were evaluated against MX-1, L1210FR and ID8 cancer cells (BR+) as well as L1210 cells and WI38 normal human lung fibroblast cells (biotin-receptor negative: BR-). In particular, we designed and performed an assay in the presence of glutathione ethyl ester (GSH-OEt) wherein only 1 molecules internalized into cells via RME in the first 24 h period exert cytotoxic effect. The observed selectivity of 1 was remarkable, with 2 orders of magnitude difference in IC50 values between BR+ cancer cells and WI38 cells, demonstrating a salient feature of this tumor-targeted drug delivery system.

  4. Mechanism and in vivo evaluation :photodynamic antibacterial chemotherapy of lysine-porphyrin conjugate

    Directory of Open Access Journals (Sweden)

    Zengping eXu

    2016-03-01

    Full Text Available We previously reported lysine-porphyrin conjugate 4i, which had potent photosensitive antibacterial effect on clinical isolated Methicillin-resistant Staphylococcus aureus (MRSA, Escherichia coli (E. coli and Pseudomonas aeruginosa (P. aeruginosa bacterial strains. The aim of this paper is to evaluate the mechanism of photodynamic antibacterial chemotherapy of 4i (4i-PACT in vitro and the treatment effect in vivo. Atomic force microscopy (AFM revealed 4i-PACT could effectively destroy bacterial membrane and wall, making the bacterial content leakage, which was confirmed by dual fluorescent staining with acridine orange/ethidium bromide (AO/EB and absorbance at 260 nm, agarose gel electrophoresis indicated 4i-PACT could damage genomic DNA. The results combined AFM and DNA electrophoresis revealed why the bacterial strains had no resistance to 4i-PACT. Wound healing in rat model with mixed bacteria infected wounds showed the efficiency of 4i-PACT was light-dose dependent. These results showed 4i-PACT had promising bactericidal effect both in vitro and in vivo.

  5. Folate/NIR 797-conjugated albumin magnetic nanospheres: synthesis, characterisation, and in vitro and in vivo targeting evaluation.

    Directory of Open Access Journals (Sweden)

    Qiusha Tang

    Full Text Available A practical and effective strategy for synthesis of Folate-NIR 797-conjugated Magnetic Albumin Nanospheres (FA-NIR 797-MAN was developed. For this strategy, Magnetic Albumin Nanospheres (MAN, composed of superparamagnetic iron oxide nanoparticles (SPIONs and bovine serum albumin (BSA, were covalently conjugated with folic acid (FA ligands to enhance the targeting capability of the particles to folate receptor (FR over-expressing tumours. Subsequently, a near-infrared (NIR fluorescent dye NIR 797 was conjugated with FA-conjugated MAN for in vivo fluorescence imaging. The FA-NIR 797-MAN exhibited low toxicity to a human nasopharyngeal epidermal carcinoma cell line (KB cells. Additionally, in vitro and in vivo evaluation of the dynamic behaviour and targeting ability of FA-NIR 797-MAN to KB tumours validated the highly selective affinity of FA-NIR 797-MAN for FR-positive tumours. In summary, the FA-NIR 797-MAN prepared here exhibited great potential for tumour imaging, since the near-infrared fluorescence contrast agents target cells via FR-mediated endocytosis. The high fluorescence intensity together with the targeting effect makes FA-NIR 797-MAN a promising candidate for imaging, monitoring, and early diagnosis of cancer at the molecular and cellular levels.

  6. Multifunctional adhesive polymers: Preactivated thiolated chitosan-EDTA conjugates.

    Science.gov (United States)

    Netsomboon, Kesinee; Suchaoin, Wongsakorn; Laffleur, Flavia; Prüfert, Felix; Bernkop-Schnürch, Andreas

    2017-02-01

    The aim of this study was to synthesis preactivated thiolated chitosan-EDTA (Ch-EDTA-cys-2MNA) conjugates exhibiting in particular high mucoadhesive, cohesive and chelating properties. Thiol groups were coupled with chitosan by carbodiimide reaction and further preactivated by attachment with 2-mercaptonicotinic acid (2MNA) via disulfide bond formation. Determinations of primary amino and sulfhydryl groups were performed by TNBS and Ellman's tests, respectively. Cytotoxicity was screened by resazurin assay in Caco-2 cells. Mucoadhesive properties and bivalent cation binding capacity with Mg(2+) and Ca(2+) in comparison to chitosan-EDTA (Ch-EDTA) and thiolated Ch-EDTA (Ch-EDTA-cys) were evaluated. Determination of 2MNA and total sulfhydryl groups indicated that 80% of thiol groups were preactivated. The results from cytotoxicity studies demonstrated that Ch-EDTA-cys and Ch-EDTA-cys-2MNA were not toxic to the cells at the polymer test concentration of 0.25% (w/v) while cell viability decreased by increasing the concentration of Ch-EDTA. Although EDTA molecule was modified by thiolation and preactivation, approximately 50% of chelating properties of the conjugates were maintained compared to Ch-EDTA. Ch-EDTA-cys-2MNA adhered on freshly excised porcine intestinal mucosa up to 6h while Ch-EDTA adhered for just 1h. According to the combination of mucoadhesive and chelating properties of the conjugates synthesized in this study, Ch-EDTA-cys-2MNA might be useful for various mucosal drug delivery systems. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Comparison of blood pool and extracellular gadolinium chelate for functional MR evaluation of vascular thoracic outlet syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Ruth P., E-mail: ruthplim74@gmail.com [New York University School of Medicine, Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, 660 1st Avenue, New York, NY 10016 (United States); Austin Health, Department of Radiology, Heidelberg, Victoria 3084 (Australia); The University of Melbourne, School of Medicine, Parkville, Victoria 3010 (Australia); Bruno, Mary, E-mail: mary.bruno@nyumc.org [New York University School of Medicine, Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, 660 1st Avenue, New York, NY 10016 (United States); Rosenkrantz, Andrew B., E-mail: Andrew.rosenkrantz@nyumc.org [New York University School of Medicine, Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, 660 1st Avenue, New York, NY 10016 (United States); Kim, Danny C., E-mail: danny.kim@nyumc.org [New York University School of Medicine, Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, 660 1st Avenue, New York, NY 10016 (United States); Mulholland, Thomas, E-mail: Thomas.mulholland@nyumc.org [New York University School of Medicine, Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, 660 1st Avenue, New York, NY 10016 (United States); Kwon, Jane, E-mail: jane.kwon@nyumc.org [New York University School of Medicine, Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, 660 1st Avenue, New York, NY 10016 (United States); Palfrey, Amy P., E-mail: amy.pastva10@stjohns.edu [St John' s University, Department of Psychology, 8000 Utopia Parkway, Jamaica-Queens, NY 11439 (United States); Ogedegbe, Olugbenga, E-mail: Olugbenga.Ogedegbe@nyumc.org [New York University School of Medicine, Clinical and Translational Science Institute, 227 E30th St, 8th Floor, New York, NY 10016 (United States)

    2014-07-15

    Objective: To compare performance of single-injection blood pool agent (gadofosveset trisodium, BPA) against dual-injection extracellular contrast (gadopentetate dimeglumine, ECA) for MRA/MRV in assessment of suspected vascular TOS. Materials and methods: Thirty-one patients referred for vascular TOS evaluation were assessed with BPA (n = 18) or ECA (n = 13) MRA/MRV in arm abduction and adduction. Images were retrospectively assessed for: image quality (1 = non-diagnostic, 5 = excellent), vessel contrast (1 = same signal as muscle, 4 = much brighter than muscle) and vascular pathology by two independent readers, with a separate experienced reader providing reference assessment of vascular pathology. Results: Median image quality was diagnostic or better (score ≥3) for ECA and BPA at all time points, with BPA image quality superior at abduction late (BPA 4.5, ECA 4, p = 0.042) and ECA image quality superior at adduction-early (BPA 4.5; ECA 4.0, p = 0.018). High qualitative vessel contrast (mean score ≥3) was observed at all time points with both BPA and ECA, with superior BPA vessel contrast at abduction-late (BPA 3.97 ± 0.12; ECA 3.73 ± 0.26, p = 0.007) and ECA at adduction-early (BPA 3.42 ± 0.52; ECA 3.96 ± 0.14, p < 0.001). Readers readily identified arterial and venous pathology with BPA, similar to ECA examinations. Conclusion: Single-injection BPA MRA/MRV for TOS evaluation demonstrated diagnostic image quality and high vessel contrast, similar to dual-injection ECA imaging, enabling identification of fixed and functional arterial and venous pathology.

  8. Evaluation of chemical fluorescent dyes as a protein conjugation partner for live cell imaging.

    Directory of Open Access Journals (Sweden)

    Yoko Hayashi-Takanaka

    Full Text Available To optimize live cell fluorescence imaging, the choice of fluorescent substrate is a critical factor. Although genetically encoded fluorescent proteins have been used widely, chemical fluorescent dyes are still useful when conjugated to proteins or ligands. However, little information is available for the suitability of different fluorescent dyes for live imaging. We here systematically analyzed the property of a number of commercial fluorescent dyes when conjugated with antigen-binding (Fab fragments directed against specific histone modifications, in particular, phosphorylated H3S28 (H3S28ph and acetylated H3K9 (H3K9ac. These Fab fragments were conjugated with a fluorescent dye and loaded into living HeLa cells. H3S28ph-specific Fab fragments were expected to be enriched in condensed chromosomes, as H3S28 is phosphorylated during mitosis. However, the degree of Fab fragment enrichment on mitotic chromosomes varied depending on the conjugated dye. In general, green fluorescent dyes showed higher enrichment, compared to red and far-red fluorescent dyes, even when dye:protein conjugation ratios were similar. These differences are partly explained by an altered affinity of Fab fragment after dye-conjugation; some dyes have less effect on the affinity, while others can affect it more. Moreover, red and far-red fluorescent dyes tended to form aggregates in the cytoplasm. Similar results were observed when H3K9ac-specific Fab fragments were used, suggesting that the properties of each dye affect different Fab fragments similarly. According to our analysis, conjugation with green fluorescent dyes, like Alexa Fluor 488 and Dylight 488, has the least effect on Fab affinity and is the best for live cell imaging, although these dyes are less photostable than red fluorescent dyes. When multicolor imaging is required, we recommend the following dye combinations for optimal results: Alexa Fluor 488 (green, Cy3 (red, and Cy5 or CF640 (far-red.

  9. Fabrication and biological evaluation of chitosan coated hyaluronic acid-docetaxel conjugate nanoparticles in CD44(+) cancer cells.

    Science.gov (United States)

    Shabani Ravari, Nazanin; Goodarzi, Navid; Alvandifar, Farhad; Amini, Mohsen; Souri, Effat; Khoshayand, Mohammad Reza; Hadavand Mirzaie, Zahra; Atyabi, Fatemeh; Dinarvand, Rassoul

    2016-07-29

    Hyaluronic acid (HA) has been used for target-specific drug delivery because of strong affinity to CD44, a marker in which overexpressed in cancer cells and cancer stem cells. Conjugation of HA to the cytotoxic agents via active targeting can improve efficacy, biodistribution, and water solubility. To be able to benefit from passive targeting as well, a nanoparticulate system by counter ion using a polycation like chitosan may lead to a perfect delivery system. Water soluble Hyaluronic acid-Docetaxel (HA-DTX) conjugate was prepared and used to formulate chitosan-coated HA-DTX nanoparticles by polyelectrolyte complex (PEC) method and optimized using Box-Behnken design. Biological evaluation of nanoparticles was done in CD44+ cancer cells. Biological evaluation of optimized formula showed IC50 of nanoparticles for 4 T1 and MCF-7 cell lines were 45.34 μM and 354.25 μM against 233.8 μM and 625.9 μM for DTX, respectively with increased cellular uptake showed by inverted confocal microscope. Chitosan-coated HA-DTX nanoparticles were more effective against CD44+ cells than free DTX. Chitosan coated hyaluronic acid-docetaxel conjugate nanoparticles fabricated and evaluated in CD44+ cancer cells.

  10. Synthesis and biological evaluation of new water-soluble photoactive chlorin conjugate for targeted delivery.

    Science.gov (United States)

    Otvagin, Vasilii F; Nyuchev, Alexander V; Kuzmina, Natalia S; Grishin, Ivan D; Gavryushin, Andrei E; Romanenko, Yuliya V; Koifman, Oscar I; Belykh, Dmitrii V; Peskova, Nina N; Shilyagina, Natalia Yu; Balalaeva, Irina V; Fedorov, Alexey Yu

    2018-01-20

    A new water-soluble conjugate, consisting of a chlorin-based photosensitizing part, and a 4-arylaminoquinazoline moiety with high potential affinity to an epidermal growth factor receptors (EGFR) and vascular endothelial growth factor receptors (VEGFR), suitable for photodynamic therapy (PDT), was synthesized starting from methylpheophorbide-a in seven steps. An increased accumulation of this compound in A431 cells with high level of EGFR expression, in comparison with CHO and HeLa cells with low EGFR expression was observed. The prepared conjugate exhibits dark and photoinduced cytotoxicity at micromolar concentrations with IC 50dark /IC 50light ratio of 11-18. In tumor-bearing mice, the conjugate preferentially accumulates in the tumor tissue. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  11. Post-introduction economic evaluation of pneumococcal conjugate vaccination in Ecuador, Honduras, and Paraguay.

    Science.gov (United States)

    Constenla, Dagna O

    2015-11-01

    A decision-analytic model was constructed to evaluate the economic impact of post-introduction pneumococcal conjugate vaccine (PCV) programs in Ecuador, Honduras, and Paraguay from the societal perspective. Hypothetical birth cohorts were followed for a 20-year period in each country. Estimates of disease burden, vaccine effectiveness, and health care costs were derived from primary and secondary data sources. Costs were expressed in 2014 US$. Sensitivity analyses were performed to assess the impact of model input uncertainties. Over the 20 years of vaccine program implementation, the health care costs per case ranged from US$ 764 854 to more than US$ 1 million. Vaccination prevented more than 50% of pneumococcal cases and deaths per country. At a cost of US$ 16 per dose, the cost per disability-adjusted life year (DALY) averted for the 10-valent PCV (PCV10) and the 13-valet PCV (PCV13) ranged from US$ 796 (Honduras) to US$ 1 340 (Ecuador) and from US$ 691 (Honduras) to US$ 1 166 (Ecuador) respectively. At a reduced price (US$ 7 per dose), the cost per DALY averted ranged from US$ 327 (Honduras) to US$ 528 (Ecuador) and from US$ 281 (Honduras) to US$ 456 (Ecuador) for PCV10 and PCV13 respectively. Several model parameters influenced the results of the analysis, including vaccine price, vaccine efficacy, disease incidence, and costs. The economic impact of post-introduction PCV needs to be assessed in a context of uncertainty regarding changing antibiotic resistance, herd and serotype replacement effects, differential vaccine prices, and government budget constraints.

  12. Synthesis of the copper chelator TGTA and evaluation of its ability to protect biomolecules from copper induced degradation during copper catalyzed azide-alkyne bioconjugation reactions.

    Science.gov (United States)

    Ekholm, F S; Pynnönen, H; Vilkman, A; Koponen, J; Helin, J; Satomaa, T

    2016-01-21

    One of the most successful bioconjugation strategies to date is the copper(I)-catalyzed cycloaddition reaction (CuAAC), however, the typically applied reaction conditions have been found to degrade sensitive biomolecules. Herein, we present a water soluble copper chelator which can be utilized to protect biomolecules from copper induced degradation.

  13. [Synthesis of novel terpenophenol-chlorin conjugates and evaluation of their membranotropic and membrane protective properties].

    Science.gov (United States)

    Belykh, D V; Buravlev, E V; Chukicheva, I Iu; Tarabukina, I S; Shevchenko, O G; Pliusnina, S N; Kuchin, A V

    2012-01-01

    A series of terpenophenol-chlorin conjugates where terpenophenolic fragment has amide bond with macrocycle of methylpheophorbide a, formed by amidation of 13(2)-ester group were obtained by interaction of methylpheophorbide a and ortho-aminomethyl derivatives of 2-isobornyl-4-methylphenol. The substances investigated ability to interact with the cell membrane was shown in blood erythrocytes surface structure with scanning electron microscope. The conjugates studied were established to have antioxidant and membrane protective properties resulted from inhibiting H2O2-induced erythrocytes hemolysis and decrease of lipid peroxidation secondary product accumulation.

  14. Rational Design of Nucleoside–Bile Acid Conjugates Incorporating a Triazole Moiety for Anticancer Evaluation and SAR Exploration

    Directory of Open Access Journals (Sweden)

    Maria Luisa Navacchia

    2017-10-01

    Full Text Available Herein we report a study on the synthesis and biological evaluation of a library of nucleoside-bile acid conjugates prepared by combining 2′-deoxyadenosine, 2′-deoxyguanosine, 2′-deoxyuridine as well as adenosine and guanosine derivatives with cheno-, urso-, nor-cheno-, nor-urso- and taurourso-desoxycholic acid derivatives by means of the click reaction. The new nucleoside-bile acid conjugates incorporating a triazole moiety were tested in vitro against leukemic K562 and HCT116 colon carcinoma, as well as on normal fibroblast cells. Six compounds displayed interesting anti-proliferative activity against the selected cancer lines and no cytotoxic effects against normal fibroblasts. A possible structure activity relationship was also investigated.

  15. Synthesis and Biological Evaluation of Novel Water-Soluble Poly-(ethylene glycol-10-hydroxycamptothecin Conjugates

    Directory of Open Access Journals (Sweden)

    Na Guo

    2015-05-01

    Full Text Available In order to improve the antitumor activity and water solubility of 10-hydroxycamptothecin (HCPT, a series of novel HCPT conjugates were designed and synthesized by conjugating polyethylene glycol (PEG to the 10-hydroxyl group of HCPT via a valine spacer. The in vitro stability of these synthesized compounds was determined in pH 7.4 buffer at 37 °C, and the results showed that they released HCPT at different rates. All the compounds demonstrated significant antitumor activity in vitro against K562, HepG2 and HT-29 cells. Among them, compounds, 4a, 4d, 4e and 4f, exhibited 2–5 times higher potency than HCPT. The stability and antitumor activity of these conjugates were found to be closely related to the length of PEG and the linker type, conjugates with a relatively short PEG chain and carbamate linkages (compounds 4a and 4f exhibited controlled release of HCPT and excellent antitumor in vitro activity.

  16. Synthesis and immunological evaluation of protein conjugates of Neisseria meningitidis X capsular polysaccharide fragments

    Directory of Open Access Journals (Sweden)

    Laura Morelli

    2014-10-01

    Full Text Available A vaccine to prevent infections from the emerging Neisseria meningitidis X (MenX is becoming an urgent issue. Recently MenX capsular polysaccharide (CPS fragments conjugated to CRM197 as carrier protein have been confirmed at preclinical stage as promising candidates for vaccine development. However, more insights about the minimal epitope required for the immunological activity of MenX CPS are needed. We report herein the chemical conjugation of fully synthetic MenX CPS oligomers (monomer, dimer, and trimer to CRM197. Moreover, improvements in some crucial steps leading to the synthesis of MenX CPS fragments are described. Following immunization with the obtained neoglycoconjugates, the conjugated trimer was demonstrated as the minimal fragment possessing immunogenic activity, even though significantly lower than a pentadecamer obtained from the native polymer and conjugated to the same protein. This finding suggests that oligomers longer than three repeating units are possibly needed to mimic the activity of the native polysaccharide.

  17. Synthesis and biological evaluation of novel conjugates of camptothecin and 5-Flurouracil as cytotoxic agents

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Liu, E-mail: yqliu@lzu.edu.c [Lanzhou Jiaotong University (China). Environmental and Municipal Engineering School; Chun-Yan Zhaob; Ying-Qian Liu [Lanzhou University (China). School of Pharmacy

    2011-07-01

    A series of novel conjugates of camptothecin and 5-fluorouracil were first synthesized and their cytotoxic activities against two human tumor cell lines (SGC-7901 and A-549) as well as in vitro pharmacokinetic determination of lactone stability were studied. Among these compounds, most tested conjugates showed comparable or superior cytotoxic activities to 2, but less potent compared with 1. Particularly, conjugates 10b and 10d were highly active against A-549 with IC{sub 50} values of 0.45 and 0.38 {mu}mol L{sup -1}, respectively. Also, the in vitro pharmacokinetic determination of lactone levels of representative compound 10b showed that the biological life span of their lactone forms in human and mouse plasma significantly increased compared with their mother compound 1. Quantitative structure-activity relationship (QSAR) method was then applied for developing linear models to predict the cytotoxic activities of these derivatives that have not yet been synthesized or experimentally tested. In addition, molecular docking was used to clarify the binding mode of these derivatives to human DNA topoisomerase I. The important hydrogen-bonding interactions were observed between these derivatives and their receptor. The results from molecular modeling and QSAR study can guide the design of novel conjugates with higher antitumor activity. (author)

  18. 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)

  19. Evaluation of the Role of Cisplatin-conjugated-soluble Gelatin Sponge: Feasibility Study in a Swine Model

    Energy Technology Data Exchange (ETDEWEB)

    Ikoma, Akira; Kawai, Nobuyuki; Sato, Morio, E-mail: morisato@wakayama-med.ac.jp; Minamiguchi, Hiroyuki; Nakata, Kouhei; Nakai, Motoki; Sanda, Hiroki; Sonomura, Tetsuo [Wakayama Medical University, Department of Radiology (Japan); Kanayama, Yoshitaka; Sakai, Yasuo [Central Research Institute, Jellice Co., Ltd (Japan)

    2013-08-01

    PurposeTo evaluate the safety and the delivery function of cisplatin-conjugated-soluble gelatin sponge in a swine model.MethodsFifteen healthy young swine were assigned into three groups: transarterial cisplatin infusion group, transarterial chemoembolization (TACE) with cisplatin-conjugated 120-min soluble gelatin sponge (TACE-120) group, and TACE with cisplatin-conjugated 360-min soluble gelatin sponge (TACE-360) group. A total volume of 0.8 mL/kg cisplatin in each group and 8 mg/kg soluble gelatin sponge in TACE-120 and TACE-360 groups were injected from the left hepatic artery in small increments for 10 min. Common hepatic angiography and whole-blood sampling via the left hepatic vein were conducted to explore recanalization immediately after the procedure and again at 10, 30, 60, 90, 120, 180, 240, 300, 360, and 420 min later. The area under the plasma concentration curve (AUC) of non-protein-bound platinum was compared among the three groups. Each liver was removed and cut into 10-cm-thick sections for calculating liver-damaged volume ratio.ResultsSequential angiography depicted gradual recanalization of the occluded hepatic artery and total recanalization at 120 and 360 min after embolization in the TACE-120 and TACE-360 groups, respectively. Of the three groups, AUC{sub 0-30}, AUC{sub 30-120}, and AUC{sub 120-420} were significantly highest in the transarterial cisplatin infusion group (p < 0.001), the TACE-120 group (p < 0.001), and the TACE-360 group (p < 0.001), respectively. The liver-damaged volume ratio in the TACE-360 group was small (8.20 %) but significantly higher than that in the TACE-120 group (2.67 %, p = 0.014).ConclusionCisplatin-conjugated soluble gelatin sponge functions as a cisplatin carrier and is associated with tolerable liver damage.

  20. Biological evaluation of a novel Herceptin-platinum (II) conjugate for efficient and cancer cell specific delivery.

    Science.gov (United States)

    Huang, Rong; Sun, Yu; Zhang, Xiang-yang; Sun, Bai-wang; Wang, Qiu-cui; Zhu, Jin

    2015-07-01

    Platinum-based drugs have been widely used for the treatment of malignant tumors. However, their applications are limited by severe side effects for their lack of selectivity for cancer cells. The development of antibody drug conjugates (ADCs) have provided a platform to reduce drug toxicity and improve drug efficacy. Here we describe a nover conjugate comprising of Herceptin (an anti-HER2 antibody) and platinum drug via a cathepsin B cleavable dipetide for enhancing drug accumulation and HER2-positive cancer cell specific delivery. This conjugate is believed to be cleaved by cathepsin B, leading to a 1,6-elimination reaction and activation of drug release. Herceptin-Pt(II) is evaluated to have approximately loaded with 6.4 moles platinum drugs per mole of antibody. We demonstrate that Herceptin-Pt(II) retain high and selective binding affinity for HER2 protein and HER2-positive SK-BR-3 cancer cells. The in vitro cytotoxicity tests indicate that Herceptin-Pt(II) exhibits much higher cytotoxicity than oxaliplatin against SK-BR-3 cells. More importantly, Herceptin-Pt(II) shows no obvious inhibition against the growth of both MCF-7 and MDA-MB-231 cells, which express lower levels of HER2. Furthermore, compared with free oxaliplatin, Herceptin significantly improved the cellular uptake of platinum drugs in SK-BR-3 cells. In summary, Herceptin-platinum (II) conjugate is a remarkable and potent platform for efficient and cancer cell specific delivery. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  1. Evaluation of a polysaccharide conjugate vaccine to reduce colonization by Campylobacter jejuni in broiler chickens.

    Science.gov (United States)

    Hodgins, Douglas C; Barjesteh, Neda; St Paul, Michael; Ma, Zuchao; Monteiro, Mario A; Sharif, Shayan

    2015-06-02

    Campylobacter jejuni is a leading bacterial cause of food-borne illness in humans. Symptoms range from mild gastroenteritis to dysentery. Contaminated chicken meat is the most common cause of infection. Broiler chickens become colonized with high numbers of C. jejuni in the intestinal tract, but do not become clinically ill. Vaccination of broiler chicks to control colonization by C. jejuni is challenging because immune function is limited in the first 2 weeks post-hatch and immune suppressive maternal antibodies are common. In addition, there is little time for induction of immunity, since broilers reach slaughter weight by 5-6 weeks of age. In the current study the immunogenicity of a C. jejuni capsular polysaccharide-diphtheria toxoid conjugated vaccine (CPSconj), administered subcutaneously with various adjuvants was assessed and the efficacy of vaccination for reducing cecal colonization after experimental challenge was evaluated by determining colony-forming units (CFU) of C. jejuni in cecal contents. The CPSconj vaccine was immunogenic when administered as three doses at 3, 4 and 5 weeks of age to specific pathogen free chicks lacking maternal antibodies (seroconversion rates up to 75%). Commercial broiler chicks (having maternal antibodies) receiving two doses of CPSconj vaccine at 7 and 21 days of age did not seroconvert before oral challenge at 29 days, but 33% seroconverted post challenge; none of the placebo-injected, challenged birds seroconverted. Vaccinated birds had significantly lower numbers of C. jejuni in cecal contents than control birds at necropsy (38 days of age). CFU of C. jejuni did not differ significantly among groups of birds receiving CPSconj vaccine with different adjuvants. In two trials, the mean reduction in CFU associated with vaccination was 0.64 log10 units. The CPSconj vaccine was immunogenic in chicks lacking maternal antibodies, vaccinated beginning at 3 weeks of age. In commercial broiler birds (possessing maternal

  2. Characterization and evaluation of amphotericin B loaded MDP conjugated poly(propylene imine) dendrimers.

    Science.gov (United States)

    Jain, Keerti; Verma, Ashwni Kumar; Mishra, Prabhat Ranjan; Jain, Narendra Kumar

    2015-04-01

    This paper describes a novel strategy for targeted delivery of amphotericin B (AmB) to macrophages with muramyl dipeptide (MDP) conjugated multimeric poly(propyleneimine) (PPI) dendrimers. Synergistic antiparasitic activity due to immunostimulation by multimeric presentation of MDP on dendrimers was anticipated. MDP conjugated 5.0G PPI (MdPPI) dendrimers were synthesized and characterized. Therapeutic activity and toxicity of dendrimeric formulation of AmB (MdPPIA) were compared with marketed formulations of AmB. Highly significant (P<0.01) reduction in toxicity was observed in hemolytic toxicity and cytotoxicity studies in erythrocytes and J774A.1 macrophage cells, respectively. Formulation MdPPIA showed appreciable macrophage targeting potential and higher or equivalent antiparasitic activity against parasite infected macrophage cell lines and in vivo infection in Balb/c mice. These results suggest the developed MDP conjugated dendrimeric formulation of AmB as a promising immunostimulant targeted drug delivery system and a safer alternative to marketed formulations. From the clinical editor: Parasitic infections remain a significant issue in the clinical setting. The authors in this article studied the use of ligand anchored dendrimeric formulation of Amphotericin B to target infected macrophages and showed reduced toxicity, high anti-leishmanial activity. This may add another treatment option to available formulations in the future. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Evaluation of quantum dot conjugated antibodies for immunofluorescent labelling of cellular targets

    Directory of Open Access Journals (Sweden)

    Jennifer E. Francis

    2017-06-01

    Full Text Available Semiconductor quantum dots (Qdots have been utilised as probes in fluorescence microscopy and provide an alternative to fluorescent dyes and fluorescent proteins due to their brightness, photostability, and the possibility to excite different Qdots with a single wavelength. In spite of these attractive properties, their implemenation by biologists has been somewhat limited and only a few Qdot conjugates are commercially available for the labelling of cellular targets. Although many protocols have been reported for the specific labelling of proteins with Qdots, the majority of these relied on Qdot-conjugated antibodies synthesised specifically by the authors (and therefore not widely available, which limits the scope of applications and complicates replication. Here, the specificity of a commercially available, Qdot-conjugated secondary antibody (Qdot-Ab was tested against several primary IgG antibodies. The antigens were labelled simultaneously with a fluorescent dye coupled to a secondary antibody (Dye-Ab and the Qdot-Ab. Although, the Dye-Ab labelled all of the intended target proteins, the Qdot-Ab was found bound to only some of the protein targets in the cytosol and could not reach the nucleus, even after extensive cell permeabilisation.

  4. Chelation for Coronary Heart Disease

    Science.gov (United States)

    ... procedures, and cardiac rehabilitation (a program consisting of education, counseling, and exercise training) are among the mainstays of conventional treatment . Some heart patients also turn to chelation therapy using disodium EDTA ( ...

  5. Development of new folate-based PET radiotracers: preclinical evaluation of {sup 68}Ga-DOTA-folate conjugates

    Energy Technology Data Exchange (ETDEWEB)

    Fani, Melpomeni; Maecke, Helmut R. [University Hospital Basel, Division of Radiological Chemistry, Basel (Switzerland); University Hospital Freiburg, Clinic for Nuclear Medicine, Freiburg (Germany); Wang, Xuejuan [University Hospital Basel, Division of Radiological Chemistry, Basel (Switzerland); Nicolas, Guillaume [University Hospital Basel, Department of Nuclear Medicine, Basel (Switzerland); Medina, Christelle; Raynal, Isabelle; Port, Marc [Guerbet, Research Department, Aulnay-sous-Bois (France)

    2011-01-15

    A number of {sup 111}In- and {sup 99m}Tc-folate-based tracers have been evaluated as diagnostic agents for imaging folate receptor (FR)-positive tumours. A {sup 68}Ga-folate-based radiopharmaceutical would be of great interest, combining the advantages of PET technology and the availability of {sup 68}Ga from a generator. The aim of the study was to develop a new {sup 68}Ga-folate-based PET radiotracer. Two new DOTA-folate conjugates, named P3026 and P1254, were synthesized using the 1,2-diaminoethane and 3-{l_brace}2-[2-(3-amino-propoxy)-ethoxy]-ethoxy{r_brace}-propylamine as a spacer, respectively. Both conjugates were labelled with {sup 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 {sup 111}In-DTPA-folate ({sup 111}In-P3139). The K{sub d} values of {sup 67/68}Ga-P3026 (4.65 {+-} 0.82 nM) and {sup 67/68}Ga-P1254 (4.27 {+-} 0.42 nM) showed high affinity for the FR. The internalization rate followed the order {sup 67/68}Ga-P3026 >{sup 67/68}Ga-P1254 >{sup 111}In-P3139, while almost double cellular retention was found for {sup 67/68}Ga-P3026 and {sup 67/68}Ga-P1254, compared to {sup 111}In-P3139. The biodistribution data of {sup 67/68}Ga-DOTA-folates showed high and receptor-mediated uptake on the FR-positive tumours and kidneys, with no significant differences compared to {sup 111}In-P3139. PET/CT images, performed with {sup 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 {sup 68}Ga in labelling yields and specific activities which allow clinical application. The characteristics of the {sup 67/68}Ga-DOTA-folates are comparable to {sup 111}In

  6. {sup 99m}Tc-chelator engineering to improve tumour targeting properties of a HER2-specific Affibody molecule

    Energy Technology Data Exchange (ETDEWEB)

    Engfeldt, Torun; Eriksson Karlstroem, Amelie [Royal Institute of Technology, School of Biotechnology, Stockholm (Sweden); Tran, Thuy [Uppsala University, Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden); Orlova, Anna; Feldwisch, Joachim; Tolmachev, Vladimir [Uppsala University, Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden); Affibody AB, Bromma (Sweden); Widstroem, Charles [Uppsala University Hospital, Section of Hospital Physics, Department of Oncology, Uppsala (Sweden); Abrahmsen, Lars; Wennborg, Anders [Affibody AB, Bromma (Sweden)

    2007-11-15

    Monitoring HER2 expression is crucial for selection of breast cancer patients amenable to HER2-targeting therapy. The Affibody molecule Z{sub HER2:342} binds to HER2 with picomolar affinity and enables specific imaging of HER2 expression. Previously, Z{sub HER2:342} with the additional N-terminal mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) sequence was labelled with {sup 99m}Tc and demonstrated specific targeting of HER2-expressing xenografts. However, hepatobiliary excretion caused high radioactivity accumulation in the abdomen. We investigated whether the biodistribution of Z{sub HER2:342} can be improved by substituting glycyl residues in the chelating sequence with more hydrophilic seryl residues. The Affibody molecule Z{sub HER2:342}, carrying the chelators mercaptoacetyl-glycyl-seryl-glycyl (maGSG), mercaptoacetyl-glycyl-D-seryl-glycyl [maG(D-S)G] and mercaptoacetyl-seryl-seryl-seryl (maSSS), were prepared by peptide synthesis and labelled with {sup 99m}Tc. The differences in the excretion pathways were evaluated in normal mice. The tumour targeting capacity of {sup 99m}Tc-maSSS-Z{sub HER2:342} was studied in nude mice bearing SKOV-3 xenografts and compared with the capacity of radioiodinated Z{sub HER2:342}. A shift towards renal excretion was obtained when glycine was substituted with serine in the chelating sequence. The radioactivity in the gastrointestinal tract was reduced threefold for the maSSS conjugate in comparison with the maGGG conjugate 4 h post injection (p.i.). The tumour uptake of {sup 99m}Tc-maSSS-Z{sub HER2:342} was 11.5 {+-} 0.5% IA/g 4 h p.i., and the tumour-to-blood ratio was 76. The pharmacokinetics and uptake characteristics of technetium-labelled Z{sub HER2:342} were better than those of radioiodinated Z{sub HER2:342}. The introduction of serine residues in the chelator results in better tumour imaging properties of the Affibody molecule Z{sub HER2:342} compared with glycyl-containing chelators and is favourable for imaging of tumours

  7. Synthesis and antimicrobial evaluation of two peptide LyeTx I derivatives modified with the chelating agent HYNIC for radiolabeling with technetium-{sup 99m}

    Energy Technology Data Exchange (ETDEWEB)

    Fuscaldi, Leonardo Lima; Santos, Daniel Moreira dos; Pinheiro, Natalia Gabriela Silva; Araujo, Raquel Silva; Barros, Andre Luis Branco de; Resende, Jarbas Magalhaes; Fernandes, Simone Odilia Antunes; Lima, Maria Elena de; Cardoso, Valbert Nascimento, E-mail: valbertncardoso@gmail.com [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Departamento de Analises Clinicas Toxicologica

    2016-11-01

    Background: Current diagnostic methods and imaging techniques are not able to differentiate septic and aseptic inflammation. Thus, reliable methods are sought to provide this distinction and scintigraphic imaging is an interesting option, since it is based on physiological changes. In this context, radiolabeled antimicrobial peptides have been investigated as they accumulate in infectious sites instead of aseptic inflammation. The peptide LyeTx I, from the venom of Lycosa erythrognatha, has potent antimicrobial activity. Therefore, this study aimed to synthesize LyeTx I derivatives with the chelating compound HYNIC, to evaluate their antimicrobial activity and to radiolabel them with {sup 99m}Tc. Methods: Two LyeTx I derivatives, HYNIC-LyeTx I (N-terminal modification) and LyeTx I-K-HYNIC (C-terminal modification), were synthesized by Fmoc strategy and purified by RP-HPLC. The purified products were assessed by RP-HPLC and MALDI-ToF-MS analysis. Microbiological assays were performed against S. aureus (ATCC® 6538) and E. coli (ATCC® 10536) in liquid medium to calculate the MIC. The radiolabeling procedure of LyeTx I-K-HYNIC with {sub 99m}Tc was performed in the presence of co-ligands (tricine and EDDA) and reducing agent (SnCl{sub 2} . 2H{sub 2}O), and standardized taking into account the amount of peptide, reducing agent, pH and heating. Radiochemical purity analysis was performed by thin-layer chromatography on silica gel strips and the radiolabeled compound was assessed by RP-HPLC and radioactivity measurement of the collected fractions. Data were analyzed by ANOVA, followed by Tukey test (p-values < 0.05). Results: Both LyeTx I derivatives were suitably synthesized and purified, as shown by RP-HPLC and MALDI-ToF-MS analysis. The microbiological test showed that HYNIC-LyeTx I (N-terminal modification) did not inhibit bacterial growth, whereas LyeTx I-K-HYNIC (C-terminal modification) showed a MIC of 5.05 μmol. L−1 (S. aureus) and 10.10 μmol. L−1 (E. coli

  8. Antioxidant evaluation and oxidative stability of structured lipids from extravirgin olive oil and conjugated linoleic acid.

    Science.gov (United States)

    Lee, Jeung Hee; Lee, Ki-teak; Akoh, Casimir C; Chung, Shin Kyo; Kim, Mee Ree

    2006-07-26

    Structured lipid (SL) was synthesized from extravirgin olive oil (EVOO) and conjugated linoleic acid (CLA) via a lipase-catalyzed reaction. CLA provides a variety of health benefits, but it is not consumed in free fatty acid form. The synthesized SL olive oil contained 42.5 mol % CLA isomers, and the major isomers were cis-9,trans-11-CLA (16.9 mol %) and trans-10,cis-12-CLA (24.2 mol %). The antioxidant activity determined by the radical scavenging capacity with the 2,2-diphenyl-1-picrylhydrazyl radical was lower in SL olive oil than in EVOO. The oxidative stability was also lower in SL olive oil since it had a higher peroxide value, rho-anisidine value, and 2-thiobarbituric acid reactive substances values during 20 days of storage at 60 degrees C. This observation could be due to the reduction in the natural phenolic compounds (97%) and tocopherols (56%), and the incorporated CLA with two conjugated double bonds in the SL olive oil. The oxidative stability of SL olive oil was increased by added rosemary extracts at concentrations of 100, 200, and 300 ppm. The present study suggests that the SL olive oil may be a suitable way to incorporate or deliver CLA into human diets. However, the addition of a proper antioxidant would be required for improving its oxidative stability.

  9. Synthesis and evaluation of a technetium-99m labeled cytotoxic bombesin peptide conjugate for targeting bombesin receptor-expressing tumors

    Energy Technology Data Exchange (ETDEWEB)

    Okarvi, Subhani M. [Cyclotron and Radiopharmaceuticals Department, King Faisal Specialist Hospital and Research Centre, MBC-03, PO Box 3354, Riyadh 11211 (Saudi Arabia)], E-mail: sokarvi@kfshrc.edu.sa; Al Jammaz, Ibrahim [Cyclotron and Radiopharmaceuticals Department, King Faisal Specialist Hospital and Research Centre, MBC-03, PO Box 3354, Riyadh 11211 (Saudi Arabia)

    2010-04-15

    concern, particularly for radionuclide therapy. This initial study towards the development of a novel cytotoxic BN conjugate suggest that the combination of favorable in vitro and in vivo properties may render {sup 99m}Tc-MTX-BN a potential candidate for the targeted imaging and eventually for radionuclide therapy (when labeled with an appropriate radionuclide) of BN receptor-positive tumors and deserves further evaluation.

  10. Conjugates of 1'-Aminoferrocene-1-carboxylic Acid and Proline: Synthesis, Conformational Analysis and Biological Evaluation

    Directory of Open Access Journals (Sweden)

    Monika Kovačević

    2014-08-01

    Full Text Available Our previous studies showed that alteration of dipeptides Y-Fca-Ala-OMe (III into Y-Ala-Fca-OMe (IV (Y = Ac, Boc; Fca = 1'-aminoferrocene-1-carboxylic acid significantly influenced their conformational space. The novel bioconjugates Y-Fca-Pro-OMe (1, Y = Ac; 2, Y = Boc and Y-Pro-Fca-OMe (3, Y = Boc; 4, Y = Ac have been prepared in order to investigate the influence of proline, a well-known turn-inducer, on the conformational properties of small organometallic peptides with an exchanged constituent amino acid sequences. For this purpose, peptides 1–4 were subjected to detailed spectroscopic analysis (IR, NMR, CD spectroscopy in solution. The conformation of peptide 3 in the solid state was determined. Furthermore, the ability of the prepared conjugates to inhibit the growth of estrogen receptor-responsive MCF-7 mammary carcinoma cells and HeLa cervical carcinoma cells was tested.

  11. Click-to-Chelate: Development of Technetium and Rhenium-Tricarbonyl Labeled Radiopharmaceuticals

    Directory of Open Access Journals (Sweden)

    Thomas L. Mindt

    2013-03-01

    Full Text Available The Click-to-Chelate approach is a highly efficient strategy for the radiolabeling of molecules of medicinal interest with technetium and rhenium-tricarbonyl cores. Reaction of azide-functionalized molecules with alkyne prochelators by the Cu(I-catalyzed azide-alkyne cycloaddition (CuAAC; click reaction enables the simultaneous synthesis and conjugation of tridentate chelating systems for the stable complexation of the radiometals. In many cases, the functionalization of (biomolecules with the ligand system and radiolabeling can be achieved by convenient one-pot procedures. Since its first report in 2006, Click-to-Chelate has been applied to the development of numerous novel radiotracers with promising potential for translation into the clinic. This review summarizes the use of the Click-to-Chelate approach in radiopharmaceutical sciences and provides a perspective for future applications.

  12. Development of Corn Starch-Neusilin UFL2 Conjugate as Tablet Superdisintegrant: Formulation and Evaluation of Fast Disintegrating Tablets

    Directory of Open Access Journals (Sweden)

    Prateek Juneja

    2014-01-01

    Full Text Available In the present study, corn Starch-Neusilin UFL2 conjugates were prepared by physical, chemical, and microwave methods with the aim of using the conjugates as tablet superdisintegrant. Various powder tests, namely, angle of repose, bulk density, tapped density, Hausner’s ratio, Carr’s index, swelling index, and powder porosity were conducted on the samples. The conjugates were characterized by ATR-FTIR, XRD, DSC, and SEM techniques. Heckel and Kawakita models were applied to carry out compression studies for the prepared conjugates. Fast disintegrating tablets of domperidone were prepared using corn starch and corn Starch-Neusilin UFL2 conjugates as tablet superdisintegrants in different concentrations. Conjugates were found to possess good powder flow and tabletting properties. Heckel analysis indicated that the conjugates prepared by microwave method showed the slowest onset of plastic deformation while Kawakita analysis indicated that the conjugates prepared by microwave method exhibited the highest amount of total plastic deformation. The study revealed that the corn Starch-Neusilin UFL2 conjugates possess improved powder flow properties and could be a promising superdisintegrant for preparing fast disintegrating tablet. Also, the results sugessted that the microwave method was found to be most effective for the preparation of corn Starch-Neusilin UFL2 conjugates.

  13. An efficient impedance method for induced field evaluation based on a stabilized Bi-conjugate gradient algorithm.

    Science.gov (United States)

    Wang, Hua; Liu, Feng; Xia, Ling; Crozier, Stuart

    2008-11-21

    This paper presents a stabilized Bi-conjugate gradient algorithm (BiCGstab) that can significantly improve the performance of the impedance method, which has been widely applied to model low-frequency field induction phenomena in voxel phantoms. The improved impedance method offers remarkable computational advantages in terms of convergence performance and memory consumption over the conventional, successive over-relaxation (SOR)-based algorithm. The scheme has been validated against other numerical/analytical solutions on a lossy, multilayered sphere phantom excited by an ideal coil loop. To demonstrate the computational performance and application capability of the developed algorithm, the induced fields inside a human phantom due to a low-frequency hyperthermia device is evaluated. The simulation results show the numerical accuracy and superior performance of the method.

  14. 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.

  15. Synthesis and Biological Evaluation of a New Polymeric Conjugate and Nanocarrier with Osteotropic Properties

    Directory of Open Access Journals (Sweden)

    Rosario Pignatello

    2012-01-01

    Full Text Available Bone-seeking (osteotropic drug delivery systems (ODDS represent an interesting solution for targeting different types of drugs to the bones. In particular, anticancer and antibacterial agents could take advantage of such therapeutic strategy. We have recently developed an innovative approach to this aim: a new osteotropic biomaterial was prepared, based on the conjugation of a poly(lactide-co-glycolide (PLGA with the bisphosphonate drug alendronate (PLGA-ALE; its hemo- and cytocompatibility were verified. Starting with this copolymer, an osteotropic nanoparticle system (NP was produced for the targeted delivery of antineoplastic drugs to osteolytic bone metastases; in particular, doxorubicin was tested as a model drug. The in vitro and in vivo results of the new ODDS are validated in this article. All the experimental data confirmed that the drug retained its activity after loading in the PLGA-ALE NP; they can be thus considered a new promising strategy for active targeting of drugs to bone tissues in different pathological situations.

  16. Conjugal violence

    Directory of Open Access Journals (Sweden)

    Simona Mihaiu

    2015-10-01

    Full Text Available Scientific knowledge of different aspects related to conjugal violence is highly important for people directly involved, such as researchers, practitioners and the entire society. In this respect, globally, specialised studies continue to advance, offer correct definitions, clear descriptions, convincing assessments to certain issues, encouraging thus long-term research, since some specialists have managed to overcome restrictive or ideological methods and explanations. Moreover, in practice, debates reach almost all social, political and legal dimensions regarding appropriate and efficient forms of preventing conjugal violence. Unfortunately, in Romania there are fewer research and prevention approaches of this social problem. In general, attention is directed to domestic violence and conjugal violence is dealt with only implicitly. Considering the given context, the aim of the paper is to outline, by analysing specialised literature, a new research direction and implicitly, social intervention. I specify that this article represents a stage in the ongoing postdoctoral research project, entitled "Conjugal homicide. Aggressors and victims".

  17. Improving Capture of Vaccine History: Case Study from an Evaluation of 10-Valent Pneumococcal Conjugate Vaccine Introduction in Kenya

    National Research Council Canada - National Science Library

    Harris, Aaron M; Aol, George; Ouma, Dominic; Bigogo, Godfrey; Montgomery, Joel M; Whitney, Cynthia G; Breiman, Robert F; Kim, Lindsay

    2016-01-01

    .... We sought to improve immunization history acquisition from Ministry of Health vaccination cards during a vaccine impact study of 10-valent pneumococcal conjugate vaccine on pneumococcal carriage...

  18. Overview of current chelation practices

    Directory of Open Access Journals (Sweden)

    Y. Aydinok

    2011-12-01

    Full Text Available Deferoxamine (DFO is reference standard therapy for transfusional iron overload since the 1980s. Although it is a highly effective iron chelator, the compliance problem to subcutaneous administration of DFO remains as the major problem. The oral chelator Deferiprone (DFP has no marketing licence in North America, however, it has been licensed in India since 1994 and the European Union (EU granted marketing approval for DFP in 1999, specifically for patients with thalassemia major when DFO is inadequate, intolerable or unacceptable. There are still limited data available on the use of DFP in children between 6 and 10 years of age, and no data on DFP use in children under 6 years of age. Subsequently the oral chelator Deferasirox (DFX was approved by FDA and EMA for the treatment of patients with transfusional iron overload -older than 2 years of age- as first line therapy, in 2005 and 2006 respectively. The primary objective of iron chelation is to maintain body iron at safe levels at all times but once iron is accumulated, the objective of iron chelation is to reduce tissue iron to safe levels which is a slow process. The chelation regimen, dose and frequency of administration, of the chelator(s are mainly determined based on body iron burden, presence of myocardial iron and the transfusional iron loading rate. A proper monitoring of chelation is of importance for measuring the response rate to a particular regimen and providing dose adjustments to enhance chelation efficacy and to avoid toxicity. Efficacy of a chelation regimen may exhibit individual variability resulting from factors such as absorbtion and metabolism of the chelator. Tolerability and compliance are also individual variables effecting the response to chelation. Understanding of advantages and limitations of chelators, accurately determining chelation needs of patients with iron overload and designing individualized chelation regimens with less toxicity but optimum efficacy

  19. Synthesis and biological evaluation of novel podophyllotoxin-NSAIDs conjugates as multifunctional anti-MDR agents against resistant human hepatocellular carcinoma Bel-7402/5-FU cells.

    Science.gov (United States)

    Zhang, Lei; Liu, Lai; Zheng, Chengyue; Wang, Yang; Nie, Xuqiang; Shi, Dabin; Chen, Yongzheng; Wei, Gang; Wang, Jing

    2017-05-05

    Currently, multi-drug resistance (MDR) to chemotherapy agents is a major hindrance to the treatment of hepatocellular carcinoma. Development of novel antineoplastic drug with anti-MDR activity is an effectively way to overcome cancer resistance. In present study, novel podophyllotoxin-NSAIDs conjugates were synthesized, and their antiproliferative activities were evaluated in vitro. The most potent conjugate, A1, displayed selective cytotoxicity against resistant Bel-7402/5-FU cells with an IC50 value of 0.065 ± 0.016 μM and a lower resistant factor value of 0.32. In addition, all conjugate molecules efficiently triggered cell cycle arrest at S + G2 phase, induced apoptosis, disrupted the microtubule network and showed antimigratory activity in Bel-7402/5-FU cells. Finally, three conjugates regulated the levels of cell cycle arrest-, apoptosis-, migratory-, inflammatory- and MDR-related proteins, as well as three signaling in Bel-7402/5-FU cells by some but not all similar molecular mechanisms. Together, these findings highlighted the cytotoxic and multifunctional anti-MDR properties of podophyllotoxin-NSAIDs conjugates for the first time, which may be promising candidates for intervention of resistant hepatocellular carcinoma. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  20. Preparation and evaluation of Salmonella Enteritidis antigen conjugated with nanogold for screening of poultry flocks

    Directory of Open Access Journals (Sweden)

    Hazem Mohammed Ibrahim

    2017-08-01

    Full Text Available Aim: The present work aimed to develop lateral flow immunochromatographic strip (ICS test for detection of Salmonella Enteritidis (SE specific antibodies in chicken sera. Materials and Methods: A rapid lateral flow immunochromatographic test (LFIT has been developed, in which SE Group D antigen labeled with the gold chloride molecules laid on the conjugate pad. Staphylococcus aureus protein A was used as capture antibody at the test line (T of a nitrocellulose (NC membrane and anti-SE antigen-specific rabbit antibodies were used as capture antibody at the control line (C of the NC strip in the lateral flow layout device. Results: Using the developed LFIT, the minimal amount of SE-specific antibodies that can be detected in chicken serum sample was 1427 enzyme-linked immunosorbent assay (ELISA unit/100 μl that was equal to 0.1 μg (Ab/100 μl sample. 100 suspected serum samples collected from a poultry flock were tested with the prepared SE-LFIT kits and the locally prepared stained Salmonella antigen, and the results were compared with those obtained from examination of these samples with Salmonella Group D antibody ELISA kit as the gold standard test. The sensitivity, specificity, and accuracy of the prepared SE-LFIT antigen kits were 94.4%, 90%, and 94%, respectively, while those obtained with stained Salmonella antigen were 88.8%, 90%, and 89%, respectively. Conclusion: The developed test is a simple field rapid test of high sensitivity, specificity, and accuracy that can improve and facilitates rapid field surveillance of salmonellosis among chickens.

  1. Evaluation of a new biotin-DOTA conjugate for pretargeted antibody-guided radioimmunotherapy (PAGRIT {sup registered})

    Energy Technology Data Exchange (ETDEWEB)

    Urbano, Nicoletta; Papi, Stefano; Paganelli, Giovanni; Chinol, Marco [European Institute of Oncology, Division of Nuclear Medicine, Milan (Italy); Ginanneschi, Mauro [University of Florence and CNR-ICOM, Polo Scientifico, Laboratory of Peptides and Proteins, Chemistry and Biology, Sesto Fiorentino (Italy); De Santis, Rita; Pace, Silvia; Lindstedt, Ragnar; Ferrari, Liliana [Sigma Tau SpA R and D, Pomezia, Rome (Italy); Choi, Sun Ju [Korea Atomic Energy Research Institute, Taejeon (Korea)

    2007-01-15

    A novel biotin-DOTA conjugate (r-BHD: reduced biotinamidohexylamine-DOTA) was investigated in order to provide an efficient pretargeted antibody-guided radioimmunotherapy (PAGRIT {sup registered}) application. Preclinical and clinical results are described. {sup 90}Y and {sup 177}Lu were used to label r-BHD. The effect of pH and a wide range of specific activities were studied. Radiolabelled r-BHD was tested for affinity towards avidin and for stability in saline or in human serum with and without ascorbic acid. Pharmacokinetic data were collected and organ biodistribution evaluated in a tumour-bearing pretargeted animal model. A pilot study was performed in a metastatic melanoma patient and dosimetry was estimated. High radiochemical purity (>99%) was routinely achieved with {sup 90}Y or {sup 177}Lu in sodium acetate buffer (1.0 M, pH 5.0) at a specific activity of 2.6 MBq/nmol. Both {sup 90}Y- and {sup 177}Lu-r-BHD were also prepared at higher specific activities. Radiolabelled r-BHD was stable up to 96 h in human serum and saline with the addition of ascorbic acid. The structural modifications proposed for the r-BHD stabilised it against enzymatic degradation while retaining high binding affinity for avidin. Renal clearance appeared to be the main route of excretion in animals, and high tumour uptake was observed in the pretargeted animals. The patient study showed a total body clearance of {proportional_to}85% in 24 h, with a kidney absorbed dose of 1.5 mGy/MBq. Tumour uptake was rapid and the calculated dose to a 10-mm tumour lesion was {proportional_to}12 mGy/MBq. These results indicate that the new biotin-DOTA conjugate may be a suitable candidate for pretargeting trials. (orig.)

  2. Evaluation of gadobutrol, a macrocyclic, nonionic gadolinium chelate in a brain glioma model: comparison with gadoterate meglumine and gadopentetate dimeglumine at 1.5 T, combined with an assessment of field strength dependence, specifically 1.5 versus 3 T.

    Science.gov (United States)

    Attenberger, Ulrike I; Runge, Val M; Morelli, John N; Williams, Jonathan; Jackson, Carney B; Michaely, Henrik J

    2010-03-01

    To evaluate in a rat brain glioma model intraindividual tumor enhancement at 1.5 T using gadobutrol (Gadovist), a nonionic, macrocyclic chelate currently in clinical trials in the United States, in comparison with both an ionic macrocyclic chelate, gadoterate meglumine (Dotarem), and an ionic linear chelate, gadopentetate dimeglumine (Magnevist), and to compare the degree of tumor enhancement with gadobutrol at 1.5 and 3 T. A total of 24 rats, divided into three groups with n = 8 animals per group, were evaluated. Animals in group 1 received injections of gadobutrol and gadopentetate dimeglumine, whereas those in group 2 received gadobutrol and gadoterate meglumine. Injections were performed in random order and separated by 24 hours. Magnetic resonance imaging (MRI) examinations were performed immediately following each contrast injection with a 1.5 T MR system. Animals in group 3 received gadobutrol injections using the same protocol but with scans performed at 1.5 and 3 T. In all examinations, T1-weighted images were acquired precontrast, 1 minute postcontrast, and at 4 consecutive 2-minute intervals thereafter. A contrast dose of 0.1 mmol/kg was used in all instances. In groups 1 and 2, tumor signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were higher for gadobutrol compared to both other agents at each timepoint postcontrast injection. The improvement in tumor CNR with gadobutrol, depending on time, was between 12% and 40% versus gadopentetate dimeglumine, with the difference achieving statistical significance at 7 minutes. The improvement in tumor CNR with gadobutrol, depending on time, was between 15% and 27% versus gadoterate meglumine, with the difference statistically significant at 5 and 9 minutes. In group 3 the improvement in tumor SNR and CNR seen with the increase in field strength from 1.5 to 3 T for gadobutrol was statistically significant at all acquired timepoints (P gadopentetate dimeglumine and gadoterate meglumine at 1.5 T. A

  3. Studies in Multifunctional Drug Development: Preparation and Evaluation of 11beta-Substituted Estradiol-Drug Conjugates, Cell Membrane Targeting Imaging Agents, and Target Multifunctional Nanoparticles

    Science.gov (United States)

    Dao, KinhLuan Lenny D.

    Cancer is the second leading cause of death after cardiovascular disease in the United State. Despite extensive research in development of antitumor drugs, most of these therapeutic entities often possess nonspecific toxicity, thus they can only be used to treat tumors in higher doses or more frequently. Because of the cytotoxicity and severe side effects, the drug therapeutic window normally is limited. Beside the toxicity issue, antitumor drug are also not selectively taken up by tumor cells, thus the necessitating concentrations that would eradicate the tumor can often not be used. In addition, tumor cells tend to develop resistance against the anticancer drugs after prolonged treatment. Therefore, alleviating the systemic cytotoxicity and side effects, improving in tumor selectivity, high potency, and therapeutic efficacy are still major obstacles in the area of anticancer drug development. A more promising approach for developing a selective agent for cancer is to conjugate a potent therapeutic drug, or an imaging agent with a targeting group, such as antibody or a high binding-specificity small molecule, that selectively recognize the overexpressed antigens or proteins on tumor cells. My research combines several approaches to describe this strategy via using different targeting molecules to different diseases, as well as different potent cytotoxic drugs for different therapies. Three studies related to the preparation and biological evaluation of new therapeutic agents, such as estradiol-drug hybrids, cell membrane targeted molecular imaging agents, and multifunctional NPs will be discussed. The preliminary results of these studies indicated that our new reagents achieved their initial objectives and can be further improved for optimized synthesis and in vivo experiments. The first study describes the method in which we employed a modular assembly approach to synthesize a novel 11beta-substituted steroidal anti-estrogen. The key intermediate was synthesized

  4. Synthesis and evaluation of the biostability and cell compatibility of novel conjugates of nucleobase, peptidic epitope, and saccharide

    Directory of Open Access Journals (Sweden)

    Dan Yuan

    2015-08-01

    Full Text Available This article reports the synthesis of a new class of conjugates containing a nucleobase, a peptidic epitope, and a saccharide and the evalution of their gelation, biostability, and cell compatibility. We demonstrate a facile synthetic process, based on solid-phase peptide synthesis of nucleopeptides, to connect a saccharide with the nucleopeptides for producing the target conjugates. All the conjugates themselves (1–8 display excellent solubility in water without forming hydrogels. However, a mixture of 5 and 8 self-assembles to form nanofibers and results in a supramolecular hydrogel. The proteolytic stabilities of the conjugates depend on the functional peptidic epitopes. We found that TTPV is proteolytic resistant and LGFNI is susceptible to proteolysis. In addition, all the conjugates are compatible to the mammalian cells tested.

  5. DOTAGA-trastuzumab. A new antibody conjugate targeting HER2/Neu antigen for diagnostic purposes.

    Science.gov (United States)

    Moreau, Mathieu; Raguin, Olivier; Vrigneaud, Jean-Marc; Collin, Bertrand; Bernhard, Claire; Tizon, Xavier; Boschetti, Frédéric; Duchamp, Olivier; Brunotte, François; Denat, Franck

    2012-06-20

    Improved bifunctional chelating agents (BFC) are required for indium-111 radiolabeling of monoclonal antibodies (mAbs) under mild conditions to yield stable, target-specific agents. 2,2',2"-(10-(2,6-Dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DOTAGA-anhydride) was evaluated for mAb conjugation and labeling with indium-111. The DOTA analogue was synthesized and conjugated to trastuzumab-which targets the HER2/neu receptor-in mild conditions (PBS pH 7.4, 25 °C, 30 min) and gave a mean degree of conjugation of 2.6 macrocycle per antibody. Labeling of this immunoconjugate with indium-111 was performed in 75% yield after 1 h at 37 °C, and the proportion of (111)In-DOTAGA-trastuzumab reached 97% after purification. The affinity of DOTAGA-trastuzumab was 5.5 ± 0.6 nM as evaluated by in vitro saturation assays using HCC1954 breast cancer cell line. SPECT/CT imaging and biodistribution studies were performed in mice bearing breast cancer BT-474 xenografts. BT-474 tumors were clearly visualized on SPECT images at 24, 48, and 72 h postinjection. The tumor uptake of [(111)In-DOTAGA]-trastuzumab reached 65%ID/g 72 h postinjection. These results show that the DOTAGA BFC appears to be a valuable tool for biologics conjugation.

  6. REGIONAL SIDEROSIS: A NEW CHALLENGE FOR IRON CHELATION THERAPY

    Directory of Open Access Journals (Sweden)

    Zvi Ioav Cabantchik

    2013-12-01

    Full Text Available The traditional role of iron chelation therapy has been to reduce body iron burden via chelation of excess metal from organs and fluids and its excretion via biliary-fecal and/or urinary routes. In their present use for hemosiderosis, chelation regimens might not be suitable for treating disorders of iron maldistribution, as those are characterized by toxic islands of siderosis appearing in a background of normal or subnormal iron levels (e.g. sideroblastic anemias, neuro- and cardio-siderosis in Friedreich ataxia- and neurosiderosis in Parkinson’s disease. We aimed at clearing local siderosis from aberrant labile metal that promotes oxidative damage, without interfering with essential local functions or with hematological iron-associated properties. For this purpose we introduced a conservative mode of iron chelation based on dual activity based on scavenging labile metal but also redeploying it to cell acceptors or to physiological transferrin. The scavenging and redeployment mode of action was designed both for correcting aberrant iron distribution and also for minimizing/preventing systemic loss of chelated metal. We first examine cell models that recapitulate iron maldistribution and associated dysfunctions identified with Friedreich ataxia and Parkinson’s disease and use them to explore the ability of the double-acting agent deferiprone, an orally active chelator, to mediate iron scavenging and redeployment and thereby causing functional improvement. We subsequently evaluate the concept in translational models of disease and finally assess its therapeutic potential in prospective double-blind pilot clinical trials. We claim that any chelator applied to diseases of regional siderosis, cardiac, neuronal or endocrine ought to preserve both systemic and regional iron levels. The proposed deferiprone-based therapy has provided a paradigm for treating regional types of siderosis without affecting hematological parameters and systemic

  7. A New Synthesis of TE2A-a Potential Bifunctional Chelator for {sup 64}Cu

    Energy Technology Data Exchange (ETDEWEB)

    Pandya, Darpan N.; Kwak, Won Jung; Park, Jeong Chan; Gawande, Manoj B.; Yoo, Jeong Soo [Kyungpook National University, Daegu (Korea, Republic of); Kim, Jung Young; An, Gwang Il [Molecular Imaging Research Center, Seoul (Korea, Republic of); Ryu, Eun Kyoung [Korea Basic Science Institute, Chungbuk (Korea, Republic of)

    2010-09-15

    The development of a new bifunctional chelator, which holds radio metals strongly in living systems, is a prerequisite for the successful application of disease-specific biomolecules to medical diagnosis and therapy. Recently, TE2A was reported to make kinetically more stable Cu({Pi}) complexes than TETA. Herein, we report a new synthetic route to TE2A and explore its potential as a bifunctional chelator. TE2A was synthesized using the regioselective alkylation of benzyl bromoacetate and successive de protection of the methylene bridge and benzyl group. Salt-free TE2A was radiolabeled with {sup 64}Cu and micro PET imaging was performed to follow the clearance pattern of the {sup 64}Cu-TE2A complex. TE2A was conjugated with cyclic RGD peptide and the TE2A-c(RGDyK) conjugate was radiolabeled with {sup 64}Cu. TE2A was prepared in salt-free form cyclam in an overall yield of 74%. The micro PET images showed that {sup 64}Cu-TE2A is excreted rapidly from the body by the kidney and liver. TE2A was successfully conjugated with c(RGDyK) peptide through on carboxylate group and the TE2A-c(RGDyK) conjugate was radiolabeled with {sup 64}Cu in 94% yield within 30 min. TE2A can be used by itself as a bifunctional chelator without any further structural modification.

  8. Luminescent lanthanide chelates and methods of use

    Science.gov (United States)

    Selvin, Paul R.; Hearst, John

    1997-01-01

    The invention provides lanthanide chelates capable of intense luminescence. The celates comprise a lanthanide chelator covalently joined to a coumarin-like or quinolone-like sensitizer. Exemplary sensitzers include 2- or 4-quinolones, 2- or 4-coumarins, or derivatives thereof e.g. carbostyril 124 (7-amino-4-methyl-2-quinolone), coumarin 120 (7-amino-4-methyl-2-coumarin), coumarin 124 (7-amino-4-(trifluoromethyl)-2-coumarin), aminomethyltrimethylpsoralen, etc. The chelates form high affinity complexes with lanthanides, such as terbium or europium, through chelator groups, such as DTPA. The chelates may be coupled to a wide variety of compounds to create specific labels, probes, diagnostic and/or therapeutic reagents, etc. The chelates find particular use in resonance energy transfer between chelate-lanthanide complexes and another luminescent agent, often a fluorescent non-metal based resonance energy acceptor. The methods provide useful information about the structure, conformation, relative location and/or interactions of macromolecules.

  9. Antioxidant, Iron-chelating and Anti-glucosidase Activities of Typha ...

    African Journals Online (AJOL)

    Antioxidant, Iron-chelating and Anti-glucosidase Activities of Typha domingensis Pers (Typhaceae). T Chai, M Mohan, H Ong, F Wong. Abstract. Purpose: To evaluate the phytochemical profile as well as in vitro antioxidant, iron-chelating, and antiglucosidase activities of Typha domingensis Pers. (Typhaceae) Methods: Total ...

  10. Some Linguistic Detail on Chelation

    Science.gov (United States)

    Haworth, Daniel T.

    1998-01-01

    The term chelate was first applied by Morgan and Drew in 1920 to describe the heterocyclic rings formed from bidentate ligands bonding to a central atom. The history of the word ch_l_ is traced from its original Greek meaning through the Latin language to its anglicized form, chela. This word has a very rich history and has been cited by both Greek (Aristotle) and Latin (Cicero, Vergil) philosophers and poets.

  11. Study of conjugation and radiolabeling of monoclonal antibody rituximab for use in radionuclide therapy; Estudo da conjugacao e radiomarcacao do anticorpo monoclonal rituximab para aplicacao em terapia radionuclidica

    Energy Technology Data Exchange (ETDEWEB)

    Massicano, Adriana Vidal Fernandes

    2011-07-01

    Lymphomas are tumors originated from the transformation of a lymphocyte in the lymphatic system. The most common lymphoma is the Non-Hodgkin Lymphoma (NHL). Advances in immunology and molecular biology have been improving NHL's detection and treatment strategies development, such as Radioimmunotherapy (RIT). Rituximab is an anti-CD20 monoclonal antibody used as immunotherapeutic to treat refractory or relapsed NHL. The goal of the present work was to conjugate this antibody to DOTA-NHS-ester bifunctional chelator and to radiolabel it with {sup 177}Lu radioisotope in order to develop a radio immunotherapeutic agent for NHL's treatment. Different rituximab to DOTA molar ratios (1:5, 1:10, 1:20, 1:50, 1:250, 1:500 and 1:1000) were evaluated in order to determine the best condition for obtaining the highest radiochemical purity of radio immunotherapeutic. The stability of the unlabeled immuno conjugated was evaluated by high performance liquid chromatography (HPLC) for up to 240 days in different storage conditions. The stability of the labeled preparations was evaluated either after storing at 2-8 degree C or incubation in human serum at 37 degree C. The binding to serum proteins was also determined. In vivo studies were performed in healthy Swiss mice, in order to characterize the biological properties of labeled conjugate. Finally, preliminary studies of radio immuno conjugated competitive binding to CD20 positive Raji cells were carried out in order to analyze if the process of conjugation and radiolabeling compromises the immunoreactivity of the antibody. The conjugation applying lower antibody to chelator molar ratios (1:5, 1:10 and 1:20) showed high stability when stored for up to 240 days in different conditions. The HPLC analysis showed that the monoclonal antibody conjugated in molar ratio 1:50 was labeled with higher radiochemical purity (> 95%) when purified in PD-10 column. This conjugate showed reasonable stability at 2-8 degree C. The analysis

  12. Biochemical and Functional Evaluation of the Intramolecular Disulfide Bonds in the Zinc-Chelating Antimicrobial Protein Human S100A7 (Psoriasin).

    Science.gov (United States)

    Cunden, Lisa S; Brophy, Megan Brunjes; Rodriguez, Grayson E; Flaxman, Hope A; Nolan, Elizabeth M

    2017-10-31

    Human S100A7 (psoriasin) is a metal-chelating protein expressed by epithelial cells. It is a 22-kDa homodimer with two EF-hand domains per subunit and two transition-metal-binding His3Asp sites at the dimer interface. Each subunit contains two cysteine residues that can exist as free thiols (S100A7red) or as an intramolecular disulfide bond (S100A7ox). Herein, we examine the disulfide bond redox behavior, the Zn(II) binding properties, and the antibacterial activity of S100A7, as well as the effect of Ca(II) ions on these properties. In agreement with prior work [Hein, K. Z., et al. (2013) Proc. Natl. Acad. Sci. U. S. A. 112, 13039-13044], we show that apo S100A7ox is a substrate for the mammalian thioredoxin system; however, negligible reduction of the disulfide bond is observed for Ca(II)- and Zn(II)-bound S100A7ox. Furthermore, metal binding depresses the midpoint potential of the disulfide bond. S100A7ox and S100A7red each coordinate 2 equiv of Zn(II) with subnanomolar affinity in the absence and presence of Ca(II) ions, and the cysteine thiolates in S100A7red do not form a third high-affinity Zn(II) site. These results refute a prior model implicating the Cys thiolates of S100A7red in high-affinity Zn(II) binding [Hein, K. Z., et al. (2013) Proc. Natl. Acad. Sci. U. S. A. 112, 13039-13044]. S100A7ox and the disulfide-null variants show comparable Zn(II)-depletion profiles; however, only S100A7ox exhibits antibacterial activity against select bacterial species. Metal substitution experiments suggest that the disulfide bonds in S100A7 may enhance metal sequestration by the His3Asp sites and thereby confer growth inhibitory properties to S100A7ox.

  13. Paclitaxel-loaded, folic-acid-targeted and TAT-peptide-conjugated polymeric liposomes: in vitro and in vivo evaluation.

    Science.gov (United States)

    Zhao, Peiqi; Wang, Hanjie; Yu, Man; Cao, Shuzhen; Zhang, Fei; Chang, Jin; Niu, Ruifang

    2010-09-01

    Folic acid and TAT peptide were conjugated on the octadecyl-quaternized, lysine-modified chitosan-cholesterol polymeric liposomes (FA-TATp-PLs) to investigate their potential feasibility for tumor-targeted drug delivery. FA-TATp-PLs encapsulating paclitaxel or calcein were synthesized and characterized. Cellular uptake of PLs, FA-PLs, TATp-PLs and FA-TATp-PLs was studied by confocal laser scanning microscopy (CLSM) in folate receptor (FR)-positive KB nasopharyngeal epidermal carcinoma cells and FR-deficient A549 lung cancer cells. In vitro and in vivo antitumor activity of paclitaxel-loaded FA-TATp-PLs were also evaluated in KB and A549 cells as well as in a murine KB xenograft model. Our data showed that 80% paclitaxel released from FA-TATp-PLs in 2 weeks. Different from other various PLs, CLSM analyses showed that FA-TATp-PLs had a significantly high efficient intracellular uptake in both KB and A549 cells. These data revealed the targeting effects of folate decoration, the transmembrane ability of TAT peptide as well as a synergistic interaction between them. In addition, paclitaxel-loaded FA-TATp-PLs exhibited a more superior antitumor effect in vitro and in vivo as compared to that with Taxol. FA-TATp-PLs possessing both targeting effect and transmembrane ability may serve as a promising carrier for the intracellular delivery of therapeutic agents.

  14. Identification of transplanted pancreatic islet cells by radioactive dithizone-[131I]-histamine conjugate. Preliminary report.

    Science.gov (United States)

    Garnuszek, P; Licińska, I; Mrozek, A; Wardawa, A; Fiedor, P S; Mazurek, A P

    2000-01-01

    The unique mechanism of dithizone action in the interior of the viable pancreatic islet suggests the possible development of a specific radiopharmaceutical that may have a potential clinical application in the diagnosis of the pancreatic organ allografts or islets rejection. The radiodiagnostic properties of the newly developed radioactive analogue of dithizone, i.e. Dithizone-[(131)I]-Histamine conjugate have been evaluated in the present study. The four islet cells transplantation models were chosen for this purpose. The most important feature of the Dithizone-[(131)I]-Histamine conjugate is its possessed ability of zinc chelation. As was presented in the recent study, the conjugate stains pink-reddish the isolated pancreatic islets in vitro. Among the studied transplantation models, only the islets grafting under testis capsule enabled determination of the pancreatic islets in rats by radioactive Dithizone-[(131)I]-Histamine conjugate. The level of the radioactivity in the recipient testis (right) was almost two times higher compared to the controls (0.24 vs. 0.13% ID/g, respectively). These preliminary data demonstrate the ability of the developed radioactive analogue of dithizone for in vivo identification of transplanted pancreatic islets, and suggests a potential clinical application of the radiodithizone in the diagnosis of the pancreatic islet rejection.

  15. Anti-oxidative, metal chelating and radical scavenging effects of ...

    African Journals Online (AJOL)

    Purpose: To evaluate protein hydrolysates and membrane ultrafiltration fractions of blue-spotted stingray for metal chelating and radical scavenging activities, as well as protection against oxidative protein damage. Methods: Stingray protein isolates were hydrolysed with alcalase, papain and trypsin for 3 h. Alcalase ...

  16. The study of conjugation of anti-CD20 monoclonal antibody for labeling with metallic or lanthanides radionuclides; Estudo de conjugacao do anticorpo anti-CD20 para marcacao com radionuclideos metalicos ou lantanideos

    Energy Technology Data Exchange (ETDEWEB)

    Akanji, Akinkunmi Ganiyu

    2012-07-01

    Lymphomas are malignancies or cancers that start from the malign transformation of a lymphocyte in the lymphatic system. Generally, lymphomas start from the lymph nodes or from the agglomeration of the lymphatic tissues, organs like stomach, intestines, in some cases it can involve the bone marrow and the blood, it can also disseminate to other organs. Lymphomas are divided in two major categories: Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). Patient with NHL are generally treated with radiotherapy alone or combined with immunotherapy using monoclonal antibody rituximab (MabThera Registered-Sign ). Currently, monoclonal antibodies (Acm) conjugated with bifunctional chelate agents and radiolabeled with metallic or lanthanides radionuclides are a treatment reality for patients with NHL by the principle of radioimmunotherapy (RIT). This study focused on the conditions of conjugation of Acm rituximab (MabThera Registered-Sign ) with bifunctional chelating agents DOTA and DTPA. Various parameters were studied: method of Acm purification, conditions of Acm conjugation, the method for determination of number of chelate agent coupled to the Acm, method for purification of the conjugated antibody Acm, conditions of labeling of the conjugated antibody with lutetium-177, method of purification of the radiolabeled immuno conjugate, method of radiochemical purity (RP), specific binding in vitro Raji cells (Human Burkitt) and biological distribution performed in normal Balb-c mouse. The three methodologies employed in pre-purification of Acm (dialysis, size exclusion chromatograph and dial filtration) demonstrated to be efficient; they provided sample recovery exceeding 90%. However, the methodology of dial filtration presents minimal sample loss, and gave the final recovery of the sample in micro liters; thereby facilitating sample use in subsequent experiments. Numbers of chelators attached to the Acm molecule was proportional to the molar ratio studied. When we evaluated

  17. Synthesis and Evaluation of Ciprofloxacin-Nitroxide Conjugates as Anti-Biofilm Agents

    Directory of Open Access Journals (Sweden)

    Anthony D. Verderosa

    2016-06-01

    Full Text Available As bacterial biofilms are often refractory to conventional antimicrobials, the need for alternative and/or novel strategies for the treatment of biofilm related infections has become of paramount importance. Herein, we report the synthesis of novel hybrid molecules comprised of two different hindered nitroxides linked to the piperazinyl secondary amine of ciprofloxacin via a tertiary amine linker achieved utilising reductive amination. The corresponding methoxyamine derivatives were prepared alongside their radical-containing counterparts as controls. Subsequent biological evaluation of the hybrid compounds on preformed P. aeruginosa flow cell biofilms divulged significant dispersal and eradication abilities for ciprofloxacin-nitroxide hybrid compound 10 (up to 95% eradication of mature biofilms at 40 μM. Importantly, these hybrids represent the first dual-action antimicrobial-nitroxide agents, which harness the dispersal properties of the nitroxide moiety to circumvent the well-known resistance of biofilms to treatment with antimicrobial agents.

  18. Conjugal violence

    OpenAIRE

    Simona Mihaiu

    2015-01-01

    Scientific knowledge of different aspects related to conjugal violence is highly important for people directly involved, such as researchers, practitioners and the entire society. In this respect, globally, specialised studies continue to advance, offer correct definitions, clear descriptions, convincing assessments to certain issues, encouraging thus long-term research, since some specialists have managed to overcome restrictive or ideological methods and explanations. Moreover, in practice,...

  19. Characterization of Tumor-Avid Antibody Fragments Genetically Engineered for Mono-Specific Radionuclide Chelation

    Energy Technology Data Exchange (ETDEWEB)

    Quinn, T.P.

    2003-12-31

    The successful clinical application of targeted-radiopharmaceuticals depends on the development of molecules that optimize tumor specific radionuclide deposition and minimize non-specific organ irradiation. To this end, this proposal outlines a research effort to identify and evaluate novel antibodies and antibody fragments that bind breast tumors. The tumor-avid antibodies will be investigated for as imaging and therapeutic agents and to gain a better understanding of the pharmacokinetics and metabolism of radiolabeled tumor-avid antibody fragments through the use of site-specifically labeled molecules. Antibodies or antibody fragments, that bind breast carcinoma carbohydrate antigens, will be obtained from hybridoma or bacteriophage library screening. More specifically, antibody fragments that bind the carcinoma-associated Thomsen-Friedenreich (T) antigen will be radiolabeled with {sup 99m}Tc and {sup 188}Re at a natural amino acid chelation site and will be investigated in vivo for their abilities to target human breast tumors. In addition, site-specific radiolabeled antibody fragments will be biosynthesized using misacylated suppressor tRNAs. Homogeneously radiolabeled populations of antibody fragments will be used to investigate the effects of radionuclide location and chelation chemistries on their biodistribution and metabolism. It is hypothesized that site-specifically radiolabeled antibody fragments will possess enhanced tumor imaging and therapeutic properties due to optimal label location and conjugation chemistries. New insights into the factors that govern antibody metabolism in vivo are also expected from this work. Results from these studies should enhance our ability to design and synthesize radiolabeled antibody fragments that have improved pharmacokinetic properties. The studies in this proposal involve basic research into the development of antibody-based radiopharmaceuticals, with the ultimate goal of application in humans. This type of basic

  20. Knigth's Move in the Periodic Table, From Copper to Platinum, Novel Antitumor Mixed Chelate Copper Compounds, Casiopeinas, Evaluated by an in Vitro Human and Murine Cancer Cell Line Panel.

    Science.gov (United States)

    Gracia-Mora, I; Ruiz-Ramírez, L; Gómez-Ruiz, C; Tinoco-Méndez, M; Márquez-Quiñones, A; Lira, L R; Marín-Hernández, A; Macías-Rosales, L; Bravo-Gómez, M E

    2001-01-01

    We synthesized a novel anticancer agents based on mixed chelate copper (II) complexes, named Casiopeínas((R)) has of general formula [Cu(N-N)(N-O)H(2)O]NO(3) (where, N-N = diimines as 1,10- phenanthroline, 2,2-bipyridine, or substituted and N-O=aminoeidate or [Cu(N-N)(O-O)H(2)O]NO(3) (where NN= diimines as 10-phenanthroline, 2,2-bipyridine or substituted Casiopeínas I, II, IV, V, VI, VII VIII and O-O=acetylacetonate, salicylaldehidate Casiopínas III). We evaluated the in vitro antitumor activity using a human cancer cell panel and some nurine cancer cells. Eleven Casiopeinas are evaluated in order to acquire some structure-activity correlations and some monodentated Casiopeinäs analogues; cisplatinum was used as control drug. The 50% growth inhibition observed is, in all cases reach with concentrations of Casiopeina's 10 or 100 times lower than cisplatinum. In a previous work we reported the induction of apoptosis by Casiopeina II. The results indicate that Casiopeinass are a promising new anticancer drug candidates to be developed further toward clinical trials.

  1. Antibody Conjugates: From Heterogeneous Populations to Defined Reagents

    Directory of Open Access Journals (Sweden)

    Patrick Dennler

    2015-08-01

    Full Text Available Monoclonal antibodies (mAbs and their derivatives are currently the fastest growing class of therapeutics. Even if naked antibodies have proven their value as successful biopharmaceuticals, they suffer from some limitations. To overcome suboptimal therapeutic efficacy, immunoglobulins are conjugated with toxic payloads to form antibody drug conjugates (ADCs and with chelating systems bearing therapeutic radioisotopes to form radioimmunoconjugates (RICs. Besides their therapeutic applications, antibody conjugates are also extensively used for many in vitro assays. A broad variety of methods to functionalize antibodies with various payloads are currently available. The decision as to which conjugation method to use strongly depends on the final purpose of the antibody conjugate. Classical conjugation via amino acid residues is still the most common method to produce antibody conjugates and is suitable for most in vitro applications. In recent years, however, it has become evident that antibody conjugates, which are generated via site-specific conjugation techniques, possess distinct advantages with regard to in vivo properties. Here, we give a comprehensive overview on existing and emerging strategies for the production of covalent and non-covalent antibody conjugates.

  2. Real-world use of iron chelators

    National Research Council Canada - National Science Library

    Kwiatkowski, Janet L

    2011-01-01

    .... Three chelators are currently available worldwide-deferoxamine, deferasirox, and deferiprone, although the latter is available in North America only in research protocols and compassionate use programs...

  3. Synthesis of novel conjugates of a saccharide, amino acids, nucleobase and the evaluation of their cell compatibility

    Directory of Open Access Journals (Sweden)

    Dan Yuan

    2014-10-01

    Full Text Available This article reports the synthesis of a novel type of conjugate of three fundamental biological build blocks (i.e., saccharide, amino acids, and nucleobase and their cell compatibility. The facile synthesis starts with the synthesis of nucleobase and saccharide derivatives, then uses solid-phase peptide synthesis (SPPS to build the peptide segment (Phe-Arg-Gly-Asp or naphthAla-Phe-Arg-Gly-Asp with fully protected groups, and later, an amidation reaction in liquid phase connects these three parts together. The overall yield of these multiple step synthesis is about 34%. Besides exhibiting excellent solubility, these conjugates of saccharide–amino acids–nucleobase (SAN, like the previously reported conjugates of nucleobase–amino acids–saccharide (NAS and nucleobase–saccharide–amino acids (NSA, are mammalian cell compatible.

  4. In vitro and in vivo evaluation of a (18F-labeled high affinity NOTA conjugated bombesin antagonist as a PET ligand for GRPR-targeted tumor imaging.

    Directory of Open Access Journals (Sweden)

    Zohreh Varasteh

    Full Text Available Expression of the gastrin-releasing peptide receptor (GRPR in prostate cancer suggests that this receptor can be used as a potential molecular target to visualize and treat these tumors. We have previously investigated an antagonist analog of bombesin (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, RM26 conjugated to 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA via a diethylene glycol (PEG2 spacer (NOTA-P2-RM26 labeled with (68Ga and (111In. We found that this conjugate has favorable properties for in vivo imaging of GRPR-expression. The focus of this study was to develop a (18F-labelled PET agent to visualize GRPR. NOTA-P2-RM26 was labeled with (18F using aluminum-fluoride chelation. Stability, in vitro binding specificity and cellular processing tests were performed. The inhibition efficiency (IC50 of the [(natF]AlF-NOTA-P2-RM26 was compared to that of the (natGa-loaded peptide using (125I-Tyr(4-BBN as the displacement radioligand. The pharmacokinetics and in vivo binding specificity of the compound were studied. NOTA-P2-RM26 was labeled with (18F within 1 h (60-65% decay corrected radiochemical yield, 55 GBq/µmol. The radiopeptide was stable in murine serum and showed high specific binding to PC-3 cells. [(natF]AlF-NOTA-P2-RM26 showed a low nanomolar inhibition efficiency (IC50=4.4±0.8 nM. The internalization rate of the tracer was low. Less than 14% of the cell-bound radioactivity was internalized after 4 h. The biodistribution of [(18F]AlF-NOTA-P2-RM26 demonstrated rapid blood clearance, low liver uptake and low kidney retention. The tumor uptake at 3 h p.i. was 5.5±0.7 %ID/g, and the tumor-to-blood, -muscle and -bone ratios were 87±42, 159±47, 38±16, respectively. The uptake in tumors, pancreas and other GRPR-expressing organs was significantly reduced when excess amount of non-labeled peptide was co-injected. The low uptake in bone suggests a high in vivo stability of the Al-F bond. High contrast PET image was obtained 3 h p

  5. Stereoselective synthesis of light-activatable perfluorophenylazide-conjugated carbohydrates for glycoarray fabrication and evaluation of structural effects on protein binding by SPR imaging†

    Science.gov (United States)

    Deng, Lingquan; Norberg, Oscar; Uppalapati, Suji; Yan, Mingdi; Ramström, Olof

    2014-01-01

    A series of light-activatable perfluorophenylazide (PFPA)-conjugated carbohydrate structures have been synthesized and applied to glycoarray fabrication. The glycoconjugates were structurally varied with respect to anomeric attachment, S-, and O-linked carbohydrates, respectively, as well as linker structure and length. Efficient stereoselective synthetic routes were developed, leading to the formation of the PFPA-conjugated structures in good yields over few steps. The use of glycosyl thiols as donors proved especially efficient and provided the final compounds in up to 70% total yield with high anomeric purities. PFPA-based photochemistry was subsequently used to generate carbohydrate arrays on a polymeric surface, and surface plasmon resonance imaging (SPRi) was applied for evaluation of carbohydrate-protein interactions using the plant lectin Concanavalin A (Con A) as a probe. The results indicate better performance and equal efficiency of S- and O-linked structures with intermediate linker length. PMID:21423935

  6. Stereoselective synthesis of light-activatable perfluorophenylazide-conjugated carbohydrates for glycoarray fabrication and evaluation of structural effects on protein binding by SPR imaging.

    Science.gov (United States)

    Deng, Lingquan; Norberg, Oscar; Uppalapati, Suji; Yan, Mingdi; Ramström, Olof

    2011-05-07

    A series of light-activatable perfluorophenylazide (PFPA)-conjugated carbohydrate structures have been synthesized and applied to glycoarray fabrication. The glycoconjugates were structurally varied with respect to anomeric attachment, S-, and O-linked carbohydrates, respectively, as well as linker structure and length. Efficient stereoselective synthetic routes were developed, leading to the formation of the PFPA-conjugated structures in good yields over few steps. The use of glycosyl thiols as donors proved especially efficient and provided the final compounds in up to 70% total yield with high anomeric purities. PFPA-based photochemistry was subsequently used to generate carbohydrate arrays on a polymeric surface, and surface plasmon resonance imaging (SPRi) was applied for evaluation of carbohydrate-protein interactions using the plant lectin Concanavalin A (Con A) as a probe. The results indicate better performance and equal efficiency of S- and O-linked structures with intermediate linker length.

  7. 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

  8. Macrocyclic chelator-coupled gastrin-based radiopharmaceuticals for targeting of gastrin receptor-expressing tumours

    Energy Technology Data Exchange (ETDEWEB)

    Good, Stephan; Wang, Xuejuan; Maecke, Helmut R. [University Hospital Basel, Division of Radiological Chemistry, Basel (Switzerland); Walter, Martin A.; Mueller-Brand, Jan [University Hospital, Institute of Nuclear Medicine, Basel (Switzerland); Waser, Beatrice; Reubi, Jean-Claude [University of Berne, Department of Pathology, Bern (Switzerland); Behe, Martin P. [Philipps-University of Marburg, Department of Nuclear Medicine, Marburg (Germany)

    2008-10-15

    Diethylenetriamine-pentaacetic acid (DTPA)-coupled minigastrins are unsuitable for therapeutic application with the available {beta}-emitting radiometals due to low complex stability. Low tumour-to-kidney ratio of the known radiopharmaceuticals is further limiting their potency. We used macrocyclic chelators for coupling to increase complex stability, modified the peptide sequence to enhance radiolytic stability and studied tumour-to-kidney ratio and metabolic stability using {sup 111}In-labelled derivatives. Gastrin derivatives with decreasing numbers of glutamic acids were synthesised using {sup 111}In as surrogate for therapeutic radiometals for in vitro and in vivo studies. Gastrin receptor affinities of the {sup nat}In-metallated compounds were determined by receptor autoradiography using {sup 125}I-CCK as radioligand. Internalisation was evaluated in AR4-2J cells. Enzymatic stability was determined by incubating the {sup 111}In-labelled peptides in human serum. Biodistribution was performed in AR4-2J-bearing Lewis rats. IC{sub 50} values of the {sup nat}In-metallated gastrin derivatives vary between 1.2 and 4.8 nmol/L for all methionine-containing derivatives. Replacement of methionine by norleucine, isoleucine, methionine-sulfoxide and methionine-sulfone resulted in significant decrease of receptor affinity (IC{sub 50} between 9.9 and 1,195 nmol/L). All cholecystokinin receptor affinities were >100 nmol/L. All {sup 111}In-labelled radiopeptides showed receptor-specific internalisation. Serum mean-life times varied between 2.0 and 72.6 h, positively correlating with the number of Glu residues. All {sup 111}In-labelled macrocyclic chelator conjugates showed higher tumour-to-kidney ratios after 24 h (0.37-0.99) compared to {sup 111}In-DTPA-minigastrin 0(0.05). Tumour wash out between 4 and 24 h was low. Imaging studies confirmed receptor-specific blocking of the tumour uptake. Reducing the number of glutamates increased tumour-to-kidney ratio but resulted in

  9. Antimicrobial Properties of Copper Nanoparticles and Amino Acid Chelated Copper Nanoparticles Produced by Using a Soya Extract

    OpenAIRE

    DeAlba-Montero, I.; Guajardo-Pacheco, Jesús; Morales-Sánchez, Elpidio; Araujo-Martínez, Rene; Loredo-Becerra, G. M.; Martínez-Castañón, Gabriel-Alejandro; Ruiz, Facundo; Compeán Jasso, M. E.

    2017-01-01

    This paper reports a comparison of the antibacterial properties of copper-amino acids chelates and copper nanoparticles against Escherichia coli, Staphylococcus aureus, and Enterococcus faecalis. These copper-amino acids chelates were synthesized by using a soybean aqueous extract and copper nanoparticles were produced using as a starting material the copper-amino acids chelates species. The antibacterial activity of the samples was evaluated by using the standard microdilution method (CLSI M...

  10. Anticancer agents coupled to N-(2-hydroxypropyl)methacrylamide copolymers. I. Evaluation of daunomycin and puromycin conjugates in vitro.

    Science.gov (United States)

    Duncan, R.; Kopecková-Rejmanová, P.; Strohalm, J.; Hume, I.; Cable, H. C.; Pohl, J.; Lloyd, J. B.; Kopecek, J.

    1987-01-01

    During recent years N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers have been developed as targetable drug carriers. These soluble synthetic polymers are internalized by cells by pinocytosis and they can be tailor-made to include peptidyl side-chains degradable intracellularly by specific lysosomal enzymes. Thus they provide the opportunity fo achieve controlled intracellular delivery of anticancer agents. The anthracycline antibiotic daunomycin, and protein synthesis inhibitor puromycin, were bound to HPMA copolymers via several different peptide side-chains, including Gly-Gly, Gly-Phe-Leu-Gly and Gly-Phe-Phe-Leu. Incubation of polymer-drug conjugates with isolated lysosomal enzymes (either a mixture of rat liver lysosomal enzymes or purified thiol-dependent lysosomal proteinases, cathepsins L and B) showed that significant release of drug occurred over 20 h, more than 20% of daunomycin and more than 80% of puromycin being liberated. To test their pharmacological activity conjugates were incubated with either the mouse leukaemia L1210, or the human lymphoblastoid leukaemia CCRF in vitro. The conjugates tested were all less effective than free daunomycin, but they showed differential toxicity against L1210 depending on the aminoacid sequence of their drug-polymer linkage. Inclusion of fucosylamine-terminating side-chains into the HPMA copolymer structure increased the affinity of conjugates for the L1210 cell membrane and resulted in increased toxicity. In contrast HPMA-daunomycin conjugates with or without fucosylamine affected CCRF cells equally, but this cell line was more sensitive than the mouse leukaemia to both free and polymer-bound daunomycin. Incubation of L1210 cells in polymer-bound daunomycin for 72 h, followed by plating cells out in low density in drug-free medium, showed that a concentration of polymer-bound drug (184 micrograms ml-1) could be selected to achieve a cytotoxic effect. PMID:3468994

  11. Preparation of free, soluble conjugate, and insoluble-bound phenolic compounds from peels of rambutan (Nephelium lappaceum) and evaluation of antioxidant activities in vitro.

    Science.gov (United States)

    Sun, Liping; Zhang, Huilin; Zhuang, Yongliang

    2012-02-01

    The soluble phenolic compounds of rambutan peels (RP) were extracted by microwave-assisted extraction (MAE) and the operating parameters were optimized. The optimal conditions obtained were ethanol concentration of 80.85%, extraction time of 58.39 s, and the ratio of liquid to solid of 24.51:1. The soluble phenolic content by MAE was 213.76 mg GAE/g DW. The free, soluble conjugate, and insoluble-boaund phenolic compounds were prepared by alkaline hydrolysis, and the contents of 3 fractions were 185.12, 27.98 and 9.37 mg GAE/g DW, respectively. The contents of syringic acid and p-coumaric acid were high in the free fraction, showing 16.86 and 19.44 mg/g DW, and the soluble conjugate and insoluble-bound phenolics were mainly composed of gallic acid and caffeic acid. Furthermore, the antioxidant activities of 3 fractions were evaluated in 5 model systems. Results indicated that the free fraction had high antioxidant activities, compared with the soluble conjugate and insoluble-bound fractions. © 2012 Institute of Food Technologists®

  12. Preparation of [In-111]-labeled-DTPA-bombesin conjugates at high specific activity and stability: Evaluation of labeling parameters and potential stabilizers

    Energy Technology Data Exchange (ETDEWEB)

    Pujatti, P.B., E-mail: pujatti.pb@gmail.com [Directory of Radiopharmacy, Nuclear and Energy Research Institute (IPEN/CNEN), Av. Prof. Lineu Prestes, 2242 - Cidade Universitaria da USP - Butanta, Sao Paulo - SP - Brazil - CEP: 05508-000 (Brazil); Massicano, A.V.F.; Mengatti, J.; Araujo, E.B. de [Directory of Radiopharmacy, Nuclear and Energy Research Institute (IPEN/CNEN), Av. Prof. Lineu Prestes, 2242 - Cidade Universitaria da USP - Butanta, Sao Paulo - SP - Brazil - CEP: 05508-000 (Brazil)

    2012-05-15

    The aim of the present work was to obtain stabilized high specific activity (HSA) {sup 111}In-labeled bombesin conjugates for preclinical evaluations. Parameters influencing the kinetics of labeling were investigated and the effect of stabilizers on HSA radiopeptides stability at room temperature were systematically categorized applying chromatography techniques. A SA of 174 GBq/{mu}mol was achieved with high radiochemical purity, but the labeled compounds exhibited low stability. The addition of stabilizers avoided their radiolysis and significantly increased their stability. - Highlights: Black-Right-Pointing-Pointer We aimed to obtain stabilized high specific activity (SA) {sup 111}In-labeled bombesin conjugates. Black-Right-Pointing-Pointer The effect of stabilizers on high SA radiopeptides stability were investigated. Black-Right-Pointing-Pointer A maximum specific activity of 174 GBq/{mu}mol was achieved. Black-Right-Pointing-Pointer The studied stabilizers significantly increased the stability of high SA radiopeptides. Black-Right-Pointing-Pointer These stabilized bombesin conjugates will be applied in preclinical studies.

  13. Importance of iron chelation therapy

    Directory of Open Access Journals (Sweden)

    A. Varoğlu

    2011-12-01

    Full Text Available It is necessary to remember that today patients have different options of chelation treatment, as desferrioxamine, deferiprone and deferasirox are available. However, a patient has to be compliant with treatments. They have always to remember that too much iron causes different complications and could be a barrier for a definitive cure from thalassemia. 由于出现了去铁胺、去铁酮和去铁斯若等药物,病人现在可以选择不同的螯合治疗方式。 然而,病人必须适应这几种治疗方式。 他们必须时刻记住太多的铁元素会引发多种并发症,并对地中海贫血的彻底治疗造成阻碍。

  14. Evaluation of impact of 23 valent pneumococcal polysaccharide vaccine following 7 valent pneumococcal conjugate vaccine in Australian Indigenous children.

    Science.gov (United States)

    Jayasinghe, Sanjay; Chiu, Clayton; Menzies, Rob; Lehmann, Deborah; Cook, Heather; Giele, Carolien; Krause, Vicki; McIntyre, Peter

    2015-11-27

    High incidence and serotype diversity of invasive pneumococcal disease (IPD) in Indigenous children in remote Australia led to rapid introduction of 7-valent conjugate pneumococcal vaccine (7vPCV) at 2, 4 and 6 months in 2001, followed by 23-valent polysaccharide pneumococcal vaccine (23vPPV) in the second year of life. All other Australian children were offered 3 doses of 7vPCV without a booster from 2005. This study evaluated the impact of the unique pneumococcal vaccine schedule of 7vPCV followed by the 23vPPV booster among Indigenous Australian children. Changes in IPD incidence derived from population-based passive laboratory surveillance in Indigenous children vaccine introduction period (Indigenous 1994-2000; non-Indigenous 2002-2004) to the post-vaccine period (2008-2010 in both groups) using incidence rate ratios (IRRs) stratified by age into serotype groupings of vaccine (7v and 13vPCV and 23vPPV) and non-vaccine types. Vaccine coverage was assessed from the Australian Childhood Immunisation Register. At baseline, total IPD incidence per 100,000 was 216 (n=230) in Indigenous versus 55 (n=1993) in non-Indigenous children. In 2008-2010, IRRs for 7vPCV type IPD were 0.03 in both groups, but for 23v-non7v type IPD 1.2 (95% CI 0.8-1.8) in Indigenous versus 3.1 (95% CI 2.5-3.7) in non-Indigenous, difference driven primarily by serotype 19A IPD (IRR 0.6 in Indigenous versus 4.3 in non-Indigenous). For non-7vPCV type IPD overall, IRR was significantly higher in those age-eligible for 23vPPV booster compared to those younger, but in both age groups was lower than for non-Indigenous children. These ecologic data suggest a possible "serotype replacement sparing" effect of 23vPPV following 7vPCV priming, especially for serotype 19A with supportive evidence from other immunogenicity and carriage studies. Applicability post 10vPCV or 13v PCV priming in similar settings would depend on local serotype distribution of IPD. Copyright © 2015 Elsevier Ltd. All rights

  15. Synthesis and antiulcer activity evaluation of conjugates of amino acids with N-aroyl- N, N'-dicyclohexyl urea

    Directory of Open Access Journals (Sweden)

    Subudhi Bharat

    2011-12-01

    Full Text Available Abstract Amino acids are safe molecules with variable efficacy against ulceration. Considering the good antioxidant potential of N-aroyl- N, N'-dicyclohexyl urea and antiulcer activities of amino acids, a series of amino acid conjugates of N-aroyl- N, N'-dicyclohexyl urea was synthesized and the effect against ulceration in albino rats induced by pyloric ligation was screened. All these compounds were found to be safe and active. Reduction of ulcer index was significant for all compounds. Conjugates of methionine and histidine exhibited enhanced antiulcer activity comparable to omeprazole in terms of inhibition of release of gastric juice, hydrochloric acid and neutralization activity. The promising efficacy and safety of these compounds is interesting for further investigation.

  16. Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Yun Wu

    2013-11-01

    Full Text Available Two novel series of RGD-MEKI conjugates derived from a MEK1/2 kinase inhibitor—PD0325901—have been developed for integrin receptor mediated anticancer therapy. The first series, alkoxylamine analog RGD-MEKI conjugates 9a–g showed anti-proliferation activity in melanoma A375 cells by the same mechanism as that of PD0325901. PEGylation increased the IC50 value of 9f three-fold in the A375 assay, and the multi-cRGD peptide cargo significantly improved the receptor specific anti-proliferation activity of 9g in integrin-overexpressing U87 cells. In the second series, RGD-PD0325901 13 exhibited significantly increased antitumor properties compared to the alkoxylamine analogs by both inhibition of the ERK pathway activity and DNA replication of the cancer cells. Furthermore, 13 displayed more potent anti-proliferation activity in the U87 assay than PD0325901 in a dose-dependent manner. All these data demonstrate that RGD-MEKI conjugates with an ester bond linkage enhanced anticancer efficacy with improved targeting capability toward integrin-overexpressing tumor cells.

  17. Synthesis of S-Layer Conjugates and Evaluation of Their Modifiability as a Tool for the Functionalization and Patterning of Technical Surfaces

    Directory of Open Access Journals (Sweden)

    Ulrike Weinert

    2015-05-01

    Full Text Available Chemical functional groups of surface layer (S-layer proteins were chemically modified in order to evaluate the potential of S-layer proteins for the introduction of functional molecules. S-layer proteins are structure proteins that self-assemble into regular arrays on surfaces. One general feature of S-layer proteins is their high amount of carboxylic and amino groups. These groups are potential targets for linking functional molecules, thus producing reactive surfaces. In this work, these groups were conjugated with the amino acid tryptophan. In another approach, SH-groups were chemically inserted in order to extend the spectrum of modifiable groups. The amount of modifiable carboxylic groups was further evaluated by potentiometric titration in order to evaluate the potential efficiency of S-layer proteins to work as matrix for bioconjugations. The results proved that S-layer proteins can work as effective matrices for the conjugation of different molecules. The advantage of using chemical modification methods over genetic methods lies in its versatile usage enabling the attachment of biomolecules, as well as fluorescent dyes and inorganic molecules. Together with their self-assembling properties, S-layer proteins are suitable as targets for bioconjugates, thus enabling a nanostructuring and bio-functionalization of surfaces, which can be used for different applications like biosensors, filter materials, or (biocatalytic surfaces.

  18. MRI marrow observations in thalassemia: the effects of the primary disease, transfusional therapy, and chelation

    Energy Technology Data Exchange (ETDEWEB)

    Levin, T.L. [Department of Pediatric Radiology, Columbia-Presbyterian Medical Center, Babies and Children`s Hospital, New York, NY (United States); Sheth, S.S. [Department of Pediatrics, Columbia-Presbyterian Medical Center, Babies and Children`s Hospital, 3959 Broadway, New York, NY 10032 (United States); Ruzal-Shapiro, C. [Department of Pediatric Radiology, Columbia-Presbyterian Medical Center, Babies and Children`s Hospital, New York, NY (United States); Abramson, S. [Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021 (United States); Piomelli, S. [Department of Pediatrics, Columbia-Presbyterian Medical Center, Babies and Children`s Hospital, 3959 Broadway, New York, NY 10032 (United States); Berdon, W.E. [Department of Pediatric Radiology, Columbia-Presbyterian Medical Center, Babies and Children`s Hospital, New York, NY (United States)

    1995-11-01

    The magnetic resonance bone marrow patterns in thalassemia were evaluated to determine changes produced by transfusion and chelation therapy. Thirteen patients had T1- and T2-weighted images of the spine, pelvis and femurs. Three received no therapy (age range 2.5-3 years). Three were ``hypertransfused`` (transfused to maintain a hemoglobin greater than 10 g/dl) and not chelated because of age (age range 6 months-8 years). Seven were ``hypertransfused`` and chelated (age range 12-35 years). Signal characteristics of marrow were compared with those of surrounding muscle and fat. Fatty marrow (isointense with subcutaneous fat) was compared with red marrow (hypointense to fat and slightly hyperintense to muscle). Marrow hypointense to muscle was identified as iron deposition within red marrow. The untreated group demonstrated signal consistent with red marrow throughout the central and peripheral skeleton. Hypertransfused but not chelated patients demonstrated marked iron deposition in the central and peripheral skeleton. Hypertransfused and chelated patients demonstrated iron deposition in the central skeleton and a mixed appearance of marrow in the peripheral skeleton. The MR appearance of marrow in thalassemia is a reflection of the patient`s transfusion and chelation therapy. Iron deposition occurs despite chelation therapy in sites of active red marrow. As red marrow retreats centrally with age, so does the pattern of iron deposition. The long-term biological effects of this iron deposition are unknown. (orig.). With 8 figs., 1 tab.

  19. Design, synthesis and biological evaluation of novel L-ascorbic acid-conjugated pentacyclic triterpene derivatives as potential influenza virus entry inhibitors.

    Science.gov (United States)

    Wang, Han; Xu, Renyang; Shi, Yongying; Si, Longlong; Jiao, Pingxuan; Fan, Zibo; Han, Xu; Wu, Xingyu; Zhou, Xiaoshu; Yu, Fei; Zhang, Yongmin; Zhang, Liangren; Zhang, Lihe; Zhou, Demin; Xiao, Sulong

    2016-03-03

    Since the influenza viruses can rapidly evolve, it is urgently required to develop novel anti-influenza agents possessing a novel mechanism of action. In our previous study, two pentacyclic triterpene derivatives (Q8 and Y3) have been found to have anti-influenza virus entry activities. Keeping the potential synergy of biological activity of pentacyclic triterpenes and l-ascorbic acid in mind, we synthesized a series of novel l-ascorbic acid-conjugated pentacyclic triterpene derivatives (18-26, 29-31, 35-40 and 42-43). Moreover, we evaluated these novel compounds for their anti-influenza activities against A/WSN/33 virus in MDCK cells. Among all evaluated compounds, the 2,3-O,O-dibenzyl-6-deoxy-l-ascorbic acid-betulinic acid conjugate (30) showed the most significant anti-influenza activity with an EC50 of 8.7 μM, and no cytotoxic effects on MDCK cells were observed. Time-of-addition assay indicated that compound 30 acted at an early stage of the influenza life cycle. Further analyses revealed that influenza virus-induced hemagglutination of chicken red blood cells was inhibited by treatment of compound 30, and the interaction between the influenza hemagglutinin (HA) and compound 30 was determined by surface plasmon resonance (SPR) with a dissociation constant of KD = 3.76 μM. Finally, silico docking studies indicated that compound 30 and its derivative 31 were able to occupy the binding pocket of HA for sialic acid receptor. Collectively, these results suggested that l-ascorbic acid-conjugated pentacyclic triterpenes were promising anti-influenza entry inhibitors, and HA protein associated with viral entry was a promising drug target. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  20. Evaluation of copper speciation in model solutions of humic acid by mini-columns packed with Chelex-100 and new chelating agents: Application to speciation of selected heavy metals in environmental water samples

    Energy Technology Data Exchange (ETDEWEB)

    Kiptoo, Jackson K., E-mail: kiptoojac@yahoo.com [Department of Chemistry, Jomo Kenyatta University of Agriculture and Technology, P.O. Box 62000-00200, Nairobi (Kenya); Ngila, J. Catherine [School of Chemistry, University of KwaZulu-Natal, Westville Campus, Private Bag X54001, Westville, Durban 4000 (South Africa); Silavwe, Ned D. [Department of Chemistry, University of Swaziland, P/Bag 4, Kwaluseni (Swaziland)

    2009-12-30

    A solid-phase extraction procedure using mini-columns packed with Chelex-100 and two new chelating agents based on poly(vinyl chloride) functionalized with 3-ferrocenyl-3-hydroxydithioacrylic acid and N,N'-[1,1'-dithiobis(ethylene)]-bis(salicylideneimine) (H{sub 2}sales) loaded on microcrystalline naphthalene, is reported. The columns were used to separate labile copper fractions in model solutions and in real samples with subsequent determination using electrothermal atomic absorption spectrometry (ETAAS). Various model solutions containing 20 {mu}g L{sup -1} of Cu{sup 2+} and 0.0, 0.2, 2.0 and 20.0 mg L{sup -1} of humic acid, respectively, and buffered to pH 6.0, 7.0 and 8.0 were considered. Results showed a decrease in labile copper fraction with increase in humic acid concentration. Application of the procedure to speciation of Cu, Ni, Zn and Pb in various environmental water samples yielded labile fractions in the range of 1.67-55.75% against a total dissolved fraction of 44.08-69.77%. Comparison of the three chelating agents showed that H{sub 2}sales had a weaker metal chelating strength than Chelex-100, but PVC-FSSH had comparable chelating strength to Chelex-100.

  1. Lateral flow immunoassay using europium chelate-loaded silica nanoparticles as labels.

    Science.gov (United States)

    Xia, Xiaohu; Xu, Ye; Zhao, Xilin; Li, Qingge

    2009-01-01

    Despite their ease of use, lateral flow immunoassays (LFIAs) often suffer from poor quantitative discrimination and low analytical sensitivity. We explored the use of a novel class of europium chelate-loaded silica nanoparticles as labels to overcome these limitations. Antibodies were covalently conjugated onto europium chelate-loaded silica nanoparticles with dextran as a linker. The resulting conjugates were used as labels in LFIA for detection of hepatitis B surface antigen (HBsAg). We performed quantification with a digital camera and Adobe Photoshop software. We also used 286 clinical samples to compare the proposed method with a quantitative ELISA. A detection limit of 0.03 microg/L was achieved, which was 100 times lower than the colloidal gold-based LFIAs and lower than ELISA. A precise quantitative dose-response curve was obtained, and the linear measurement range was 0.05-3.13 microg/L, within which the CVs were 2.3%-10.4%. Regression analysis of LFIA on ELISA results gave: log (LFIA) = -0.14 log (ELISA) + 1.03 microg/L with r = 0.99 for the quantification of HBsAg in 35 positive serum samples. Complete agreement was observed for the qualitative comparison of 286 clinical samples assayed with LFIA and ELISA. Europium chelate-loaded silica nanoparticle labels have great potential to improve LFIAs, making them useful not only for simple screening applications but also for more sensitive and quantitative immunoassays.

  2. The Evaluation of Colorectal Cancer Risk in Serum by anti-DESMIN-conjugated CdTe/CdS Quantum Dots.

    Science.gov (United States)

    Wang, Yao; Li, Yuanting; Chen, Zhiyong; Wang, Tianhao; Gu, Jie; Wu, Xianhua; Yin, Yi; Wang, Maosheng; Pan, Zhigang

    2017-03-01

    DESMIN is a novel prognostic predictor and therapeutic target for colorectal cancer (CRC). Enzyme-linked immunosorbent assay (ELISA) and electrochemiluminescence (ELC) assays are large-scale and highcost projects; therefore, it is necessary to develop a new, fast, and simple yet highly sensitive and specific method to detect DESMIN in serum. Semiconducting quantum dots (QDs) possess high fluorescence quantum yield, stability against photobleaching, and size-controlled luminescence properties, thus being utilized in photoelectrochemical tumor marker detection, especially in ameliorating the diagnostic value in complex biological ambient ionization. However, CdTe/CdS quantum dots (QDs) have not been applied in detecting DESMIN in serum. DESMIN in serum has been established using anti-DESMIN-conjugated CdTe/CdS quantum dots (QDs) and measurements. The assay sensitivity was determined by measurement of quenched fluorescence intensity of DESMIN at 0.1, 0.5, 1.0, 2.0, or 5.0 ng/mL in PBS or 0.25%, 0.5%, 1.0%, 2.0%, or 5% human serum diluted in PBS. The assay was optimized under different pH (7.00 - 7.40) for different reaction durations (10 - 60 minutes). The specificity of anti-DESMIN-QDs was determined by testing the interference of DESMIN activity with CEA, IgG, or AFP, each at 1 ng/mL. Under the optimized incubation time (30 minutes) at room temperature and optimal pH 7.1 - 7.2, a correlation between the decreased fluorescence intensity of anti-DESMIN-conjugated CdTe/CdS QDs and the concentration of DESMIN in the range from 0.05 to 100 ng/mL, was established. The sensitivity for the detection of DESMIN in the range from 0.05 to 100 ng/mL, with a detection limit of 0.02 ng/mL. The assay presented a high specificity because the anti-DESMIN-conjugated CdTe/CdS QDs only reacted with ABR1B10 in the sera in the presence of CEA, IgG or AFP. The immunofluorescence assay to detect DESMIN in serum using anti-DEMSIN-conjugated CdTe/ CdS QDs was fast and simple yet presented

  3. Metal ions, Alzheimer's disease and chelation therapy

    National Research Council Canada - National Science Library

    Budimir, Ana

    2011-01-01

    .... In contrast to the direct chelation approach in metal ion overload disorders, in neurodegeneration the goal seems to be a better and subtle modulation of metal ion homeostasis, aimed at restoring ionic balance...

  4. 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

  5. Phenolic compounds based conjugates from dextran aldehyde and BSA: Preparation, characterization and evaluation of their anti-cancer efficacy for therapeutic applications.

    Science.gov (United States)

    Rai, Sudheer; Kureel, Amit Kumar; Dutta, P K; Mehrotra, G K

    2017-11-10

    Here, we have synthesized phenolic compounds (pc) based on conjugates from dextran aldehyde (dex-ald) and bovine serum albumin (BSA) and screening their potential activity as therapeutic agents in cancer disease. The synthesized conjugates were analyzed by UV-vis, FT-IR, XRD and SEM analysis. UV-vis spectra of conjugates showed the shifting of spectral peak at UV to visible region revealed the enhanced conjugation due to formation of linkage. The XRD peaks of conjugates found broader and indicating the amorphous phase of conjugating materials in compared to free components. The SEM images showed that the conjugated materials having numerous pores on its surface, which proved its porous nature. The amount of phenolic compounds conjugated with (dex-ald-pc) and (BSA-pc) were found to be 65.4 and 73.91mg/g of conjugates, respectively. Cells viability was significantly decreased approximately 80-85% at concentration of 100μg conjugates whereas the free polymers or phenolics did not affect the viability of cancer cells. Generation of high quantity of reactive oxygen species (ROS) in cells treated with conjugate materials, which may caused cell apoptosis in cancer cell line. The results clearly showed that conjugation of phenolic compounds were an effective method to improve the functional properties for therapeutic applications. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. 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.

  7. Evaluation of the interactions of HIV-1 integrase with small ubiquitin-like modifiers and their conjugation enzyme Ubc9.

    Science.gov (United States)

    Li, Zhihui; Wu, Shuwen; Wang, Jingjing; Li, Wenjuan; Lin, Yun; Ji, Chaoneng; Xue, Jinglun; Chen, Jinzhong

    2012-11-01

    Human immunodeficiency virus type 1 (HIV-1) integrase mediates the integration of reverse-transcribed viral cDNA into the genome of the host for the stable maintenance of the viral genome and the persistence of HIV-1 infection. In this study, the relationships between HIV-1 integrase (HIV-1 IN) and three SUMO conjugation pathway proteins, as well as the effects of these associations, were investigated. The overexpression of SUMO1/SUMO2 and Ubc9 changed the intracellular localization of HIV-1 IN from a diffuse distribution to a punctate localization. SUMO1, SUMO2 and Ubc9 were shown to interact with HIV-1 IN. The SUMOylation of HIV-1 IN was verified. In addition, SUMO1, SUMO2 and Ubc9 were shown to influence the integration of both lentivirus and HIV-1. The overexpression of Ubc9 inhibited viral genome integration, and the upregulation of SUMO1 or SUMO2 enhanced the inhibitory effect of Ubc9. Knockdown of the endogenous levels of SUMO1, SUMO2 and Ubc9 increased the level of viral integration, while reverse transcription and the nuclear import of preintegration complex (PIC) were not affected. Our findings suggest that SUMO conjugation pathway proteins may act as cellular restriction factors and be detrimental to HIV-1 infection. These findings merit further investigation because of their potentially significant implications for the cellular antiviral response to HIV-1 infection.

  8. Hydroxyurea could be a good clinically relevant iron chelator.

    Directory of Open Access Journals (Sweden)

    Khushnooma Italia

    Full Text Available Our previous study showed a reduction in serum ferritin of β-thalassemia patients on hydroxyurea therapy. Here we aimed to evaluate the efficacy of hydroxyurea alone and in combination with most widely used iron chelators like deferiprone and deferasirox for reducing iron from experimentally iron overloaded mice. 70 BALB/c mice received intraperitonial injections of iron-sucrose. The mice were then divided into 8 groups and were orally given hydroxyurea, deferiprone or deferasirox alone and their combinations for 4 months. CBC, serum-ferritin, TBARS, sTfr and hepcidin were evaluated before and after iron overload and subsequently after 4 months of drug therapy. All animals were then killed. Iron staining of the heart and liver tissue was done using Perl's Prussian Blue stain. Dry weight of iron in the heart and liver was determined by atomic absorption spectrometry. Increased serum-ferritin, TBARS, hepcidin and dry weight of iron in the liver and heart showed a significant reduction in groups treated with iron chelators with maximum reduction in the group treated with a combination of deferiprone, deferasirox and hydroxyurea. Thus hydroxyurea proves its role in reducing iron from iron overloaded mice. The iron chelating effect of these drugs can also be increased if given in combination.

  9. The Management of Iron Chelation Therapy: Preliminary Data from a National Registry of Thalassaemic Patients

    Directory of Open Access Journals (Sweden)

    Adriana Ceci

    2011-01-01

    Full Text Available Thalassaemia and other haemoglobinopathies constitute an important health problem in Mediterranean countries, placing a tremendous emotional, psychological, and economic burden on their National Health systems. The development of new chelators in the most recent years had a major impact on the treatment of thalassaemia and on the quality of life of thalassaemic patients. A new initiative was promoted by the Italian Ministry of Health, establishing a Registry for thalassaemic patients to serve as a tool for the development of cost-effective diagnostic and therapeutic approaches and for the definition of guidelines supporting the most appropriate management of the iron-chelating therapy and a correct use of the available iron-chelating agents. This study represents the analysis of the preliminary data collected for the evaluation of current status of the iron chelation practice in the Italian thalassaemic population and describes how therapeutic interventions can widely differ in the different patients' age groups.

  10. Imaging tumor vasculature noninvasively with positron emission tomography and RGD peptides labeled with copper 64 using the bifunctonal chelates DOTA, oxo-DO3a. and PCTA.

    Science.gov (United States)

    Yapp, Donald T T; Ferreira, Cara L; Gill, Rajanvir K; Boros, Eszter; Wong, May Q; Mandel, Derek; Jurek, Paul; Kiefer, Garry E

    2013-06-01

    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.

  11. 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.

  12. Synthesis of novel 1H-1,2,3-triazole tethered C-5 substituted uracil-isatin conjugates and their cytotoxic evaluation

    KAUST Repository

    Kumar, Kewal

    2012-12-01

    The present manuscript describes the synthesis of uracil-isatin hybrids via azide-alkyne cycloadditions and their cytotoxic evaluation against three human cancer cell lines viz. HeLa (cervix), MCF-7 (breast) and DU145 (prostate) using MTT assay. The evaluation studies revealed the dependence of cytotoxicity on C-5 substituents of both uracil and isatin as well as the alkyl chain length with compounds 6g and 6k showing IC50 values 18.21 and 13.90 μM respectively against DU145 cell lines. Most of the synthesized conjugates exhibited considerable selectivity against MCF-7 and DU145 cell lines. © 2012 Elsevier Masson SAS. All rights reserved.

  13. Evaluation of a preconditioned conjugate-gradient algorithm for weighted least-squares unwrapping of digital speckle-pattern interferometry phase maps.

    Science.gov (United States)

    Kaufmann, G H; Galizzi, G E; Ruiz, P D

    1998-05-10

    Inasmuch as current fringe analysis techniques used in digital speckle-pattern interferometry (DSPI) yield a phase map modulo 2pi, phase unwrapping is the final step of any data evaluation process. The performance of a recently published algorithm used to unwrap DSPI phase maps is investigated. The algorithm is based on a least-squares minimization technique that is solvable by the discrete cosine transform. When phase inconsistencies are present, they are handled by exclusion of invalid pixels from the unwrapping process through the assignment of zero-valued weights. Then the weighted unwrapping problem is solved in an iterative manner by a preconditioned conjugate-gradient method. The evaluation is carried out with computer-simulated DSPI phase maps, an approach that permits the generation of phase fields without inconsistencies, which are then used to calculate phase deviations as a function of the iteration number. Real data are also used to illustrate the performance of the algorithm.

  14. Synthesis of novel 1H-1,2,3-triazole tethered C-5 substituted uracil-isatin conjugates and their cytotoxic evaluation.

    Science.gov (United States)

    Kumar, Kewal; Sagar, Sunil; Esau, Luke; Kaur, Mandeep; Kumar, Vipan

    2012-12-01

    The present manuscript describes the synthesis of uracil-isatin hybrids via azide-alkyne cycloadditions and their cytotoxic evaluation against three human cancer cell lines viz. HeLa (cervix), MCF-7 (breast) and DU145 (prostate) using MTT assay. The evaluation studies revealed the dependence of cytotoxicity on C-5 substituents of both uracil and isatin as well as the alkyl chain length with compounds 6g and 6k showing IC(50) values 18.21 and 13.90 μM respectively against DU145 cell lines. Most of the synthesized conjugates exhibited considerable selectivity against MCF-7 and DU145 cell lines. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  15. Studies and syntheses of siderophores, microbial iron chelators, and analogs as potential drug delivery agents.

    Science.gov (United States)

    Roosenberg, J M; Lin, Y M; Lu, Y; Miller, M J

    2000-02-01

    Siderophores (microbial iron chelators) play an extremely important role in microbial pathogenicity. Microbial uptake of siderophore-iron complexes through active transport systems allow microbes to survive and proliferate even under iron deficient environments during invasion of a host. Due to their structural complexity, unique iron (III) chelation, acquisition properties, and their therapeutic potential, siderophores have attracted much attention in a broad range of disciplines. Tremendous progress has been made in siderophore syntheses, in determination of the structures and functions of outer membrane receptors (e.g. FhuA and FepA), and in the mechanistic insight into siderophore-iron-mediated active transport processes. One of the important practical applications of this active transport system is development of species-selective active drug transport (the Trojan Horse approach) to potentially treat infections due to drug resistant strains of microbes. Siderophore-drug conjugates have shown great potential in active drug delivery to target pathogenic microbes.

  16. The truncated conjugate gradient (TCG), a non-iterative/fixed-cost strategy for computing polarization in molecular dynamics: Fast evaluation of analytical forces

    Science.gov (United States)

    Aviat, Félix; Lagardère, Louis; Piquemal, Jean-Philip

    2017-10-01

    In a recent paper [F. Aviat et al., J. Chem. Theory Comput. 13, 180-190 (2017)], we proposed the Truncated Conjugate Gradient (TCG) approach to compute the polarization energy and forces in polarizable molecular simulations. The method consists in truncating the conjugate gradient algorithm at a fixed predetermined order leading to a fixed computational cost and can thus be considered "non-iterative." This gives the possibility to derive analytical forces avoiding the usual energy conservation (i.e., drifts) issues occurring with iterative approaches. A key point concerns the evaluation of the analytical gradients, which is more complex than that with a usual solver. In this paper, after reviewing the present state of the art of polarization solvers, we detail a viable strategy for the efficient implementation of the TCG calculation. The complete cost of the approach is then measured as it is tested using a multi-time step scheme and compared to timings using usual iterative approaches. We show that the TCG methods are more efficient than traditional techniques, making it a method of choice for future long molecular dynamics simulations using polarizable force fields where energy conservation matters. We detail the various steps required for the implementation of the complete method by software developers.

  17. Protocol for Evaluating the Permissiveness of Bacterial Communities Toward Conjugal Plasmids by Quantification and Isolation of Transconjugants

    DEFF Research Database (Denmark)

    Klümper, Uli; Dechesne, Arnaud; Smets, Barth F.

    2014-01-01

    The transfer of conjugal plasmids is the main bacterial process of horizontal gene transfer to potentially distantly related bacteria. These extrachromosomal, circular DNA molecules host genes that code for their own replication and transfer to other organisms. Because additional accessory genes...... transfer, the ability of a plasmid to invade a mixed community is crucial. The main parameter that controls the possible extent of horizontal plasmid transfer (HGT) in a bacterial community is the in situ community permissiveness for the considered plasmid. Permissiveness describes the fraction...... a gfp-tagged plasmid in a mCherry red fluorescently tagged donor strain repressing gfp expression. We take advantage of fluorescent marker genes to microscopically detect plasmid transfer events and use subsequent high-throughput fluorescence-activated cell sorting (FACS) to isolate...

  18. Design and evaluation of novel pH-sensitive ureido-conjugated chitosan/TPP nanoparticles targeted to Helicobacter pylori.

    Science.gov (United States)

    Jing, Zi-Wei; Jia, Yi-Yang; Wan, Ning; Luo, Min; Huan, Meng-Lei; Kang, Tai-Bin; Zhou, Si-Yuan; Zhang, Bang-Le

    2016-04-01

    The covalently modified ureido-conjugated chitosan/TPP multifunctional nanoparticles have been developed as targeted nanomedicine delivery system for eradication of Helicobacter pylori. H. pylori can specifically express the urea transport protein on its membrane to transport urea into cytoplasm for urease to produce ammonia, which protects the bacterium in the acid milieu of stomach. The clinical applicability of topical antimicrobial agent is needed to eradicate H. pylori in the infected fundal area. In this study, we designed and synthesized two ureido-conjugated chitosan derivatives UCCs-1 and UCCs-2 for preparation of multifunctional nanoparticles. The process was optimized in order to prepare UCCs/TPP nanoparticles for encapsulation of amoxicillin. The results showed that the amoxicillin-UCCs/TPP nanoparticles exhibited favorable pH-sensitive characteristics, which could procrastinate the release of amoxicillin at gastric acids and enable the drug to deliver and target to H. pylori at its survival region effectively. Compared with unmodified amoxicillin-chitosan/TPP nanoparticles, a more specific and effective H. pylori growth inhibition was observed for amoxicillin-UCCs/TPP nanoparticles. Drug uptake analysis tested by flow cytometry and confocal laser scanning microscopy verified that the uptake of FITC-UCCs-2/TPP nanoparticles was associated with urea transport protein on the membrane of H. pylori and reduced with the addition of urea as competitive transport substrate. These findings suggest that the multifunctional amoxicillin-loaded nanoparticles have great potential for effective therapy of H. pylori infection. They may also serve as pharmacologically effective nanocarriers for oral targeted delivery of other therapeutic drugs to treat H. pylori. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Do Dose Numbers Matter?: Evaluation of Differing Infant and Toddler Meningococcal C Conjugate Vaccine Programs in Canadian Children.

    Science.gov (United States)

    Bettinger, Julie A; Vanderkooi, Otto G; Scheifele, David W; Halperin, Scott A; Kellner, James D; Schryvers, Anthony; De Serres, Gaston; Alcantara, Joenel

    2016-11-01

    The diversity of Canadian infant meningococcal C conjugate (MenC) vaccine programs is unique among countries providing MenC vaccines and offers a valuable opportunity to determine the optimal vaccine program. This longitudinal study assessed differences in seroprotection by 3 different vaccine schedules in children two years after receiving either 1 toddler MenC vaccine dose (1 dose), 1 infant and 1 toddler dose (2 doses), or 2 infant and 1 toddler MenC vaccine dose (3 doses). Three similar cohorts of healthy infants from 1, 2 and 3 dose program areas were enrolled before to their 12 month toddler dose and vaccinated with MenC-tetanus toxoid (MenC-TT) conjugate vaccine. Sera obtained 2 years later were assayed for serogroup C bactericidal activity using standardized procedures with rabbit as the exogenous complement source. Serum bactericidal activity titers ≥1:8 were considered protective. Results were available for 384 children. Rates of seroprotection at 36 months of age were significantly different between the 1 and 3 dose programs, but confidence intervals overlapped between the 1 and 2 dose programs and between the 2 and 3 dose programs: 1 dose 92% (95% confidence interval: 86%-96%) versus 99% (95%-100%) with 2 doses and 100% (97%-100%) with 3 doses. Geometric mean titers were significantly different at 12.1 (10.8-13.5), 32.4 (28.9-36.2) and 50.6 (45.7-55.9) in the 1, 2 and 3 dose programs, respectively. At 36 months of age, evidence of seroprotection remained for greater than 90% of participants. Our results indicate that 1 toddler dose or 1 infant plus 1 toddler dose with MenC-TT vaccine provides seroprotection against MenC disease in early childhood.

  20. Effect of chelate-ring over the stabilization of copper-dioxygen adducts

    Indian Academy of Sciences (India)

    Administrator

    Effect of chelate-ring over the stabilization of copper-dioxygen adducts. RAJEEV GUPTA and RABINDRANATH MUKHERJEE. Department of Chemistry, Indian Institute of Technology,. Kanpur 208 016, India. Copper-dioxygen adducts are very important in biological systems as well as in synthetic oxidation chemistry.

  1. 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

  2. Solution thermodynamic evaluation of hydroxypyridinonate chelators 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO) for UO{sub 2}(VI) and Th(IV) decorporation

    Energy Technology Data Exchange (ETDEWEB)

    Sturzbecher-Hoehne, M.; Deblonde, G.J.P.; Abergel, R.J. [Lawrence Berkeley National Laboratory, CA (United States). Chemical Sciences Div.

    2013-08-01

    Solution thermodynamic studies were performed to characterize the coordination of U(VI) and Th(IV) by the multidentate hydroxypyridinonate chelating agents 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO). Species distribution and conditional stability pM profiles were calculated based on the determined formation constants, showing that both ligands form extremely stable uranyl and thorium complexes in solution. At physiological pH, the formation of 1:1 ligand:uranyl complexes is favored for both ligands, while a 2:1 ligand:thorium complex is predominant with the tetradentate 5-LIO(Me-3,2-HOPO). Comparisons with functionally similar bidentate ligands as well as with the common actinide chelator diethylenetriamine pentaacetic acid emphasized the superior affinity for U(VI) and Th(IV) of both experimental compounds over a wide pH range. These analytical results corroborate the in vivo chelation efficacy of 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO) and validate their selection for further development as therapeutic actinide decorporation agents. (orig.)

  3. Pt(IV/Re(I Chitosan Conjugates as a Flexible Platform for the Transport of Therapeutic and/or Diagnostic Anticancer Agents

    Directory of Open Access Journals (Sweden)

    Elisabetta Gabano

    2017-12-01

    Full Text Available New chitosan derivatives modified with (3-carboxypropyltrimethylammonium chloride (1 and coupled with (OC-6-44-diammine(4-carboxypropanoatodichloridoethanolatoplatinum(IV (2, were synthesized and their preliminary biological evaluation carried out in human tumor cells. Some of these derivatives were also loaded with a chelating ligand (3 that was derived from bis(quinolin-2-ylmethylamine to obtain chitosan-based nanoparticles for an EPR-mediated delivery of Pt(IV prodrugs and Re(I tricarbonyl complexes (4, to explore a multimodal theranostic approach to cancer. The cytotoxicity of the different chitosan conjugates (C12, C123, and C1234, carrying different combinations of the Pt(IV complex, the chelator and the Re(I complex, was evaluated in the A2780 human ovarian cancer cell line using the MTT assay. The Pt(IV-containing nanosystems showed low to moderate cytotoxic activity (IC50 values in the range 13.5–33.7 µM and was comparable to that found for the free Pt(IV complex (IC50 = 13.7 µM. Therefore, the Pt(IV-chitosan conjugation did not enhance the cytotoxic activity of the Pt(IV prodrug, which certainly reflects the inefficient cellular uptake of the nanoconjugates. Nevertheless, a clearer view of their potential for the delivery of anticancer agents requires further in vivo tests because the EPR effect increases extravasation and retention within the tumor tissue, not necessarily within the tumor cells.

  4. Copper Chelation in Alzheimer's Disease Protein

    Science.gov (United States)

    Rose, Frisco; Hodak, Miroslav; Bernholc, Jerry

    2013-03-01

    Alzheimer's disease (AD) is a neurodegenerative disorder affecting millions of people in the U.S. AD is primarily characterized at the cellular level by densely tangled fibrils of amyloid- β protein. These protein clusters have been found in association with elevated levels of multiple transition metals, with copper being the most egregious. Interestingly, metal chelation has shown promise in attenuating the symptoms of AD in recent clinical studies. We investigate this process by constructing an atomistic model of the amyloid- β-copper complex and profile the energetic viability in each of its subsequent disassociation stages. Our results indicate that five energetic barriers must be overcome for full metal chelation. The energy barriers are biologically viable in the presence water mediated bond and proton transfer between the metal and the protein. We model the chelation reaction using a consecutive path nudged elastic band method implemented in our ab initio real-space multi-grid code to obtain a viable sequence. This reaction model details a physically consistent explanation of the chelation process that could lead to the discovery of more effective chelation agents in the treatment of AD.

  5. Effect of roasting on properties of the zinc-chelating substance in coffee brews.

    Science.gov (United States)

    Wen, Xu; Enokizo, Akiko; Hattori, Harumi; Kobayashi, Satiko; Murata, Masatsune; Homma, Seiichi

    2005-04-06

    ApV is a brownish polymer with zinc-chelating activity in brewed coffee. We investigated in this study the effects of roasting on the zinc-chelating, reducing, and antioxidative activities of ApV from light-, medium-, and dark-roasted coffee. We also discuss the effect on the zinc-chelating activity of adding milk to the brewed coffee. The chelating activities of ApVs were evaluated by the tetramethyl murexide method. As the intensity of roasting increased, the yield of ApV increased, and the brown color and molecular weight of ApV respectively became darker and higher. Increasing the degree of roasting also decreased the zinc-chelating activity of ApV. The reducing activities of ApVs estimated by the indophenol method were stronger than those of ascorbic acid. Both the antioxidative activity estimated by the ABTS assay and the reducing activity of ApV increased with roasting. When milk was added to instant coffee and its ApV was prepared, the zinc-chelating activity of ApV was not changed.

  6. Wood impregnated with metal chelates dissolved in organic media tested for termite resistance

    Directory of Open Access Journals (Sweden)

    Lara Maistrello

    2011-08-01

    Full Text Available Wood manufactured products are subjected to biological decay due to fungi and insects. The use of copper chelates as biocides was proposed, due to their high stability which minimizes copper leaching into the environment. Considering the remarkable effectiveness showed by copper chelates on brown rot fungi, zinc and copper salicylate complexes were prepared in order to have metal chelates soluble in organic media available. The present study aimed at evaluating these metal chelates complexes as preservative agents for wood treatment against termites. Trials were performed on Reticulitermes lucifugus (Rossi and Kalotermes flavicollis (Fabricius. Results showed that in both termite species wood consumption was significantly lower on Cu-chelates treated samples compared to untreated wood, whereas the wood slices impregnated with Zn-chelates and the organic media alone gave an intermediate response. Interestingly, in one case solvent-impregnated wood was significantly more attractive than untreated wood for both species and further investigations are being carried out to clarify this behaviour.

  7. Design, synthesis and DNA-cleavage of Gly-Gly-His-naphthalene diimide conjugates.

    Science.gov (United States)

    Steullet, V; Dixon, D W

    1999-10-18

    Naphthalene diimides with one and two metal-chelating Gly-Gly-His (GGH) motifs have been synthesized. Both conjugates induce single-stranded cleavage of plasmid pBR322 DNA in the presence of nickel and Oxone and are approximately 100-fold more efficient than Ni(II) x GH-CONH2 itself.

  8. Improvement of Oxidative and Metabolic Parameters by Cellfood Administration in Patients Affected by Neurodegenerative Diseases on Chelation Treatment

    Directory of Open Access Journals (Sweden)

    Alessandro Fulgenzi

    2014-01-01

    Full Text Available Objective. This prospective pilot study aimed at evaluating the effects of therapy with antioxidant compounds (Cellfood, and other antioxidants on patients affected by neurodegenerative diseases (ND, who displayed toxic metal burden and were subjected to chelation treatment with the chelating agent calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA or EDTA. Methods. Two groups of subjects were studied: (a 39 patients affected by ND and (b 11 subjects unaffected by ND (controls. The following blood parameters were analyzed before and after three months’ treatment with chelation + Cellfood or chelation + other antioxidants: oxidative status (reactive oxygen species, ROS; total antioxidant capacity, TAC; oxidized LDL, oxLDL; glutathione, homocysteine, vitamin B12, and folate. Results. After 3-months’ chelation + Cellfood administration oxLDL decreased, ROS levels were significantly lower, and TAC and glutathione levels were significantly higher than after chelation + other antioxidants treatment, both in ND patients and in controls. Moreover, homocysteine metabolism had also improved in both groups. Conclusions. Chelation + Cellfood treatment was more efficient than chelation + other antioxidants improving oxidative status and homocysteine metabolism significantly in ND patients and controls. Although limited to a small number of cases, this study showed how helpful antioxidant treatment with Cellfood was in improving the subjects’ metabolic conditions.

  9. Segmented conjugated polymers

    Indian Academy of Sciences (India)

    Abstract. Segmented conjugated polymers, wherein the conjugation is randomly truncated by varying lengths of non-conjugated segments, form an interesting class of polymers as they not only represent systems of varying stiffness, but also ones where the backbone can be construed as being made up of chromophores of ...

  10. Segmented conjugated polymers

    Indian Academy of Sciences (India)

    Segmented conjugated polymers, wherein the conjugation is randomly truncated by varying lengths of non-conjugated segments, form an interesting class of polymers as they not only represent systems of varying stiffness, but also ones where the backbone can be construed as being made up of chromophores of varying ...

  11. Evaluation of the pinocytic uptake and cellular processing of antibody-N-(2-hydroxypropyl)methacrylamide copolymer conjugates and estimation of their potential use in targeted drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Flanagan, P.A.

    1987-01-01

    {sup 125}I-labelled protein (antibody or transferrin)--N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates were characterized using gel permeation chromatography and their average molecular weight (Mw) determined. It was estimated that within a protein-HPMA copolymer conjugate each protein residue was probably bound to 10-20 molecules of HPMA copolymer. The human transferrin receptor was used as a model target antigen/receptor. Pinocytic uptake of HPMA copolymer conjugated to monoclonal antibody B3/25 or transferrin was up to 9-fold higher than the uptake of parent copolymer. The ability of these conjugates to bind specifically was confirmed by Scatchard analysis of their cell-surface binding. Also, using a Percoll density gradient, it was shown that internalization of protein-HPMA copolymer conjugates is dependent upon their Mw and that internalized conjugates reach the lysosomal compartment. The transferrin receptor was found to have limited potential as an in vivo model antigen/receptor.

  12. Trypanotoxic activity of thiosemicarbazone iron chelators.

    Science.gov (United States)

    Ellis, Samuel; Sexton, Darren W; Steverding, Dietmar

    2015-03-01

    Only a few drugs are available for treating sleeping sickness and nagana disease; parasitic infections caused by protozoans of the genus Trypanosoma in sub-Saharan Africa. There is an urgent need for the development of new medicines for chemotherapy of these devastating diseases. In this study, three newly designed thiosemicarbazone iron chelators, TSC24, Dp44mT and 3-AP, were tested for in vitro activity against bloodstream forms of Trypanosoma brucei and human leukaemia HL-60 cells. In addition to their iron chelating properties, TSC24 and Dp44mT inhibit topoisomerase IIα while 3-AP inactivates ribonucleotide reductase. All three compounds exhibited anti-trypanosomal activity, with minimum inhibitory concentration (MIC) values ranging between 1 and 100 µM and 50% growth inhibition (GI50) values of around 250 nM. Although the compounds did not kill HL-60 cells (MIC values >100 µM), TSC24 and Dp44mT displayed considerable cytotoxicity based on their GI50 values. Iron supplementation partly reversed the trypanotoxic and cytotoxic activity of TSC24 and Dp44mT but not of 3-AP. This finding suggests possible synergy between the iron chelating and topoisomerase IIα inhibiting activity of the compounds. However, further investigation using separate agents, the iron chelator deferoxamine and the topoisomerase II inhibitor epirubicin, did not support any synergy for the interaction of iron chelation and topoisomerase II inhibition. Furthermore, TSC24 was shown to induce DNA degradation in bloodstream forms of T. brucei indicating that the mechanism of trypanotoxic activity of the compound is topoisomerase II independent. In conclusion, the data support further investigation of thiosemicarbazone iron chelators with dual activity as lead compounds for anti-trypanosomal drug development. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Asymmetric Synthesis and Evaluation of Danshensu-Cysteine Conjugates as Novel Potential Anti-Apoptotic Drug Candidates

    Directory of Open Access Journals (Sweden)

    Li-Long Pan

    2014-12-01

    Full Text Available We have previously reported that the danshensu-cysteine conjugate N-((R-3-benzylthio-1-methoxy-1-oxo-2-propanyl-2-acetoxy-3-(3,4-diacetoxyphenyl propanamide (DSC is a potent anti-oxidative and anti-apoptotic agent. Herein, we further design and asymmetrically synthesize two diastereoisomers of DSC and explore their potential bioactivities. Our results show that DSC and its two diastereoisomers exert similar protective effects in hydrogen peroxide (H2O2-induced cellular injury in SH-SY5Y cells, as evidenced by the increase of cell viability, superoxide dismutase (SOD, and reduced glutathione (GSH activity, and glutathione peroxidase (GPx expression, and the decrease of cellular morphological changes and nuclear condensation, lactate dehydrogenase (LDH release, and malondialdehyde (MDA production. In H2O2-stimulated human umbilical vein endothelial cells (HUVEC, DSC concentration-dependently attenuates H2O2-induced cell death, LDH release, mitochondrial membrane potential collapse, and modulates the expression of apoptosis-related proteins (Bcl-2, Bax, caspase-3, and caspase-9. Our results provide strong evidence that DSC and its two diastereoisomers have similar anti-oxidative activity and that DSC exerts significant vascular-protective effects, at least in part, through inhibition of apoptosis and modulation of endogenous antioxidant enzymes.

  14. Cage-like bifunctional chelators, copper-64 radiopharmaceuticals and PET imaging using the same

    Energy Technology Data Exchange (ETDEWEB)

    Conti, Peter S.; Cai, Hancheng; Li, Zibo; Liu, Shuanglong

    2016-08-02

    Disclosed is a class of versatile Sarcophagine based bifunctional chelators (BFCs) containing a hexa-aza cage for labeling with metals having either imaging, therapeutic or contrast applications radiolabeling and one or more linkers (A) and (B). The compounds have the general formula ##STR00001## where A is a functional group selected from group consisting of an amine, a carboxylic acid, an ester, a carbonyl, a thiol, an azide and an alkene, and B is a functional group selected from the group consisting of hydrogen, an amine, a carboxylic acid, and ester, a carbonyl, a thiol, an azide and an alkene. Also disclosed are conjugate of the BFC and a targeting moiety, which may be a peptide or antibody. Also disclosed are metal complexes of the BFC/targeting moiety conjugates that are useful as radiopharmaceuticals, imaging agents or contrast agents.

  15. Truncated Conjugate Gradient: An Optimal Strategy for the Analytical Evaluation of the Many-Body Polarization Energy and Forces in Molecular Simulations.

    Science.gov (United States)

    Aviat, Félix; Levitt, Antoine; Stamm, Benjamin; Maday, Yvon; Ren, Pengyu; Ponder, Jay W; Lagardère, Louis; Piquemal, Jean-Philip

    2017-01-10

    We introduce a new class of methods, denoted as Truncated Conjugate Gradient(TCG), to solve the many-body polarization energy and its associated forces in molecular simulations (i.e. molecular dynamics (MD) and Monte Carlo). The method consists in a fixed number of Conjugate Gradient (CG) iterations. TCG approaches provide a scalable solution to the polarization problem at a user-chosen cost and a corresponding optimal accuracy. The optimality of the CG-method guarantees that the number of the required matrix-vector products are reduced to a minimum compared to other iterative methods. This family of methods is non-empirical, fully adaptive, and provides analytical gradients, avoiding therefore any energy drift in MD as compared to popular iterative solvers. Besides speed, one great advantage of this class of approximate methods is that their accuracy is systematically improvable. Indeed, as the CG-method is a Krylov subspace method, the associated error is monotonically reduced at each iteration. On top of that, two improvements can be proposed at virtually no cost: (i) the use of preconditioners can be employed, which leads to the Truncated Preconditioned Conjugate Gradient (TPCG); (ii) since the residual of the final step of the CG-method is available, one additional Picard fixed point iteration ("peek"), equivalent to one step of Jacobi Over Relaxation (JOR) with relaxation parameter ω, can be made at almost no cost. This method is denoted by TCG-n(ω). Black-box adaptive methods to find good choices of ω are provided and discussed. Results show that TPCG-3(ω) is converged to high accuracy (a few kcal/mol) for various types of systems including proteins and highly charged systems at the fixed cost of four matrix-vector products: three CG iterations plus the initial CG descent direction. Alternatively, T(P)CG-2(ω) provides robust results at a reduced cost (three matrix-vector products) and offers new perspectives for long polarizable MD as a production

  16. Synthesis of DOTA-conjugated multimeric [Tyr3]octreotide peptides via a combination of Cu(I)-catalyzed "click" cycloaddition and thio acid/sulfonyl azide "sulfo-click" amidation and their in vivo evaluation.

    NARCIS (Netherlands)

    Yim, C.B.; Dijkgraaf, I.; Merkx, R.; Versluis, C.; Eek, A.; Mulder, G.E.; Rijkers, D.T.; Boerman, O.C.; Liskamp, R.M.

    2010-01-01

    Herein, we describe the design, synthesis, and biological evaluation of a series of DOTA-conjugated monomeric, dimeric, and tetrameric [Tyr(3)]octreotide-based analogues as a tool for tumor imaging and/or radionuclide therapy. These compounds were synthesized using a Cu(I)-catalyzed 1,3-dipolar

  17. Synthesis and evaluation of {sup 99m}Tc/{sup 99}Tc-MAG3-biotin conjugates for antibody pretargeting strategies

    Energy Technology Data Exchange (ETDEWEB)

    Gog, Frank B. van; Visser, Gerard W.M.; Gowrising, Radjish W.A.; Snow, Gordon B.; Dongen, Guus A.M.S. van E-mail: gams.vandongen@azvu.nl

    1998-10-01

    Four {sup 99m}Tc-MAG3-biotin conjugates were synthesized to determine their potential use in antibody pretargeting strategies for radioimmunoscintigraphy (RIS). To use these {sup 99m}Tc-MAG3-biotin conjugates as model compounds for {sup 186}Re-MAG3-biotin conjugates for radioimmunotherapy (RIT), nanomolar amounts of {sup 99}Tc were added as carrier to {sup 99m}Tc. The biotin derivatives used for the preparation of the conjugates - biocytin, biotin hydrazide, biotinyl-piperazine, and biotinyl-diaminosuccinic acid - differed at the site that is regarded to be susceptible to hydrolysis by biotinidase present in human plasma. All four conjugates were produced with high radiochemical purity, were stable in PBS, and demonstrated full binding capacity to streptavidin. The {sup 99m}Tc/{sup 99}Tc-MAG3-labeled biotinyl-piperazine and biotinyl-diaminosuccinic acid conjugates were stable in mouse as well as human plasma, whereas the corresponding biocytin and biotin hydrazide conjugates were rapidly degraded. The biodistribution in nude mice at 30 min after injection was similar for all conjugates, and a rapid blood clearance and high intestinal excretion were both observed. It is concluded that the metabolic routing of a conjugate containing biotin and MAG3 is dominated by these two moieties. For this reason, MAG3-biotin conjugates do not seem suited for pretargeted RIT, for which quantitative and fast renal excretion is a prerequisite to minimize radiation toxicity. However, in a pretargeted RIS approach the {sup 99m}Tc-MAG3-biotin conjugates might have potential.

  18. Biosynthesis of insulin-silk fibroin nanoparticles conjugates and in vitro evaluation of a drug delivery system

    Science.gov (United States)

    Yan, Hai-Bo; Zhang, Yu-Qing; Ma, Yong-Lei; Zhou, Li-Xia

    2009-11-01

    Silk fibroin derived from Bombyx mori is a biomacromolecular protein with outstanding biocompatibility. When it was dissolved in highly concentrated CaCl2 solution and then the mixture of the protein and salt was subjected to desalting treatments for long time in flowing water, the resulting liquid silk was water-soluble polypeptides with different molecular masses, ranging from 8 to 70 kDa. When the liquid silk was introduced rapidly into acetone, silk protein nanoparticles with a range of 40-120 nm in diameter could be obtained. The crystalline silk nanoparticles could be conjugated covalently with insulin alone with cross-linking reagent glutaraldehyde. In vitro properties of the insulin-silk fibroin nanoparticles (Ins-SFN) bioconjugates were determined by Enzyme-Linked Immunosorbent Assay (ELISA). The optimal conditions for the biosynthesis of Ins-SFN bioconjugates were investigated. The Ins-SFN constructs obtained by 8 h of covalent cross-linking with 0.7% cross-linking reagent and the proportion of insulin and SFN being 30 IU: 15 mg showed much higher recoveries (90-115%). When insulin was coupled covalently with silk nanoparticles, the resistance of the modified insulin to trypsin digestion and in vitro stability in human serum were greatly enhanced as compared with insulin alone. The results in human serum indicated that the half-life in vitro of the biosynthesized Ins-SFN derivatives was about 2.5 times more than that of native insulin. Therefore, the silk protein nanoparticles have the potential values for being studied and developed as a new bioconjugate for enzyme/polypeptide drug delivery system.

  19. Recent developments centered on orally active iron chelators

    Directory of Open Access Journals (Sweden)

    Robert Hider

    2014-09-01

    Full Text Available Over the past twenty years there has been a growing interest in the orally active iron chelators, deferiprone and deferasirox, both have been extensively studied. The ability of these compounds to mobilize iron from the heart and endocrine tissue has presented the clinician with some advantages over desferrioxamine, the first therapeutic iron chelator. Other orally active iron chelators are currently under development. The critical features necessary for the design of therapeutically useful orally active iron chelators are presented in this review, together with recent studies devoted to the design of such chelators. This newly emerging range of iron chelators will enable clinicians to apply iron chelation methodology to other disease states and to begin to design personalized chelation regimes.

  20. Chelates for Micronutrient Nutrition among Crops

    Indian Academy of Sciences (India)

    playa major role in bringing stability and sustainability in the production of food grains, pulses and oilseeds in the coming decade. The three main classes of micronutrient sources are inorganic, synthetic chelates and organic complexes. Inorganic sources such as sulphates of Cu, Mn, Fe and Zn are the most common.

  1. Chelates for Micronutrient Nutrition among Crops

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 8; Issue 7. Chelates for Micronutrient Nutrition among Crops. B S Sekhon. General Article Volume 8 Issue 7 July 2003 pp 46-53. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/008/07/0046-0053. Keywords.

  2. CHELATING LIGANDS: ENHANCERS OF QUALITY AND PURITY ...

    African Journals Online (AJOL)

    Nwokem et al.

    ABSTRACT. The quality of biogas depends largely on the percentage of methane and hydrogen sulphide gas present. High concentration of hydrogen sulphide results in low quality biogas. This work employed the use of chelating ligands in scrubbing hydrogen sulphide gas while improving the yield of methane gas.

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

    Energy Technology Data Exchange (ETDEWEB)

    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 /sup 111/In labeled antibodies for tumor imaging. We have investigated /sup 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 /sup 203/Pb and /sup 111/In with 60 and 90% labeling yields, respectively. The biodistribution of /sup 203/Pb-17-1A conjugates was compared with the corresponding /sup 111/In-labeled preparations and with /sup 203/Pb-DTPA, /sup 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.

  4. Design, synthesis and biological evaluation of a multifunctional HER2-specific Affibody molecule for molecular imaging

    Energy Technology Data Exchange (ETDEWEB)

    Tran, Thuy A. [Uppsala University, Department of Radiology, Oncology and Clinical Immunology, Rudbeck Laboratory, Uppsala (Sweden); Rosik, Daniel; Abrahmsen, Lars; Sjoeberg, Anna [Affibody AB, Bromma (Sweden); Sandstroem, Mattias [Uppsala University Hospital, Hospital Physics, Department of Oncology, Uppsala (Sweden); Waallberg, Helena [Royal Institute of Technology, School of Biotechnology, Division of Molecular Biotechnology, Stockholm (Sweden); Ahlgren, Sara [Uppsala University, Division of Nuclear Medicine, Department of Medical Sciences, Uppsala (Sweden); Orlova, Anna [Uppsala University, Department of Radiology, Oncology and Clinical Immunology, Rudbeck Laboratory, Uppsala (Sweden); Affibody AB, Bromma (Sweden); Tolmachev, Vladimir [Uppsala University, Department of Radiology, Oncology and Clinical Immunology, Rudbeck Laboratory, Uppsala (Sweden); Affibody AB, Bromma (Sweden); Uppsala University, Division of Nuclear Medicine, Department of Medical Sciences, Uppsala (Sweden)

    2009-11-15

    The purpose of this study was to design and evaluate a novel platform for labelling of Affibody molecules, enabling both recombinant and synthetic production and site-specific labelling with {sup 99m}Tc or trivalent radiometals. The HER2-specific Affibody molecule PEP05352 was made by peptide synthesis. The chelator sequence SECG (serine-glutamic acid-cysteine-glycine) was anchored on the C-terminal to allow {sup 99m}Tc labelling. The cysteine can alternatively serve as a conjugation site of the chelator DOTA for indium labelling. The resulting {sup 99m}Tc- and {sup 111}In-labelled Affibody molecules were evaluated both in vitro and in vivo. Both conjugates retained their capacity to bind to HER2 receptors in vitro and in vivo. The tumour to blood ratio in LS174T xenografts was 30 at 4 h post-injection for both conjugates. Biodistribution data showed that the {sup 99m}Tc-labelled Affibody molecule had a fourfold lower kidney accumulation compared with the {sup 111}In-labelled Affibody molecule while the accumulation in other organs was similar. Gamma camera imaging of the conjugates could clearly visualise the tumours 4 h after injection. Incorporation of the C-terminal SECG sequence in Affibody molecules provides a general multifunctional platform for site-specific labelling with different nuclides (technetium, indium, gallium, cobalt or yttrium) and for a flexible production (chemical synthesis or recombinant). (orig.)

  5. Influence of a novel, versatile bifunctional chelator on theranostic properties of a minigastrin analogue.

    Science.gov (United States)

    Pfister, Joachim; Summer, Dominik; Rangger, Christine; Petrik, Milos; von Guggenberg, Elisabeth; Minazzi, Paolo; Giovenzana, Giovanni B; Aloj, Luigi; Decristoforo, Clemens

    2015-12-01

    6-[Bis(carboxymethyl)amino]-1,4-bis(carboxymethyl)-6-methyl-1,4-diazepane (AAZTA ) is a promising chelator with potential advantages over 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for radiopharmaceutical applications. Its mesocyclic structure enables fast radiolabelling under mild conditions with trivalent metals including not only (68)Ga for positron emission tomography (PET) but also (177)Lu and (111)In for single-photon emission computed tomography (SPECT) and radionuclide therapy. Here, we describe the evaluation of a bifunctional AAZTA derivative conjugated to a model minigastrin derivative as a potential theranostic agent. An AAZTA derivative with an aliphatic C9 chain as linker was coupled to a minigastrin, namely [AAZTA(0), D-Glu(1), desGlu(2-6)]-minigastrin (AAZTA-MG), and labelled with (68)Ga, (177)Lu and (111)In. The characterisation in vitro included stability studies in different media and determination of logD (octanol/PBS). Affinity determination (IC50) and cell uptake studies were performed in A431-CCK2R cells expressing the human CCK2 receptor. μPET/CT and ex vivo biodistribution studies were performed in CCK2 tumour xenograft-bearing nude mice and normal mice. AAZTA-MG showed high radiochemical yields for (68)Ga (>95 %), (177)Lu (>98 %) and (111)In (>98 %). The logD value of -3.7 for both [(68)Ga]- and [(177)Lu]-AAZTA-MG indicates a highly hydrophilic character. Stability tests showed overall high stability in solution with some degradation in human plasma for [(68)Ga]- and transchelation towards DTPA for and [(177)Lu]-AAZTA-MG. An IC50 value of 10.0 nM was determined, which indicates a high affinity for the CCK2 receptor. Specific cell uptake after 60 min was >7.5 % for [(68)Ga]-AAZTA-MG and >9.5 % for [(177)Lu]-AAZTA-MG, comparable to other DOTA-MG-analogues. μPET/CT studies in CCK2 receptor tumour xenografted mice not only revealed high selective accumulation in A431-CCK2R positive tumours of (68)Ga-labelled AAZTA

  6. Assessment of iron chelates efficiency for photo-Fenton at neutral pH.

    Science.gov (United States)

    De Luca, Antonella; Dantas, Renato F; Esplugas, Santiago

    2014-09-15

    In this study, homogeneous photo-Fenton like at neutral pH was applied to remove sulfamethoxazole from water. The process was performed using different chelating agents in order to solubilize iron in a neutral water solution. The chelating agents tested were: ethylenediaminetetraacetic acid (EDTA); nitrilotriacetic acid (NTA); oxalic acid (OA) and tartaric acid (TA). The iron leaching was monitored over reaction time to evaluate the chelates stability and their resistance to HO· and UV-A radiation. Chelates of EDTA and NTA presented more stability than OA and TA, which also confirmed their higher efficiency. Total Organic Carbon (TOC) analyses were also performed to evaluate the contribution in terms of solution contamination related to the use of chelating agents. The better properties of biodegradability in respect of EDTA combined with better efficiency in terms of microcontaminant removal and the smallest TOC contribution indicate that NTA could represent a useful option to perform photo-Fenton processes at neutral pH. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Disaggregation ability of different chelating molecules on copper ion-triggered amyloid fibers.

    Science.gov (United States)

    Zhu, Linyi; Han, Yuchun; He, Chengqian; Huang, Xu; Wang, Yilin

    2014-08-07

    Dysfunctional interaction of amyloid-β (Aβ) with excess metal ions is proved to be related to the etiology of Alzheimer's disease (AD). Using metal-binding compounds to reverse metal-triggered Aβ aggregation has become one of the potential therapies for AD. In this study, the ability of a carboxylic acid gemini surfactant (SDUC), a widely used metal chelator (EDTA), and an antifungal drug clioquinol (CQ) in reversing the Cu(2+)-triggered Aβ(1-40) fibers have been systematically studied by using turbidity essay, BCA essay, atomic force microscopy, transmission electron microscopy, and isothermal titration microcalorimetry. The results show that the binding affinity of Cu(2+) with CQ, SDUC, and EDTA is in the order of CQ > EDTA > SDUC, while the disaggregation ability to Cu(2+)-triggered Aβ(1-40) fibers is in the order of CQ > SDUC > EDTA. Therefore, the disaggregation ability of chelators to the Aβ(1-40) fibers does not only depend on the binding affinity of the chelators with Cu(2+). Strong self-assembly ability of SDUC and π-π interaction of the conjugate group of CQ also contributes toward the disaggregation of the Cu(2+)-triggered Aβ(1-40) fibers and result in the formation of mixed small aggregates.

  8. In vitro Evaluation of a Bombesin Antagonistic Analogue Conjugated with DOTA-Ala(SO{sub 3}H)-Aminooctanoyl for Targeting of the Gastrin-releasing Peptide Receptor

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Jae Cheong; Cho, Eun Ha; Kim, Jin Joo; Lee, So Young; Choi, Sang Mu [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2014-05-15

    As Bombesin (BBS) binds with high affinity to GRPR, BBS derivatives have been labeled with various radionuclides such as {sup 99}mTc, {sup 111}In, {sup 90}Y, {sup 64}Cu, {sup 177}Lu, {sup 68}Ga, or {sup 18}F and have proved to be successful candidates for peptide receptor radiotherapy (PRRT). In this study, we employed Ala(SO{sub 3}H)-Aminooctanoyl as a linker of BBS antagonistic peptide sequence, Gln-Trp-Ala-Val-N methyl Gly-His-Statine-Leu-NH{sub 2}, with DOTA to prepare radiolabeled candidates for GRPR targeting. A DOTA-conjugated BBS antagonistic analogue was synthesized and radiolabeled with {sup 177}Lu, and in vitro characteristics on GRPR-overexpressing human prostate tumor cells were evaluated. In conclusion, a novel BBS antagonistic analogue, {sup 177}Lu-DOTA-sBBNA, is a promising candidate for the targeting of GRPR-over-expressing tumors. Further investigations to evaluate its in vivo characteristics and therapeutic efficacy are needed.

  9. Iron Chelators and Antioxidants Regenerate Neuritic Tree and Nigrostriatal Fibers of MPP+/MPTP-Lesioned Dopaminergic Neurons.

    Directory of Open Access Journals (Sweden)

    Pabla Aguirre

    Full Text Available Neuronal death in Parkinson's disease (PD is often preceded by axodendritic tree retraction and loss of neuronal functionality. The presence of non-functional but live neurons opens therapeutic possibilities to recover functionality before clinical symptoms develop. Considering that iron accumulation and oxidative damage are conditions commonly found in PD, we tested the possible neuritogenic effects of iron chelators and antioxidant agents. We used three commercial chelators: DFO, deferiprone and 2.2'-dypyridyl, and three 8-hydroxyquinoline-based iron chelators: M30, 7MH and 7DH, and we evaluated their effects in vitro using a mesencephalic cell culture treated with the Parkinsonian toxin MPP+ and in vivo using the MPTP mouse model. All chelators tested promoted the emergence of new tyrosine hydroxylase (TH-positive processes, increased axodendritic tree length and protected cells against lipoperoxidation. Chelator treatment resulted in the generation of processes containing the presynaptic marker synaptophysin. The antioxidants N-acetylcysteine and dymetylthiourea also enhanced axodendritic tree recovery in vitro, an indication that reducing oxidative tone fosters neuritogenesis in MPP+-damaged neurons. Oral administration to mice of the M30 chelator for 14 days after MPTP treatment resulted in increased TH- and GIRK2-positive nigra cells and nigrostriatal fibers. Our results support a role for oral iron chelators as good candidates for the early treatment of PD, at stages of the disease where there is axodendritic tree retraction without neuronal death.

  10. Antimicrobial Properties of Copper Nanoparticles and Amino Acid Chelated Copper Nanoparticles Produced by Using a Soya Extract

    Science.gov (United States)

    DeAlba-Montero, I.; Morales-Sánchez, Elpidio; Araujo-Martínez, Rene

    2017-01-01

    This paper reports a comparison of the antibacterial properties of copper-amino acids chelates and copper nanoparticles against Escherichia coli, Staphylococcus aureus, and Enterococcus faecalis. These copper-amino acids chelates were synthesized by using a soybean aqueous extract and copper nanoparticles were produced using as a starting material the copper-amino acids chelates species. The antibacterial activity of the samples was evaluated by using the standard microdilution method (CLSI M100-S25 January 2015). In the antibacterial activity assays copper ions and copper-EDTA chelates were included as references, so that copper-amino acids chelates can be particularly suitable for acting as an antibacterial agent, so they are excellent candidates for specific applications. Additionally, to confirm the antimicrobial mechanism on bacterial cells, MTT assay (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) was carried out. A significant enhanced antimicrobial activity and a specific strain were found for copper chelates over E. faecalis. Its results would eventually lead to better utilization of copper-amino acids chelate for specific application where copper nanoparticles can be not used. PMID:28286459

  11. Chelating Properties of Peptides from Red Seaweed Pyropia columbina and Its Effect on Iron Bio-Accessibility.

    Science.gov (United States)

    Cian, Raúl E; Garzón, Antonela G; Ancona, David Betancur; Guerrero, Luis Chel; Drago, Silvina R

    2016-03-01

    The aim of this work was to evaluate copper-chelating, iron-chelating and anticariogenic activity of peptides obtained by enzymatic hydrolysis of P. columbina protein concentrate and to study the effects of chelating peptides on iron bio-accessibility. Two hydrolyzates were obtained from P. columbina protein concentrate (PC) using two hydrolysis systems: alkaline protease (A) and alkaline protease + Flavourzyme (AF). FPLC gel filtration profile of PC shows a peak having molecular weight (MW) higher than 7000 Da (proteins). A and AF hydrolyzates had peptides with medium and low MW (1013 and 270 Da), respectively. Additionally, AF presented free amino acids with MW around 82 Da and higher content of His and Ser. Peptides from AF showed the highest chelating properties measured as copper-chelating activity (the lowest β-carotene oxidation rate: Ro; 0.7 min(-1)), iron-chelating activity (33%), and phosphorous and Ca(2+) release inhibition (87 and 81%, respectively). These properties could indicate antioxidant properties, promotion of iron absorption and anticariogenic activity, respectively. In fact, hydrolyzates promoted iron dialyzability (≈ 16%), values being higher than that found for P. columbina seaweed. Chelating peptides from both hydrolyzates can maintain the iron in a soluble and bio-accessible form after gastrointestinal digestion.

  12. Effect of different chelated zinc sources on the growth and yield of maize (Zea mays L.

    Directory of Open Access Journals (Sweden)

    M. Tahir

    2009-05-01

    Full Text Available A field study was conducted at Agronomic Research Area, University of Agriculture, Faisalabad during spring, 2007 to evaluate the effect of different chelated zinc sources on growth and yield of maize (Zea mays L.. Crop was sown on well prepared soil in 1st week of March, 2007. The experiment was laid out according to randomized complete block design. The treatments comprised of different chelated zinc sources: ZnSO4-DTPA, ZnSO4-Fulvate, ZnSO4-Lignosulphonate, ZnSO4-EDTA and ZnSO4-H2O along with control (no zinc, repeated three times. Results showed that number of cobs plant-1, grain rows cob-1 and oil contents did not differ significantly. However, differences among treatments for plant height at harvest (cm, leaf area plant-1 (cm2, stem diameter (cm, cob length (cm, cob diameter (cm, 100-grains weight (g, number of grains cob-1, grains weight cob-1(g, biological yield (tons ha-1, grain yield (tons ha-1 and protein contents (% were significantly higher. Moreover, results also revealed that ZnSO4-DPTA was found the most effective Zn chelated source among all the treatments. Rest of the chelating agents were not too impressive as they showed varied response for different variables. The result of this experiment suggest further experimentation to explore behaviour of Zn-DTPA with other macro and micro nutrients and to calculate cost benefit ratio for use ofZn chelated compounds.

  13. IRON CHELATION THERAPY IN THALASSEMIA SYNDROMES

    Directory of Open Access Journals (Sweden)

    Paolo Cianciulli

    2009-06-01

    Full Text Available Transfusional hemosiderosis is a frequent complication in patients with transfusion dependent chronic diseases such as  thalassemias and severe type of sickle cell diseases. As there are no physiological mechanisms to excrete the iron contained in transfused red cells (1 unit of blood contains approximately 200 mg of iron the excess of iron is stored in various organs. Cardiomyopathy is the most severe complication covering more than 70% of the causes of death of thalassemic patients. Although the current reference standard iron chelator deferoxamine (DFO has been used clinically for over four decades, its effectiveness is limited by a demanding therapeutic regimen that leads to poor compliance. Despite poor compliance, because of the inconvenience of subcutaneous infusion, DFO improved considerably the survival and quality of life of patients with thalassemia. Deferiprone since 1998 and Deferasirox since 2005 were licensed for clinical use. The oral chelators have a better compliance because of oral use, a comparable efficacy to DFO in iron excretion and probably a better penetration to myocardial cells. Considerable increase in iron excretion was documented with combination therapy of DFO and Deferiprone. The proper use of the three chelators will improve the prevention and treatment of iron overload, it will reduce  complications, and improve survival and quality of life of transfused patients

  14. Evaluation of biodistribution and anti-tumor effect of a dimeric RGD peptide-paclitaxel conjugate in mice with breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Cao, Qizhen; Li, Zi-Bo; Chen, Kai; Wu, Zhanhong; He, Lina; Chen, Xiaoyuan [Stanford University School of Medicine, The Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Biophysics, and Bio-X Program, Stanford P095, CA (United States); Neamati, Nouri [University of Southern California, School of Pharmacy, Department of Pharmacology and Pharmaceutical Sciences, Los Angeles, CA (United States)

    2008-08-15

    Targeting drugs to receptors involved in tumor angiogenesis has been demonstrated as a novel and promising approach to improve cancer treatment. In this study, we evaluated the anti-tumor efficacy of a dimeric RGD peptide-paclitaxel conjugate (RGD2-PTX) in an orthotopic MDA-MB-435 breast cancer model. To assess the effect of conjugation and the presence of drug moiety on the MDA-MB-435 tumor and normal tissue uptake, the biodistribution of {sup 3}H-RGD2-PTX was compared with that of {sup 3}H-PTX. The treatment effect of RGD2-PTX and RGD2+PTX was measured by tumor size, {sup 18}F-FDG/PET, {sup 18}F-FLT/PET, and postmortem histopathology. By comparing the biodistribution of {sup 3}H-RGD2-PTX and {sup 3}H-PTX, we found that {sup 3}H-RGD2-PTX had higher initial tumor exposure dose and prolonged tumor retention than {sup 3}H-PTX. Metronomic low-dose treatment of breast cancer indicated that RGD2-PTX is significantly more effective than PTX+RGD2 combination and solvent control. Although in vivo {sup 18}F-FLT/PET imaging and ex vivo Ki67 staining indicated little effect of the PTX-based drug on cell proliferation, {sup 18}F-FDG/PET imaging showed significantly reduced tumor metabolism in the RGD2-PTX-treated mice versus those treated with RGD2+PTX and solvent control. Terminal uridine deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining also showed that RGD2-PTX treatment also had significantly higher cell apoptosis ratio than the other two groups. Moreover, the microvessel density was significantly reduced after RGD2-PTX treatment as determined by CD31 staining. Our results demonstrate that integrin-targeted delivery of paclitaxel allows preferential cytotoxicity to integrin-expressing tumor cells and tumor vasculature. The targeted delivery strategies developed in this study may also be applied to other chemotherapeutics for selective tumor killing. (orig.)

  15. In vivo evaluation of cetuximab-conjugated poly(γ-glutamic acid)-docetaxel nanomedicines in EGFR-overexpressing gastric cancer xenografts

    Science.gov (United States)

    Sreeranganathan, Maya; Uthaman, Saji; Sarmento, Bruno; Mohan, Chethampadi Gopi; Park, In-Kyu; Jayakumar, Rangasamy

    2017-01-01

    Epidermal growth factor receptor (EGFR), upregulated in gastric cancer patients, is an oncogene of interest in the development of targeted cancer nanomedicines. This study demonstrates in silico modeling of monoclonal antibody cetuximab (CET MAb)-conjugated docetaxel (DOCT)-loaded poly(γ-glutamic acid) (γ-PGA) nanoparticles (Nps) and evaluates the in vitro/in vivo effects on EGFR-overexpressing gastric cancer cells (MKN-28). Nontargeted DOCT-γ-PGA Nps (NT Nps: 110±40 nm) and targeted CET MAb-DOCT-γ-PGA Nps (T Nps: 200±20 nm) were prepared using ionic gelation followed by 1-Ethyl-3-(3-dimethyl aminopropyl)carbodiimide–N-Hydoxysuccinimide (EDC–NSH) chemistry. Increased uptake correlated with enhanced cytotoxicity induced by targeted Nps to EGFR +ve MKN-28 compared with nontargeted Nps as evident from MTT and flow cytometric assays. Nanoformulated DOCT showed a superior pharmacokinetic profile to that of free DOCT in Swiss albino mice, indicating the possibility of improved therapeutic effect in the disease model. Qualitative in vivo imaging showed early and enhanced tumor targeted accumulation of CET MAb-DOCT-γ-PGA Nps in EGFR +ve MKN-28–based gastric cancer xenograft, which exhibited efficient arrest of tumor growth compared with nontargeted Nps and free DOCT. Thus, actively targeted CET MAb-DOCT-γ-PGA Nps could be developed as a substitute to conventional nonspecific chemotherapy, and hence could become a feasible strategy for cancer therapy for EGFR-overexpressing gastric tumors. PMID:29033568

  16. In vivo evaluation of cetuximab-conjugated poly(γ-glutamic acid)-docetaxel nanomedicines in EGFR-overexpressing gastric cancer xenografts.

    Science.gov (United States)

    Sreeranganathan, Maya; Uthaman, Saji; Sarmento, Bruno; Mohan, Chethampadi Gopi; Park, In-Kyu; Jayakumar, Rangasamy

    2017-01-01

    Epidermal growth factor receptor (EGFR), upregulated in gastric cancer patients, is an oncogene of interest in the development of targeted cancer nanomedicines. This study demonstrates in silico modeling of monoclonal antibody cetuximab (CET MAb)-conjugated docetaxel (DOCT)-loaded poly(γ-glutamic acid) (γ-PGA) nanoparticles (Nps) and evaluates the in vitro/in vivo effects on EGFR-overexpressing gastric cancer cells (MKN-28). Nontargeted DOCT-γ-PGA Nps (NT Nps: 110±40 nm) and targeted CET MAb-DOCT-γ-PGA Nps (T Nps: 200±20 nm) were prepared using ionic gelation followed by 1-Ethyl-3-(3-dimethyl aminopropyl)carbodiimide-N-Hydoxysuccinimide (EDC-NSH) chemistry. Increased uptake correlated with enhanced cytotoxicity induced by targeted Nps to EGFR +ve MKN-28 compared with nontargeted Nps as evident from MTT and flow cytometric assays. Nanoformulated DOCT showed a superior pharmacokinetic profile to that of free DOCT in Swiss albino mice, indicating the possibility of improved therapeutic effect in the disease model. Qualitative in vivo imaging showed early and enhanced tumor targeted accumulation of CET MAb-DOCT-γ-PGA Nps in EGFR +ve MKN-28-based gastric cancer xenograft, which exhibited efficient arrest of tumor growth compared with nontargeted Nps and free DOCT. Thus, actively targeted CET MAb-DOCT-γ-PGA Nps could be developed as a substitute to conventional nonspecific chemotherapy, and hence could become a feasible strategy for cancer therapy for EGFR-overexpressing gastric tumors.

  17. Antioxidant and mercury chelating activity of Psidium guajava var. pomifera L. leaves hydroalcoholic extract.

    Science.gov (United States)

    Pinho, Antonio Ivanildo; Oliveira, Cláudia Sirlene; Lovato, Fabricio Luís; Waczuk, Emily Pansera; Piccoli, Bruna Candia; Boligon, Aline Augusti; Leite, Nadghia Figueredo; Coutinho, Henrique Douglas Melo; Posser, Thais; Da Rocha, João Batista Teixeira; Franco, Jeferson Luis

    2017-01-01

    Mercury (Hg) is widely distributed in the environment and is known to produce several adverse effects in organisms. The aim of the present study was to examine the in vitro antioxidant activity and Hg chelating ability of the hydroalcoholic extract of Psidium guajava leaves (HEPG). In addition, the potential protective effects of HEPG against Hg(II) were evaluated using a yeast model (Saccharomyces cerevisiae). HEPG was found to exert significant antioxidant activity in 2,2-diphenyl-1-picrylhydrazyl scavenger and inhibition of lipid peroxidation induced by Fe(II) assays in a concentration-dependent manner. The extract also exhibited significant Hg(II) chelating activity. In yeast, Hg(II) induced a significant decrease in cell viability. In contrast, HEPG partially prevented the fall in cell viability induced by Hg(II). In conclusion, HEPG exhibited protective effects against Hg(II)-mediated toxicity, which may be related to both antioxidant and Hg(II)-chelating activities.

  18. N-acetylcysteine protects rats with chronic renal failure from gadolinium-chelate nephrotoxicity.

    Directory of Open Access Journals (Sweden)

    Leonardo Victor Barbosa Pereira

    Full Text Available The aim of this study was to evaluate the effect of Gd-chelate on renal function, iron parameters and oxidative stress in rats with CRF and a possible protective effect of the antioxidant N-Acetylcysteine (NAC. Male Wistar rats were submitted to 5/6 nephrectomy (Nx to induced CRF. An ionic-cyclic Gd (Gadoterate Meglumine was administrated (1.5 mM/KgBW, intravenously 21 days after Nx. Clearance studies were performed in 4 groups of anesthetized animals 48 hours following Gd- chelate administration: 1--Nx (n = 7; 2--Nx+NAC (n = 6; 3--Nx+Gd (n = 7; 4--Nx+NAC+Gd (4.8 g/L in drinking water, initiated 2 days before Gd-chelate administration and maintained during 4 days (n = 6. This group was compared with a control. We measured glomerular filtration rate, GFR (inulin clearance, ml/min/kg BW, proteinuria (mg/24 hs, serum iron (µg/dL; serum ferritin (ng/mL; transferrin saturation (%, TIBC (µg/dL and TBARS (nmles/ml. Normal rats treated with the same dose of Gd-chelate presented similar GFR and proteinuria when compared with normal controls, indicating that at this dose Gd-chelate is not nephrotoxic to normal rats. Gd-chelate administration to Nx-rats results in a decrease of GFR and increased proteinuria associated with a decrease in TIBC, elevation of ferritin serum levels, transferrin oversaturation and plasmatic TBARS compared with Nx-rats. The prophylactic treatment with NAC reversed the decrease in GFR and the increase in proteinuria and all alterations in iron parameters and TBARS induced by Gd-chelate. NAC administration to Nx rat did not modify the inulin clearance and iron kinetics, indicating that the ameliorating effect of NAC was specific to Gd-chelate. These results suggest that NAC can prevent Gd-chelate nephrotoxicity in patients with chronic renal failure.

  19. Optical phase conjugation

    CERN Document Server

    Fisher, Robert A

    1983-01-01

    This book appears at a time of intense activity in optical phase conjugation. We chose not to await the maturation of the field, but instead to provide this material in time to be useful in its development. We have tried very hard to elucidate and interrelate the various nonlinear phenomena which can be used for optical phase conjugation.

  20. p-Hydroxy benzoic acid-conjugated dendrimer nanotherapeutics as potential carriers for targeted drug delivery to brain: an in vitro and in vivo evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Swami, Rajan; Singh, Indu [National Institute of Pharmaceutical Education & Research (NIPER), Department of Pharmaceutics (India); Kulhari, Hitesh [CSIR-Indian Institute of Chemical Technology, Medicinal Chemistry & Pharmacology Division (India); Jeengar, Manish Kumar [National Institute of Pharmaceutical Education & Research (NIPER), Departmentof Pharmacology (India); Khan, Wahid, E-mail: wahid@niperhyd.ac.in; Sistla, Ramakrishna, E-mail: sistla@iict.res.in, E-mail: rksistla@yahoo.com [National Institute of Pharmaceutical Education & Research (NIPER), Department of Pharmaceutics (India)

    2015-06-15

    Dendrimers which are discrete nanostructures/nanoparticles are emerging as promising candidates for many nanomedicine applications. Ligand-conjugated dendrimer facilitate the delivery of therapeutics in a targeted manner. Small molecules such as p-hydroxyl benzoic acid (pHBA) were found to have high affinity for sigma receptors which are prominent in most parts of central nervous system and tumors. The aim of this study was to synthesize pHBA-dendrimer conjugates as colloidal carrier for site-specific delivery of practically water insoluble drug, docetaxel (DTX) to brain tumors and to determine its targeting efficiency. pHBA, a small molecule ligand was coupled to the surface amine groups of generation 4-PAMAM dendrimer via a carbodiimide reaction and loaded with DTX. The conjugation was confirmed by {sup 1}HNMR and FT-IR spectroscopy. In vitro release of drug from DTX-loaded pHBA-conjugated dendrimer was found to be less as compared to unconjugated dendrimers. The prepared drug delivery system exhibited good physico-chemical stability and decrease in hemolytic toxicity. Cell viability and cell uptake studies were performed against U87MG human glioblastoma cells and formulations exerted considerable anticancer effect than plain drug. Conjugation of dendrimer with pHBA significantly enhanced the brain uptake of DTX which was shown by the recovery of a higher percentage of the dose from the brain following administration of pHBA-conjugated dendrimers compared with unconjugated dendrimer or formulation in clinical use (Taxotere{sup ®}). Therefore, pHBA conjugated dendrimers could be an efficient delivery vehicle for the targeting of anticancer drugs to brain tumors.

  1. The effect of the molecular weight of hyaluronic acid on the physicochemical characterization of hyaluronic acid-curcumin conjugates and in vitro evaluation in glioma cells.

    Science.gov (United States)

    Tian, Cihui; Asghar, Sajid; Xu, Yurui; Chen, Zhipeng; Zhang, Mei; Huang, Lin; Ye, Junxiu; Ping, Qineng; Xiao, Yanyu

    2018-02-11

    In this study, a redox-sensitive glioma-targeting micelle system was designed to deliver curcumin (CUR) by conjugating it to hyaluronic acid (HA-s-s-CUR, HSC) via disulfide linkage. The effect of the molecular weight of HA on the physicochemical characteristics of HSC conjugates and their in vitro effects in glioma cells were also explored. These conjugates formed nano-scale micelles (209-926 nm) independently in aqueous solution. The micelles greatly increased the solubility of CUR and improved its stability, which is crucial for harnessing the therapeutic potential of this active molecule. The redox sensitivities of different HSC micelles were measured by using a dynamic light scattering method and in vitro release assay, which showed that the low (50 kDa) and medium molecular weight (200 kDa and 500 kD) HA-based conjugates were sensitive to GSH, whereas higher molecular weights (1000 kDa and 2000 kDa) did not show redox-sensitivity. Increased cytotoxicity and uptake of low and medium molecular weight-modified HSC conjugates by the glioma cells further confirmed that the sensitive micelles are more effective for intracellular drug delivery compared to the high molecular weight-modified HSC conjugates or the plain CUR. In summary, the molecular weight of HA affects the physicochemical attributes of HSC conjugates. Only HSC micelles made with HA molecules less than 500 kDa exhibit redox sensitivity. Copyright © 2018 Elsevier B.V. All rights reserved.

  2. A New Water-Soluble Nanomicelle Formed through Self-Assembly of Pectin-Curcumin Conjugates: Preparation, Characterization, and Anticancer Activity Evaluation.

    Science.gov (United States)

    Bai, Feng; Diao, Jiajing; Wang, Ying; Sun, Shixin; Zhang, Hongmei; Liu, Yunyun; Wang, Yanqing; Cao, Jian

    2017-08-16

    Curcumin is a dominating active component of Curcuma longa and has been studied widely because of its prominent biological activities. The extremely low aqueous solubility, stability, and bioavailability of curcumin limit its application in the field of medicine. In this study, we developed pectin-curcumin (PEC-CCM) conjugates that could self-assemble water-soluble nanomicelles in aqueous solution. The structure of PEC-CCM conjugates was characterized by ultraviolet-visible spectra, fluorescence spectra, Fourier transform infrared spectroscopy, and (1)H nuclear magnetic resonance spectroscopy. The thermal property of PEC-CCM conjugates was investigated by thermogravimetric analysis. It was found that PEC-CCM conjugates had formed nanomicelles in aqueous medium via self-assembly. These nanomicelles were observed as small spheres or ellipsoids and aggregated with a size range of 70-190 nm by transmission electron microscopy analysis. In a solution of nanomicelles, the stability of curcumin was improved, and its antioxidant property was preserved. The anticancer activity of PEC-CCM conjugates was quantified by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay using a hepatic cancer cell line (HepG2), a breast cancer cell line (MCF-7), a cervical cancer cell line (HeLa), and a human normal kidney cell line (293A). It was found that the curcumin of PEC-CCM conjugates had a more significant inhibitory effect on cancer cells and was less cytotoxic to normal cells than free curcumin was. PEC-CCM conjugates have great potential for some food and pharmaceutical applications.

  3. 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...... or tetrathiomolybdate may be more suitable alternatives today. In copper-toxicity, a free radical scavenger might be recommended as adjuvant to the chelator therapy...

  4. Conjugate Gaze Palsies

    Science.gov (United States)

    ... version Home Brain, Spinal Cord, and Nerve Disorders Cranial Nerve Disorders Conjugate Gaze Palsies Horizontal gaze palsy Vertical ... Version. DOCTORS: Click here for the Professional Version Cranial Nerve Disorders Overview of the Cranial Nerves Internuclear Ophthalmoplegia ...

  5. Polymers for Protein Conjugation

    Directory of Open Access Journals (Sweden)

    Gianfranco Pasut

    2014-01-01

    Full Text Available Polyethylene glycol (PEG at the moment is considered the leading polymer for protein conjugation in view of its unique properties, as well as to its low toxicity in humans, qualities which have been confirmed by its extensive use in clinical practice. Other polymers that are safe, biodegradable and custom-designed have, nevertheless, also been investigated as potential candidates for protein conjugation. This review will focus on natural polymers and synthetic linear polymers that have been used for protein delivery and the results associated with their use. Genetic fusion approaches for the preparation of protein-polypeptide conjugates will be also reviewed and compared with the best known chemical conjugation ones.

  6. Qualidade conjugal: mapeando conceitos

    Directory of Open Access Journals (Sweden)

    Clarisse Mosmann

    2006-12-01

    Full Text Available Apesar da ampla utilização do conceito de qualidade conjugal, identifica-se falta de clareza conceitual acerca das variáveis que o compõem. Esse artigo apresenta revisão da literatura na área com o objetivo de mapear o conceito de qualidade conjugal. Foram analisadas sete principais teorias sobre o tema: Troca Social, Comportamental, Apego, Teoria da Crise, Interacionismo Simbólico. Pelos postulados propostos nas diferentes teorias, podem-se identificar três grupos de variáveis fundamentais na definição da qualidade conjugal: recursos pessoais dos cônjuges, contexto de inserção do casal e processos adaptativos. Neste sentido, a qualidade conjugal é resultado do processo dinâmico e interativo do casal, razão deste caráter multidimensional.

  7. Hydroxypyridinone and 5-Aminolaevulinic Acid Conjugates for Photodynamic Therapy.

    Science.gov (United States)

    Battah, Sinan; Hider, Robert C; MacRobert, Alexander J; Dobbin, Paul S; Zhou, Tao

    2017-04-27

    Photodynamic therapy (PDT) is a promising treatment strategy for malignant and nonmalignant lesions. 5-Aminolaevulinic acid (ALA) is used as a precursor of the photosensitizer, protoporphyrin IX (PpIX), in dermatology and urology. However, the effectiveness of ALA-PDT is limited by the relatively poor bioavailability of ALA and rapid conversion of PpIX to haem. The main goal of this study was to prepare and investigate a library of single conjugates designed to coadminister the bioactive agents ALA and hydroxypyridinone (HPO) iron chelators. A significant increase in intracellular PpIX levels was observed in all cell lines tested when compared to the administration of ALA alone. The higher PpIX levels observed using the conjugates correlated well with the observed phototoxicity following exposure of cells to light. Passive diffusion appears to be the main mechanism for the majority of ALA-HPOs investigated. This study demonstrates that ALA-HPOs significantly enhance phototherapeutic metabolite formation and phototoxicity.

  8. MYELODYSPLASTIC SYNDROMES AND IRON CHELATION THERAPY

    Directory of Open Access Journals (Sweden)

    Emanuele Angelucci

    2017-03-01

    Full Text Available Over recent decades we have been fortunate to witness the advent of new technologies and of an expanded knowledge and application of chelation therapies to the benefit of patients with iron overload. However, extrapolation of learnings from thalassemia to the myelodysplastic syndromes (MDS has resulted in a fragmented and uncoordinated clinical evidence base. We’re therefore forced to change our understanding of MDS, looking with other eyes to observational studies that inform us about the relationship between iron and tissue damage in these subjects. The available evidence suggests that iron accumulation is prognostically significant in MDS, but levels of accumulation historically associated with organ damage (based on data generated in the thalassemias are infrequent. Emerging experimental data have provided some insight into this paradox, as our understanding of iron-induced tissue damage has evolved from a process of progressive bulking of organs through high-volumes iron deposition, to one of ‘toxic’ damage inflicted through multiple cellular pathways. Damage from iron may therefore occur prior to reaching reference thresholds, and similarly, chelation may be of benefit before overt iron overload is seen. In this review, we revisit the science and clinical evidence for iron overload in MDS to better characterise the iron overload phenotype in these patients, which is distinct from the classical transfusional and non-transfusional iron overload syndrome. We hope this will provide a conceptual framework to better understand the complex associations between anemia, iron and clinical outcomes, to accelerate progress in this area.

  9. New Chelators for Low Temperature Al(18)F-Labeling of Biomolecules.

    Science.gov (United States)

    Cleeren, Frederik; Lecina, Joan; Billaud, Emilie M F; Ahamed, Muneer; Verbruggen, Alfons; Bormans, Guy M

    2016-03-16

    The Al(18)F labeling method is a relatively new approach that allows radiofluorination of biomolecules such as peptides and proteins in a one-step procedure and in aqueous solution. However, the chelation of the {Al(18)F}(2+) core with the macrocyclic chelators NOTA or NODA requires heating to 100-120 °C. Therefore, we have developed new polydentate ligands for the complexation of {Al(18)F}(2+) with good radiochemical yields at a temperature of 40 °C. The stability of the new Al(18)F-complexes was tested in phosphate buffered saline (PBS) at pH 7.4 and in rat serum. The stability of the Al(18)F-L3 complex was found to be comparable to that of the previously reported Al(18)F-NODA complex up to 60 min in rat serum. Moreover, the biodistribution of Al(18)F-L3 in healthy mice showed the absence of in vivo defluorination since no significant bone uptake was observed, whereas the major fraction of activity at 60 min p.i. was observed in liver and intestines, indicating hepatobiliary clearance of the radiolabeled ligand. The acyclic chelator H3L3 proved to be a good lead candidate for labeling of heat-sensitive biomolecules with fluorine-18. In order to obtain a better understanding of the different factors influencing the formation and stability of the complex, we carried out more in-depth experiments with ligand H3L3. As a proof of concept, we successfully conjugated the new AlF-chelator with the urea-based PSMA inhibitor Glu-NH-CO-NH-Lys to form Glu-NH-CO-NH-Lys(Ahx)L3, and a biodistribution study in healthy mice was performed with the Al(18)F-labeled construct. This new class of AlF-chelators may have a great impact on PET radiochemical space as it will stimulate the rapid development of new fluorine-18 labeled peptides and other heat-sensitive biomolecules.

  10. {sup 99m}Tc(CO){sub 3}-DTMA bombesin conjugates having high affinity for the GRP receptor

    Energy Technology Data Exchange (ETDEWEB)

    Lane, Stephanie R. [Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201 (United States); Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211 (United States); Veerendra, Bhadrasetty [Department of Radiology, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States); Rold, Tammy L. [Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States); Sieckman, Gary L. [Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201 (United States); Hoffman, Timothy J. [Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201 (United States); Radiopharmaceutical Sciences Institute, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States); Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211 (United States); Jurisson, Silvia S. [Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211 (United States); Smith, Charles J. [Department of Radiology, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States); Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201 (United States); University of Missouri Research Reactor Center, University of Missouri-Columbia, Columbia, MO 65211 (United States); Radiopharmaceutical Sciences Institute, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States)], E-mail: smithcj@health.missouri.edu

    2008-04-15

    Introduction: Targeted diagnosis of specific human cancer types continues to be of significant interest in nuclear medicine. {sup 99m}Tc is ideally suited as a diagnostic radiometal for in vivo tumor targeting due to its ideal physical characteristics and diverse labeling chemistries in numerous oxidation states. Methods: In this study, we report a synthetic approach toward design of a new tridentate amine ligand for the organometallic aqua-ion [{sup 99m}Tc(H{sub 2}O){sub 3}(CO){sub 3}]{sup +}. The new chelating ligand framework, 2-(N,N'-Bis(tert-butoxycarbonyl)diethylenetriamine) acetic acid (DTMA), was synthesized from a diethylenetriamine precursor and fully characterized by mass spectrometry and nuclear magnetic resonance spectroscopy ({sup 1}H and {sup 13}C). DTMA was conjugated to H{sub 2}N-(X)-BBN(7-14)NH{sub 2}, where X=an amino acid or aliphatic pharmacokinetic modifier and BBN=bombesin peptide, by means of solid phase peptide synthesis. DTMA-(X)-BBN(7-14)NH{sub 2} conjugates were purified by reversed-phase high-performance chromatography and characterized by electrospray-ionization mass spectrometry. Results: The new conjugates were radiolabeled with [{sup 99m}Tc(H{sub 2}O){sub 3}(CO){sub 3}]{sup +} produced via Isolink radiolabeling kits to produce [{sup 99m}Tc(CO){sub 3}-DTMA-(X)-BBN(7-14)NH{sub 2}]. Radiolabeled conjugates were purified by reversed-phase high-performance chromatography. Effective receptor binding behavior was evaluated in vitro and in vivo. Conclusions: [{sup 99m}Tc(CO){sub 3}-DTMA-(X)-BBN(7-14)NH{sub 2}] conjugates displayed very high affinity for the gastrin releasing peptide receptor in vitro and in vivo. Therefore, these conjugates hold some propensity to be investigated as molecular imaging agents that specifically target human cancers uniquely expressing the gastrin releasing peptide receptor subtypes.

  11. Design, Synthesis, and Antimicrobial Evaluation of a Novel Bone-Targeting Bisphosphonate-Ciprofloxacin Conjugate for the Treatment of Osteomyelitis Biofilms.

    Science.gov (United States)

    Sedghizadeh, Parish P; Sun, Shuting; Junka, Adam F; Richard, Eric; Sadrerafi, Keivan; Mahabady, Susan; Bakhshalian, Neema; Tjokro, Natalia; Bartoszewicz, Marzenna; Oleksy, Monika; Szymczyk, Patrycja; Lundy, Mark W; Neighbors, Jeffrey D; Russell, R Graham G; McKenna, Charles E; Ebetino, Frank H

    2017-03-23

    Osteomyelitis is a major problem worldwide and is devastating due to the potential for limb-threatening sequelae and mortality. Osteomyelitis pathogens are bone-attached biofilms, making antibiotic delivery challenging. Here we describe a novel osteoadsorptive bisphosphonate-ciprofloxacin conjugate (BV600022), utilizing a "target and release" chemical strategy, which demonstrated a significantly enhanced therapeutic index versus ciprofloxacin for the treatment of osteomyelitis in vivo. In vitro antimicrobial susceptibility testing of the conjugate against common osteomyelitis pathogens revealed an effective bactericidal profile and sustained release of the parent antibiotic over time. Efficacy and safety were demonstrated in an animal model of periprosthetic osteomyelitis, where a single dose of 10 mg/kg (15.6 μmol/kg) conjugate reduced the bacterial load by 99% and demonstrated nearly an order of magnitude greater activity than the parent antibiotic ciprofloxacin (30 mg/kg, 90.6 μmol/kg) given in multiple doses. Conjugates incorporating a bisphosphonate and an antibiotic for bone-targeted delivery to treat osteomyelitis biofilm pathogens constitute a promising approach to providing high bone-antimicrobial potency while minimizing systemic exposure.

  12. Site-Selective Conjugation of Native Proteins with DNA.

    Science.gov (United States)

    Trads, Julie B; Tørring, Thomas; Gothelf, Kurt V

    2017-06-20

    Conjugation of DNA to proteins is increasingly used in academia and industry to provide proteins with tags for identification or handles for hybridization to other DNA strands. Assay technologies such as immuno-PCR and proximity ligation and the imaging technology DNA-PAINT require DNA-protein conjugates. In DNA nanotechnology, the DNA handle is exploited to precisely position proteins by self-assembly. For these applications, site-selective conjugation is almost always desired because fully functional proteins are required to maintain the specificity of antibodies and the activity of enzymes. The introduction of a bioorthogonal handle at a specific position of a protein by recombinant techniques provides an excellent approach to site-specific conjugation, but for many laboratories and for applications where several proteins are to be labeled, the expression of recombinant proteins may be cumbersome. In recent years, a number of chemical methods that target conjugation to specific sites at native proteins have become available, and an overview of these methods is provided in this Account. Our laboratory has investigated DNA-templated protein conjugation (DTPC), which offers an alternative approach to site-selective conjugation of DNA to proteins. The method is inspired by the concept of DNA-templated synthesis where functional groups conjugated to DNA strands are preorganized by DNA hybridization to dramatically increase the reaction rate. In DPTC, we target metal binding sites in proteins to template selective covalent conjugation reactions. By chelation of a DNA-metal complex with a metal binding site of the protein, an electrophile on a second DNA strand is aligned for reaction with a lysine side chain on the protein in the proximity of the metal binding site. The method is quite general because approximately one-third of all wild-type proteins contain metal-binding sites, including many IgG antibodies, and it is also applicable to His-tagged proteins. This

  13. A chelating dendritic ligand capped quantum dot: preparation, surface passivation, bioconjugation and specific DNA detection

    Science.gov (United States)

    Zhou, Dejian; Li, Yang; Hall, Elizabeth A. H.; Abell, Chris; Klenerman, David

    2011-01-01

    Herein we report the synthesis of a new chelating dendritic ligand (CDL) and its use in the preparation a compact, stable and water-soluble quantum dot (QD), and further development of specific DNA sensor. The CDL, which contains a chelative dihydrolipoic acid moiety for strong QD surface anchoring and four dendritic carboxylic acidgroups, provides a stable, compact and entangled hydrophilic coating around the QD that significantly increases the stability of the resulting water-soluble QD. A CDL-capped CdSe/ZnS core/shell QD (CDL-QD) has stronger fluorescence than that capped by a monodendate single-chain thiol, 3-mercapto-propionic acid (MPA-QD). In addition, the fluorescence of the CDL-QD can be enhanced by 2.5-fold by treatments with Zn2+ or S2- ions, presumably due to effective passivation of the surface defects. This level of fluorescence enhancement obtained for the CDL-QD is much greater than that for the MPA-QD. Further, by coupling a short single-stranded DNA target to the QD via the CDL carboxylic acidgroup, a functional QD-DNA conjugate that can resist non-specific adsorption and hybridize quickly to its complementary DNAprobe has been obtained. This functional QD-DNA conjugate is suitable for specific quantification of short, labelled complementary probes at the low DNAprobe:QD copy numbers via a QD-sensitised dyefluorescence resonance energy transfer (FRET) response with 500 pM sensitivity on a conventional fluorimeter.Herein we report the synthesis of a new chelating dendritic ligand (CDL) and its use in the preparation a compact, stable and water-soluble quantum dot (QD), and further development of specific DNA sensor. The CDL, which contains a chelative dihydrolipoic acid moiety for strong QD surface anchoring and four dendritic carboxylic acidgroups, provides a stable, compact and entangled hydrophilic coating around the QD that significantly increases the stability of the resulting water-soluble QD. A CDL-capped CdSe/ZnS core/shell QD (CDL-QD) has

  14. Potentials and drawbacks of chelate-enhanced phytoremediation of soils

    NARCIS (Netherlands)

    Römkens, P.F.A.M.; Bouwman, L.A.; Japenga, J.; Draaisma, C.

    2002-01-01

    Chelate-enhanced phytoremediation has been proposed as an effective tool for the extraction of heavy metals from soils by plants. However, side-effects related to the addition of chelates, e.g. metal leaching and effects on soil micro-organisms, were usually neglected. Therefore, greenhouse and

  15. Chelated ruthenium catalysts for Z-selective olefin metathesis.

    Science.gov (United States)

    Endo, Koji; Grubbs, Robert H

    2011-06-08

    We report the development of ruthenium-based metathesis catalysts with chelating N-heterocyclic carbene (NHC) ligands that catalyze highly Z-selective olefin metathesis. A very simple and convenient procedure for the synthesis of such catalysts has been developed. Intramolecular C-H bond activation of the NHC ligand, promoted by anion ligand substitution, forms the appropriate chelate for stereocontrolled olefin metathesis.

  16. Chelation Treatment for Autism Spectrum Disorders: A Systematic Review

    Science.gov (United States)

    Davis, Tonya N.; O'Reilly, Mark; Kang, Soyeon; Lang, Russell; Rispoli, Mandy; Sigafoos, Jeff; Lancioni, Giulio; Copeland, Daelynn; Attai, Shanna; Mulloy, Austin

    2013-01-01

    Chelation treatment is used to eliminate specific metals from the body, such as mercury. It has been hypothesized that mercury poisoning may be a factor in autism and data suggest that perhaps 7% of individuals with autism spectrum disorder (ASD) have received chelation treatment. It would therefore seem timely to review studies investigating the…

  17. Quantitative measurement of metal chelation by fourier transform infrared spectroscopy

    Directory of Open Access Journals (Sweden)

    Monika E. Miller

    2015-12-01

    Full Text Available Nutritionally important minerals are more readily absorbed by living systems when complexed with organic acids, resulting in higher consumer demand and premium prices for these products. These chelated metals are produced by reaction of metal oxides and acids in aqueous solution. However, unreacted dry blends are sometimes misrepresented as metal chelates, when in reality they are only simple mixtures of the reactants typically used to synthesize them. This practice has increased interest in developing analytical methods that are capable of measuring the extent of metal chelation for quality control and regulatory compliance. We describe a novel method to rapidly measure the percent chelation of citric and malic acids with calcium, magnesium, and zinc. Utilization of attenuated total reflectance (FTIR-ATR provides for the direct, rapid measurement of solid samples. The inclusion of an internal standard allows independent determination of either free or chelated acids from integrated areas in a single spectrum.

  18. Treating Lead Toxicity: Possibilities beyond Synthetic Chelation

    Directory of Open Access Journals (Sweden)

    Shambhavi Tannir

    2013-01-01

    Full Text Available Lead, a ubiquitous metal, is one of the most abundant elements present on earth. Its easy availability and cost effectiveness made it an extremely popular component in the industrial revolution. However, its hazardous health effects were not considered at the time. Over the last few decades, with the adverse effects of lead coming to the forefront, nations across the world have started to recognize and treat lead toxicity. The most reliable and used method until now has been chelation therapy. Recent research has suggested the use of natural products and sources to treat lead poisoning with minimal or no side effects. This review has tried to summarize a few of the natural products/sources being investigated by various groups.

  19. Double conjugate laser amplifier

    Energy Technology Data Exchange (ETDEWEB)

    Chandra, S.; Daunt, G.H.

    1991-01-29

    This paper describes a double conjugate laser amplifier system for producing a stable output laser beam in line with a laser oscillator input beam. It comprises: a laser oscillator which produces a low energy oscillator laser beam therefrom directly along a laser beam axis of the system; an amplification means comprised of double conjugate laser amplifiers further comprised of a first and a second singly phase conjugate amplifiers laterally opposite each other about the laser beam axis; polarizers with one of the polarizers positioned between each of the first and second singly phase conjugate amplifiers on the laser beam axis; Pockels cells with on of the Pockels cells positioned on the laser beam axis immediately prior to one of the polarizers; and a means for selectively switching the amplifier means comprised of applying a half-wave voltage at each of the Pockels cells to provide a polarization rotation of the input beam through 90{degrees} for routing of the oscillator laser beam directly through or reflected off the polarizes as an input beam to the amplification means wherein the amplification means amplifies the input beam twice in each of the first and second singly phase conjugate amplifiers and reflects the amplified laser beam off the polarizers as an amplified laser output beam in exactly the same direction as the input laser beam.

  20. Conjugates of Superoxide Dismutase 1 with Amphiphilic Poly(2-oxazoline) Block Copolymers for Enhanced Brain Delivery: Synthesis, Characterization and Evaluation in Vitro and in Vivo

    KAUST Repository

    Tong, Jing

    2013-01-07

    Superoxide dismutase 1 (SOD1) efficiently catalyzes dismutation of superoxide, but its poor delivery to the target sites in the body, such as brain, hinders its use as a therapeutic agent for superoxide-associated disorders. Here to enhance the delivery of SOD1 across the blood-brain barrier (BBB) and in neurons the enzyme was conjugated with poly(2-oxazoline) (POx) block copolymers, P(MeOx-b-BuOx) or P(EtOx-b-BuOx), composed of (1) hydrophilic 2-methyl-2-oxazoline (MeOx) or 2-ethyl-2-oxazoline (EtOx) and (2) hydrophobic 2-butyl-2-oxazoline (BuOx) repeating units. The conjugates contained from 2 to 3 POx chains joining the protein amino groups via cleavable -(ss)- or noncleavable -(cc)- linkers at the BuOx block terminus. They retained 30% to 50% of initial SOD1 activity, were conformationally and thermally stable, and assembled in 8 or 20 nm aggregates in aqueous solution. They had little if any toxicity to CATH.a neurons and displayed enhanced uptake in these neurons as compared to native or PEGylated SOD1. Of the two conjugates, SOD1-(cc)-P(MeOx-b-BuOx) and SOD1-(cc)-P(EtOx-b-BuOx), compared, the latter was entering cells 4 to 7 times faster and at 6 h colocalized predominantly with endoplasmic reticulum (41 ± 3%) and mitochondria (21 ± 2%). Colocalization with endocytosis markers and pathway inhibition assays suggested that it was internalized through lipid raft/caveolae, also employed by the P(EtOx-b-BuOx) copolymer. The SOD activity in cell lysates and ability to attenuate angiotensin II (Ang II)-induced superoxide in live cells were increased for this conjugate compared to SOD1 and PEG-SOD1. Studies in mice showed that SOD1-POx had ca. 1.75 times longer half-life in blood than native SOD1 (28.4 vs 15.9 min) and after iv administration penetrated the BBB significantly faster than albumin to accumulate in brain parenchyma. The conjugate maintained high stability both in serum and in brain (77% vs 84% at 1 h postinjection). Its amount taken up by the brain

  1. Chelating ionic liquids for reversible zinc electrochemistry.

    Science.gov (United States)

    Kar, Mega; Winther-Jensen, Bjorn; Forsyth, Maria; MacFarlane, Douglas R

    2013-05-21

    Advanced, high energy-density, metal-air rechargeable batteries, such as zinc-air, are of intense international interest due to their important role in energy storage applications such as electric and hybrid vehicles, and to their ability to deal with the intermittency of renewable energy sources such as solar and wind. Ionic liquids offer a number of ideal thermal and physical properties as potential electrolytes in such large-scale energy storage applications. We describe here the synthesis and characterisation of a family of novel "chelating" ILs designed to chelate and solubilize the zinc ions to create electrolytes for this type of battery. These are based on quaternary alkoxy alkyl ammonium cations of varying oligo-ether side chains and anions such as p-toluene sulfonate, bis(trifluoromethylsulfonyl)amide and dicyanoamides. This work shows that increasing the ether chain length in the cation from two to four oxygens can increase the ionic conductivity and reduce the melting point from 67 °C to 15 °C for the tosylate system. Changing the anion also plays a significant role in the nature of the zinc deposition electrochemistry. We show that zinc can be reversibly deposited from [N(222(20201))][NTf2] and [N(222(202020201))][NTf2] beginning at -1.4 V and -1.7 V vs. SHE, respectively, but not in the case of tosylate based ILs. This indicates that the [NTf2] is a weaker coordinating anion with the zinc cation, compared to the tosylate anion, allowing the coordination of the ether chain to dominate the behavior of the deposition and stripping of zinc ions.

  2. Fixation kinetics of chelated and non-chelated zinc in semi-arid alkaline soils: application to zinc management

    Science.gov (United States)

    Udeigwe, Theophilus K.; Eichmann, Madeleine; Menkiti, Matthew C.

    2016-07-01

    This study was designed to examine the fixation pattern and kinetics of zinc (Zn) in chelated (ethylenediaminetetraacetic acid, EDTA) and non-chelated mixed micronutrient systems of semi-arid alkaline soils from the Southern High Plains, USA. Soils were characterized for a suite of chemical and physical properties and data obtained from extraction experiments fitted to various kinetic models. About 30 % more plant-available Zn was fixed in the non-chelated system within the first 14 days with only about 18 % difference observed between the two systems by day 90, suggesting that the effectiveness of the chelated compounds tended to decrease over time. The strengths of the relationships of change in available Zn with respect to other micronutrients (copper, iron, and manganese) were higher and more significant in the non-chelated system (average R2 of 0.83), compared to the chelated (average R2 of 0.42). Fixation of plant-available Zn was best described by the power-function model (R2 = 0.94, SE = 0.076) in the non-chelated system, and was poorly described by all the models examined in the chelated system. Reaction rate constants and relationships generated from this study can serve as important tools for micronutrient management and for future micronutrient modeling studies on these soils and other semi-arid regions of the world.

  3. Hyperbranched-dendrimer architectural copolymer gene delivery using hyperbranched PEI conjugated to poly(propyleneimine) dendrimers: synthesis, characterization, and evaluation of transfection efficiency

    Science.gov (United States)

    Alavi, Seyyed Jamal; Gholami, Leila; Askarian, Saeedeh; Darroudi, Majid; Massoudi, Abdolhossein; Rezaee, Mehdi; Kazemi Oskuee, Reza

    2017-02-01

    The applications of dendrimer-based vectors seem to be promising in non-viral gene delivery because of their potential for addressing the problems with viral vectors. In this study, generation 3 poly(propyleneimine) (G3-PPI) dendrimers with 1, 4-diaminobutane as a core initiator was synthesized using a divergent growth approach. To increase the hydrophobicity and reduce toxicity, 10% of primary amines of G3-PPI dendrimers were replaced with bromoalkylcarboxylates with different chain lengths (6-bromohexanoic and 10-bromodecanoic). Then, to retain the overall buffering capacity and enhance transfection, the alkylcarboxylate-PPIs were conjugated to 10 kDa branched polyethylenimine (PEI). The results showed that the modified PPI was able to form complexes with the diameter of less than 60 nm with net-positive surface charge around 20 mV. No significant toxicity was observed in modified PPIs; however, the hexanoate conjugated PPI-PEI (PPI-HEX-10% PEI) and the decanoate conjugated PPI-PEI (PPI-DEC-10%-PEI) showed the best transfection efficiency in murine neuroblastoma (Neuro-2a) cell line, even PPI-HEX-10%-PEI showed transfection efficiency equal to standard PEI 25 kDa with reduced toxicity. This study suggested a new series of hyperbranched (PEI)-dendrimer (PPI) architectural copolymers as non-viral gene delivery vectors with high transfection efficiency and low toxicity.

  4. Hyperbranched–dendrimer architectural copolymer gene delivery using hyperbranched PEI conjugated to poly(propyleneimine) dendrimers: synthesis, characterization, and evaluation of transfection efficiency

    Energy Technology Data Exchange (ETDEWEB)

    Alavi, Seyyed Jamal [Ferdowsi University of Mashhad, Department of Chemistry, Faculty of Science (Iran, Islamic Republic of); Gholami, Leila [Mashhad University of Medical Sciences, Department of Modern Sciences and Technologies, School of Medicine (Iran, Islamic Republic of); Askarian, Saeedeh [Mashhad University of Medical Sciences, Department of Medical Biotechnology, School of Medicine (Iran, Islamic Republic of); Darroudi, Majid [Mashhad University of Medical Sciences, Nuclear Medicine Research Center (Iran, Islamic Republic of); Massoudi, Abdolhossein [University of Payam noor, Department of Chemistry (Iran, Islamic Republic of); Rezaee, Mehdi; Kazemi Oskuee, Reza, E-mail: Oskueekr@mums.ac.ir [Mashhad University of Medical Sciences, Department of Medical Biotechnology, School of Medicine (Iran, Islamic Republic of)

    2017-02-15

    The applications of dendrimer-based vectors seem to be promising in non-viral gene delivery because of their potential for addressing the problems with viral vectors. In this study, generation 3 poly(propyleneimine) (G3-PPI) dendrimers with 1, 4-diaminobutane as a core initiator was synthesized using a divergent growth approach. To increase the hydrophobicity and reduce toxicity, 10% of primary amines of G3-PPI dendrimers were replaced with bromoalkylcarboxylates with different chain lengths (6-bromohexanoic and 10-bromodecanoic). Then, to retain the overall buffering capacity and enhance transfection, the alkylcarboxylate–PPIs were conjugated to 10 kDa branched polyethylenimine (PEI). The results showed that the modified PPI was able to form complexes with the diameter of less than 60 nm with net-positive surface charge around 20 mV. No significant toxicity was observed in modified PPIs; however, the hexanoate conjugated PPI–PEI (PPI-HEX-10% PEI) and the decanoate conjugated PPI–PEI (PPI-DEC-10%-PEI) showed the best transfection efficiency in murine neuroblastoma (Neuro-2a) cell line, even PPI-HEX-10%-PEI showed transfection efficiency equal to standard PEI 25 kDa with reduced toxicity. This study suggested a new series of hyperbranched (PEI)–dendrimer (PPI) architectural copolymers as non-viral gene delivery vectors with high transfection efficiency and low toxicity.

  5. Synthesis, characterization and in vitro evaluation of methotrexate conjugated fluorescent carbon nanoparticles as drug delivery system for human lung cancer targeting.

    Science.gov (United States)

    Ajmal, Muhammad; Yunus, Uzma; Matin, Abdul; Haq, Noaman Ul

    2015-12-01

    Nanotechnology based cancer therapeutics have rapidly advanced towards the solution of many limitations associated with other drug delivery agents such as nonspecific distribution within the body, low water solubility and non-biocompatibility. Carbon nanoparticles have demonstrated unique properties that are useful to combat with these issues, including their properties dependent on size, high stability in different solvents, compatible size for drug delivery and ease of surface modifications. Fluorescent carbon nanoparticles with good water solubility were obtained from a carbohydrate source by acid assisted ultrasonic treatment at 35kHz for 4h. This simple and economical method can be used for large scale production. Electron microscopic, spectroscopic and thermo gravimetric analysis techniques were used to characterize these carbon nanoparticles. Functionalized CNPs were further conjugated with anticancer drug-methotrexate and used as fluorescent nano-carriers. In this research work, we determined the in vitro bioactivity of CNPs-methotrexate conjugates by lactate dehydrogenase assay, cell adhesion assay and sulforhodamine B assay in human lung carcinoma cell line (H157). The CNPs showed promising biocompatibility and CNPs-MTX conjugates demonstrated potent cytotoxic effects and high anticancer activities in human lung cancer cell line. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Comparison of the octadentate bifunctional chelator DFO*-pPhe-NCS and the clinically used hexadentate bifunctional chelator DFO-pPhe-NCS for {sup 89}Zr-immuno-PET

    Energy Technology Data Exchange (ETDEWEB)

    Vugts, Danielle J.; Klaver, Chris; Sewing, Claudia; Poot, Alex J.; Adamzek, Kevin; Visser, Gerard W.M.; Dongen, Guus A.M.S. van [VU University Medical Center, Department of Radiology and Nuclear Medicine, Amsterdam (Netherlands); Huegli, Seraina; Mari, Cristina; Gasser, Gilles [University of Zurich, Department of Chemistry, Zurich (Switzerland); Valverde, Ibai E. [University of Basel Hospital, Division of Radiopharmaceutical Chemistry, Basel (Switzerland); Mindt, Thomas L. [Institute of Pharmaceutical Sciences, ETH Zurich, Zurich (Switzerland); General Hospital of Vienna, Ludwig Boltzmann Institute for Applied Diagnostics, Vienna (Austria)

    2017-02-15

    All clinical {sup 89}Zr-immuno-PET studies are currently performed with the chelator desferrioxamine (DFO). This chelator provides hexadentate coordination to zirconium, leaving two coordination sites available for coordination with, e.g., water molecules, which are relatively labile ligands. The unsaturated coordination of DFO to zirconium has been suggested to result in impaired stability of the complex in vivo and consequently in unwanted bone uptake of {sup 89}Zr. Aiming at clinical improvements, we report here on a bifunctional isothiocyanate variant of the octadentate chelator DFO* and the in vitro and in vivo comparison of its {sup 89}Zr-DFO*-mAb complex with {sup 89}Zr-DFO-mAb. The bifunctional chelator DFO*-pPhe-NCS was prepared from previously reported DFO* and p-phenylenediisothiocyanate. Subsequently, trastuzumab was conjugated with either DFO*-pPhe-NCS or commercial DFO-pPhe-NCS and radiolabeled with Zr-89 according to published procedures. In vitro stability experiments were carried out in saline, a histidine/sucrose buffer, and blood serum. The in vivo performance of the chelators was compared in N87 tumor-bearing mice by biodistribution studies and PET imaging. In 0.9 % NaCl {sup 89}Zr-DFO*-trastuzumab was more stable than {sup 89}Zr-DFO-trastuzumab; after 72 h incubation at 2-8 C 95 % and 58 % intact tracer were left, respectively, while in a histidine-sucrose buffer no difference was observed, both products were ≥ 92 % intact. In vivo uptake at 144 h post injection (p.i.) in tumors, blood, and most normal organs was similar for both conjugates, except for skin, liver, spleen, ileum, and bone. Tumor uptake was 32.59 ± 11.95 and 29.06 ± 8.66 % ID/g for {sup 89}Zr-DFO*-trastuzumab and {sup 89}Zr-DFO-trastuzumab, respectively. The bone uptake was significantly lower for {sup 89}Zr-DFO*-trastuzumab compared to {sup 89}Zr-DFO-trastuzumab. At 144 h p.i. for {sup 89}Zr-DFO*-trastuzumab and {sup 89}Zr-DFO-trastuzumab, the uptake in sternum was 0.92

  7. Order of amino acids in C-terminal cysteine-containing peptide-based chelators influences cellular processing and biodistribution of 99mTc-labeled recombinant Affibody molecules.

    Science.gov (United States)

    Altai, Mohamed; Wållberg, Helena; Orlova, Anna; Rosestedt, Maria; Hosseinimehr, Seyed Jalal; Tolmachev, Vladimir; Ståhl, Stefan

    2012-05-01

    Affibody molecules constitute a novel class of molecular display selected affinity proteins based on non-immunoglobulin scaffold. Preclinical investigations and pilot clinical data have demonstrated that Affibody molecules provide high contrast imaging of tumor-associated molecular targets shortly after injection. The use of cysteine-containing peptide-based chelators at the C-terminus of recombinant Affibody molecules enabled site-specific labeling with the radionuclide 99mTc. Earlier studies have demonstrated that position, composition and the order of amino acids in peptide-based chelators influence labeling stability, cellular processing and biodistribution of Affibody molecules. To investigate the influence of the amino acid order, a series of anti-HER2 Affibody molecules, containing GSGC, GEGC and GKGC chelators have been prepared and characterized. The affinity to HER2, cellular processing of 99mTc-labeled Affibody molecules and their biodistribution were investigated. These properties were compared with that of the previously studied 99mTc-labeled Affibody molecules containing GGSC, GGEC and GGKC chelators. All variants displayed picomolar affinities to HER2. The substitution of a single amino acid in the chelator had an appreciable influence on the cellular processing of 99mTc. The biodistribution of all 99mTc-labeled Affibody molecules was in general comparable, with the main difference in uptake and retention of radioactivity in excretory organs. The hepatic accumulation of radioactivity was higher for the lysine-containing chelators and the renal retention of 99mTc was significantly affected by the amino acid composition of chelators. The order of amino acids influenced renal uptake of some conjugates at 1 h after injection, but the difference decreased at later time points. Such information can be helpful for the development of other scaffold protein-based imaging and therapeutic radiolabeled conjugates.

  8. 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.

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

    Science.gov (United States)

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

    2018-01-02

    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.

  10. DNA-cell conjugates

    Science.gov (United States)

    Hsiao, Shih-Chia; Francis, Matthew B.; Bertozzi, Carolyn; Mathies, Richard; Chandra, Ravi; Douglas, Erik; Twite, Amy; Toriello, Nicholas; Onoe, Hiroaki

    2016-05-03

    The present invention provides conjugates of DNA and cells by linking the DNA to a native functional group on the cell surface. The cells can be without cell walls or can have cell walls. The modified cells can be linked to a substrate surface and used in assay or bioreactors.

  11. Conjugate Meningococcal Vaccines Development: GSK Biologicals Experience

    Directory of Open Access Journals (Sweden)

    Jacqueline M. Miller

    2011-01-01

    Full Text Available Meningococcal diseases are serious threats to global health, and new vaccines specifically tailored to meet the age-related needs of various geographical areas are required. This paper focuses on the meningococcal conjugate vaccines developed by GSK Biologicals. Two combined conjugate vaccines were developed to help protect infants and young children in countries where the incidence of meningococcal serogroup C or serogroup C and Y disease is important: Hib-MenC-TT vaccine, which offers protection against Haemophilus influenzae type b and Neisseria meningitidis serogroup C diseases, is approved in several countries; and Hib-MenCY-TT vaccine, which adds N. meningitidis serogroup Y antigen, is currently in the final stages of development. Additionally, a tetravalent conjugate vaccine (MenACWY-TT designed to help protect against four meningococcal serogroups is presently being evaluated for global use in all age groups. All of these vaccines were shown to be highly immunogenic and to have clinically acceptable safety profiles.

  12. [Evaluation of safety of haemophilus influenza type b(Hib) conjugate vaccine in postmarketing based on the immunization information management system].

    Science.gov (United States)

    Wang, Zhiguo; Ma, Fubao; Zhang, Jinlin; Yu, Jing; Kang, Guodong; Gao, Jun

    2015-06-01

    To analyze the occurrence feature of adverse events following immunization (AEFI) of Hib conjugate vaccine (HibCV) and to evaluate the safety of HibCV in postmarketing. 2008-2013 HibCV AEFI data were collected through national AEFI information management system, which were downloaded in March 18, 2014.The demographic information and inoculation quantity of HibCV were from Immunization information management system in Jiangsu province. The incidence rate and 95% CI value of AEFI, common vaccine reaction and rare vaccine reaction following immunization of HibCV were calculated. The differences in the incidence rate of common vaccine reaction and rare vaccine reaction among sex, months of age, and number of injections were compared by means of (χ² tests. A total of 6.16 million doses of vaccine were administered in Jiangsu province during 2008-2013, and 4 718 vaccinees reported having adverse event, for a rate of 76.60/100 000 (95% CI: 74.42/100 000-78.79/100 000). The incidence rate of common vaccine reaction and rare vaccine reaction was 71.10/100 000 (95% CI: 68.99/100 000-73.20/100 000) and 5.16/100 000 (95% CI: 4.60/100 000-5.73/100 000), respectively. The main symptoms of common vaccine reactions were fever, swelling, indurations and gastrointestinal reactions. The incidence rates of them were 40.54/100 000, 35.09/100 000, 12.94/100 000 and 0.36/100 000 in turn. The main symptoms of rare vaccine reactions were anaphylactic rashes and angioedema, the incidence rates of which were 4.77/100 000 and 0.15/100 000 respectively. 91.39% (4 002/4 379) of common vaccine reactions and 88.36% (281/318) of rare vaccine reactions happened within 1 d after vaccination. Anaphylactic shock (3 cases) and laryngeal edema (1 case) all happened within 1 d after vaccination. The incidence rate of common vaccine reactions among boys (79.72/100 000, 2 641/3 313 071) was higher than that of girls (61.07/100 000, 1 738/2 846 001) (χ² = 74.92, P < 0.001). The incidence rate of common

  13. Aminothiol multidentate chelators against Chagas disease.

    Science.gov (United States)

    Deharo, E; Loyevsky, M; John, C; Balanza, E; Ruiz, G; Muñoz, V; Gordeuk, V R

    2000-03-01

    Three compounds of an aminothiol family of iron chelators were examined for activity against trypomastigote (human) and epimastigote (vector) forms of Trypanosoma cruzi: tetraethyl and tetramethyl derivatives of ethane-1,2-bis (N-1-amino-3-ethyl butyl-3-thiol) (BAT-TE and BAT-TM) and N',N',N'-tris-(2-methyl-2-mercaptopriopyl)- 1,4,7-triazacyclonane (TAT). BAT-TE at 270 microM completely arrested the growth of trypomastigote forms in mouse blood stored at 4 degrees C for 24 h (IC(50) 67.7+/-7 microM), while BAT-TM arrested growth at 630 microM (IC(50) 158+/-17 microM) and TAT at concentrations >800 microM (IC(50) 415+/-55 microM). In T. cruzi-infected mice, BAT-TE and BAT-TM had no anti-trypanosomal activity in doses up to 200 mg/kg, whether the route of administration was intraperitoneal or oral, and TAT was not tested due to insufficient quantity. TAT had an IC(50) of 52+/-7 microM against the epimastigote forms while BAT-TM and BAT-TE were inhibitory only at concentrations >250 microM. The trypanocidal activity of BAT derivatives in blood stored at 4 degrees C makes these compounds potential candidates for the purpose of clearing donated blood of trypomastigotes. Copyright 2000 Academic Press.

  14. Chelation in metal intoxication XVI. Influence of chelating agents on chromate poisoned rats

    Energy Technology Data Exchange (ETDEWEB)

    Tandon, S.K.; Srivastava, L.

    1985-01-01

    The ability of selective polyaminocarboxylic acids and common drugs to reduce the body burden of chromium and restore Cr induced biochemical alterations in chromate intoxicated rats was investigated. 1,2 Cychlohexylene dinitrilotetraacetic acid (CDTA) and triethylenetetramine hexacetic acid (TTHA) were more effective than p-aminosalicylic acid (PAS) and isoniazid (INH) in enhancing urinary excretion of Cr, lowering hepatic and blood levels of Cr and restoring inhibited activity of hepatic aldolase. The chromate antidotal property of chelators seem to be related to the combination of nitrogen and oxygen as the electron donating centres.

  15. Chelation: Harnessing and Enhancing Heavy Metal Detoxification—A Review

    National Research Council Canada - National Science Library

    Sears, Margaret E

    2013-01-01

    .... 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...

  16. Comparing potential copper chelation mechanisms in Parkinson's disease protein

    Science.gov (United States)

    Rose, Frisco; Hodak, Miroslav; Bernholc, Jerry

    2011-03-01

    We have implemented the nudged elastic band (NEB) as a guided dynamics framework for our real-space multigrid method of DFT-based quantum simulations. This highly parallel approach resolves a minimum energy pathway (MEP) on the energy hypersurface by relaxing intermediates in a chain-of-states. As an initial application we present an investigation of chelating agents acting on copper ion bound to α -synuclein, whose misfolding is implicated in Parkinson's disease (PD). Copper ions are known to act as highly effective misfolding agents in a-synuclein and are thus an important target in understanding PD. Furthermore, chelation therapy has shown promise in the treatment of Alzheimer's and other neuro-degenerative diseases with similar metal-correlated pathologies. At present, our candidate chelating agents include nicotine, curcumin and clioquinol. We examine their MEP activation barriers in the context of a PD onset mechanism to assess the viability of various chelators for PD remediation.

  17. Polymer-peptide conjugates for angiogenesis targeted tumor radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Mitra, Amitava [Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD 21201 (United States); Center for Nanomedicine and Cellular Delivery, University of Maryland, Baltimore, MD 21201 (United States); Nan, Anjan [Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD 21201 (United States); Center for Nanomedicine and Cellular Delivery, University of Maryland, Baltimore, MD 21201 (United States); Papadimitriou, John C. [Department of Pathology, University of Maryland, Baltimore, MD 21201 (United States); Ghandehari, Hamidreza [Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD 21201 (United States) and Center for Nanomedicine and Cellular Delivery, University of Maryland, Baltimore, MD 21201 (United States) and Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201 (United States)]. E-mail: hghandeh@rx.umaryland.edus; Line, Bruce R. [Center for Nanomedicine and Cellular Delivery, University of Maryland, Baltimore, MD 21201 (United States) and Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201 (United States) and Division of Nuclear Medicine, Department of Radiology, University of Maryland, Baltimore, MD 21201 (United States)]. E-mail: bline@umm.edu

    2006-01-15

    Introduction: New methods of delivering radiotherapy to sites of occult or disseminated cancer are needed to control the disease and address the failure of conventional therapy. Because tumor cells rely on angiogenesis for survival, we assessed the effectiveness of {beta}-emitter radiotherapy delivered by polymer-peptide conjugates that target tumor neovasculature. This molecularly targeted radiation is intended to damage both the endothelial bed and surrounding neoplastic cells. Methods: N-(2-Hydroxypropyl) methacrylamide (HPMA), a biocompatible and water-soluble copolymer, was derivatized to incorporate side chains for {sup 99m}Tc and {sup 9}Y chelation and was further conjugated to a {alpha}{sub V}{beta}{sub 3} integrin-targeting peptide (RGD4C). The HPMA copolymer-RGD4C conjugate was characterized by its side-chain contents, in vitro endothelial cell adhesion assay and its biodistribution and antitumor effectiveness in a SCID mouse xenograft model of human prostate carcinoma. Results: The conjugate contained about 16 RGD4C moieties per polymer backbone. Tumor accumulation significantly increased (P<.01) over time from 1.05{+-}0.03 % injected dose (%ID)/g tissue at 1 h to 4.32{+-}0.32% at 72 h. The activity in major normal tissues significantly decreased (P<.05) during that period. At 21 days, the control tumors increased 442% in volume from baseline. In contrast, a 7% and a 63% decrease of tumor volume were observed for the 100- and 250-{mu}Ci {sup 9}Y treatment groups, respectively. Histopathological examination revealed increased apoptosis in the treated tumors with no acute signs of radiation-induced toxicity to other organs. Conclusion: This copolymer-peptide conjugate targets tumor angiogenic vessels and delivers sufficient radiotherapy to arrest tumor growth.

  18. Chelated Ruthenium Catalysts for Z-Selective Olefin Metathesis

    OpenAIRE

    Endo, Koji; Grubbs, Robert H

    2011-01-01

    We report the development of ruthenium-based metathesis catalysts with chelating N-heterocyclic carbene (NHC) ligands which catalyze highly Z-selective olefin metathesis. A very simple and convenient synthetic procedure of such a catalyst has been developed. An intramolecular C-H bond activation of the NHC ligand, which is promoted by anion ligand substitution, forms the appropriate chelate for stereo- controlled olefin metathesis.

  19. Reversible immobilization of laccase to poly(4-vinylpyridine) grafted and Cu(II) chelated magnetic beads: biodegradation of reactive dyes.

    Science.gov (United States)

    Bayramoğlu, Gülay; Yilmaz, Meltem; Arica, M Yakup

    2010-09-01

    Poly(4-vinyl pyridine), poly(VP), as a novel metal-chelating fibrous polymer was grafted on the magnetic beads. Poly(4-VP) grafted and/or Cu(II) ions chelated magnetic beads were used for reversible immobilization of Trametes versicolor laccase, and the amounts of immobilized laccase on the beads were determined as 36.8 and 56.4 mg/g beads, respectively. The adsorption of laccase on both modified magnetic beads appeared to follow the Langmuir isotherm model. The degradation of textile dyes with immobilized laccase on the metal chelated magnetic beads was evaluated in a batch system. Three different reactive textile dyes (i.e., Reactive Green 19, Reactive Red 2 and Reactive Brown 10) were successfully degraded in the enzyme reactor. It was observed that the decolorization rate varied widely with chemical structure and types of the substitute group of the reactive dye molecules. (c) 2010 Elsevier Ltd. All rights reserved.

  20. 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.)

  1. {sup 186}Re-maSGS-Z{sub HER2:342}, a potential affibody conjugate for systemic therapy of HER2-expressing tumours

    Energy Technology Data Exchange (ETDEWEB)

    Orlova, Anna; Tran, Thuy A. [Uppsala University, Division of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden); Ekblad, Torun; Karlstroem, Amelie Eriksson [Royal Institute of Technology, School of Biotechnology, Division of Molecular Biotechnology, Stockholm (Sweden); Tolmachev, Vladimir [Uppsala University, Division of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden); Uppsala University, Division of Nuclear Medicine, Department of Medical Sciences, Uppsala (Sweden)

    2010-02-15

    Affibody molecules are a novel class of tumour-targeting proteins, which combine small size (7 kDa) and picomolar affinities. The Affibody molecule Z{sub HER2:342} has been suggested for imaging of HER2 expression in order to select patients for trastuzumab therapy. When optimizing chelators for {sup 99m}Tc-labelling, we have found that synthetic Z{sub HER2:342} conjugated with mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) and mercaptoacetyl-glycyl-seryl-glycyl (maGSG) chelators provides relatively low renal uptake of radioactivity and could be suitable for therapy. maGGG-Z{sub HER2:342} and maGSG-Z{sub HER2:342} were labelled with {sup 186}Re and their biodistribution was studied in normal mice. Dosimetric evaluation and tumour targeting to HER2-overexpressed xenografts (SKOV-3) by {sup 186}Re-maGSG-Z{sub HER2:342} were studied. Gluconate-mediated labelling of maGGG-Z{sub HER2:342} and maGSG-Z{sub HER2:342} with {sup 186}Re provided a yield of more than 95% within 60 min. The conjugates were stable and demonstrated specific binding to HER2-expressing SKOV-3 cells. Biodistribution in normal mice demonstrated rapid blood clearance, low accumulation of radioactivity in the kidney and other organs, accumulating free perrhenate. Both {sup 186}Re-maGGG-Z{sub HER2:342} and {sup 186}Re-maGSG-Z{sub HER2:342} demonstrated lower renal uptake than their {sup 99m}Tc-labelled counterparts. {sup 186}Re-maGSG-Z{sub HER2:342} provided the lowest uptake in healthy tissues. Biodistribution of {sup 186}Re-maGSG-Z{sub HER2:342} in nude mice bearing SKOV-3 xenografts showed specific targeting of tumours. Tumour uptake 24 h after injection (5.84{+-}0.54%ID/g) exceeded the concentration in blood by more than 500-fold, and uptake in kidneys by about 8-fold. Preliminary dosimetric evaluation showed that dose-to-tumour should exceed dose-to-kidney by approximately 5-fold. Optimization of chelators improves biodistribution properties of rhenium-labelled small scaffold proteins and enables

  2. Aerosolization of a chelating agent, Ca-DTPA, for emergent inhalation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Yamada, Yuji; Koizumi, Akira; Fukuda, Satoshi [National Inst. of Radiological Sciences, Chiba (Japan)

    1997-06-01

    Aerosolization of the chelating agent, Ca-DTPA (diethylenetriaminepentaacetic acid), was studied for removal of inhaled radioactive particles. Four methods of generating aerosols from the powder and from the solution were examined. The particle size and concentration of the Ca-DTPA aerosols were measured by the API Aero-Sizer. The aerosol particles generated by the dry powder inhaler were over 40 {mu}m in MMAD (Mass Median Aerodynamic Diameter) and might be too large for administration to the deep lung. The sizes of aerosol particles generated by other three methods (dispersion dust generator, compressed air nebulizer and ultrasonic nebulizer) ranged from 2 to 15 {mu}m in MMAD, and those concentrations were over 10 mg/m{sup 3} at maximum. The generated chelate aerosols were evaluated as inhalable and applicable for inhalation therapy. (author)

  3. Spectral and colorimetric characteristics of metal chelates of acylated cyanidin derivatives.

    Science.gov (United States)

    Sigurdson, G T; Robbins, R J; Collins, T M; Giusti, M M

    2017-04-15

    Colorants derived from nature are increasingly popular due to consumer demand. Anthocyanins are a class of naturally occurring pigments that produce red-purple-blue hues in nature, especially when interacting with metal ions and co-pigments. The role of various acylations of cyanidin (Cy) derivatives on color expression and stability of Al(3+) and Fe(3+) chelates in pH 6-7 were evaluated by spectrophotometry (380-700nm) and colorimetry (CIE-L(∗)a(∗)b(∗)) during dark, ambient storage (48h). Increased substitution generally increased λmax of Cy chelates: malonic acid monoacylationimproved with increasing proportions of metal ions and acylation. Stability followed that diacylated cyanidin (p-coumaric-sinapic>ferulic-sinapic>sinapic-sinapic)>monoacylated (malonic≈sinapic>ferulic>p-coumaric). Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Reversible immobilization of invertase on Cu-chelated polyvinylimidazole-grafted iron oxide nanoparticles.

    Science.gov (United States)

    Uzun, Kerem; Çevik, Emre; Şenel, Mehmet; Baykal, Abdülhadi

    2013-12-01

    Polyvinylimidazole (PVI)-grafted iron oxide nanoparticles (PVIgMNP) were prepared by grafting of telomere of PVI on the iron oxide nanoparticles. Different metal ions (Cu(2+), Zn(2+), Cr(2+), Ni(2+)) ions were chelated on polyvinylimidazole-grafted iron oxide nanoparticles, and then the metal-chelated magnetic particles were used in the adsorption of invertase. The maximum invertase immobilization capacity of the PVIgMNP-Cu(2+) beads was observed to be 142.856 mg/g (invertase/PVIgMNP) at pH 5.0. The values of the maximum reaction rate (V max) and Michaelis-Menten constant (Km) were determined for the free and immobilized enzymes. The enzyme adsorption-desorption studies, pH effect on the adsorption efficiency, affinity of different metal ions, the kinetic parameters and storage stability of free and immobilized enzymes were evaluated.

  5. Lipophilic aroylhydrazone chelator HNTMB and its multiple effects on ovarian cancer cells

    Directory of Open Access Journals (Sweden)

    Singh Rakesh K

    2010-02-01

    Full Text Available Abstract Background Metal chelators have gained much attention as potential anti-cancer agents. However, the effects of chelators are often linked solely to their capacity to bind iron while the potential complexation of other trace metals has not been fully investigated. In present study, we evaluated the effects of various lipophilic aroylhydrazone chelators (AHC, including novel compound HNTMB, on various ovarian cancer cell lines (SKOV-3, OVCAR-3, NUTU-19. Methods Cell viability was analyzed via MTS cytotoxicity assays and NCI60 cancer cell growth screens. Apoptotic events were monitored via Western Blot analysis, fluorescence microscopy and TUNEL assay. FACS analysis was carried out to study Cell Cycle regulation and detection of intracellular Reactive Oxygen Species (ROS Results HNTMB displayed high cytotoxicity (IC50 200-400 nM compared to previously developed AHC (oVtBBH, HNtBBH, StBBH/206, HNTh2H/315, HNI/311; IC50 0.8-6 μM or cancer drug Deferoxamine, a hexadentate iron-chelator (IC50 12-25 μM. In a NCI60 cancer cell line screen HNTMB exhibited growth inhibitory effects with remarkable differences in specificity depending on the cell line studied (GI50 10 nM-2.4 μM. In SKOV-3 ovarian cancer cells HNTMB treatment led to chromatin fragmentation and activation of the extrinsic and intrinsic pathways of apoptosis with specific down-regulation of Bcl-2. HNTMB caused delayed cell cycle progression of SKOV-3 through G2/M phase arrest. HNTMB can chelate iron and copper of different oxidation states. Complexation with copper lead to high cytotoxicity via generation of reactive oxygen species (ROS while treatment with iron complexes of the drug caused neither cytotoxicity nor increased ROS levels. Conclusions The present report suggests that both, non-complexed HNTMB as a chelator of intracellular trace-metals as well as a cytotoxic HNTMB/copper complex may be developed as potential therapeutic drugs in the treatment of ovarian and other

  6. Long-term treatment of transfusional iron overload with the oral iron chelator deferiprone (L1): a Dutch multicenter trial

    NARCIS (Netherlands)

    Kersten, M. J.; Lange, R.; Smeets, M. E.; Vreugdenhil, G.; Roozendaal, K. J.; Lameijer, W.; Goudsmit, R.

    1996-01-01

    We performed an open, nonrandomized, multicenter phase-II trial to evaluate the efficacy and toxicity of 1 year of treatment with the oral iron chelator deferiprone in 38 mainly nonthalassemic patients with transfusional iron overload. Initial serum ferritin varied between 996 and 11.644

  7. On Hydrogen Bonding in the Intramolecularly Chelated Taitomers of Enolic Malondialdehyde and its Mono- and Dithio-Analogues

    DEFF Research Database (Denmark)

    Carlsen, Lars; Duus, Fritz

    1980-01-01

    The intramolecular hydrogen bondings in enolic malondialdehyde and it mono- and dithio-analogues have been evaluated by a semiempricial SCF–MO–CNDO method. The calculations predict that the hydrogen bonds play an important part in the stabilities of malondialdehyde and monothiomalondialdehyde, wh......, whereas dithiomalondialdehyde hardly exists as a hydrogen-chelated tautomeric form....

  8. High Relaxivity Gadolinium Hydroxypyridonate-Viral Capsid Conjugates: Nano-sized MRI Contrast Agents

    Energy Technology Data Exchange (ETDEWEB)

    Meux, Susan C.; Datta, Ankona; Hooker, Jacob M.; Botta, Mauro; Francis, Matthew B.; Aime, Silvio; Raymond, Kenneth N.

    2007-08-29

    High relaxivity macromolecular contrast agents based on the conjugation of gadolinium chelates to the interior and exterior surfaces of MS2 viral capsids are assessed. The proton nuclear magnetic relaxation dispersion (NMRD) profiles of the conjugates show up to a five-fold increase in relaxivity, leading to a peak relaxivity (per Gd{sup 3+} ion) of 41.6 mM{sup -1}s{sup -1} at 30 MHz for the internally modified capsids. Modification of the exterior was achieved through conjugation to flexible lysines, while internal modification was accomplished by conjugation to relatively rigid tyrosines. Higher relaxivities were obtained for the internally modified capsids, showing that (1) there is facile diffusion of water to the interior of capsids and (2) the rigidity of the linker attaching the complex to the macromolecule is important for obtaining high relaxivity enhancements. The viral capsid conjugated gadolinium hydroxypyridonate complexes appear to possess two inner-sphere water molecules (q = 2) and the NMRD fittings highlight the differences in the local motion for the internal ({tau}{sub RI} = 440 ps) and external ({tau}{sub RI} = 310 ps) conjugates. These results indicate that there are significant advantages of using the internal surface of the capsids for contrast agent attachment, leaving the exterior surface available for the installation of tissue targeting groups.

  9. The Effect of Different Tea Varieties on Iron Chelation

    Science.gov (United States)

    Truong, S. K.; Karim, R.

    2016-12-01

    The chief objectives of this experiment are to distinguish which type of tea of four variants, pomegranate blackberry green, green, lemon chamomile (herbal), and earl grey (black), are capable of chelating the most iron (III) chloride (FeCl3) through titration. We hypothesized that if each tea variety chelates differing amounts of iron chloride, and if we conduct an experiment in which four different teas are mixed in the same amount of water, iron chloride, and iron chloride indicator EDTA, then the pomegranate blackberry green tea will bind to the most iron due to its large amount of fruit antioxidants. To summarize our methodology, we prepared three solutions of each tea, dissolved with 1 gram of FeCl3 to test three trials per tea variety. The chelation process took place overnight as teas cooled. Six drops of iron chloride indicator added to each solution began the titration. The necessary amount of 0.1M EDTA (ethylenediaminetetraacetic acid) drops required for each solution to turn to a universal amber color from its original dark tone indicates how many free iron molecules were left unbound by the tea solution. After careful analysis of the data, we discovered that blackberry pomegranate green tea possessed the best chelating abilities with 97.48% of FeCl3 adsorbed. Green tea followed with 96.67%. Herbal tea chelated 94.24% of the iron while earl grey absorbed the least amount at 93.43%. From our conclusion, we drew that since blackberry pomegranate green tea contained the highest amount of polyphenols and antioxidants as well as epigallocatechin gallate (EGCG) found in green teas, it was able to chelate the most amount of iron. The substances mentioned in blackberry pomegranate green tea possess the ability to form strong bonds with multiple heavy metals, such as iron (III) chloride atoms. Overall, each variety of tea contains different organic substances. Each of these substances possesses a unique chelating ability, determining how well the type of tea can

  10. Imaging of HER2-expressing tumours using a synthetic Affibody molecule containing the {sup 99m}Tc-chelating mercaptoacetyl-glycyl-glycyl-glycyl (MAG3) sequence

    Energy Technology Data Exchange (ETDEWEB)

    Engfeldt, Torun; Eriksson Karlstroem, Amelie [Royal Institute of Technology, School of Biotechnology, Division of Molecular Biotechnology, Stockholm (Sweden); Orlova, Anna; Tolmachev, Vladimir [Uppsala University, Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden); Affibody AB, Bromma (Sweden); Tran, Thuy; Bruskin, Alexander [Uppsala University, Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden); Widstroem, Charles [Uppsala University Hospital, Department of Hospital Physics, Uppsala (Sweden)

    2007-05-15

    Expression of human epidermal growth factor receptor type 2 (HER2) in malignant tumours possesses well-documented prognostic and predictive value. Non-invasive imaging of expression can provide valuable diagnostic information, thereby influencing patient management. Previously, we reported a phage display selection of a small (about 7 kDa) protein, the Affibody molecule Z{sub HER2:342}, which binds HER2 with subnanomolar affinity, and demonstrated the feasibility of targeting of HER2-expressing xenografts using radioiodinated Z{sub HER2:342}. The goal of this study was to develop a method for {sup 99m}Tc labelling of Z{sub HER2:342} using the MAG3 chelator, which was incorporated into Z{sub HER2:342} using peptide synthesis, and evaluate the targeting properties of the labelled conjugate. MAG3-Z{sub HER2:342} was assembled using Fmoc/tBu solid phase peptide synthesis. Biochemical characterisation of the agent was performed using RP-HPLC, ESI-MS, biosensor studies and circular dichroism. A procedure for {sup 99m}Tc labelling in the presence of sodium/potassium tartrate was established. Tumour targeting was evaluated by biodistribution study and gamma camera imaging in xenograft-bearing mice. Biodistribution of {sup 99m}Tc-MAG3-Z{sub HER2:342} and {sup 125}I-para-iodobenzoate -Z{sub HER2:342} was compared 6 h p.i. Synthetic MAG3-Z{sub HER2:342} possessed an affinity of 0.2 nM for HER2 receptors. The peptide was labelled with {sup 99m}Tc with an efficiency of about 75-80%. Labelled {sup 99m}Tc-MAG3-Z{sub HER2:342} retained capacity to bind specifically HER2-expressing SKOV-3 cells in vitro. {sup 99m}Tc-MAG3-Z{sub HER2:342} showed specific tumour targeting with a contrast similar to a radioiodinated analogue in mice bearing LS174T xenografts. Gamma camera imaging demonstrated clear and specific visualisation of HER2 expression. Incorporation of a mercaptoacetyl-containing chelating sequence during chemical synthesis enabled site-specific {sup 99m}Tc labelling of the Z

  11. Design, synthesis, and evaluation of Trolox-conjugated amyloid-β C-terminal peptides for therapeutic intervention in an in vitro model of Alzheimer's disease.

    Science.gov (United States)

    Arai, Takuya; Ohno, Akiko; Kazunori, Mori; Kakizawa, Taeko; Kuwata, Hiroshi; Ozawa, Toshihiko; Shibanuma, Motoko; Hara, Shuntaro; Ishida, Seiichi; Kurihara, Masaaki; Miyata, Naoki; Nakagawa, Hidehiko; Fukuhara, Kiyoshi

    2016-09-15

    Two hallmarks of Alzheimer's disease (AD) observed in the brains of patients with the disease include oxidative injury and deposition of protein aggregates comprised of amyloid-β (Aβ) variants. To inhibit these toxic processes, we synthesized antioxidant-conjugated peptides comprised of Trolox and various C-terminal motifs of Aβ variants, TxAβx-n (x=34, 36, 38, 40; n=40, 42, 43). Most of these compounds were found to exhibit anti-aggregation activities. Among them, TxAβ36-42 significantly inhibited Aβ1-42 aggregation, showed potent antioxidant activity, and protected SH-SY5Y cells from Aβ1-42-induced cytotoxicity. Thus, this method represents a promising strategy for developing multifunctional AD therapeutic agents. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. A Powerful Mitochondria-Targeted Iron Chelator Affords High Photoprotection against Solar Ultraviolet A Radiation.

    Science.gov (United States)

    Reelfs, Olivier; Abbate, Vincenzo; Hider, Robert C; Pourzand, Charareh

    2016-08-01

    Mitochondria are the principal destination for labile iron, making these organelles particularly susceptible to oxidative damage on exposure to ultraviolet A (UVA, 320-400 nm), the oxidizing component of sunlight. The labile iron-mediated oxidative damage caused by UVA to mitochondria leads to necrotic cell death via adenosine triphosphate depletion. Therefore, targeted removal of mitochondrial labile iron via highly specific tools from these organelles may be an effective approach to protect the skin cells against the harmful effects of UVA. In this work, we designed a mitochondria-targeted hexadentate (tricatechol-based) iron chelator linked to mitochondria-homing SS-like peptides. The photoprotective potential of this compound against UVA-induced oxidative damage and cell death was evaluated in cultured primary skin fibroblasts. Our results show that this compound provides unprecedented protection against UVA-induced mitochondrial damage, adenosine triphosphate depletion, and the ensuing necrotic cell death in skin fibroblasts, and this effect is fully related to its potent iron-chelating property in the organelle. This mitochondria-targeted iron chelator has therefore promising potential for skin photoprotection against the deleterious effects of the UVA component of sunlight. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  13. Methods for Generating Highly Magnetically Responsive Lanthanide-Chelating Phospholipid Polymolecular Assemblies.

    Science.gov (United States)

    Isabettini, Stéphane; Baumgartner, Mirjam E; Reckey, Pernille Q; Kohlbrecher, Joachim; Ishikawa, Takashi; Fischer, Peter; Windhab, Erich J; Kuster, Simon

    2017-06-27

    Mixtures of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and its lanthanide ion (Ln3+) chelating phospholipid conjugate, 1,2-dimyristoyl-sn-glycero-3-phospho-ethanolamine-diethylene triaminepentaacetate (DMPE-DTPA), assemble into highly magnetically responsive polymolecular assemblies such as DMPC/DMPE-DTPA/Ln3+ (molar ratio 4:1:1) bicelles. Their geometry and magnetic alignability is enhanced by introducing cholesterol into the bilayer in DMPC/Cholesterol/DMPE-DTPA/Ln3+ (molar ratio 16:4:5:5). However, the reported fabrication procedures remain tedious and limit the generation of highly magnetically alignable species. Herein, a simplified procedure where freeze thawing cycles and extrusion are replaced by gentle heating and cooling cycles for the hydration of the dry lipid film was developed. Heating above the phase transition temperature Tm of the lipids composing the bilayer before cooling back below the Tm was essential to guarantee successful formation of the polymolecular assemblies composed of DMPC/DMPE-DTPA/Ln3+ (molar ratio 4:1:1). Planar polymolecular assemblies in the size range of hundreds of nanometers are achieved and deliver unprecedented gains in magnetic response. The proposed heating and cooling procedure further allowed to regenerate the highly magnetically alignable DMPC/Cholesterol/DMPE-DTPA/Ln3+ (molar ratio 16:4:5:5) species after storage for one month frozen at -18 °C. The simplicity and viability of the proposed fabrication procedure offers a new set of highly magnetically responsive lanthanide ion chelating phospholipid polymolecular assemblies as building blocks for the smart soft materials of tomorrow.

  14. New Antibody Conjugates in Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Serengulam V. Govindan

    2010-01-01

    Full Text Available Targeting of radiation, drugs, and protein toxins to cancers selectively with monoclonal antibodies (MAbs has been a topic of considerable interest and an area of continued development. Radioimmunotherapy (RAIT of lymphoma using directly labeled MAbs is of current interest after approval of two radiolabeled anti-CD20 MAbs, as illustrated with the near 100% overall response rate obtained in a recent clinical trial using an investigational radiolabeled anti-CD22 MAb, 90Y-epratuzumab. The advantage of pretargeted RAIT over directly labeled MAbs is continuing to be validated in preclinical models of lymphoma and solid tumors. Importantly, the advantages of combining RAIT with radiation sensitizers, with immunotherapy, or a drug conjugate targeting a different antigen are being studied clinically and preclinically. The area of drug-conjugated antibodies is progressing with encouraging data published for the trastuzumab-DM1 conjugate in a phase I clinical trial in HER2-positive breast cancer. The Dock-and-Lock platform technology has contributed to the design and the evaluation of complex antibody-cytokine and antibody-toxin conjugates. This review describes the advances made in these areas, with illustrations taken from advances made in the authors' institutions.

  15. Ab initio coordination chemistry for nickel chelation motifs.

    Science.gov (United States)

    Sudan, R Jesu Jaya; Kumari, J Lesitha Jeeva; Sudandiradoss, C

    2015-01-01

    Chelation therapy is one of the most appreciated methods in the treatment of metal induced disease predisposition. Coordination chemistry provides a way to understand metal association in biological structures. In this work we have implemented coordination chemistry to study nickel coordination due to its high impact in industrial usage and thereby health consequences. This paper reports the analysis of nickel coordination from a large dataset of nickel bound structures and sequences. Coordination patterns predicted from the structures are reported in terms of donors, chelate length, coordination number, chelate geometry, structural fold and architecture. The analysis revealed histidine as the most favored residue in nickel coordination. The most common chelates identified were histidine based namely HHH, HDH, HEH and HH spaced at specific intervals. Though a maximum coordination number of 8 was observed, the presence of a single protein donor was noted to be mandatory in nickel coordination. The coordination pattern did not reveal any specific fold, nevertheless we report preferable residue spacing for specific structural architecture. In contrast, the analysis of nickel binding proteins from bacterial and archeal species revealed no common coordination patterns. Nickel binding sequence motifs were noted to be organism specific and protein class specific. As a result we identified about 13 signatures derived from 13 classes of nickel binding proteins. The specifications on nickel coordination presented in this paper will prove beneficial for developing better chelation strategies.

  16. Ab initio coordination chemistry for nickel chelation motifs.

    Directory of Open Access Journals (Sweden)

    R Jesu Jaya Sudan

    Full Text Available Chelation therapy is one of the most appreciated methods in the treatment of metal induced disease predisposition. Coordination chemistry provides a way to understand metal association in biological structures. In this work we have implemented coordination chemistry to study nickel coordination due to its high impact in industrial usage and thereby health consequences. This paper reports the analysis of nickel coordination from a large dataset of nickel bound structures and sequences. Coordination patterns predicted from the structures are reported in terms of donors, chelate length, coordination number, chelate geometry, structural fold and architecture. The analysis revealed histidine as the most favored residue in nickel coordination. The most common chelates identified were histidine based namely HHH, HDH, HEH and HH spaced at specific intervals. Though a maximum coordination number of 8 was observed, the presence of a single protein donor was noted to be mandatory in nickel coordination. The coordination pattern did not reveal any specific fold, nevertheless we report preferable residue spacing for specific structural architecture. In contrast, the analysis of nickel binding proteins from bacterial and archeal species revealed no common coordination patterns. Nickel binding sequence motifs were noted to be organism specific and protein class specific. As a result we identified about 13 signatures derived from 13 classes of nickel binding proteins. The specifications on nickel coordination presented in this paper will prove beneficial for developing better chelation strategies.

  17. Supercritical Fluid Extraction of Metal Chelate: A Review.

    Science.gov (United States)

    Ding, Xin; Liu, Qinli; Hou, Xiongpo; Fang, Tao

    2017-03-04

    Supercritical fluid extraction (SFE), as a new green extraction technology, has been used in extracting various metal species. The solubilities of chelating agents and corresponding metal chelates are the key factors which influence the efficiency of SFE. Other main properties of them such as stability and selectivity are also reviewed. The extraction mechanisms of mainly used chelating agents are explained by typical examples in this paper. This is the important aspect of SFE of metal ions. Moreover, the extraction efficiencies of metal species also depend on other factors such as temperature, pressure, extraction time and matrix effect. The two main complexation methods namely in-situ and on-line chelating SFE are described in detail. As an efficient chelating agent, tributyl phosphate-nitric acid (TBP-HNO 3 ) complex attracts much attention. The SFE of metal ions, lanthanides and actinides as well as organometallic compounds are also summarized. With the proper selection of ligands, high efficient extraction of metal species can be obtained. As an efficient sample analysis method, supercritical fluid chromatography (SFC) is introduced in this paper. Recently, the extraction method combining ionic liquids (ILs) with supercritical fluid has been becoming a novel technology for treating metal ions. The kinetics related to SFE of metal species is discussed with some specific examples.

  18. Eltrombopag: a powerful chelator of cellular or extracellular iron(III) alone or combined with a second chelator.

    Science.gov (United States)

    Vlachodimitropoulou, Evangelia; Chen, Yu-Lin; Garbowski, Maciej; Koonyosying, Pimpisid; Psaila, Bethan; Sola-Visner, Martha; Cooper, Nichola; Hider, Robert; Porter, John

    2017-10-26

    Eltrombopag (ELT) is a thrombopoietin receptor agonist reported to decrease labile iron in leukemia cells. Here we examine the previously undescribed iron(III)-coordinating and cellular iron-mobilizing properties of ELT. We find a high binding constant for iron(III) (log β 2 =35). Clinically achievable concentrations (1 µM) progressively mobilized cellular iron from hepatocyte, cardiomyocyte, and pancreatic cell lines, rapidly decreasing intracellular reactive oxygen species (ROS) and also restoring insulin secretion in pancreatic cells. Decrements in cellular ferritin paralleled total cellular iron removal, particularly in hepatocytes. Iron mobilization from cardiomyocytes exceeded that obtained with deferiprone, desferrioxamine, or deferasirox at similar iron-binding equivalents. When combined with these chelators, ELT enhanced cellular iron mobilization more than additive (synergistic) with deferasirox. Iron-binding speciation plots are consistent with ELT donating iron to deferasirox at clinically relevant concentrations. ELT scavenges iron citrate species faster than deferasirox, but rapidly donates the chelated iron to deferasirox, consistent with a shuttling mechanism. Shuttling is also suggested by enhanced cellular iron mobilization by ELT when combined with the otherwise ineffective extracellular hydroxypyridinone chelator, CP40. We conclude that ELT is a powerful iron chelator that decreases cellular iron and further enhances iron mobilization when combined with clinically available chelators. © 2017 by The American Society of Hematology.

  19. Synthesis and biological evaluation of cationic fullerene quinazolinone conjugates and their binding mode with modeled Mycobacterium tuberculosis hypoxanthine-guanine phosphoribosyltransferase enzyme.

    Science.gov (United States)

    Patel, Manishkumar B; Kumar, Sivakumar Prasanth; Valand, Nikunj N; Jasrai, Yogesh T; Menon, Shobhana K

    2013-08-01

    The present work reports a series of novel cationic fullerene derivatives bearing a substituted-quinazolinone moiety as a side arm. Fullerene-quinazolinone conjugates synthesized using the 1,3-dipolar cycloaddition reaction of C60 with azomethine ylides generated from the corresponding Schiff bases of substituted quinazolinone were characterized by elemental analysis, FT-IR, (1)H NMR, (13)C NMR and ESI-MS and screened for their antibacterial activity against Mycobacterium tuberculosis (H 37 Rv strain). All the compounds exhibited significant activity with the most effective having MIC in the range of 1.562-3.125 μg/mL. Compound 9f exhibited good biological activity compared to standard drugs. We developed a computational strategy based on the modeled M. tuberculosis hypoxanthine-guanine phosphoribosyltransferase (HGPRT) using homology modeling techniques and studied its binding pattern with synthesized fullerene derivatives. We then explored the surface geometry of the protein to place the cage adjacent to the active site while optimizing its quinazolinone side arm to establish H bonding with active site residues.

  20. Progressing Toward a Cohesive Pediatric 18F-FDG PET/MR Protocol: Is Administration of Gadolinium Chelates Necessary?

    Science.gov (United States)

    Klenk, Christopher; Gawande, Rakhee; Tran, Vy Thao; Leung, Jennifer Trinh; Chi, Kevin; Owen, Daniel; Luna-Fineman, Sandra; Sakamoto, Kathleen M; McMillan, Alex; Quon, Andy; Daldrup-Link, Heike E

    2016-01-01

    With the increasing availability of integrated PET/MR scanners, the utility and need for MR contrast agents for combined scans is questioned. The purpose of our study was to evaluate whether administration of gadolinium chelates is necessary for evaluation of pediatric tumors on (18)F-FDG PET/MR images. First, in 119 pediatric patients with primary and secondary tumors, we used 14 diagnostic criteria to compare the accuracy of several MR sequences: unenhanced T2-weighted fast spin-echo imaging; unenhanced diffusion-weighted imaging; and-before and after gadolinium chelate contrast enhancement-T1-weighted 3-dimensional spoiled gradient echo LAVA (liver acquisition with volume acquisition) imaging. Next, in a subset of 36 patients who had undergone (18)F-FDG PET within 3 wk of MRI, we fused the PET images with the unenhanced T2-weighted MR images (unenhanced (18)F-FDG PET/MRI) and the enhanced T1-weighted MR images (enhanced (18)F-FDG PET/MRI). Using the McNemar test, we compared the accuracy of the two types of fused images using the 14 diagnostic criteria. We also evaluated the concordance between (18)F-FDG avidity and gadolinium chelate enhancement. The standard of reference was histopathologic results, surgical notes, and follow-up imaging. There was no significant difference in diagnostic accuracy between the unenhanced and enhanced MR images. Accordingly, there was no significant difference in diagnostic accuracy between the unenhanced and enhanced (18)F-FDG PET/MR images. (18)F-FDG avidity and gadolinium chelate enhancement were concordant in 30 of the 36 patients and 106 of their 123 tumors. Gadolinium chelate administration is not necessary for accurate diagnostic characterization of most solid pediatric malignancies on (18)F-FDG PET/MR images, with the possible exception of focal liver lesions. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  1. Efficacy of chelation therapy to remove aluminium intoxication.

    Science.gov (United States)

    Fulgenzi, Alessandro; De Giuseppe, Rachele; Bamonti, Fabrizia; Vietti, Daniele; Ferrero, Maria Elena

    2015-11-01

    There is a distinct correlation between aluminium (Al) intoxication and neurodegenerative diseases (ND). We demonstrated how patients affected by ND showing Al intoxication benefit from short-term treatment with calcium disodium ethylene diamine tetraacetic acid (EDTA) (chelation therapy). Such therapy further improved through daily treatment with the antioxidant Cellfood. In the present study we examined the efficacy of long-term treatment, using both EDTA and Cellfood. Slow intravenous treatment with the chelating agent EDTA (2 g/10 mL diluted in 500 mL physiological saline administered in 2 h) (chelation test) removed Al, which was detected (using inductively coupled plasma mass spectrometry) in urine samples collected from patients over 12 h. Patients that revealed Al intoxication (expressed in μg per g creatinine) underwent EDTA chelation therapy once a week for ten weeks, then once every two weeks for a further six or twelve months. At the end of treatment (a total of 22 or 34 chelation therapies, respectively), associated with daily assumption of Cellfood, Al levels in the urine samples were analysed. In addition, the following blood parameters were determined: homocysteine, vitamin B12, and folate, as well as the oxidative status e.g. reactive oxygen species (ROS), total antioxidant capacity (TAC), oxidized LDL (oxLDL), and glutathione. Our results showed that Al intoxication reduced significantly following EDTA and Cellfood treatment, and clinical symptoms improved. After treatment, ROS, oxLDL, and homocysteine decreased significantly, whereas vitamin B12, folate and TAC improved significantly. In conclusion, our data show the efficacy of chelation therapy associated with Cellfood in subjects affected by Al intoxication who have developed ND.

  2. A Novel Molecular Fluorescent Technique for Imaging the Somatostatin Receptor 2, Using a DOTATOC Lanthanide Conjugate

    DEFF Research Database (Denmark)

    Andersen, Rune Wiik; Prakash, Vineet; Stensballe, Allan

    for synaptophysin.                         RESULTS            It is feasible to usefully chelate Samarium and Europium to DOTATOC. There is a distinct higher fluorescent signal arising from the chelation of the two ions than by the DOTA functional group alone. The unparaffinated pancreatic tumor tissues demonstrate.......                       CLINICAL RELEVANCE/APPLICATION            We propose a method for the histopatholgical receptor verification using fluorescent DOTATOC imaging. This potentially permits  ex-vivo developmental platforms for DOTA-conjugated molecules.        ...

  3. Organometallic B12-DNA conjugate

    DEFF Research Database (Denmark)

    Hunger, Miriam; Mutti, Elena; Rieder, Alexander

    2014-01-01

    Design, synthesis, and structural characterization of a B12-octadecanucleotide are presented herein, a new organometallic B12-DNA conjugate. In such covalent conjugates, the natural B12 moiety may be a versatile vector for controlled in vivo delivery of oligonucleotides to cellular targets in hum...

  4. Conjugated Polymer Nanoparticles for Bioimaging

    Directory of Open Access Journals (Sweden)

    Yasmine Braeken

    2017-12-01

    Full Text Available During the last decade, conjugated polymers have emerged as an interesting class of fluorescence imaging probes since they generally show high fluorescence brightness, high photostability, fast emission rates, non-blinking behavior and low cytotoxicity. The main concern related to most conjugated polymers is their lack of hydrophilicity and thereby poor bio-availability. This can, however, be overcome by the formulation of conjugated polymer nanoparticles in aqueous medium. This review provides an overview of the different techniques employed for the preparation of conjugated polymer nanoparticles, together with methods to improve their photoluminescence quantum yields. For selective targeting of specific cells, dedicated surface functionalization protocols have been developed, using different functional groups for ligand immobilization. Finally, conjugated polymer nanoparticles have recently also been employed for theranostic applications, wherein the particles are simultaneously used as fluorescent probes and carriers for anti-tumor drugs.

  5. Glutathione conjugation and contaminant transformation

    Science.gov (United States)

    Field, Jennifer A.; Thurman, E.M.

    1996-01-01

    The recent identification of a novel sulfonated metabolite of alachlor in groundwater and metolachlor in soil is likely the result of glutathione conjugation. Glutathione conjugation is an important biochemical reaction that leads, in the case of alachlor, to the formation of a rather difficult to detect, water-soluble, and therefore highly mobile, sulfonated metabolite. Research from weed science, toxicology, and biochemistry is discussed to support the hypothesis that glutathione conjugation is a potentially important detoxification pathway carried out by aquatic and terrestrial plants and soil microorganisms. A brief review of the biochemical basis for glutathione conjugation is presented. We recommend that multidisciplinary research focus on the occurrence and expression of glutathione and its attendant enzymes in plants and microorganisms, relationships between electrophilic substrate structure and enzyme activity, and the potential exploitation of plants and microorganisms that are competent in glutathione conjugation for phytoremediation and bioremediation.

  6. Evaluation of a SUMO E2 conjugating enzyme involved in resistance to Clavibacter michiganensis subsp. michiganensis in Solanum peruvianum, through a tomato mottle virus VIGS assay

    Directory of Open Access Journals (Sweden)

    Mayra Janeth Esparza-Araiza

    2015-12-01

    Full Text Available Clavibacter michiganensis subsp. michiganensis (Cmm causes bacterial wilt and canker of tomato. Currently, no Solanum lycopersicum resistant varieties are commercially available, but some degree of Cmm resistance has been identified in Solanum peruvianum. Previous research showed up-regulation of a SUMO E2 conjugating enzyme (SCEI transcript in resistant S. peruvianum compared to susceptible S. lycopersicum following infection by Cmm. In order to test the role of SCEI in resistance to Cmm, a fragment of the gene from S. peruvianum was cloned into a novel virus-induced gene-silencing (VIGS vector based on the geminivirus Tomato Mottle Virus (ToMoV. Using biolistic inoculation, the ToMoV-based VIGS vector was shown to be effective in S. peruvianum by silencing the magnesium chelatase gene, which resulted in leaf bleaching. The ToMoV_SCEI construct resulted in approx. 61% silencing of SCEI in leaves of S. peruvianum as determined by quantitative RT-PCR. VIGS of SCEI in S. peruvianum resulted in unilateral wilting (15 dpi and subsequent death (20 dpi of the entire plant after Cmm inoculation, whereas empty vector-treated plants only showed wilting in the Cmm-inoculated leaf. SCEI-silenced plants also showed higher Cmm colonization with an average of 4.5 times more damaged tissue compared to the empty vector control plants. SCEI appears to play an important role in the innate immunity of S. peruvianum against Cmm, perhaps through the regulation of WRKY transcription factors, which may lead to expression of proteins involved in salicylic acid-dependent defense responses.

  7. Evaluation of a SUMO E2 Conjugating Enzyme Involved in Resistance to Clavibacter michiganensis Subsp. michiganensis in Solanum peruvianum, Through a Tomato Mottle Virus VIGS Assay

    Science.gov (United States)

    Esparza-Araiza, Mayra J.; Bañuelos-Hernández, Bernardo; Argüello-Astorga, Gerardo R.; Lara-Ávila, José P.; Goodwin, Paul H.; Isordia-Jasso, María I.; Castillo-Collazo, Rosalba; Rougon-Cardoso, Alejandra; Alpuche-Solís, Ángel G.

    2015-01-01

    Clavibacter michiganensis subsp. michiganensis (Cmm) causes bacterial wilt and canker of tomato. Currently, no Solanum lycopersicum resistant varieties are commercially available, but some degree of Cmm resistance has been identified in Solanum peruvianum. Previous research showed up-regulation of a SUMO E2 conjugating enzyme (SCEI) transcript in S. peruvianum compared to S. lycopersicum following infection with Cmm. In order to test the role of SCEI in resistance to Cmm, a fragment of SCEI from S. peruvianum was cloned into a novel virus-induced gene-silencing (VIGS) vector based on the geminivirus, Tomato Mottle Virus (ToMoV). Using biolistic inoculation, the ToMoV-based VIGS vector was shown to be effective in S. peruvianum by silencing the magnesium chelatase gene, resulting in leaf bleaching. VIGS with the ToMoV_SCEI construct resulted in ~61% silencing of SCEI in leaves of S. peruvianum as determined by quantitative RT-PCR. The SCEI-silenced plants showed unilateral wilting (15 dpi) and subsequent death (20 dpi) of the entire plant after Cmm inoculation, whereas the empty vector-treated plants only showed wilting in the Cmm-inoculated leaf. The SCEI-silenced plants showed higher Cmm colonization and an average of 4.5 times more damaged tissue compared to the empty vector control plants. SCEI appears to play an important role in the innate immunity of S. peruvianum against Cmm, perhaps through the regulation of transcription factors, leading to expression of proteins involved in salicylic acid-dependent defense responses. PMID:26734014

  8. Hot topic: Fatty acid and conjugated linoleic acid (CLA) isomer composition of commercial CLA-fortified dairy products: evaluation after processing and storage.

    Science.gov (United States)

    Rodríguez-Alcalá, L M; Fontecha, J

    2007-05-01

    Conjugated linoleic acid (CLA) exerts a strong positive influence on human health but intake of these fatty acids is typically too low, and increased consumption of CLA is recommended. A good way to raise the CLA content in the diet without a radical change in eating habits seems to be the enrichment of commonly consumed food products with CLA supplements. This study analyzed the total fatty acid content and the CLA isomer composition of 6 commercially available CLA-fortified dairy products during processing and 10 wk of refrigerated storage. Research was carried out by combining gas chromatography and silver-ion HPLC. The tested samples were a CLA oil supplement, and several skim milk dairy products fortified with the supplement (milk, milk powder, fermented milk, yogurt, fresh cheese, and milk-juice blend). The CLA oil supplement was added such that the consumer received 2.4 g/d of CLA by consuming 2 servings. The predominant isomers present, C18:2 cis-9, trans-11 CLA and C18:2 cis-10, trans-12 CLA, were in at a similar ratio, which ranged from 0.97 to 1.05. These major isomers were not significantly affected by processing but a decrease in total CLA in fresh cheese samples was detected after 10 wk of refrigerated storage. Refrigerated storage and thermal treatment resulted in significant decreases or disappearance of some of the minor CLA isomers and a significant increase of trans, trans isomers from both cis, trans, trans, cis, and cis, cis isomers especially in CLA-fortified milk powder but also in fermented milk, yogurt, and milk-juice blend.

  9. Generalisability of vaccine effectiveness estimates: an analysis of cases included in a postlicensure evaluation of 13-valent pneumococcal conjugate vaccine in the USA

    Science.gov (United States)

    Link-Gelles, Ruth; Westreich, Daniel; Aiello, Allison E; Shang, Nong; Weber, David J; Rosen, Jennifer B; Motala, Tasneem; Mascola, Laurene; Eason, Jeffery; Scherzinger, Karen; Holtzman, Corinne; Reingold, Arthur L; Barnes, Meghan; Petit, Susan; Farley, Monica M; Harrison, Lee H; Zansky, Shelley; Thomas, Ann; Schaffner, William; McGee, Lesley; Whitney, Cynthia G; Moore, Matthew R

    2017-01-01

    Objectives External validity, or generalisability, is the measure of how well results from a study pertain to individuals in the target population. We assessed generalisability, with respect to socioeconomic status, of estimates from a matched case–control study of 13-valent pneumococcal conjugate vaccine effectiveness for the prevention of invasive pneumococcal disease in children in the USA. Design Matched case–control study. Setting Thirteen active surveillance sites for invasive pneumococcal disease in the USA. Participants Cases were identified from active surveillance and controls were age and zip code matched. Outcome measures Socioeconomic status was assessed at the individual level via parent interview (for enrolled individuals only) and birth certificate data (for both enrolled and unenrolled individuals) and at the neighbourhood level by geocoding to the census tract (for both enrolled and unenrolled individuals). Prediction models were used to determine if socioeconomic status was associated with enrolment. Results We enrolled 54.6% of 1211 eligible cases and found a trend toward enrolled cases being more affluent than unenrolled cases. Enrolled cases were slightly more likely to have private insurance at birth (p=0.08) and have mothers with at least some college education (p<0.01). Enrolled cases also tended to come from more affluent census tracts. Despite these differences, our best predictive model for enrolment yielded a concordance statistic of only 0.703, indicating mediocre predictive value. Variables retained in the final model were assessed for effect measure modification, and none were found to be significant modifiers of vaccine effectiveness. Conclusions We conclude that although enrolled cases are somewhat more affluent than unenrolled cases, our estimates are externally valid with respect to socioeconomic status. Our analysis provides evidence that this study design can yield valid estimates and the assessing generalisability of

  10. Gold-conjugated green tea nanoparticles for enhanced anti-tumor activities and hepatoprotection--synthesis, characterization and in vitro evaluation.

    Science.gov (United States)

    Mukherjee, Sudeshna; Ghosh, Sayan; Das, Dipesh Kr; Chakraborty, Priyanka; Choudhury, Sreetama; Gupta, Payal; Adhikary, Arghya; Dey, Sanjit; Chattopadhyay, Sreya

    2015-11-01

    Green tea (GT)-based chemoprevention has shown promising results in various cancer models. However, the effective dose may not be far from the toxic dose because of inefficient systemic delivery and limited bio-availability of GT polyphenols. We have used GT polyphenols to successfully reduce gold to corresponding gold nanoparticles (NPs) in a single step; a process that fulfils all criteria of green nanotechnology as no "man-made" chemical other than gold acids are used. GT and (-) - epigallocatechin-3-gallate (EGCG) conjugated gold NPs (diameters <50 nm), showed remarkable stability, significantly rapid cellular uptake and excellent in vitro anti-oxidant activities. These NPs were observed to be selectively toxic towards cancer cells (Ehrlich's Ascites Carcinoma and MCF-7) while showing absolutely no lethality towards normal primary mouse hepatocytes. In cancer cells, NPs altered the redox status and limited Nrf2 activation by almost 50%. These NPs significantly decreased nuclear translocation of NF-κB, coupled with decreased phosphorylation of IĸB and down-regulation of NF-κB-dependent anti-apoptotic proteins Bcl2 and Akt in a dose-dependent manner, triggering onset of apoptosis. Culturing normal hepatocytes with tumor-conditioned media prompted apoptosis by increasing reactive oxygen species (ROS) and depleting the anti-oxidant defense mechanism of hepatocytes. Pre-treatment with NPs protected hepatocytes from tumor-induced cellular damage by scavenging excess ROS, increasing the levels of reduced glutathione and anti-oxidant enzymes. There was evidence of decreased Bax/Bcl2 ratio and active Caspase 3 levels in these hepatocytes, indicating apoptosis escape. Nanoformulations of GT-based polyphenols might serve as an operative platform for effective delivery, increased bio-availability, enhanced effects and minimal chemotherapy-associated toxicities. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. In silico strategies for the selection of chelating compounds with potential application in metal-promoted neurodegenerative diseases

    Science.gov (United States)

    Rodríguez-Rodríguez, Cristina; Rimola, Albert; Alí-Torres, Jorge; Sodupe, Mariona; González-Duarte, Pilar

    2011-01-01

    The development of new strategies to find commercial molecules with promising biochemical features is a main target in the field of biomedicine chemistry. In this work we present an in silico-based protocol that allows identifying commercial compounds with suitable metal coordinating and pharmacokinetic properties to act as metal-ion chelators in metal-promoted neurodegenerative diseases (MpND). Selection of the chelating ligands is done by combining quantum chemical calculations with the search of commercial compounds on different databases via virtual screening. Starting from different designed molecular frameworks, which mainly constitute the binding site, the virtual screening on databases facilitates the identification of different commercial molecules that enclose such scaffolds and, by imposing a set of chemical and pharmacokinetic filters, obey some drug-like requirements mandatory to deal with MpND. The quantum mechanical calculations are useful to gauge the chelating properties of the selected candidate molecules by determining the structure of metal complexes and evaluating their stability constants. With the proposed strategy, commercial compounds containing N and S donor atoms in the binding sites and capable to cross the BBB have been identified and their chelating properties analyzed.

  12. Chelated Nitrogen-Sulphur-Codoped TiO2: Synthesis, Characterization, Mechanistic, and UV/Visible Photocatalytic Studies

    Directory of Open Access Journals (Sweden)

    Hayat Khan

    2017-01-01

    Full Text Available This study presents in detail the physicochemical, photoluminescent, and photocatalytic properties of carboxylic acid chelated nitrogen-sulphur-codoped TiO2. From the Fourier transform infrared spectroscopic study, it was revealed that the formate group formed bidentate bridging linkage while the acetate group coordinated in a bidentate chelating mode with a titanium precursor. In compliance with X-ray diffraction data, the anatase to rutile transformation temperature was extended due to carboxylic acid chelation and NS codoping. Raman analysis indicated four Raman peaks at 146, 392, 512, and 632 cm−1 for the precalcined chelated TiO2; on incorporation with NS dopants, an increase in Raman intensity for these peaks was recorded, indicating the structure stability of the anatase phase. Furthermore, X-ray photoelectron spectroscopic study revealed the presence of anionic doping of nitrogen and cationic doping of sulphur in the lattice of TiO2. When evaluating the UV-visible photodegradation rate of 4-chlorophenol, the modified TiO2 (NS0.06-TFA showed the highest photocatalytic activity. In connection with the activity tests, several scavenger agents were employed to elucidate the significance of the different reactive oxidizing species during the photocatalytic process. Moreover, the transfer pathways of photogenerated carriers and the photocatalytic reaction mechanism of modified TiO2 were also explained in detail.

  13. Resinas quelantes amidoxímicas Amidoxime chelating resins

    Directory of Open Access Journals (Sweden)

    Fernanda M. B. Coutinho

    1999-12-01

    Full Text Available Resinas quelantes com grupos amidoxima foram sintetizadas por copolimerização em suspensão de acrilonitrila (AN e divinilbenzeno (DVB e subsequente modificação química dos grupos ciano por reação com hidroxilamina. Na copolimerização, a proporção de divinilbenzeno e o grau de diluição foram variados. Gelatina e carbonato de cálcio foram usados como estabilizadores de suspensão e sulfato de sódio foi adicionado para reduzir a solubilidade da acrilonitrila em água, por meio do efeito salting out. Os copolímeros de AN/DVB e as resinas amidoxímicas obtidos foram caracterizados por meio de densidade aparente, área específica, volume de poros e teor de nitrogênio. As resinas amidoxímicas foram também avaliadas em relação a capacidade de complexação de íons cobre.Chelating resins with amidoxime groups were synthesized by suspension copolymerization of acrylonitrile (AN and divinylbenzene (DVB and subsequent chemical modification of cyano groups by reaction with hydroxylamine. In the copolymerization, the proportion of divinylbenzene and the dilution degree were varied. Gelatin and calcium carbonate were used as suspension stabilizers and sodium sulphate was added in order to reduce acrylonitrile solubility in water, by salting out effect. The AN/DVB copolymers and amidoxime resins obtained were characterized by apparent density, surface area, pore volume and by the content of nitrogen. The amidoxime resins were also evaluated in relation to the complexation capacity of copper ion.

  14. Dihydroazulene-buckminsterfullerene conjugates

    DEFF Research Database (Denmark)

    Santella, Marco; Mazzanti, Virginia; Jevric, Martyn

    2012-01-01

    The dihydroazulene (DHA)/vinylheptafulvene (VHF) photo/thermoswitch has recently attracted interest as a molecular switch for molecular electronics. In this field, Buckminsterfullerene, C(60), has been shown to be a useful anchoring group for adhering a molecular wire to an electrode. Here we have...... combined the two units with the overall aim to elucidate how C(60) influences the DHA-VHF switching events. Efficient synthetic protocols for making covalently linked DHA-C(60) conjugates were developed, using Prato, Sonogashira, Hay, and Cadiot-Chodkiewicz reactions. These syntheses provide as well...... a variety of potentially useful DHA and C(60) building blocks for acetylenic scaffolding. The two units were separated by bridges of various lengths, such as oligo(phenyleneethynylene) (OPE2 and OPE3) wires. The distance of separation was found to influence strongly the light-induced ring-opening reaction...

  15. Generalized conjugate gradient squared

    Energy Technology Data Exchange (ETDEWEB)

    Fokkema, D.R.; Sleijpen, G.L.G. [Utrecht Univ. (Netherlands)

    1994-12-31

    In order to solve non-symmetric linear systems of equations, the Conjugate Gradient Squared (CGS) is a well-known and widely used iterative method. In practice the method converges fast, often twice as fast as the Bi-Conjugate Gradient method. This is what you may expect, since CGS uses the square of the BiCG polynomial. However, CGS may suffer from its erratic convergence behavior. The method may diverge or the approximate solution may be inaccurate. BiCGSTAB uses the BiCG polynomial and a product of linear factors in an attempt to smoothen the convergence. In many cases, this has proven to be very effective. Unfortunately, the convergence of BiCGSTAB may stall when a linear factor (nearly) degenerates. BiCGstab({ell}) is designed to overcome this degeneration of linear factors. It generalizes BiCGSTAB and uses both the BiCG polynomial and a product of higher order factors. Still, CGS may converge faster than BiCGSTAB or BiCGstab({ell}). So instead of using a product of linear or higher order factors, it may be worthwhile to look for other polynomials. Since the BiCG polynomial is based on a three term recursion, a natural choice would be a polynomial based on another three term recursion. Possibly, a suitable choice of recursion coefficients would result in method that converges faster or as fast as CGS, but less erratic. It turns out that an algorithm for such a method can easily be formulated. One particular choice for the recursion coefficients leads to CGS. Therefore one could call this algorithm generalized CGS. Another choice for the recursion coefficients leads to BiCGSTAB. It is therefore possible to mix linear factors and some polynomial based on a three term recursion. This way one may get the best of both worlds. The authors will report on their findings.

  16. Nanoencapsulation of DMSA monoester for better therapeutic efficacy of the chelating agent against arsenic toxicity.

    Science.gov (United States)

    Yadav, Abhishek; Mathur, Rashi; Samim, Mohammed; Lomash, Vinay; Kushwaha, Pramod; Pathak, Uma; Babbar, Anil Kumar; Flora, Swaran Jeet Singh; Mishra, Anil Kumar; Kaushik, Mahabir Parshad

    2014-04-01

    Exposure to toxic metals remains a widespread occupational and environmental problem in world. Chelation therapy is a mainstream treatment used to treat heavy metal poisoning. This paper describes the synthesis, characterization and therapeutic evaluation of monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA)-encapsulated polymeric nanoparticles as a detoxifying agent for arsenic poisoning. Polymeric nanoparticles entrapping the DMSA monoester, which can evade the reticulo-endothelial system and have a long circulation time in the blood, were prepared. Particle characterization was carried out by transmission electron microscopy and dynamic light scattering. An in vivo study was conducted to investigate the therapeutic efficacy of MiADMSA-encapsulated polymeric nanoparticles (nano- MiADMSA; 50 mg/kg orally for 5 days) and comparison drawn with bulk MiADMSA. Swiss albino mice exposed to sodium arsenite for 4 weeks were treated for 5 days to evaluate alterations in blood, brain, kidney and liver oxidative stress variables. The study also evaluated the histopathological changes in tissues and the chelating potential of the nanoformulation. Our results show that nano-MiADMSA have a narrow size distribution in the 50-nm range. We observed an enhanced chelating potential of nano-MiADMSA compared with bulk MiADMSA as evident in the reversal of biochemical changes indicative of oxidative stress and efficient removal of arsenic from the blood and tissues. Histopathological changes and urinary 8-OHdG levels also prove better therapeutic efficacy of the novel formulation for arsenic toxicity. The results from our study show better therapeutic efficacy of nano-MiADMSA in removing arsenic burden from the brain and liver.

  17. New Insights in the Design of Bioactive Peptides and Chelating Agents for Imaging and Therapy in Oncology

    Directory of Open Access Journals (Sweden)

    Anna Lucia Tornesello

    2017-08-01

    Full Text Available Many synthetic peptides have been developed for diagnosis and therapy of human cancers based on their ability to target specific receptors on cancer cell surface or to penetrate the cell membrane. Chemical modifications of amino acid chains have significantly improved the biological activity, the stability and efficacy of peptide analogues currently employed as anticancer drugs or as molecular imaging tracers. The stability of somatostatin, integrins and bombesin analogues in the human body have been significantly increased by cyclization and/or insertion of non-natural amino acids in the peptide sequences. Moreover, the overall pharmacokinetic properties of such analogues and others (including cholecystokinin, vasoactive intestinal peptide and neurotensin analogues have been improved by PEGylation and glycosylation. Furthermore, conjugation of those peptide analogues to new linkers and bifunctional chelators (such as AAZTA, TETA, TRAP, NOPO etc., produced radiolabeled moieties with increased half life and higher binding affinity to the cognate receptors. This review describes the most important and recent chemical modifications introduced in the amino acid sequences as well as linkers and new bifunctional chelators which have significantly improved the specificity and sensitivity of peptides used in oncologic diagnosis and therapy.

  18. Phthalic anhydride allergy: development and characterization of optimized hapten-carrier conjugates for improved diagnosis.

    Science.gov (United States)

    Pakarinen, M; Koivuluhta, M; Kalkkinen, N; Keskinen, H; Nordman, H; Estlander, T; Tupasela, O; Jolanki, R; Lauerma, A I; Pfäffli, P; Alenius, H

    2002-10-01

    At present the diagnosis of IgE-mediated hypersensitivity to phthalic anhydride (PA) is based on conjugates that are not characterized or standardized. The aim of this study was to develop optimized and molecularly characterized PA conjugates that can be used to improve the diagnosis of PA-allergy. The PA conjugates were synthesized and the number of haptens bound on a carrier protein was estimated by matrix-assisted laser desorption/ionization time of light (MALDI-TOF) mass spectrometry. The ability of conjugates to bind IgE and IgG antibodies was measured by enzyme-linked immunosorbent assay (ELISA). Reactivity of the conjugates in vivo was evaluated by skin prick testing. The most active IgE-binding conjugates had a PA : HSA molar ratio of 80 : 1. In the optimal conjugates the average numbers of PA haptens per carrier molecule of human serum albumin (HSA) were 14-16. In ELISA, all 13 patients and none of the 20 controls had IgE antibodies to optimized PA conjugate. The sensitivity and specificity of the ELISA was comparable to commercial CAP RAST. PA conjugates elicited positive test results in skin prick testing showing that conjugates are immunologically active also in vivo. These results indicate that optimized and molecularly characterized PA-HSA conjugates can be used both in vitro and in vivo assays to improve the diagnosis of PA allergy.

  19. Fluorescein isothiocyanate labeled, magnetic nanoparticles conjugated D-penicillamine-anti-metadherin and in vitro evaluation on breast cancer cells; Avaliacao do isotiocianato de fluoresceina marcado, das nanoparticulas magneticas conjugadas da D-penicilamina antimetaderina e in vitro nas celulas do cancer de mama

    Energy Technology Data Exchange (ETDEWEB)

    Akca, Ozlet; Unak, Perihan; Medine, E. Ylker [Ege University (Turkey). Institute of Nuclear Sciences. Department of Nuclear Applications; Sakarya, Serhan [Adnan Menderes University (Turkey). ADUBILTEM Science and Technology Research and Development Center; Ozdemir, Caglar; Timur, Suna [Ege University (Turkey). Science Faculty. Department of Nuclear Applications

    2011-07-01

    Silane modified magnetic nanoparticles were prepared after capped with silica generated from the hydrolyzation of tetraethyl orthosilicate (TEOS). Amino silane (SG-Si900) was added to this solution for surface modification of silica coated magnetic particles. Finally, D-penicillamine (D-PA)-antimetadherin (anti-MTDH) was covalently linked to the amine group using glutaraldehyde as cross-linker. Magnetic nanoparticles were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), vibrating sample magnetometer (VSM), and atomic force microscopy (AFM). AFM results showed that particles are nearly monodisperse, and the average size of particles was 40 to 50 nm. An amino acid derivative D-PA was conjugated anti-MTDH, which results the increase of uptaking potential of a conjugated agent, labelled fluorescein isothiocyanate (FITC) and then conjugated to the magnetic nanoparticles. In vitro evaluation of the conjugated D-PA-anti-MTDH-FITC to magnetic nanoparticle was studied on MCF-7 breast cancer cell lines. Fluorescence microscopy images of cells after incubation of the sample were obtained to monitor the interaction of the sample with the cancerous cells. Incorporation on cells of FITC labeled and magnetic nanoparticles conjugated D-PA-anti-MTDH was found higher than FITC labeled D-PA-anti-MTDH. The results show that magnetic properties and application of magnetic field increased incorporation rates. The obtained D-PA-anti-MTDH-magnetic nanoparticles-FITC complex has been used for in vitro imaging of breast cancer cells. FITC labeled and magnetic nanoparticles conjugated D-PA-anti-MTDH may be useful as a new class of scintigraphic agents. Results of this study are sufficiently encouraging to bring about further evaluation of this and related compounds for ultraviolet magnetic resonance (UV-MR) dual imaging. (author)

  20. Chelating ligands: enhancers of quality and purity of biogas ...

    African Journals Online (AJOL)

    The quality of biogas depends largely on the percentage of methane and hydrogen sulphide gas present. High concentration of hydrogen sulphide results in low quality biogas. This work employed the use of chelating ligands in scrubbing hydrogen sulphide gas while improving the yield of methane gas. Experimental ...

  1. Iron chelating activity, phenol and flavonoid content of some ...

    African Journals Online (AJOL)

    STORAGESEVER

    2008-09-17

    Sep 17, 2008 ... Thalassemia major is characterized by anemia, iron overload, further potentiation of reactive oxygen species (ROS) and damage to major organs, especially the cardiovascular system. Antioxidant and other supportive therapies protect red blood cells (RBC) against antioxidant damage. Chelation therapy.

  2. Physiological response of Moringa oleifera to stigmasterol and chelated zinc

    Directory of Open Access Journals (Sweden)

    KARIMA GAMAL EL-DIN

    2012-11-01

    Full Text Available El-Moursi A, Talaat IM, Bekheta MA, Gamal El-Din K. 2012. Physiological response of Moringa oleifera to stigmasterol and chelated zinc. Nusantara Bioscience 4: 118-123. Two pot experiments were carried out in the screen of the National Research Centre, Dokki, Giza, Egypt, during two successive seasons (2009/2010 and 2010/2011, respectively to study the effect of foliar spray with chelated zinc (100, 200 and 300 mg/L and stigmasterol (50, 100 and 150 mg/L on growth and chemical constituents of moringa plants. The results indicated that treatment of plants with 300 mg/L chelated zinc or 150 mg/L stigmasterol significantly influenced the vegetative growth of moringa plants. The same treatments also significantly increased total sugars%, total protein%, total phosphorous and microelements contents in the leaves. The changes in the pattern of protein electrophoresis (SDS-PAGE extracted from the newly formed leaves of moringa plants treated with different concentrations of chelated Zinc (Zn or stigmasterol showed beneficial influences for improving plant growth, leaves quality and quantity.

  3. Iron chelation excludes protein synthesis inhibition in the ...

    African Journals Online (AJOL)

    We have compared the trypanocidal properties of four antibiotics that show bactericidal activities by destabilizing ribosome-mRNA complex to inhibit protein synthesis. Tetracycline and oxytetracycline that have iron chelating properties extended the lifespan of trypanosome infected rats from 6 and 5 days of control to 15 and ...

  4. Laccase Immobilization by Chelated Metal Ion Coordination Chemistry

    Directory of Open Access Journals (Sweden)

    Qingqing Wang

    2014-09-01

    Full Text Available In this work, amidoxime polyacrylonitrile (AOPAN nanofibrous membrane was prepared by a reaction between PAN nanofibers and hydroxylamine hydrochloride. The AOPAN nanofibrous membranes were used for four metal ions (Fe3+, Cu2+, Ni2+, Cd2+ chelation under different conditions. Further, the competition of different metal ions coordinating with AOPAN nanofibrous membrane was also studied. The AOPAN chelated with individual metal ion (Fe3+, Cu2+, Ni2+, Cd2+ and also the four mixed metal ions were further used for laccase (Lac immobilization. Compared with free laccase, the immobilized laccase showed better resistance to pH and temperature changes as well as improved storage stability. Among the four individual metal ion chelated membranes, the stability of the immobilized enzymes generally followed the order as Fe–AOPAN–Lac > Cu–AOPAN–Lac > Ni–AOPAN–Lac > Cd–AOPAN–Lac. In addition, the immobilized enzyme on the carrier of AOPAN chelated with four mixed metal ions showed the best properties.

  5. Sequestration of zinc oxide by fimbrial designer chelators

    DEFF Research Database (Denmark)

    Kjærgaard, Kristian; Sørensen, Jack K; Schembri, Mark

    2000-01-01

    Type 1 fimbriae are surface organelles of Escherichia coli. By engineering a structural component of the fimbriae, FimH, to display a random peptide library, we were able to isolate metal-chelating bacteria. A library consisting of 4 x 10(7) independent clones was screened for binding to Zn...

  6. Photoresponsive peptide azobenzene conjugates that specifically interact with platinum surfaces

    Science.gov (United States)

    Dinçer, S.; Tamerler, C.; Sarıkaya, M.; Pişkin, E.

    2008-05-01

    The aim of this study is to prepare photoresponsive peptide-azobenzene compounds which interacts with platinum surfaces specifically, in order to create smart surfaces for further novel applications in design of smart biosensors and array platforms. Here, a water-soluble azobenzene molecule, 4-hydroxyazo benzene,4-sulfonic acid was synthesized by diazo coupling reaction. A platinum-specific peptide, originally selected by a phage display technique was chemically synthesized/purchased, and conjugated with the azobenzene compound activated with carbonyldiimidazole. Both azobenzene and its conjugate were characterized (including photoresponsive properties) by FTIR, NMR, and UV-spectrophotometer. The yield of conjugation reaction estimated by ninhydrin assay was about 65%. Peptide incorporation did not restrict the light-sensitivity of azobenzene. Adsorption of both the peptide and its azobenzene conjugate was followed by Quartz Crystal Microbalance (QCM) system. The kinetic evaluations exhibited that both molecules interact platinum surfaces, quite rapidly and strongly.

  7. Evaluation of the induction of immune memory following infant immunisation with serogroup C Neisseria meningitidis conjugate vaccines--exploratory analyses within a randomised controlled trial.

    Directory of Open Access Journals (Sweden)

    Ameneh Khatami

    Full Text Available We measured meningococcal serogroup C (MenC-specific memory B-cell responses in infants by Enzyme-Linked Immunospot (ELISpot following different MenC conjugate vaccine schedules to investigate the impact of priming on immune memory.Infants aged 2 months were randomised to receive 1 or 2 doses of MenC-CRM197 at 3 or 3 and 4 months, 1 dose of MenC-TT at 3 months, or no primary MenC doses. All children received a Haemophilus influenzae type b (Hib-MenC booster at 12 months. Blood was drawn at 5, 12, 12 months +6 days and 13 months of age.Results were available for 110, 103, 76 and 44 children from each group respectively. Following primary immunisations, and prior to the 12-month booster, there were no significant differences between 1- or 2-dose primed children in the number of MenC memory B-cells detected. One month following the booster, children primed with 1 dose MenC-TT had more memory B-cells than children primed with either 1-dose (p = 0.001 or 2-dose (p<0.0001 MenC-CRM197. There were no differences in MenC memory B-cells detected in children who received 1 or 2 doses of MenC-CRM197 in infancy and un-primed children.MenC-specific memory B-cell production may be more dependent on the type of primary vaccine used than the number of doses administered. Although the mechanistic differences between MenC-CRM197 and MenC-TT priming are unclear, it is possible that structural differences, including the carrier proteins, may underlie differential interactions with B- and T-cell populations, and thus different effects on various memory B-cell subsets. A MenC-TT/Hib-MenC-TT combination for priming/boosting may offer an advantage in inducing more persistent antibody.EU Clinical Trials Register 2009-016579-31 ClinicalTrials.gov NCT01129518.

  8. Chelator induced phytoextraction and in situ soil washing of Cu

    Energy Technology Data Exchange (ETDEWEB)

    Kos, Bostjan; Lestan, Domen

    2004-11-01

    In a soil column experiment, we investigated the effect of 5 mmol kg{sup -1} soil addition of citric acid, ethylenediamine tetraacetate (EDTA), diethylenetriamine-pentaacetate (DTPA) and [S,S]-stereoisomer of ethylenediamine-disuccinate (EDDS) on phytoextraction of Cu from a vineyard soil with 162.6 mg kg{sup -1} Cu, into the test plant Brassica rapa var. pekinensis. We also examined the use of a horizontal permeable barrier, composed of layers of nutrient enriched sawdust and apatite, for reduction of chelator induced Cu leaching. The addition of all chelators, except citric acid, enhanced Cu mobility and caused leaching of 19.5-23% of initial total Cu from the soil column. However, Cu plant uptake did not increase accordingly; the most effective was the EDDS treatment, in which plant Cu concentration reached 37.8{+-}1.3 mg kg{sup -1} Cu and increased by 3.3-times over the control treatment. The addition of none of the chelators in the concentration range from 5 to 15 mmol kg{sup -1} exerted any toxic effect on respiratory soil microorganisms. When EDDS was applied into the columns with horizontal permeable barriers, only 0.53{+-}0.32% of the initial total Cu was leached. Cu (36.7%) was washed from the 18 cm soil layer above the barrier and accumulated in the barrier. Our results indicate that rather than for a reduction of Cu leaching during rather ineffective chelate induced Cu phytoextraction, horizontal permeable barriers could be more effective in a new remediation technique of controlled in situ soil washing of Cu with biodegradable chelates.

  9. Star-Shaped Conjugated Systems

    Directory of Open Access Journals (Sweden)

    Heiner Detert

    2010-05-01

    Full Text Available The present review deals with the preparation and the properties of star-shaped conjugated compounds. Three, four or six conjugated arms are attached to cross-conjugated cores, which consist of single atoms (B, C+, N, benzene or azine rings or polycyclic ring systems, as for example triphenylene or tristriazolotriazine. Many of these shape-persistent [n]star compounds tend to π-stacking and self-organization, and exhibit interesting properties in materials science: Linear and non-linear optics, electrical conductivity, electroluminescence, formation of liquid crystalline phases, etc.

  10. Synthesis and evaluation of {sup 99m}Tc-labeled folate-tripeptide conjugate as a folate receptor-targeeted imaging agent in a tumor-bearing mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Myoung Hyoun; Kim, Chang Guhn; Kim, Dae Weung [Dept. of Nuclear Medicine, Wonkwang University School of Medicine, Iksan (Korea, Republic of); Kim, Woo Hyoung [Dept. of Nuclear Medicine, Seoul National University Hospital, Seoul (Korea, Republic of)

    2015-09-15

    The folate receptor (FR) is an attractive molecular target since it is overexpressed in a variety of human tumors. The purpose of the present study was to synthesize and evaluate the feasibility of a novel {sup 99m}Tc-ECG-EDA (Glu-Cys-Gly-ethylenediamine)-folate as an FR-positive tumor imaging agent in a mouse tumor model. ECG-EDA-folate was synthesized using solid phase peptide synthesis (SPPS) and radiolabeled with {sup 99m}Tc using tripeptide ECG as a chelator. FR-positive KB cells were inoculated in athymic nude mice. Following injection of {sup 99m}Tc-ECG-EDA-folate, serial scintigraphy and micro-SPECT/CT imaging were performed at various time points with and without pre-administration of excess free folate. Mean count densities (MCD) for regions of interest drawn on KB tumors and major normal organs at each time point were measured, and uptake ratios of tumor to normal organs were calculated. ECG-EDA-folate was labeled with {sup 99m}Tc with high radiolabeling efficiency and stability (>96 %). FR-positive tumors were clearly visualized on both scintigraphy and micro-SPECT/CT images and the tumor uptake of {sup 99m}Tc-ECG-EDA-folate was markedly suppressed with faint visualization of tumors by pre-administration of excess free folate on serial planar scintigraphy, indicating FR-specific binding of the agent. Furthermore, semiquantitative analysis of MCD data showed again that both tumor MCD and tumor-to-normal organ ratios decreased considerably by pre-administration of excess free folate, supporting FR-specific tumor uptake. Tumor-to-normal organ ratios approximately increased with time after injection until 4 h. The present study demonstrated that 9{sup 99m}Tc-ECG-EDA-folate can bind specifically to FR with clear visualization of FR-positive tumors in a mouse tumor model.

  11. 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...

  12. Iron chelators: correlation between effects on Plasmodium spp. and immune functions.

    NARCIS (Netherlands)

    Golenser, J.; Domb, A.; Mordechai-Daniel, T.; Leshem, B.; Luty, J.F.; Kremsner, P.

    2006-01-01

    Iron chelating agents, which permeate through erythrocytic and parasite membranes, are effective against Plasmodium falciparum in vitro. However, the protective effect in humans is transient. We examined the antiplasmodial capacity of several iron chelators in vitro and in vivo. The chelators

  13. Iron(III)-chelating resins. X. Iron detoxification of human plasma with iron(III)-chelating resins

    NARCIS (Netherlands)

    Feng, M.; Feng, M.H.; van der Does, L.; Bantjes, A.; Bantjes, A.

    1994-01-01

    Iron detoxification of human blood plasma was studied with resins containing desferrioxamine B (DFO) or 3-hydroxy-2-methyl-4(1H)-pyridinone (HMP) as iron(III)-chelating groups. The behaviour of four resins was investigated: DFO-Sepharose, HMP-Sepharose and crosslinked copolymers of

  14. The Effect of Mini-PEG-Based Spacer Length on Binding and Pharmacokinetic Properties of a 68Ga-Labeled NOTA-Conjugated Antagonistic Analog of Bombesin

    Directory of Open Access Journals (Sweden)

    Zohreh Varasteh

    2014-07-01

    Full Text Available The overexpression of gastrin-releasing peptide receptor (GRPR in cancer can be used for peptide-receptor mediated radionuclide imaging and therapy. We have previously shown that an antagonist analog of bombesin RM26 conjugated to 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA via a diethyleneglycol (PEG2 spacer (NOTA-PEG2-RM26 and labeled with 68Ga can be used for imaging of GRPR-expressing tumors. In this study, we evaluated if a variation of mini-PEG spacer length can be used for optimization of targeting properties of the NOTA-conjugated RM26. A series of analogs with different PEG-length (n = 2, 3, 4, 6 was synthesized, radiolabeled and evaluated in vitro and in vivo. The IC50 values of natGa-NOTA-PEGn-RM26 (n = 2, 3, 4, 6 were 3.1 ± 0.2, 3.9 ± 0.3, 5.4 ± 0.4 and 5.8 ± 0.3 nM, respectively. In normal mice all conjugates demonstrated similar biodistribution pattern, however 68Ga-NOTA-PEG3-RM26 showed lower liver uptake. Biodistribution of 68Ga-NOTA-PEG3-RM26 was evaluated in nude mice bearing PC-3 (prostate cancer and BT-474 (breast cancer xenografts. High uptake in tumors (4.6 ± 0.6%ID/g and 2.8 ± 0.4%ID/g for PC-3 and BT-474 xenografts, respectively and high tumor-to-background ratios (tumor/blood of 44 ± 12 and 42 ± 5 for PC-3 and BT-474 xenografts, respectively were found already at 2 h p.i. of 68Ga-NOTA-PEG3-RM26. Results of this study suggest that variation in the length of the PEG spacer can be used for optimization of targeting properties of peptide-chelator conjugates. However, the influence of the mini-PEG length on biodistribution is minor when di-, tri-, tetra- and hexaethylene glycol are compared.

  15. Determination of conjugation rates on solid surfaces

    OpenAIRE

    del Campo I.; Ruiz R; Cuevas A.; Revilla C.; Vielva L.; de la Cruz F.

    2012-01-01

    A cytometric method for the estimation of end-point conjugation rates is developed and adapted to surface conjugation. This method improves the through-put of conjugation assays based on replica-plating and results in less noisy experimental data. Although conjugation on solid surfaces deviates from ideal conditions in which cells are continuously mixed, results show that, within the limits of high initial population densities and short mating times, end-point estimates of the conjugation rat...

  16. Novel hyaluronic acid-methotrexate conjugates for osteoarthritis treatment.

    Science.gov (United States)

    Homma, Akie; Sato, Haruhiko; Okamachi, Akira; Emura, Takashi; Ishizawa, Takenori; Kato, Tatsuya; Matsuura, Tetsu; Sato, Shigeo; Tamura, Tatsuya; Higuchi, Yoshinobu; Watanabe, Tomoyuki; Kitamura, Hidetomo; Asanuma, Kentaro; Yamazaki, Tadao; Ikemi, Masahisa; Kitagawa, Hironoshin; Morikawa, Tadashi; Ikeya, Hitoshi; Maeda, Kazuaki; Takahashi, Koichi; Nohmi, Kenji; Izutani, Noriyuki; Kanda, Makoto; Suzuki, Ryochi

    2009-07-01

    Hyaluronic acid (HA) provides synovial fluid viscoelasticity and has a lubricating effect. Injections of HA preparations into the knee joint are widely used as osteoarthritis therapy. The current HA products reduce pain but do not fully control inflammation. Oral methotrexate (MTX) has anti-inflammatory efficacy but is associated with severe adverse events. Based on the rationale that a conjugation of HA and MTX would combine the efficacy of the two clinically evaluated agents and avoid the risks of MTX alone, we designed HA-MTX conjugates in which the MTX connects with the HA through peptides susceptible to cleavage by lysosomal enzymes. Intra-articular injection of our HA-MTX conjugate (conjugate 4) produced a significant reduction of the knee swelling in antigen-induced arthritis rat, whereas free MTX, HA or a mixture of HA and MTX showed no or marginal effects on the model. The efficacy of conjugate 4 was almost the same as that of MTX oral treatment. Conjugate 4 has potential as a compound for the treatment of osteoarthritis.

  17. Adsorption characteristics of Ni(II) onto MA-DTPA/PVDF chelating membrane

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Xiaodan [Department of Environmental and Chemical Engineering, Yanshan University, Qinhuangdao 066004 (China); Song, Laizhou, E-mail: songlz@ysu.edu.cn [Department of Environmental and Chemical Engineering, Yanshan University, Qinhuangdao 066004 (China); Fu, Jie; Tang, Pei; Liu, Feng [Department of Environmental and Chemical Engineering, Yanshan University, Qinhuangdao 066004 (China)

    2011-05-30

    The melamine-diethylenetriaminepentaacetic acid/polyvinylidene fluoride (MA-DTPA/PVDF) chelating membrane bearing polyaminecarboxylate groups was prepared for the removal of Ni(II) from wastewater effluents. The membrane was characterized by SEM, {sup 13}C NMR and FTIR techniques. Quantitative adsorption experiments were performed in view of pH, contact time, temperature, the presence of Ca(II) and lactic acid as the controlling parameters. Adsorption kinetics and equilibrium were examined regarding the single Ni(II) system, binary Ni(II) and Ca(II) system and nickel-lactic acid complexes system. The desorption efficiency was also evaluated, and the adsorption mechanism was suggested based on experimental data. The results show that the sorption kinetics fit well to Lagergren second-order equation and the isotherms can be well described by Langmuir model. At 298 K, the second-order rate constant is calculated to be 4.171, 11.39, 6.203 cm{sup 2}/(mg min) and the equilibrium uptake is 0.0264, 0.0211 and 0.0216 mg/cm{sup 2} in the aforementioned three systems. The distribution coefficient of Ni(II) slowly decreases from 4.27 to 2.72, and the separation factor (f{sub Ni(II)/Ca(II)}) increases from 3.10 to 8.46 when the initial Ca(II) concentration varies from 20 to 200 mg/L. This reveals the chelating membrane shows more affinity for Ni(II) than Ca(II) ions. In the studied range of lactic acid concentration, Ni(II) uptake decreases with the maximum ratio of 10%. Chemical bonding (chelation) dominates in the adsorption process, and the negative {Delta}G{sup o} and {Delta}H{sup o} indicate the spontaneous and exothermic nature of adsorption.

  18. Water-soluble chelating polymers for removal of actinides from wastewater

    Energy Technology Data Exchange (ETDEWEB)

    Jarvinen, G.D. [Los Alamos National Lab., NM (United States)

    1997-10-01

    Polymer filtration is a technology under development to selectively recover valuable or regulated metal ions from process or wastewaters. The technology uses water-soluble chelating polymers that are designed to selectively bind with metal ions in aqueous solutions. The polymers have a sufficiently large molecular weight that they can be separated and concentrated using available ultrafiltration (UF) technology. The UF range is generally considered to include molecular weights from about 3000 to several million daltons and particles sizes of about 2 to 1000 nm. Water and smaller unbound components of the solution pass freely through the UF membrane. The polymers can then be reused by changing the solution conditions to release the metal ions that are recovered in concentrated form for recycle or disposal. Some of the advantages of polymer filtration relative to technology now in use are rapid binding kinetics, high selectivity, low energy and capital costs, and a small equipment footprint. Some potential commercial applications include electroplating rinse waters, photographic processing, nuclear power plant cooling water; remediation of contaminated soils and groundwater; removal of mercury contamination; and textile, paint and dye production. The purpose of this project is to evaluate this technology to remove plutonium, americium, and other regulated metal ions from various process and waste streams found in nuclear facilities. The work involves preparation of the water-soluble chelating polymers; small-scale testing of the chelating polymer systems for the required solubility, UF properties, selectivity and binding constants; followed by an engineering assessment at a larger scale to allow comparison to competing separation technologies. This project focuses on metal-ion contaminants in waste streams at the Plutonium Facility and the Waste Treatment Facility at LANL. Potential applications at other DOE facilities are also apparent.

  19. Removal of cadmium from fish sauce using chelate resin.

    Science.gov (United States)

    Sasaki, Tetsuya; Araki, Ryohei; Michihata, Toshihide; Kozawa, Miyuki; Tokuda, Koji; Koyanagi, Takashi; Enomoto, Toshiki

    2015-04-15

    Fish sauce that is prepared from squid organs contains cadmium (Cd), which may be present at hazardous concentrations. Cd molecules are predominantly protein bound in freshly manufactured fish sauce, but are present in a liberated form in air-exposed fish sauce. In the present study, we developed a new method for removing both Cd forms from fish sauce using chelate resin and a previously reported tannin treatment. Sixteen-fold decreases in Cd concentrations were observed (0.78-0.05 mg/100 mL) following the removal of liberated Cd using chelate resin treatment, and the removal of protein-bound Cd using tannin treatment. Major nutritional components of fish sauce were maintained, including free amino acids and peptides, and angiotensin I-converting enzyme inhibitory and antioxidant activities. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Encapsulation and retention of chelated-copper inside hydrophobic nanoparticles

    DEFF Research Database (Denmark)

    Hervella, Pablo; Ortiz, Elisa Parra; Needham, David

    2016-01-01

    that our endogenous-inspired nanoparticle strategies for imaging and therapeutics are focused on encapsulating and retaining imaging ions such as copper inside novel hydrophobic nanoparticles. In this paper, we describe a new approach to label the core of hydrophobic nanoparticles composed of Glyceryl...... Trioleate (Triolein) with copper using the hydrophobic chelator Octaethyl porphyrin (OEP). RESEARCH PLAN AND METHODS: The research plan for this study was to (1) Formulate nanoparticles and control nanoparticle size using a modification of the solvent injection technique, named fast ethanol injection; (2...... to nanoparticles was >95% at low OEP-Cu concentrations. In the absence of OEP, copper was not detected in nanoparticles demonstrating the role of the hydrophobic chelator OEP in the encapsulation of the otherwise water-soluble copper inside lipid nanoparticles. (4) The in vitro retention upon incubation at 37°C...

  1. CITRIC ACID FERMENTATION OF SUGARS PURIFIED WITH CHELATING RESIN1

    Science.gov (United States)

    Noguchi, Yuichi; Johnson, Marvin J.

    1961-01-01

    Noguchi, Yuichi (University of Wisconsin, Madison), and Marvin J. Johnson. Citric acid fermentation of sugars purified with chelating resin. J. Bacteriol. 82:538–541. 1961.—A new, independently isolated strain of Aspergillus niger capable of giving high yields of citric acid in submerged culture was found to show the same behavior toward iron, zinc, and manganese as a previously studied strain. Citric acid accumulation did not occur in the presence of manganese. Best citric acid production was obtained in the presence of limited amounts of iron and zinc. Use of a chelating ion exchange resin was found to be an excellent method of removing polyvalent metals from sugars, either for analytical purposes or for fermentation. Commercial glucose, after resin treatment, gave citric acid yields of more than 80% when supplemented with iron and zinc. Unpurified glucose was converted to citric acid in good yields by mycelium grown on resin-treated glucose. PMID:14480219

  2. Synthesis and Characterization of Sodium Alginate Conjugate and Study of Effect of Conjugation on Drug Release from Matrix Tablet.

    Science.gov (United States)

    Satheeshababu, B K; Mohamed, I

    2015-01-01

    The aim of the present research work to study the effect of conjugation of the polymer on drug release from the matrix tablets. Sodium alginate L-cysteine conjugate was achieved by covalent attachment of thiol group of L-cysteine with the primary amino group of sodium alginate through the amide bonds formed by primary amino groups of the sodium alginate and the carboxylic acid group of L-cysteine. The synthesised sodium alginate L-cysteine conjugate was characterised by determining of charring point, Fourier transmission-infrared and differential scanning calorimetric analysis. To study the effect of conjugation on drug release pattern, the matrix tablets were prepared using various proportions of sodium alginate and sodium alginate L-cysteine conjugate along with atorvastatin calcium as model drug. The wet granulation technique was adopted and prepared matrix tablets were evaluated for various physical parameters. The in vitro drug release study results suggested that tablet formulated in combination of sodium alginate and sodium alginate L-cysteine conjugate S4 showed 100% after 8 h drug release whereas formulated with only sodium alginate S0 released 40% in 8 h.

  3. Effect of two biodegradable chelates on metals uptake, translocation and biochemical changes of Lantana Camara growing in fly ash amended soil.

    Science.gov (United States)

    Pandey, Shikha Kumari; Bhattacharya, Tanushree

    2017-10-20

    The present work had two purposes firstly to evaluate the potential of Lantana Camara for phytoextraction of heavy metals from fly ash amended soil and to assess the suitability of a proper biodegradable chelating agent for chelate assisted phytoextraction. Plants were grown in manure mixed soil amended with various concentration of fly ash. Two biodegradable chelating agents were added (EDDS and MGDA) in the same dose separately before maturation stage. Sampling was done at different growing stages. The plant took up metal in different plant parts in the following order: for Cu, and Zn leaf >root >stem, for Cr and Mn leaf>stem >root, for Ni root >leaf>stem and for Pb root≈leaf>stem respectively. For Cu, Zn, Cr and Mn Lantana camara acted as phytoextractor. Translocation factor and bioaccumulation coefficient was>1 signifying enrichment and translocation of metals in the plant. Morphological studies showed no toxicity symptom in the plant. Among biochemical parameters protein and nitrate reductase activity decreased, whereas, chlorophyll and peroxidise activity increased with the growth stages. Finally, it was evident from the results that Lantana Camara can be used as efficient phytoextractor of metals, with proper harvesting cycle and both chelate were proved as effective chelators for phytoextraction of metals.

  4. Decontamination of process equipment using recyclable chelating solvent

    Energy Technology Data Exchange (ETDEWEB)

    Jevec, J.; Lenore, C.; Ulbricht, S. [Babcock & Wilcox, Co., R& DD, Alliance, OH (United States)

    1995-10-01

    The Department of Energy (DOE) is now faced with the task of meeting decontamination and decommissioning obligations at numerous facilities by the year 2019. Due to the tremendous volume of material involved, innovative decontamination technologies are being sought that can reduce the volumes of contaminated waste materials and secondary wastes requiring disposal. This report describes the results of the performance testing of chelates and solvents for the dissolution of uranium.

  5. Targeted Iron Chelation Will Improve Recovery after Spinal Cord Injury

    Science.gov (United States)

    2014-10-01

    life. Even though sub- stantial improvements in care have increased survival rates, people with SCI now live with significant deficits for many...can re- duce tissue damage and promote functional improvement (Klapka et al., 2005; Paterniti et al., 2010; Rathore et al., 2008; Schultke et al...attenuate post-SCI pathology ( Paterniti et al., 2010). A caveat, however, is that the drug was given 30 min prior to injury. The iron chelator

  6. Chelating agents for uranium(VI): 2. Efficacy and toxicity of tetradentate catecholate and hydroxypyridinonate ligands in mice.

    Science.gov (United States)

    Durbin, P W; Kullgren, B; Ebbe, S N; Xu, J; Raymond, K N

    2000-05-01

    Uranium(VI) (UO2(2+), uranyl) is nephrotoxic. Depending on isotopic composition and dosage, U(VI) is also chemically toxic and carcinogenic in bone. Several ligands containing two, three, or four bidentate catecholate or hydroxypyridinonate metal binding groups, developed for in vivo chelation of other actinides, were found, on evaluation in mice, to be effective for in vivo chelation of U(VI). The most promising ligands contained two bidentate groups per chelator molecule (tetradentate) attached to linear 4- or 5-carbon backbones (4-LI, butylene; 5-LI, pentylene; 5-LIO, diethyl ether). New ligands were then prepared to optimize ligand affinity for U(VI) in vivo and low acute toxicity. Five bidentate binding groups--sulfocatechol [CAM(S)], carboxycatechol [CAM(C)], methylterephthalamide (MeTAM), 1,2-hydroxypyridinone (1,2-HOPO), or 3,2-hydroxypyridinone (Me-3,2-HOPO)--were each attached to two linear backbones (4-LI and 5-LI or 5-LIO). Those ten tetradentate ligands and octadentate 3,4,3-LI(1,2-HOPO), an effective actinide chelator, were evaluated in mice for in vivo chelation of 233U(VI) (injection at 3 min, 1 h, or 24 h or oral administration at 3 min after intravenous injection of 233UO2Cl2) and for acute toxicity (100 micromol kg(-1) injected daily for 10 d). The combined efficacy and toxicity screening identified 5-LIO(Me-3,2-HOPO) and 5-LICAM(S) as the most effective low-toxicity agents. They chelate circulating U(VI) efficiently at ligand:uranium molar ratios > or = 20, remove useful amounts of newly deposited U(VI) from kidney and bone at molar ratios > or = 100, and reduce kidney U(VI) levels significantly when given orally at molar ratios > or = 100. 5-LIO(Me-3,2-HOPO) has greater affinity for kidney U(VI) while 5-LICAM(S) has greater affinity for bone U(VI), and a 1:1 mixture (total molar ratio = 91) reduced kidney and bone U(VI) to 15 and 58% of control, respectively--more than an equimolar amount of either ligand alone.

  7. The removal of strontium from the mouse by chelating agents

    Energy Technology Data Exchange (ETDEWEB)

    Ortega, A.; Gomez, M.; Domingo, J.L.; Corbella, J.

    1989-07-01

    The effects of the chelating agents monosodium glutamate, Tiron, tartaric acid, ascorbic acid, 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6), 2,3-dimercaptosuccinic acid (DMSA), succinic acid, malic acid, ethylendiaminetetraacetic acid (EDTA), ethylenglycol-bis-(beta-amino-ethylether)-N,N'tetraacetic acid (EGTA), cyclohexane-diaminetetraacetic acid (CDTA) and diethylentria-minepentaacetic acid (DTPA) on the distribution and excretion of intraperitoneally injected strontium were investigated in male Swiss mice. Strontium nitrate was given at a dose equal to 3.78 mmol/kg and ten minutes after, chelators were administered intraperitoneally at doses approximately equal to one-fourth of their respective LD50 values. DTPA, followed by CDTA, EDTA and tartaric acid, was consistently the most effective in increasing the urinary excretion of strontium. Only ascorbic acid increased significantly the fecal excretion of strontium. CDTA, DTPA and ascorbic acid were also the most effective chelators in reducing the concentration of strontium found in various tissues. CDTA, DTPA and tartaric acid are the most effective agents of those tested in the removal of strontium after a single administration.

  8. Copper and Zinc Chelation as a Treatment of Alzheimer's Disease

    Science.gov (United States)

    Hodak, Miroslav; Bernholc, Jerry

    2014-03-01

    Alzheimer's disease (AD) is a neurodegenerative disorder affecting millions of people in the U.S. The cause of the disease remains unknown, but amyloid- β (A β), a short peptide, is considered causal its pathogenesis. At cellular level, AD is characterized by deposits mainly composed of A β that also contain elevated levels of transition metals ions. Targeting metals is a promising new strategy for AD treatment, which uses moderately strong metal chelators to sequester them from A β or the environment. PBT2 is a chelating compound that has been the most promising in clinical trials. In our work, we use computer simulations to investigate complexes of a close analog of PBT2 with Cu2+ and Zn2+ ions. The calculations employ KS/FD DFT method, which combines Kohn-Sham DFT with the frozen-density DFT to achieve efficient description of explicit solvent beyond the first solvation shell. Our work is based on recent experiments and examines both 1:1 and 2:1 chelator-metal stochiometries detected experimentally. The results show that copper attaches more strongly than zinc, find that 1:1 complexes involve water in the first coordination shell and determine which one of several possible 2:1 geometries is the most preferable.

  9. Chelate forms of biometalls. Theoretical aspects of obtaining and characteristics

    Directory of Open Access Journals (Sweden)

    A. Kapustyan

    2017-04-01

    Full Text Available The problem of microelements bioavailability is highlighted and the correct ways of its solution are substantiated as a result of generalization of theoretical aspects of obtaining of the biometals chelate forms. The characteristics of the main biogenic elements, their physiological significance, electrochemical properties are presented. The main examples of the participation of biometals in various biological processes are given. The properties and the structure peculiarities of biometals coordination complexes are considered in detail. It is shown that in obtaining of biometals chelate forms, there is the mutual selectivity and the affinity of biometals and ligands. The main factors of obtaining a hard metal complex are given. Potential bioligands for obtaining bioavailable forms of microelements are detailed. Among them there are amino acids, peptides, proteins, nucleic acids, carbohydrates. The possible character of complexation depending on the nature of the bioligand is indicated. Practical examples of preparation of biometals mixed ligand complexes are given. The expediency of using metabolic products and processing of lactic acid bacteria as promising components of mixed ligand chelate complexes is substantiated. These substances contain in their composition a mass of potential donor atoms that are capable to form covalent and coordination bonds with biomethalles, and also possess high biological and immunotropic activities. The use of this system in the biocoordination compounds of the "metals of life" can provide a synergistic effect of the components, significantly to expand the range of their physiological activity and to increase the degree of assimilation by the body.

  10. Systemic aspects of conjugal resilience in couples with a child facing cancer and marrow transplantation

    Directory of Open Access Journals (Sweden)

    Julie Martin

    2016-09-01

    Full Text Available Introduction: The negative impact of paediatric cancer on parents is well known and is even greater when intensive treatments are used. This study aimed to describe how couples whose child has received a transplant for the treatment of leukaemia view conjugal resilience and to evaluate the role of we-ness as a precursor of conjugal adjustment. Methods: Four parental couples were interviewed. Interviews were analysed in two ways: inductive thematic analysis and rating of verbal content with the We-ness Coding Scale. Results: Participants report that conjugal resilience involves the identification of the couple as a team and cohesion in the couple. Being a team generates certain collaborative interactions that lead to conjugal resilience. A sense of we-ness in parents is associated with fluctuation in the frequency of themes. Discussion: Participants’ vision of conjugal resilience introduced novel themes. The sense of we-ness facilitates cohesion and the process of conjugal resilience.

  11. Novel amphiphilic PEG-hydroxycamptothecin conjugates as glutathione-responsive prodrug nanocapsules for cancer chemotherapy

    Science.gov (United States)

    Guo, Na; Hao, Tiantian; Shang, Xiuzhuan; Zhang, Tianle; Liu, Huan; Zhang, Qian; Wang, Jing; Jiang, Du; Rong, Yao; Teng, Yuou; Yu, Peng

    2017-06-01

    A series of novel hydroxycamptothecin (HCPT) conjugates ( 13a-14d), which contained a polyethylene glycol moiety and disulfide bond, were designed and synthesized in five to six steps, with overall yields of 20-39%. The anticancer activities and toxicities of these new conjugates were evaluated using an in vitro MTT assay in K562, HepG2, and HT-29 cell lines and HUVECs. The conjugates displayed enhanced antitumor activity and reduced toxicity in comparison with their parent molecule, HCPT. Among these conjugates, compound 13a exhibited 100-fold better selectivity to the tumor cells than to HUVECs. TEM and DLS experiments demonstrated that 13a formed nanosized micelles with a diameter of approximately 200 nm in aqueous solution and that the conjugate could undergo glutathione-responsive degradation to release HCPT at the tumor site. The improved potency and reduced toxicity of these conjugates may be caused by the enhanced permeation and retention (EPR) effect of nanoparticles.

  12. Water-soluble polymer–drug conjugates for combination chemotherapy against visceral leishmaniasis

    Science.gov (United States)

    Nicoletti, Salvatore; Seifert, Karin; Gilbert, Ian H.

    2010-01-01

    There is a need for new safe, effective and short-course treatments for leishmaniasis; one strategy is to use combination chemotherapy. Polymer–drug conjugates have shown promise for the delivery of anti-leishmanial agents such as amphotericin B. In this paper, we report on the preparation and biological evaluation of polymer–drug conjugates of N-(2-hydroxypropyl)methacrylamide (HPMA), amphotericin B and alendronic acid. The combinatorial polymer–drug conjugates were effective anti-leishmanial agents in vitro and in vivo, but offered no advantage over the single poly(HPMA)–amphotericin B conjugates. PMID:20338769

  13. Conjugated polymer nanoparticles, methods of using, and methods of making

    KAUST Repository

    Habuchi, Satoshi

    2017-03-16

    Embodiments of the present disclosure provide for conjugated polymer nanoparticle, method of making conjugated polymer nanoparticles, method of using conjugated polymer nanoparticle, polymers, and the like.

  14. Metallic Element Chelated Tag Labeling (MeCTL) for Quantitation of N-Glycans in MALDI-MS.

    Science.gov (United States)

    Yang, Lijun; Peng, Ye; Jiao, Jing; Tao, Tao; Yao, Jun; Zhang, Ying; Lu, Haojie

    2017-07-18

    N-glycosylation plays an important role in chief biological and pathological processes. Quantifying the N-glycan is important since glycan alterations are related to many diseases. In this study, we developed a novel N-glycan quantitation approach using metallic element chelated tag labeling (MeCTL) through reductive amination. The MeCTL strategy is of high labeling efficiency and accurate in quantitation with high reproducibility (CV 0.99) within 2 orders of magnitude of dynamic range. Additionally, it provides significant cross-ring fragmentation to distinguish N-glycan isomers. Furthermore, multiplex quantitation by chelation with several different rare earth elements can be achieved. At last, this strategy has been successfully used for evaluation of N-glycan changes in human serum associated with CRC, indicating its potential in clinical applications including disease N-glycome profiling and relative quantitation.

  15. Functionalization of hydroxy compounds with nitrilotriacetic acid for technetium-99m chelation: excretory properties of the radiolabelled chelates.

    Science.gov (United States)

    Chatterjee, M; Banerjee, S

    1991-01-01

    Substituted monoanilides of nitrilotriacetic acid (NTA) have gained much popularity in recent years as an important class of ligands for technetium-99m (99mTc) radiopharmaceutical preparations used in liver imaging and function studies. We were interested in investigating the properties of the corresponding ester analogues of this important class of ligands and for this study cyclohexanol was selected as a hydroxy component, which on condensation with nitrilotriacetic acid in the presence of acetic anhydride, furnished the monoester, N-cyclohexyloxycarbonylmethyl iminodiacetic acid 4 and the corresponding diester 5. Phenol on similar condensation produced mainly the diester, N,N-di(phenyloxycarbonylmethyl) aminoacetic acid 2, with traces of the corresponding monoester 7. A reinvestigation of the well known condensation reaction of aniline with nitrilotriacetic acid revealed that in addition to the reported monoanilide, N-phenylcarbamoylmethyl imino diacetic acid 3, the corresponding dianilide 6 was also produced in appreciable amount. The ester ligands 2, 4, 5 after 99mTc chelation exhibited good in vitro and in vivo stabilities. The biodistribution characteristics of these radiolabelled esters and amides were very similar showing thereby that esterification with NTA could be an effective method for converting alcohols to 99mTc-radiopharmaceuticals without generating any unusual properties because of the ester linkage. Residual radiopharmaceutical concentration after i.v. administration of these amide and ester 99mTc chelates at 30 min in blood, urine, liver, kidney and intestine were correlated with their lipophilicities and during this correlation it was observed that in addition to lipophilicity the anionic strength of these chelates is also an important determinant in governing their biodistribution. The ester ligand 4 after 99mTc chelation showed ultrafast hepatobiliary kinetics and was therefore compared in a rabbit model with a standard hepatobiliary

  16. Chelation therapy in Wilson's disease: from D-penicillamine to the design of selective bioinspired intracellular Cu(I) chelators.

    Science.gov (United States)

    Delangle, Pascale; Mintz, Elisabeth

    2012-06-07

    Wilson's disease is an orphan disease due to copper homeostasis dysfunction. Mutations of the ATP7B gene induces an impaired functioning of a Cu-ATPase, impaired Cu detoxification in the liver and copper overload in the body. Indeed, even though copper is an essential element, which is used as cofactor by many enzymes playing vital roles, it becomes toxic when in excess as it promotes cytotoxic reactions leading to oxidative stress. In this perspective, human copper homeostasis is first described in order to explain the mechanisms promoting copper overload in Wilson's disease. We will see that the liver is the main organ for copper distribution and detoxification in the body. Nowadays this disease is treated life-long by systemic chelation therapy, which is not satisfactory in many cases. Therefore the design of more selective and efficient drugs is of great interest. A strategy to design more specific chelators to treat localized copper accumulation in the liver will then be presented. In particular we will show how bioinorganic chemistry may help in the design of such novel chelators by taking inspiration from the biological copper cell transporters.

  17. Determination of trace indium in urine after preconcentration with a chelating-resin-packed minicolumn.

    Science.gov (United States)

    Liu, Hui-Ming; Chang, Ching-Yao; Wu, Chia-Chan; Wei, Jian-Ming; Chen, Wei-Yu; Yeh, Cheng-Tsung

    2012-04-01

    A simple and rapid chelating-resin-packed column has been developed for preconcentration of trace indium in biological samples. A large-sized urine sample was pumped through a minicolumn at a flow rate of 1.0 mL/min by using a peristaltic pump, and the eluents were analyzed using graphite furnace atomic absorption spectrometry (GFAAS). Four commercially available chelating resins including Chelex-100, Amberlite IRC-50, Duolite GT-73, and Celite 545-AW were studied for evaluating the indium sorption performance. Several parameters, such as pH, resin amount, eluent volume, eluent flow rate, and the volume of sample, were investigated and optimized. A 100-200 mL of the sample was loaded into a column containing 1.2 g of wet Chelex-100 and subjected to the ion-exchange procedure. The retained analytes were eluted with 5.0 mL of 0.1 M HNO(3) and quantified by GFAAS. The correlation coefficient in the range 10-250 ng/mL was of 0.9994. The limit of detection of the proposed method was 2.75 ng/mL. The method developed was successfully applied to analysis of spiked urine samples with good recoveries of 93-103% (n = 6) and reproducibility (relative standard deviation indium determination in spiked certified reference materials. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. OligoG CF-5/20 normalizes cystic fibrosis mucus by chelating calcium.

    Science.gov (United States)

    Ermund, Anna; Recktenwald, Christian V; Skjåk-Braek, Gudmund; Meiss, Lauren N; Onsøyen, Edvar; Rye, Philip D; Dessen, Arne; Myrset, Astrid Hilde; Hansson, Gunnar C

    2017-06-01

    The goal of this study was to determine whether the guluronate (G) rich alginate OligoG CF-5/20 (OligoG) could detach cystic fibrosis (CF) mucus by calcium chelation, which is also required for normal mucin unfolding. Since bicarbonate secretion is impaired in CF, leading to insufficient mucin unfolding and thereby attached mucus, and since bicarbonate has the ability to bind calcium, we hypothesized that the calcium chelating property of OligoG would lead to detachment of CF mucus. Indeed, OligoG could compete with the N-terminus of the MUC2 mucin for calcium binding as shown by microscale thermophoresis. Further, effects on mucus thickness and attachment induced by OligoG and other alginate fractions of different length and composition were evaluated in explants of CF mouse ileum mounted in horizontal Ussing-type chambers. OligoG at 1.5% caused effective detachment of CF mucus and the most potent alginate fraction tested, the poly-G fraction of about 12 residues, had similar potency compared to OligoG whereas mannuronate-rich (M) polymers had minimal effect. In conclusion, OligoG binds calcium with appropriate affinity without any overt harmful effect on the tissue and can be exploited for treating mucus stagnation. © 2017 John Wiley & Sons Australia, Ltd.

  19. Effect of endodontic chelating solutions on the bond strength of endodontic sealers

    Directory of Open Access Journals (Sweden)

    Behram TUNCEL

    2015-01-01

    Full Text Available The purpose of this in vitro study was to evaluate the effect of various chelating solutions on the radicular push-out bond strength of calcium silicate-based and resin-based root canal sealers. Root canals of freshly-extracted single-rooted teeth (n = 80 were instrumented by using rotary instruments. The specimens were randomly divided into 4 groups according to the chelating solutions being tested: (1 17% ethylenediaminetetraacetic acid (EDTA; (2 9% etidronic acid; (3 1% peracetic acid (PAA; and (4 distilled water (control. In each group, the roots were further assigned into 2 subgroups according to the sealer used: (1 an epoxy resin-based sealer (AH Plus and (2 a calcium silicate-based sealer (iRoot SP. Four 1 mm-thick sections were obtained from the coronal aspect of each root (n = 40 slices/group. Push-out bond strength test was performed at a crosshead speed of 1 mm/min., and the bond strength data were analyzed statistically with two-way analysis of variance (ANOVA with Bonferroni’s post hoc test (p 0.05. iRoot SP showed higher resistance to dislocation than AH Plus. Final irrigation with 17% EDTA, 9% Etidronic acid, and 1% PAA did not improve the bond strength of AH Plus and iRoot SP to radicular dentin.

  20. Mechanisms of Fe biofortification and mitigation of Cd accumulation in rice (Oryza sativa L.) grown hydroponically with Fe chelate fertilization.

    Science.gov (United States)

    Chen, Zhe; Tang, Ye-Tao; Zhou, Can; Xie, Shu-Ting; Xiao, Shi; Baker, Alan J M; Qiu, Rong-Liang

    2017-05-01

    Cadmium contaminated rice from China has become a global food safety issue. Some research has suggested that chelate addition to substrates can affect metal speciation and plant metal content. We investigated the mitigation of Cd accumulation in hydroponically-grown rice supplied with EDTANa2Fe(II) or EDDHAFe(III). A japonica rice variety (Nipponbare) was grown in modified Kimura B solution containing three concentrations (0, 10, 100 μΜ) of the iron chelates EDTANa2Fe(II) or EDDHAFe(III) and 1 μΜ Cd. Metal speciation in solution was simulated by Geochem-EZ; growth and photosynthetic efficiency of rice were evaluated, and accumulation of Cd and Fe in plant parts was determined. Net Cd fluxes in the meristematic zone, growth zone, and maturation zone of roots were monitored by a non-invasive micro-test technology. Expression of Fe- and Cd-related genes in Fe-sufficient or Fe-deficient roots and leaves were studied by QRT-PCR. Compared to Fe deficiency, a sufficient or excess supply of Fe chelates significantly enhanced rice growth by elevating photosynthetic efficiency. Both Fe chelates increased the Fe content and decreased the Cd content of rice organs, except for the Cd content of roots treated with excess EDDHAFe(III). Compared to EDDHAFe(III), EDTANa2Fe(II) exhibited better mitigation of Cd accumulation in rice by generating the EDTANa2Cd complex in solution, decreasing net Cd influx and increasing net Cd efflux in root micro-zones. Application of EDTANa2Fe(II) and EDDHAFe(III) also reduced Cd accumulation in rice by inhibiting expression of genes involved in transport of Fe and Cd in the xylem and phloem. The 'win-win' situation of Fe biofortification and Cd mitigation in rice was achieved by application of Fe chelates. Root-to-stem xylem transport of Cd and redistribution of Cd in leaves by phloem transport can be regulated in rice through the use of Fe chelates that influence Fe availability and Fe-related gene expression. Fe fertilization decreased Cd

  1. Oligonucleotide conjugates for therapeutic applications.

    Science.gov (United States)

    Winkler, Johannes

    2013-07-01

    Insufficient pharmacokinetic properties and poor cellular uptake are the main hurdles for successful therapeutic development of oligonucleotide agents. The covalent attachment of various ligands designed to influence the biodistribution and cellular uptake or for targeting specific tissues is an attractive possibility to advance therapeutic applications and to expand development options. In contrast to advanced formulations, which often consist of multiple reagents and are sensitive to a variety of preparation conditions, oligonucleotide conjugates are defined molecules, enabling structure-based analytics and quality control techniques. This review gives an overview of current developments of oligonucleotide conjugates for therapeutic applications. Attached ligands comprise peptides, proteins, carbohydrates, aptamers and small molecules, including cholesterol, tocopherol and folic acid. Important linkage types and conjugation methods are summarized. The distinct ligands directly influence biochemical parameters, uptake mechanisms and pharmacokinetic properties.

  2. Phase conjugation of acoustic beams

    Science.gov (United States)

    Bunkin, F. V.; Vlasov, D. V.; Kravtsov, Iu. A.

    The paper presents a classification of methods for the phase conjugation (PC) of wave fields of various physical natures on the basis of such nonliner interactions as stimulated scattering, and three- and four-wave interactions. Among the latter, attention is given to holographic (volume and surface) and parametric PC schemes, permitting PC with amplification. The possibility of developing phase-conjugated devices using acoustic PC devices on the basis of various nonlinear effects is considered. Experimental results pertaining to the PC of sound fields are presented, and possible applications of acoustic PC devices are indicated.

  3. Emulsifier type, metal chelation and pH affect oxidative stability of n-3-enriched emulsions

    DEFF Research Database (Denmark)

    Haahr, Anne-Mette; Jacobsen, Charlotte

    2008-01-01

    -enriched oil-in-water emulsion. The selected food emulsifiers were Tween 80, Citrem, sodium caseinate and lecithin. Lipid oxidation was evaluated by determination of peroxide values and secondary volatile oxidation products. Moreover, the zeta potential and the droplet sizes were determined. Twen resulted......Recent research has shown that the oxidative stability of oil-in-water emulsions is affected by the type of surfactant used as emulsifier. The aim of this study was to evaluate the effect of real food emulsifiers as well as metal chelation by EDTA and pH on the oxidative stability of a 10% n-3...... in the least oxidatively stable emulsions, followed by Citrem. When iron was present, caseinate-stabilized emulsions oxidized slower than lecithin emulsions at pH 3, whereas the opposite was the case at pH 7. Oxidation generally progressed faster at pH 3 than at pH 7, irrespective of the addition of iron. EDTA...

  4. 68Ga-labeling and in vivo evaluation of a uPAR binding DOTA- and NODAGA-conjugated peptide for PET imaging of invasive cancers

    DEFF Research Database (Denmark)

    Persson, Morten; Madsen, Jacob; Østergaard, Søren

    2012-01-01

    INTRODUCTION: The urokinase-type plasminogen activator receptor (uPAR) is a well-established biomarker for tumor aggressiveness and metastatic potential. DOTA-AE105 and DOTA-AE105-NH(2) labeled with (64)Cu have previously been demonstrated to be able to noninvasively monitor uPAR expression using...... positron emission tomography (PET) in human cancer xenograft mice models. Here we introduce (68)Ga-DOTA-AE105-NH(2) and (68)Ga-NODAGA-AE105-NH(2) and evaluate their imaging properties using small-animal PET. METHODS: Synthesis of DOTA-AE105-NH(2) and NODAGA-AE105-NH(2) was based on solid-phase peptide...... peptides and identical to AE105. Labeling of DOTA-AE105-NH(2) and NODAGA-AE105-NH(2) with (68)Ga was done at 95°C and room temperature, respectively. The highest radiochemical yield and purity were obtained using fractionated elution, whereas a negative effect of acetone on labeling efficiency for NODAGA...

  5. Evaluation of affibody molecule-based PNA-mediated radionuclide pretargeting: Development of an optimized conjugation protocol and (177)Lu labeling.

    Science.gov (United States)

    Altai, Mohamed; Westerlund, Kristina; Velletta, Justin; Mitran, Bogdan; Honarvar, Hadis; Karlström, Amelie Eriksson

    2017-11-01

    We have previously developed a pretargeting approach for affibody-mediated cancer therapy based on PNA-PNA hybridization. In this article we have further developed this approach by optimizing the production of the primary agent, ZHER2:342-SR-HP1, and labeling the secondary agent, HP2, with the therapeutic radionuclide (177)Lu. We also studied the biodistribution profile of (177)Lu-HP2 in mice, and evaluated pretargeting with (177)Lu-HP2 in vitro and in vivo. The biodistribution profile of (177)Lu-HP2 was evaluated in NMRI mice and compared to the previously studied (111)In-HP2. Pretargeting using (177)Lu-HP2 was studied in vitro using the HER2-expressing cell lines BT-474 and SKOV-3, and in vivo in mice bearing SKOV-3 xenografts. Using an optimized production protocol for ZHER2:342-SR-HP1 the ligation time was reduced from 15h to 30min, and the yield increased from 45% to 70%. (177)Lu-labeled HP2 binds specifically in vitro to BT474 and SKOV-3 cells pre-treated with ZHER2:342-SR-HP1. (177)Lu-HP2 was shown to have a more rapid blood clearance compared to (111)In-HP2 in NMRI mice, and the measured radioactivity in blood was 0.22±0.1 and 0.68±0.07%ID/g for (177)Lu- and (111)In-HP2, respectively, at 1h p.i. In contrast, no significant difference in kidney uptake was observed (4.47±1.17 and 3.94±0.58%ID/g for (177)Lu- and (111)In-HP2, respectively, at 1h p.i.). Co-injection with either Gelofusine or lysine significantly reduced the kidney uptake for (177)Lu-HP2 (1.0±0.1 and 1.6±0.2, respectively, vs. 2.97±0.87%ID/g in controls at 4h p.i.). (177)Lu-HP2 accumulated in SKOV-3 xenografts in BALB/C nu/nu mice when administered after injection of ZHER2:342-SR-HP1. Without pre-injection of ZHER2:342-SR-HP1, the uptake of (177)Lu-HP2 was about 90-fold lower in tumor (0.23±0.08 vs. 20.7±3.5%ID/g). The tumor-to-kidney radioactivity accumulation ratio was almost 5-fold higher in the group of mice pre-injected with ZHER2:342-SR-HP1. In conclusion, (177)Lu-HP2 was shown to

  6. Molecular Modeling of Bifunctional Chelate Peptide Conjugates. 1. Copper and Indium Parameters for the AMBER Force Field

    DEFF Research Database (Denmark)

    Reichert, David E.; Norrby, Per-Ola; Welch, Michael J.

    2001-01-01

    In this work we describe the development of parameters for In(III) and Cu(II) for the AMBER* force field as found in the modeling package MacroModel. These parameters were developed using automated procedures from a combination of crystallographic structures and ab initio calculations. The new pa...

  7. IR, UV-Vis, magnetic and thermal characterization of chelates of some catecholamines and 4-aminoantipyrine with Fe(III) and Cu(II).

    Science.gov (United States)

    Mohamed, Gehad G; Zayed, M A; El-Dien, F A Nour; El-Nahas, Reham G

    2004-07-01

    The dopamine derivatives participate in the regulation of wide variety of physiological functions in the human body and in medication life. Increase and/or decrease in the concentration of dopamine in human body reflect an indication for diseases such as Schizophrenia and/or Parkinson diseases. Alpha-methyldopa (alpha-MD) in tablets is used in medication of hypertension. The Fe(III) and Cu(II) chelates with coupled products of adrenaline hydrogen tartarate (AHT), levodopa (LD), alpha-MD and carbidopa (CD) with 4-aminoantipyrine (4-AAP) are prepared and characterized. Different physico-chemical methods like IR, magnetic and UV-Vis spectra are used to investigate the structure of these chelates. Fe(III) form 1:2 (M:catecholamines) chelates while Cu(II) form 1:1 chelates. Catecholamines behave as a bidentate mono- or dibasic ligands in binding to the metal ions. IR spectra show that the catecholamines are coordinated to the metal ions in a bidentate manner with O,O donor sites of the phenolic -OH. Magnetic moment measurements reveal the presence of Fe(III) chelates in octahedral geometry while the Cu(II) chelates are square planar. The thermal decomposition of Fe(III) and Cu(II) complexes is studied using thermogravimetric (TGA) and differential thermal analysis (DTA) techniques. The water molecules are removed in the first step followed immediately by decomposition of the ligand molecules. The activation thermodynamic parameters, such as, energy of activation, enthalpy, entropy and free energy change of the complexes are evaluated and the relative thermal stability of the complexes are discussed.

  8. IR, UV-Vis, magnetic and thermal characterization of chelates of some catecholamines and 4-aminoantipyrine with Fe(III) and Cu(II)

    Science.gov (United States)

    Mohamed, Gehad G.; Zayed, M. A.; El-Dien, F. A. Nour; El-Nahas, Reham G.

    2004-07-01

    The dopamine derivatives participate in the regulation of wide variety of physiological functions in the human body and in medication life. Increase and/or decrease in the concentration of dopamine in human body reflect an indication for diseases such as Schizophrenia and/or Parkinson diseases. α-Methyldopa (α-MD) in tablets is used in medication of hypertension. The Fe(III) and Cu(II) chelates with coupled products of adrenaline hydrogen tartarate (AHT), levodopa (LD), α-MD and carbidopa (CD) with 4-aminoantipyrine (4-AAP) are prepared and characterized. Different physico-chemical methods like IR, magnetic and UV-Vis spectra are used to investigate the structure of these chelates. Fe(III) form 1:2 (M:catecholamines) chelates while Cu(II) form 1:1 chelates. Catecholamines behave as a bidentate mono- or dibasic ligands in binding to the metal ions. IR spectra show that the catecholamines are coordinated to the metal ions in a bidentate manner with O,O donor sites of the phenolic - OH. Magnetic moment measurements reveal the presence of Fe(III) chelates in octahedral geometry while the Cu(II) chelates are square planar. The thermal decomposition of Fe(III) and Cu(II) complexes is studied using thermogravimetric (TGA) and differential thermal analysis (DTA) techniques. The water molecules are removed in the first step followed immediately by decomposition of the ligand molecules. The activation thermodynamic parameters, such as, energy of activation, enthalpy, entropy and free energy change of the complexes are evaluated and the relative thermal stability of the complexes are discussed.

  9. High pressure structural studies of conjugated molecules

    DEFF Research Database (Denmark)

    Knaapila, Matti; Torkkeli, Mika; Scherf, Ullrich

    2018-01-01

    This chapter highlights high pressure GPa level structural studies of conjugated polymers and their analogues: conjugated oligomers and molecules, and rigid rod polymers. Attention is placed on our recent studies of polyfluorenes.......This chapter highlights high pressure GPa level structural studies of conjugated polymers and their analogues: conjugated oligomers and molecules, and rigid rod polymers. Attention is placed on our recent studies of polyfluorenes....

  10. Redox-Active Quinone Chelators: Properties, Mechanisms of Action, Cell Delivery, and Cell Toxicity.

    Science.gov (United States)

    Polyakov, Nikolay; Leshina, Tatyana; Fedenok, Lidiya; Slepneva, Irina; Kirilyuk, Igor; Furso, Justyna; Olchawa, Magdalena; Sarna, Tadeusz; Elas, Martyna; Bilkis, Itzhak; Weiner, Lev

    2018-01-03

    Chemotherapy is currently the principal method for treating many malignancies. Thus, the development of improved antitumor drugs with enhanced efficacy and selectivity remains a high priority. Recent Advances: Anthracycline antibiotics (AAs), for example, doxorubicin, daunomycin, and mitomycin C, belong to an important family of antitumor agents widely used in chemotherapy. These compounds are all quinones. They are, thus, capable of being reduced by appropriate chemicals or reductases. One of their important properties is that under aerobic conditions their reduced forms undergo oxidation, with concomitant generation of reactive oxygen species (ROS), namely, superoxide anion radicals, hydrogen peroxide, and hydroxyl radicals. The presence of metal ions is essential for the generation of ROS by AAs in biological systems. A fundamental shortcoming of the AAs is their high cardiotoxicity. We have proposed, and experimentally realized, a new type of quinones that is capable of coordinating metal ions. We have demonstrated in vitro that they can be reduced by electron transfer chains and glutathione with concomitant generation of ROS. They can also produce ROS under photo-excitation. The mechanisms of these reactions have been characterized by using nuclear magnetic resonance and electron paramagnetic resonance. To enhance their therapeutic effectiveness, and decrease cardiotoxicity and other side effects, we intend to conjugate the quinone chelators with monoclonal antibodies and peptide hormones that are specifically targeted to receptors on the cancer cell surface. Some such candidates have already been synthesized. An alternative approach for delivery of our compounds involves the use of specific peptide-based nanoparticles. In addition, our novel approach for treating malignancies is also suitable for photodynamic therapy. Antioxid. Redox Signal. 00, 000-000.

  11. Investigation of metal–flavonoid chelates and the determination of flavonoids via metal–flavonoid complexing reactions

    Directory of Open Access Journals (Sweden)

    DUSAN MALESEV

    2007-10-01

    Full Text Available Flavonoids constitute a large group of polyphenolic phytochemicals with antioxidant properties which are overwhelmingly exerted through direct free radical scavenging. Flavonoids also exhibit antioxidant properties through chelating with transition metals, primarily Fe(II, Fe(III and Cu(II, which participate in reactions generating free radicals. Metal–flavonoid chelates are considerably more potent free radical scavengers than the parent flavonoids and play a prominent role in protecting from oxidative stress. To unravel the origin of their potent biological action extensive physico–chemical studies were undertaken to reveal the chemical structure, chelation sites, assess the impact of the metal/ligand ratio on the structure of the complexes and the capacity of flavonoids to bind metal ions. In spite of such extensive efforts, data on the composition, structure and complex-formation properties are incomplete and sometimes even contradictory. The aim of this paper is to give a personal account on the development of the field through a retrospective evaluation of our own research which covers approximately 40 complexes of flavonoids from different flavonoids subclasses (rutin, quercetin, 3-hydroxyflavone, morin and hesperidin with several metal ions or groups and suggest directions for future research. Special emphasis will be given to the site of the central ion, the composition of the complexes, the role of pH in complex formation, the stability of metal–flavonoid complexes and their potential application for analytical purposes.

  12. Deferoxamine pretreatment prevents Cr(VI)-induced nephrotoxicity and oxidant stress: role of Cr(VI) chelation.

    Science.gov (United States)

    Molina-Jijón, Eduardo; Zarco-Márquez, Guillermo; Medina-Campos, Omar Noel; Zataraín-Barrón, Zyanya Lucía; Hernández-Pando, Rogelio; Pinzón, Enrique; Zavaleta, Rosa Marina; Tapia, Edilia; Pedraza-Chaverri, José

    2012-01-27

    Deferoxamine (DFO) is a recognized iron chelator which has been shown to exert nephroprotection in models of toxic nephropathies. In the present work the potential protective effects of DFO against Cr(VI)-induced nephrotoxicity and oxidant stress were evaluated. Rats were injected with a single injection (15mg/kg, s.c.) of potassium dichromate (K(2)Cr(2)O(7)). DFO was given as a single i.p. injection 30min before K(2)Cr(2)O(7) administration at three different doses (100, 200 and 400mg/kg). It was found that DFO pretreatment attenuated, in a dose-dependent way, K(2)Cr(2)O(7)-induced renal dysfunction and structural alterations evaluated by serum creatinine, blood urea nitrogen, creatinine clearance, proteinuria, plasma glutathione peroxidase activity, urinary excretion of N-acetyl-β-d-glucosaminidase and histological analyses. Furthermore, DFO prevented the K(2)Cr(2)O(7)-induced renal oxidant stress and the decrease in the activity of the antioxidant enzymes superoxide dismutase, glutathione reductase, glutathione peroxidase, glutathione-S-transferase and catalase. Finally it was found that DFO, at 400mg/kg, decreases renal Cr(VI) content which prompted us to evaluate the potential Cr(VI) chelating properties of this compound. Indeed was found in an in vitro assay that DFO was an effective Cr(VI) chelator with an IC(50) of 800μg. In additional groups of rats was found that DFO posttreatment was ineffective to attenuate K(2)Cr(2)O(7)-induced nephrotoxicity and renal oxidant stress. Furthermore, DFO was unable to modify urinary excretion of total chromium. The nephroprotective effect of DFO against Cr(VI)-induced nephrotoxicity and oxidant stress may be explained, at least partially, by the ability of DFO to chelate Cr(VI) and to attenuate renal Cr(VI) content. However, it cannot be excluded that the ability of DFO to chelate iron may also be involved in the protection observed in our study. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  13. Evaluation of components of X-ray irradiated 7-valent pneumococcal conjugate vaccine and pneumococcal vaccine polyvalent and X-ray and gamma-ray irradiated acellular pertussis component of DTaP vaccine products

    Science.gov (United States)

    May, J. C.; Rey, L.; Lee, Chi-Jen; Arciniega, Juan

    2004-09-01

    Samples of pneumococcal vaccine polyvalent, 7-valent pneumococcal conjugate vaccine, and two different diphtheria and tetanus toxoids and acellular pertussis vaccines adsorbed were irradiated with X-rays and/or gamma-rays (Co-60). Mouse IgG and IgM antibody responses (ELISA) for types 9V, 14, 18C, and 19F pneumococcal polysaccharides and conjugates indicated that the polysaccharides were more tolerant of the radiation than the conjugates. The mouse antibody response for the detoxified pertussis toxin (PT) antigen, filamentous hemagglutinin antigen (FHA), pertactin (PRN), and fimbriae types 2 and 3 (FIM) antigens for the appropriate vaccine type indicated that the antibody response was not significantly changed in the 25 kGy X-ray irradiated vaccines frozen in liquid nitrogen compared to the control vaccine.

  14. Evaluation of components of X-ray irradiated 7-valent pneumococcal conjugate vaccine and pneumococcal vaccine polyvalent and X-ray and gamma-ray irradiated acellular pertussis component of DTaP vaccine products

    Energy Technology Data Exchange (ETDEWEB)

    May, J.C. E-mail: may@cber.fda.gov; Rey, L. E-mail: louis.rey@bluewin.ch; Lee, C.-J.; Arciniega, Juan

    2004-10-01

    Samples of pneumococcal vaccine polyvalent, 7-valent pneumococcal conjugate vaccine, and two different diphtheria and tetanus toxoids and acellular pertussis vaccines adsorbed were irradiated with X-rays and/or gamma-rays (Co-60). Mouse IgG and IgM antibody responses (ELISA) for types 9V, 14, 18C, and 19F pneumococcal polysaccharides and conjugates indicated that the polysaccharides were more tolerant of the radiation than the conjugates. The mouse antibody response for the detoxified pertussis toxin (PT) antigen, filamentous hemagglutinin antigen (FHA), pertactin (PRN), and fimbriae types 2 and 3 (FIM) antigens for the appropriate vaccine type indicated that the antibody response was not significantly changed in the 25 kGy X-ray irradiated vaccines frozen in liquid nitrogen compared to the control vaccine.

  15. Carbopol-lectin conjugate coated liposomes for oral peptide delivery.

    Science.gov (United States)

    Werle, Martin; Makhlof, Abdallah; Takeuchi, Hirofumi

    2010-03-01

    Within the current study, a delivery system based on a novel polymer-lectin conjugate (carbopol-lectin) was evaluated for the oral delivery of therapeutic peptides and proteins. It was demonstrated that covalent attachment of lectin to carbopol does neither decrease nor abolish the specific binding properties of lectin. Bioadhesion studies revealed that liposomes coated with carbopol lectin are more bioadhesive than liposomes coated with unmodified carbopol. Finally, the in vivo data suggest that carbopol-lectin conjugate coated liposomes are effective oral peptide delivery systems which are capable of increasing the pharmacological effect of orally administered calcitonin.

  16. A phthalocyanine--fluorescein conjugate

    OpenAIRE

    ÜN, İlker; ZORLU, YUNUS; İBİŞOĞLU, Hanife; Dumoulin, Fabienne

    2013-01-01

    A phthalocyanine--fluorescein conjugate was designed and prepared. Its photophysical properties (electronic absorption and fluorescence) were determined and compared with those of an analogous derivative functionalized by a simple triazole without chromophore. It is likely to be used as a theranostic agent in photodynamic therapy.

  17. Orderings for conjugate gradient preconditionings

    Science.gov (United States)

    Ortega, James M.

    1991-01-01

    The effect of orderings on the rate of convergence of the conjugate gradient method with SSOR or incomplete Cholesky preconditioning is examined. Some results also are presented that help to explain why red/black ordering gives an inferior rate of convergence.

  18. Subgap Absorption in Conjugated Polymers

    Science.gov (United States)

    Sinclair, M.; Seager, C. H.; McBranch, D.; Heeger, A. J; Baker, G. L.

    1991-01-01

    Along with X{sup (3)}, the magnitude of the optical absorption in the transparent window below the principal absorption edge is an important parameter which will ultimately determine the utility of conjugated polymers in active integrated optical devices. With an absorptance sensitivity of fluorination.

  19. Actinomycete integrative and conjugative elements

    NARCIS (Netherlands)

    Poele, Evelien M. te; Bolhuis, Henk; Dijkhuizen, Lubbert

    This paper reviews current knowledge on actinomycete integrative and conjugative elements (AICEs). The best characterised AICEs, pSAM2 of Streptomyces ambofaciens (10.9 kb), SLP1 (17.3 kb) of Streptomyces coelicolor and pMEA300 of Amycolatopsis methanolica (13.3 kb), are present as integrative

  20. Actinomycete integrative and conjugative elements

    NARCIS (Netherlands)

    Te Poele, E.M.; Bolhuis, H.; Dijkhuizen, L.

    2008-01-01

    This paper reviews current knowledge on actinomycete integrative and conjugative elements (AICEs). The best characterised AICEs, pSAM2 of Streptomyces ambofaciens (10.9 kb), SLP1 (17.3 kb) of Streptomyces coelicolor and pMEA300 of Amycolatopsis methanolica (13.3 kb), are present as integrative

  1. Persistence Mechanisms of Conjugative Plasmids

    DEFF Research Database (Denmark)

    Bahl, Martin Iain; Hansen, Lars H.; Sørensen, Søren Johannes

    2009-01-01

    maintenance in the host cell. These importantly include the ability to self-mobilize in a process termed conjugative transfer, which may occur across species barriers. Other plasmid stabilizing mechanisms include the multimer resolution system, active partitioning, and post-segregational-killing of plasmid...

  2. Conjugative Plasmids of Neisseria gonorrhoeae

    NARCIS (Netherlands)

    Pachulec, Emilia; van der Does, Chris

    2010-01-01

    Many clinical isolates of the human pathogen Neisseria gonorrhoeae contain conjugative plasmids. The host range of these plasmids is limited to Neisseria species, but presence of a tetracycline (tetM) determinant inserted in several of these plasmids is an important cause of the rapid spread of

  3. Enhanced photophysics of conjugated polymers

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Liaohai [Darien, IL

    2007-06-12

    A particulate fluorescent conjugated polymer surfactant complex and method of making and using same. The particles are between about 15 and about 50 nm and when formed from a lipsome surfactant have a charge density similar to DNA and are strongly absorbed by cancer cells.

  4. Galois conjugates of topological phases

    Science.gov (United States)

    Freedman, M. H.; Gukelberger, J.; Hastings, M. B.; Trebst, S.; Troyer, M.; Wang, Z.

    2012-01-01

    Galois conjugation relates unitary conformal field theories and topological quantum field theories (TQFTs) to their nonunitary counterparts. Here we investigate Galois conjugates of quantum double models, such as the Levin-Wen model. While these Galois-conjugated Hamiltonians are typically non-Hermitian, we find that their ground-state wave functions still obey a generalized version of the usual code property (local operators do not act on the ground-state manifold) and hence enjoy a generalized topological protection. The key question addressed in this paper is whether such nonunitary topological phases can also appear as the ground states of Hermitian Hamiltonians. Specific attempts at constructing Hermitian Hamiltonians with these ground states lead to a loss of the code property and topological protection of the degenerate ground states. Beyond this, we rigorously prove that no local change of basis can transform the ground states of the Galois-conjugated doubled Fibonacci theory into the ground states of a topological model whose Hermitian Hamiltonian satisfies Lieb-Robinson bounds. These include all gapped local or quasilocal Hamiltonians. A similar statement holds for many other nonunitary TQFTs. One consequence is that these nonunitary TQFTs do not describe physical realizations of topological phases. In particular, this implies that the “Gaffnian” wave function can not be the ground state of a gapped fractional quantum Hall state.

  5. Conjugal Pairing in Escherichia Coli

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 13; Issue 8. Conjugal Pairing in Escherichia Coli. Joshua Lederberg. Classics Volume 13 Issue 8 August 2008 pp 793-794. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/013/08/0793-0794 ...

  6. Glutathione conjugation as a bioactivation reaction

    NARCIS (Netherlands)

    Bladeren, P.J. van

    2000-01-01

    In general, glutathione conjugation is regarded as a detoxication reaction. However, depending on the properties of the substrate, bioactivation is also possible. Four types of activation reaction have been recognized: direct-acting compounds, conjugates that are activated through cysteine conjugate

  7. Bacteriophytochromes control conjugation in Agrobacterium fabrum.

    Science.gov (United States)

    Bai, Yingnan; Rottwinkel, Gregor; Feng, Juan; Liu, Yiyao; Lamparter, Tilman

    2016-08-01

    Bacterial conjugation, the transfer of single stranded plasmid DNA from donor to recipient cell, is mediated through the type IV secretion system. We performed conjugation assays using a transmissible artificial plasmid as reporter. With this assay, conjugation in Agrobacterium fabrum was modulated by the phytochromes Agp1 and Agp2, photoreceptors that are most sensitive in the red region of visible light. In conjugation studies with wild-type donor cells carrying a pBIN-GUSINT plasmid as reporter that lacked the Ti (tumor inducing) plasmid, no conjugation was observed. When either agp1(-) or agp2(-) knockout donor strains were used, plasmid DNA was delivered to the recipient, indicating that both phytochromes suppress conjugation in the wild type donor. In the recipient strains, the loss of Agp1 or Agp2 led to diminished conjugation. When wild type cells with Ti plasmid and pBIN-GUS reporter plasmid were used as donor, a high rate of conjugation was observed. The DNA transfer was down regulated by red or far-red light by a factor of 3.5. With agp1(-) or agp2(-) knockout donor cells, conjugation in the dark was about 10 times lower than with the wild type donor, and with the double knockout donor no conjugation was observed. These results imply that the phytochrome system has evolved to inhibit conjugation in the light. The decrease of conjugation under different temperature correlated with the decrease of phytochrome autophosphorylation. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Expeditious synthesis of coumarin-pyridone conjugates molecules ...

    Indian Academy of Sciences (India)

    RAJNI KHAJURIA

    widespread occurrence in natural products and exhibi- tion of diverse pharmacological activities including anti- ... occurrence in many biologically active natural products, therapeutics and synthetic compounds.10 .... Synthesis and anti-microbial evaluation of coumarin-pyridone conjugates. 1551 bacterial cultures and at 25.

  9. Effect of dietary conjugated linoleic acid (CLA) on the metabolism ...

    African Journals Online (AJOL)

    Giulia

    2013-07-05

    Jul 5, 2013 ... Abstract. Rumen-protected conjugated linoleic acid (CLA) reportedly improves fertility in lactating dairy cows by reducing the postpartum interval to first ovulation and enhancing the circulating insulin-like growth factor-I (IGF-I) levels. The objectives of this study were to evaluate the blood metabolites, ...

  10. Complexation and Antimicrobial Studies of Some Divalent Metal Chelates

    Directory of Open Access Journals (Sweden)

    Suparna Ghosh

    2010-01-01

    Full Text Available Metal chelates of Ni(II and Cu(II with the ligand 5-acetamido-1,3,4-thiadiazole-2-sulphonamide have been synthesized. The isolated compounds have been characterized by elemental analysis, molar conductivity, magnetic moment, electronic and IR spectral studies. The analytical data reflects the metal to ligand stoichiometry to be 1: 2. The conductivity data of the complexes also suggests their non-electrolytic nature. The stability constants and free energy change for the complexes have been calculated.. Ligand and their complexes have been screened for their biological activity and the data show good activity of these complexes and ligands.

  11. Intracellular trafficking of new anticancer therapeutics: antibody–drug conjugates

    Science.gov (United States)

    Kalim, Muhammad; Chen, Jie; Wang, Shenghao; Lin, Caiyao; Ullah, Saif; Liang, Keying; Ding, Qian; Chen, Shuqing; Zhan, Jinbiao

    2017-01-01

    Antibody–drug conjugate (ADC) is a milestone in targeted cancer therapy that comprises of monoclonal antibodies chemically linked to cytotoxic drugs. Internalization of ADC takes place via clathrin-mediated endocytosis, caveolae-mediated endocytosis, and pinocytosis. Conjugation strategies, endocytosis and intracellular trafficking optimization, linkers, and drugs chemistry present a great challenge for researchers to eradicate tumor cells successfully. This inventiveness of endocytosis and intracellular trafficking has given considerable momentum recently to develop specific antibodies and ADCs to treat cancer cells. It is significantly advantageous to emphasize the endocytosis and intracellular trafficking pathways efficiently and to design potent engineered conjugates and biological entities to boost efficient therapies enormously for cancer treatment. Current studies illustrate endocytosis and intracellular trafficking of ADC, protein, and linker strategies in unloading and also concisely evaluate practically applicable ADCs. PMID:28814834

  12. Intracellular trafficking of new anticancer therapeutics: antibody-drug conjugates.

    Science.gov (United States)

    Kalim, Muhammad; Chen, Jie; Wang, Shenghao; Lin, Caiyao; Ullah, Saif; Liang, Keying; Ding, Qian; Chen, Shuqing; Zhan, Jinbiao

    2017-01-01

    Antibody-drug conjugate (ADC) is a milestone in targeted cancer therapy that comprises of monoclonal antibodies chemically linked to cytotoxic drugs. Internalization of ADC takes place via clathrin-mediated endocytosis, caveolae-mediated endocytosis, and pinocytosis. Conjugation strategies, endocytosis and intracellular trafficking optimization, linkers, and drugs chemistry present a great challenge for researchers to eradicate tumor cells successfully. This inventiveness of endocytosis and intracellular trafficking has given considerable momentum recently to develop specific antibodies and ADCs to treat cancer cells. It is significantly advantageous to emphasize the endocytosis and intracellular trafficking pathways efficiently and to design potent engineered conjugates and biological entities to boost efficient therapies enormously for cancer treatment. Current studies illustrate endocytosis and intracellular trafficking of ADC, protein, and linker strategies in unloading and also concisely evaluate practically applicable ADCs.

  13. Recent advances in the construction of antibody-drug conjugates

    Science.gov (United States)

    Chudasama, Vijay; Maruani, Antoine; Caddick, Stephen

    2016-02-01

    Antibody-drug conjugates (ADCs) comprise antibodies covalently attached to highly potent drugs using a variety of conjugation technologies. As therapeutics, they combine the exquisite specificity of antibodies, enabling discrimination between healthy and diseased tissue, with the cell-killing ability of cytotoxic drugs. This powerful and exciting class of targeted therapy has shown considerable promise in the treatment of various cancers with two US Food and Drug Administration approved ADCs currently on the market (Adcetris and Kadcyla) and approximately 40 currently undergoing clinical evaluation. However, most of these ADCs exist as heterogeneous mixtures, which can result in a narrow therapeutic window and have major pharmacokinetic implications. In order for ADCs to deliver their full potential, sophisticated site-specific conjugation technologies to connect the drug to the antibody are vital. This Perspective discusses the strategies currently used for the site-specific construction of ADCs and appraises their merits and disadvantages.

  14. Thesis The effect of flavoinoids and chosen chelators on the oxidation of natural substances

    OpenAIRE

    Malá, Marie

    2014-01-01

    Mgr. Marie Malá, Thesis The effect of flavoinoids and chosen chelators on the oxidation of natural substances, Charles University in Prague, Faculty of Pharmacy in Hradec Králové, 2014, 67 pages. Thesis "The effect of flavonoids and chosen chelators on the oxidation of natural substances" deals with Fenton's reaction. For the needs of this work it means the effect of chosen flavonoids and chelators on oxidation of salicylic acid in presence of peroxide and ferrous ions. Chelators were efficie...

  15. Radiolabeling and Preliminary Evaluation of Ga-68 Labeled NODAGA-Ubiquicidin Fragments for Prospective Infection Imaging.

    Science.gov (United States)

    Bhatt, Jyotsna; Mukherjee, Archana; Korde, Aruna; Kumar, Mukesh; Sarma, Haladhar Dev; Dash, Ashutosh

    2017-02-01

    The present work was aimed at the development of prospective positron emission tomography (PET) agents for infection imaging. Towards this aim, ubiquicidin (UBI) fragments conjugated with the macrocyclic NODAGA chelator were radiolabeled with Ga-68 and evaluated. Conformations of custom synthesized NODAGA-UBI (29-41) and NODAGA-UBI (31-38) conjugates were compared with UBI (29-41) by circular dichroism (CD) spectroscopy. Optimization of labeling of NODAGA conjugates of UBI peptides with Ga-68 was performed and quality control analysis was carried out by chromatography techniques. In vitro uptake of [(68)Ga] NODAGA-UBI (29-41) and [(68)Ga]NODAGA-UBI (31-38) was studied in Staphylococcus aureus cells. In vivo distribution of [(68)Ga]GaCl3 and [(68)Ga]NODAGA-UBI complexes was performed in normal Swiss mice. Conformations of NODAGA-UBI (29-41) and NODAGA-UBI (31-38) conjugates were found to be similar to UBI (29-41). NODAGA-UBI conjugates could be consistently labeled with Ga-68 in high radiochemical yields (>95 %) with high radiochemical purity (>95 %). [(68)Ga]NODAGA-UBI (29-41) and [(68)Ga]NODAGA-UBI (31-38) complexes showed retention time of 14 and 14.5 min, respectively, by HPLC radiochromatogram. Specific uptake of [(68)Ga]NODAGA-UBI fragments was observed in S.aureus cells. Greater than 64 % of the injected dose was cleared via the renal route at 1 h post injection, and no significant uptake in vital organs of mice was observed with both the agents. This is the first report on Ga-68 labeled NODAGA-UBI fragments for infection imaging and the agents hold tremendous prospect in PET imaging.

  16. Iron chelation therapy with deferasirox in patients with aplastic anemia: a subgroup analysis of 116 patients from the EPIC trial

    DEFF Research Database (Denmark)

    Lee, Jong Wook; Yoon, Sung-Soo; Shen, Zhi Xiang

    2010-01-01

    The prospective 1-year Evaluation of Patients' Iron Chelation with Exjade (EPIC) study enrolled a large cohort of 116 patients with aplastic anemia; the present analyses evaluated the efficacy and safety of deferasirox in this patient population. After 1 year, median serum ferritin decreased...... neutrophil and platelet counts remained stable during treatment, and there were no drug-related cytopenias. This prospective dataset confirms the efficacy and well characterizes the tolerability profile of deferasirox in a large population of patients with aplastic anemia. This study was registered at www...

  17. Tailored Gallium(III) chelator NOPO: synthesis, characterization, bioconjugation, and application in preclinical Ga-68-PET imaging.

    Science.gov (United States)

    Simeček, Jakub; Zemek, Ondřej; Hermann, Petr; Notni, Johannes; Wester, Hans-Jürgen

    2014-11-03

    The bifunctional chelator NOPO (1,4,7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid]) shows remarkably high Ga(III) complexation efficiency and comprises one carboxylic acid moiety which is not involved into metal ion coordination. An improved synthetic protocol affords NOPO with 45% overall yield. Stepwise protonation constants (log Ka), determined by potentiometry, are 11.96, 5.22, 3.77, and 1.54; the stability constant of the Ga(III) complex is log KGaL = 25.0. Within 5 min, (68)Ga(III) incorporation by NOPO is virtually quantitative at room temperature between pH 3 and 4, and at 95 °C at pH ranging from 0.5 to 7, at NOPO concentrations of 30 μM and 10 μM, respectively. During amide bond formation at the distant carboxylate using the HATU coupling reagent, an intramolecular phosphinic acid ester (phosphilactone) is formed, which is cleaved during (68)Ga complexation or in acidic media, such as trifluoroacetic acid (TFA). Phosphilactone formation can also be suppressed by complexation of Zn(2+) prior to conjugation, the resulting zinc-containing conjugates nevertheless being suitable for direct (68)Ga-labeling. In AR42J (rat pancreatic carcinoma) xenografted CD-1 nude mice, (68)Ga-labeled NOPO-NaI(3)-octreotide conjugate ((68)Ga-NOPO-NOC) showed high and fully blockable tumor uptake (13.9 ± 5% ID/g, 120 min p.i., compared to 0.9 ± 0.4% ID/g with 5 mg/kg of nonlabeled peptide). Uptake in other tissues was generally below 3% ID/g, except appearance of excretion-related activity accumulation in kidneys. NOPO-functionalized compounds tend to be more hydrophilic than the corresponding DOTA- and NODAGA-conjugates, thus promoting fast and extensive renal excretion of (68)Ga-NOPO-radiopharmaceuticals. NOPO-functionalized peptides provide suitable pharmacokinetics in vivo and meet all requirements for efficient (68)Ga-labeling even at room temperature in a kit-like manner.

  18. Metal-chelating polymers by anionic ring-opening polymerization and their use in quantitative mass cytometry.

    Science.gov (United States)

    Illy, Nicolas; Majonis, Daniel; Herrera, Isaac; Ornatsky, Olga; Winnik, Mitchell A

    2012-08-13

    Metal-chelating polymers (MCPs) are important reagents for multiplexed immunoassays based on mass cytometry. The role of the polymer is to carry multiple copies of individual metal isotopes, typically as lanthanide ions, and to provide a reactive functionality for convenient attachment to a monoclonal antibody (mAb). For this application, the optimum combination of chain length, backbone structure, end group, pendant groups, and synthesis strategy has yet to be determined. Here we describe the synthesis of a new type of MCP based on anionic ring-opening polymerization of an activated cyclopropane (the diallyl ester of 1,1-cyclopropane dicarboxylic acid) using a combination of 2-furanmethanethiol and a phosphazene base as the initiator. This reaction takes place with rigorous control over molecular weight, yielding a polymer with a narrow molecular weight distribution, reactive pendant groups for introducing a metal chelator, and a functional end group with orthogonal reactivity for attaching the polymer to the mAbs. Following the ring-opening polymerization, a two-step transformation introduced diethylenetriaminepentaacetic acid (DTPA) chelating groups on each pendant group. The polymers were characterized by NMR, size exclusion chromatography (SEC), and thermogravimetric analysis (TGA). The binding properties toward Gd(3+) as a prototypical lanthanide (Ln) ion were also studied by isothermal titration calorimetry (ITC). Attachment to a mAb involves a Diels-Alder reaction of the terminal furan with a bismaleimide, followed by a Michael addition of a thiol on the mAb, generated by mild reduction of a disulfide bond in the hinge region. Polymer samples with a number average degree of polymerization of 35, with a binding capacity of 49.5 ± 6 Ln(3+) ions per chain, were loaded with 10 different types of Ln ions and conjugated to 10 different mAbs. A suite of metal-tagged Abs was tested by mass cytometry in a 10-plex single cell analysis of human adult peripheral blood

  19. TAT Peptide and Its Conjugates: Proteolytic Stability

    OpenAIRE

    Grunwald, Jacob; Rejtar, Tomas; Sawant, Rupa; Wang, Zhouxi; Torchilin, Vladimir P.

    2009-01-01

    The proteolytic cleavage of TATp, TATp-PEG1000-PE conjugate (TATp-conjugate), and TATp as TATp-conjugate in mixed micelles made of TATp-conjugate and PEG5000-PE (2.5% mol of TATp-conjugate, TATp-Mic) were studied by HPLC with fluorescent detection using fluorenylmethyl chloroformate (FMOC) labeling and by MALDI-TOF MS analysis. The cleavage kinetics were analyzed in human blood plasma and in trypsin-containing phosphate buffered saline (PBS), pH 7.4, to simulate the proteolytic activity of hu...

  20. Antiradical, Chelating and Antioxidant Activities of Hydroxamic Acids and Hydroxyureas

    Directory of Open Access Journals (Sweden)

    Branka Zorc

    2011-07-01

    Full Text Available Reactive oxygen species, along with reactive nitrogen species, may play an important role in the pathogenesis and progress of many diseases, including cancer, diabetes and sickle cell disease. It has been postulated that hydroxyurea, one of the main treatments in sickle cell disease, achieves its activity partly also through its antioxidant properties. A series of hydroxyurea derivatives of L- and D-amino acid amides and cycloalkyl-N-aryl-hydroxamic acids was synthesized and investigated for their radical scavenging activity, chelating properties and antioxidant activity. All the compounds showed exceptional antiradical activities. For example, free radical scavenging activities of investigated hydroxyureas were higher than the activity of standard antioxidant, butylated hydroxyanisole (BHA. Moreover, most of the investigated hydroxamic acids were stronger Fe2+ ion chelators than quercetin. In addition, the investigated compounds, especially hydroxamic acids, were proven to be excellent antioxidants. They were as effective as BHA in inhibiting b-carotene-linoleic acid coupled oxidation. It is reasonable to assume that the antioxidant activity of the investigated compounds could contribute to their previously proven biological properties as cytostatic and antiviral agents.

  1. Using iron chelating agents to enhance dermatological PDT

    Science.gov (United States)

    Curnow, Alison; Dogra, Yuktee; Winyard, Paul; Campbell, Sandra

    2009-06-01

    Topical protoporphyrin IX (PPIX) induced photodynamic therapy (PDT) of basal cell carcinoma (BCC) produces good clinical outcomes with excellent cosmesis as long as the disease remains superficial. Efficacy for nodular BCC however appears inferior to standard treatment unless repeat treatments are performed. Enhancement is therefore required and is possible by employing iron chelating agents to temporarily increase PPIX accumulation above the levels normally obtained using aminolevulinic acid (ALA) or the methyl ester of ALA (MAL) alone. In vitro studies investigated the effect of the novel iron chelator, CP94 on necrotic or apoptotic cell death in cultured human skin fibroblasts and epidermal carcinoma cells incubated with MAL. Furthermore, following a dose escalating safety study conducted with ALA in patients, an additional twelve nodular BCCs were recruited for topical treatment with standard MAL-PDT +/- increasing doses of CP94. Six weeks later following clinical assessment, the whole treatment site was excised for histological analysis. CP94 produced greater cell death in vitro when administered in conjunction with MAL than this porphyrin precursor could produce when administered alone. Clinically, PDT treatment using Metvix + CP94 was a simple and safe modification associated with a trend of reduced tumor thickness with increasing CP94 dose.

  2. Imaging cancer using PET--the effect of the bifunctional chelator on the biodistribution of a (64)Cu-labeled antibody.

    Science.gov (United States)

    Dearling, Jason L J; Voss, Stephan D; Dunning, Patricia; Snay, Erin; Fahey, Frederic; Smith, Suzanne V; Huston, James S; Meares, Claude F; Treves, S Ted; Packard, Alan B

    2011-01-01

    Use of copper radioisotopes in antibody radiolabeling is challenged by reported loss of the radionuclide from the bifunctional chelator used to label the protein. The objective of this study was to investigate the relationship between the thermodynamic stability of the (64)Cu-complexes of five commonly used bifunctional chelators (BFCs) and the biodistribution of an antibody labeled with (64)Cu using these chelators in tumor-bearing mice. The chelators [S-2-(aminobenzyl)1,4,7-triazacyclononane-1,4,7-triacetic acid (p-NH(2)-Bn-NOTA): 6-[p-(bromoacetamido)benzyl]-1, 4, 8, 11-tetraazacyclotetradecane-N, N', N'', N'''-tetraacetic acid (BAT-6): S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododocane tetraacetic acid (p-NH(2)-Bn-DOTA): 1,4,7,10-tetraazacyclododocane-N, N', N", N"'-tetraacetic acid (DOTA): and 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane-1,8-diamine (SarAr)] were conjugated to the anti-GD2 antibody ch14.18, and the modified antibody was labeled with (64)Cu and injected into mice bearing subcutaneous human melanoma tumors (M21) (n = 3-5 for each study). Biodistribution data were obtained from positron emission tomography images acquired at 1, 24 and 48 hours post-injection, and at 48 hours post-injection a full ex vivo biodistribution study was carried out. The biodistribution, including tumor targeting, was similar for all the radioimmunoconjugates. At 48 h post-injection, the only statistically significant differences in radionuclide uptake (p < 0.05) were between blood, liver, spleen and kidney. For example, liver uptake of [(64)Cu]ch14.18-p-NH(2)-Bn-NOTA was 4.74 ± 0.77 per cent of the injected dose per gram of tissue (%ID/g), and for [(64)Cu]ch14.18-SarAr was 8.06 ± 0.77 %ID/g. Differences in tumor targeting correlated with variations in tumor size rather than which BFC was used. The results of this study indicate that differences in the thermodynamic stability of these chelator-Cu(II) complexes were not associated with significant

  3. Actual clinical use of gadolinium-chelates for non-MRI applications

    Energy Technology Data Exchange (ETDEWEB)

    Strunk, Holger M.; Schild, H. [Department of Radiology, University of Bonn, Sigmund-Freud-Strasse 25, 53105, Bonn (Germany)

    2004-06-01

    For many years, alternatives to iodinated X-ray contrast media have been sought. Of the contrast media investigated to date, only CO{sub 2} and the gadolinium-chelates have been shown to be viable alternatives for selected X-ray examinations. Therefore, we have reviewed the general literature and that specific for gadopentetate (Magnevist) in particular, since this agent has been studied the most. This review indicates that diagnostic CT examinations can be achieved following the intravenous administration of gadolinium-containing contrast media (CM) for evaluation of aortic abnormalities. Gadolinium-containing CM at the dose approved for MR imaging are not useful for CT evaluation of the abdominal parenchymal organs. Intravenous/intraarterial injections have also been used in a variety of angiographic and interventional procedures. Image quality, however, is generally inferior to iodinated contrast media. Gadolinium-containing CM require no special handling and can be administered by hand injection or via conventional angiographic automated injectors with the same flow rates and pressures as are used with iodinated contrast media. For CT, a peripheral bolus injection of a diluted gadolinium agent (1:1 with saline) of 60-90 ml at 3-5 ml/s is usually performed. Similar to all other gadolinium-chelates, the non-MRI use of gadopentetate (Magnevist) is not approved by regulatory agencies. However, the literature suggests that a dose of 0.3-0.4 mmol/kg b.w. has been safely administered for CT as well as for angiography and interventional procedures intravenously and intraarterially. Even at this dose, though, this results in a relatively small overall volume to be injected, which limits utility somewhat. (orig.)

  4. Factors affecting chelating extraction of Cr, Cu, and As from CCA-treated wood.

    Science.gov (United States)

    Chang, Fang-Chih; Wang, Ya-Nang; Chen, Pin-Jui; Ko, Chun-Han

    2013-06-15

    The disposal of chromated copper arsenate (CCA)-treated waste wood is becoming a serious problem in many countries due to potential leaching of hazardous elements from in-service use in the environment or disposal of solutions after remediation; therefore, it is necessary to develop proper remediation techniques. The effects of concentration, extraction period, temperature, and sequential extraction on the extraction of Cr, Cu, and As from CCA-treated wood using [S,S]-ethylenediaminedisuccinic acid (EDDS), ethylenediaminetetraacetic acid (EDTA), and nitrilotriacetic acid (NTA) were studied. Mobility of metal in the samples was evaluated by using a sequential extraction scheme that could give the information needed to explain different extraction efficiencies for different metals. Results of long-term leaching tests of CCA-treated wood before and after EDDS extraction were used to evaluate Cr, Cu, and As leachability. Kinetic experiments showed that 6 h was the optimum extraction time for all metals and CCA-treated wood. Experimental results showed that EDDS is a very effective chelating agent for the extraction of Cr, Cu, and As from CCA-treated wood. Increased temperature significantly enhanced the extraction efficiency of CCA metals, especially Cr and As. The much better extractability of Cu compared to Cr and As by chelating agents can be attributed to the presence of larger weakly bound fractions. The CCA-treated woods after EDDS extraction have met the EPA's TCLP regulatory limit and could be classified as a non-hazardous waste according to identification standard of hazardous wastes. Copyright © 2013 Elsevier Ltd. All rights reserved.

  5. Comparative evaluation of tumor targeting using the anti-HER2 ADAPT scaffold protein labeled at the C-terminus with indium-111 or technetium-99m.

    Science.gov (United States)

    Garousi, Javad; Lindbo, Sarah; Mitran, Bogdan; Buijs, Jos; Vorobyeva, Anzhelika; Orlova, Anna; Tolmachev, Vladimir; Hober, Sophia

    2017-11-07

    ABD-Derived Affinity Proteins (ADAPTs) is a novel class of engineered scaffold proteins derived from an albumin-binding domain of protein G. The use of ADAPT6 derivatives as targeting moiety have provided excellent preclinical radionuclide imaging of human epidermal growth factor 2 (HER2) tumor xenografts. Previous studies have demonstrated that selection of nuclide and chelator for its conjugation has an appreciable effect on imaging properties of scaffold proteins. In this study we performed a comparative evaluation of the anti-HER2 ADAPT having an aspartate-glutamate-alanine-valine-aspartate-alanine-asparagine-serine (DEAVDANS) N-terminal sequence and labeled at C-terminus with (99m)Tc using a cysteine-containing peptide based chelator, glycine-serine-serine-cysteine (GSSC), and a similar variant labeled with (111)In using a maleimido derivative of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator. Both (99m)Tc-DEAVDANS-ADAPT6-GSSC and (111)In-DEAVDANS-ADAPT6-GSSC-DOTA accumulated specifically in HER2-expressing SKOV3 xenografts. The tumor uptake of both variants did not differ significantly and average values were in the range of 19-21%ID/g. However, there was an appreciable variation in uptake of conjugates in normal tissues that resulted in a notable difference in the tumor-to-organ ratios. The (111)In-DOTA label provided 2-6 fold higher tumor-to-organ ratios than (99m)Tc-GSSC and is therefore the preferable label for ADAPTs.

  6. In vitro synergistic action of geldanamycin- and docetaxel-containing HPMA copolymer-RGDfK conjugates against ovarian cancer.

    Science.gov (United States)

    Larson, Nate; Roberts, Sarah; Ray, Abhijit; Buckway, Brandon; Cheney, Darwin L; Ghandehari, Hamidreza

    2014-12-01

    HPMA copolymer-RGDfK (HPMA-RGDfK) conjugates bearing either aminohexylgeldanamycin (AHGDM) or docetaxel (DOC) were synthesized and characterized. In vitro stability and binding were evaluated. Cytotoxicity toward ovarian cancer cells was evaluated and the ability of the conjugates to induce cell death was assessed by combination index analysis. Conjugates bearing AHGDM were more stable and exhibited slower drug release than those bearing DOC. Both conjugates demonstrated the ability to bind to avb3 integrins. In combination, HPMA-RGDfK conjugates demonstrated marked synergism as compared to their non-targeted counterparts and free drug controls. HPMA-RGDfK conjugates bearing AHGDM and DOC induce synergistic cytotoxicity in vitro, suggesting their potential as a promising combination therapy. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Enhancement of the Immunostimulatory Activity of a TLR7 Ligand by Conjugation to Polysaccharides.

    Science.gov (United States)

    Shinchi, Hiroyuki; Crain, Brian; Yao, Shiyin; Chan, Michael; Zhang, Shannon S; Ahmadiiveli, Alast; Suda, Yasuo; Hayashi, Tomoko; Cottam, Howard B; Carson, Dennis A

    2015-08-19

    Toll-like receptors (TLRs) in the innate immune system recognize specific pathogen-associated molecular patterns derived from microbes. Synthetic small molecule TLR7 agonists have been extensively evaluated as topical agents for antiviral and anticancer therapy, and as adjuvants for vaccine. However, safe and reproducible administration of synthetic TLR7 ligands has been difficult to achieve due to undesirable pharmacokinetics and unacceptable side effects. Here, we conjugated a versatile low molecular weight TLR7 ligand to various polysaccharides in order to improve its water solubility, enhance its potency, and maintain low toxicity. The synthetic TLR7 ligand, 2-methoxyethoxy-8-oxo-9-(4-carboxy benzyl)adenine, designated 1V209, was stably conjugated to primary amine functionalized Ficoll or dextran using benzoic acid functional groups. The conjugation ratios using specified equivalents of TLR7 ligand were dose responsive and reproducible. The zeta potential value of the polysaccharides was decreased in inverse proportion to the ratio of conjugated TLR7 ligand. These conjugates were highly water-soluble, stable for at least 6 months at room temperature in aqueous solution, and easy to lyophilize and reconstitute without altering potency. In vitro studies with murine mononuclear leukocytes showed that the TLR7 agonist conjugated to polysaccharides had 10- to 1000-fold higher potencies than the unconjugated TLR7 ligand. In vivo pharmacodynamics studies after injection indicate that the conjugates induced systemic cytokine production. When the conjugates were used as vaccine adjuvants, they enhanced antigen specific humoral and cellular immune responses to a much greater extent than did unconjugated TLR7 ligands. These results indicated that small molecule TLR7 ligands conjugated to polysaccharides have improved immunostimulatory potency and pharmacodynamics. Polysaccharides can be conjugated to a variety of molecules such as antigens, peptides, and TLR ligands

  8. Fiber bundle phase conjugate mirror

    Science.gov (United States)

    Ward, Benjamin G.

    2012-05-01

    An improved method and apparatus for passively conjugating the phases of a distorted wavefronts resulting from optical phase mismatch between elements of a fiber laser array are disclosed. A method for passively conjugating a distorted wavefront comprises the steps of: multiplexing a plurality of probe fibers and a bundle pump fiber in a fiber bundle array; passing the multiplexed output from the fiber bundle array through a collimating lens and into one portion of a non-linear medium; passing the output from a pump collection fiber through a focusing lens and into another portion of the non-linear medium so that the output from the pump collection fiber mixes with the multiplexed output from the fiber bundle; adjusting one or more degrees of freedom of one or more of the fiber bundle array, the collimating lens, the focusing lens, the non-linear medium, or the pump collection fiber to produce a standing wave in the non-linear medium.

  9. Conjugated Polymers for Energy Production

    DEFF Research Database (Denmark)

    Livi, Francesco

    This dissertation is aimed at developing materials for flexible, large area, ITO-free polymer solar cells (PSCs) fully printed under ambient conditions. A large screening of conjugated polymers, both novel and well-known materials, has been carried out in order to find suitable candidates...... for scalable PSCs fully printed under ambient conditions [Adv. Energy Mater. 2015, 5, 1402186]. PPDTBT resulted to be the conjugated polymer with the best photovoltaic performance within the 104 synthesized macromolecules. Therefore, further studies have been done on such material. The impact of side chain...... arylation (DAr) and direct arylation polymerization (DArP) have been applied to the preparation of PPDTBT, making this polymer readily available in only 4 synthetic steps and thus easily transferable to a large scale-production setup. DArP avoids organometallic species and therefore is an appealing...

  10. Reducing power and iron chelating property of Terminalia chebula (Retz. alleviates iron induced liver toxicity in mice

    Directory of Open Access Journals (Sweden)

    Sarkar Rhitajit

    2012-08-01

    Full Text Available Abstract Background The 70% methanol extract of Terminalia chebula Retz. fruit (TCME was investigated for its in vitro iron chelating property and in vivo ameliorating effect on hepatic injury of iron overloaded mice. Methods The effect of fruit extract on Fe2+-ferrozine complex formation and Fe2+ mediated pUC-18 DNA breakdown was studied in order to find the in vitro iron chelating activity. Thirty-six Swiss Albino mice were divided into six groups of: blank, patient control and treated with 50, 100, 200 mg/kg b.w. of TCME and desirox (standard iron chelator drug with Deferasirox as parent compound. Evaluations were made for serum markers of hepatic damage, antioxidant enzyme, lipid per oxidation and liver fibrosis levels. The reductive release of ferritin iron by the extract was further studied. Results In vitro results showed considerable iron chelation with IC50 of 27.19 ± 2.80 μg/ml, and a significant DNA protection with [P]50 of 1.07 ± 0.03 μg/ml along with about 86% retention of supercoiled DNA. Iron-dextran injection (i.p. caused significant increase in the levels of the serum enzymes, viz., alanine aminotransferase (ALAT, aspartate aminotransferase (ASAT, alkaline phosphatase (ALP and Bilirubin, which were subsequently lowered by oral administration of 200 mg/kg b.w. dose of the fruit extract by 81.5%, 105.88%, 188.08% and 128.31%, respectively. Similarly, treatment with the same dose of the extract was shown to alleviate the reduced levels of liver antioxidant enzyme superoxide dismutase, catalase, glutathione S-transferase and non-enzymatic reduced glutathione, by 49.8%, 53.5%, 35.4% and 11% respectively, in comparison to the iron overloaded mice. At the same time, the fruit extract effectively lowered the iron-overload induced raised levels of lipid per oxidation, protein carbonyl, hydroxyproline and liver iron by 49%, 67%, 67% and 26%, respectively, with oral treatment of 200 mg/kg b.w. dose of TCME. The fruit extract

  11. One-Step Protein Conjugation to Upconversion Nanoparticles.

    Science.gov (United States)

    Lu, Jie; Chen, Yinghui; Liu, Deming; Ren, Wei; Lu, Yiqing; Shi, Yu; Piper, James; Paulsen, Ian; Jin, Dayong

    2015-10-20

    The emerging upconversion nanoparticles offer a fascinating library of ultrasensitive luminescent probes for a range of biotechnology applications from biomarker discovery to single molecule tracking, early disease diagnosis, deep tissue imaging, and drug delivery and therapies. The effective bioconjugation of inorganic nanoparticles to the molecule-specific proteins, free of agglomeration, nonspecific binding, or biomolecule deactivation, is crucial for molecular recognition of target molecules or cells. The current available protocols require multiple steps which can lead to low probe stability, specificity, and reproducibility. Here we report a simple and rapid protein bioconjugation method based on a one-step ligand exchange using the DNAs as the linker. Our method benefits from the robust DNA-protein conjugates as well as from multiple ions binding capability. Protein can be preconjugated via an amino group at the 3' end of a synthetic DNA molecule, so that the 5' end phosphoric acid group and multiple phosphate oxygen atoms in the phosphodiester bonds are exposed to replace the oleic acid ligands on the surface of upconversion nanoparticles due to their stronger chelating capability to lanthanides. We demonstrated that our method can efficiently pull out the upconversion nanoparticles from organic solvent into an aqueous phase. The upconversion nanoparticles then become hydrophilic, stable, and specific biomolecules recognition. This allows us to successfully functionalize the upconversion nanoparticles with horseradish peroxidise (HRP) for catalytic colorimetric assay and for streptavidin (SA)-biotin immunoassays.

  12. The mechanism of activation of amidobenzylidene ruthenium chelates - latent catalysts of olefin metathesis.

    Science.gov (United States)

    Rogalski, Szymon; Żak, Patrycja; Tadeuszyk, Natalia; Pyta, Krystian; Przybylski, Piotr; Pietraszuk, Cezary

    2017-01-24

    Amidobenzylidene ruthenium chelates - latent catalysts of olefin metathesis can be easily activated by the addition of Brønsted or Lewis acids. Their activation in the presence of hydrogen chloride involves the formation of catalytically active trans-dichloro carbamatobenzylidene ruthenium chelates.

  13. A novel BF2-chelated azadipyrromethene-fullerene dyad: synthesis, electrochemistry and photodynamics.

    Science.gov (United States)

    Amin, Anu N; El-Khouly, Mohamed E; Subbaiyan, Navaneetha K; Zandler, Melvin E; Fukuzumi, Shunichi; D'Souza, Francis

    2012-01-07

    The synthesis, structure, electrochemistry and photodynamics of a BF(2)-chelated azadipyrromethene-fullerene dyad are reported in comparison with BF(2)-chelated azadipyrromethene without fullerene. The attachment of fullerene resulted in efficient generation of the triplet excited state of the azadipyrromethene via photoinduced electron transfer. This journal is © The Royal Society of Chemistry 2012

  14. Synthesis and characterization of novel, conjugated, fluorescent DNJ derivatives for α-glucosidase recognition.

    Science.gov (United States)

    Hatano, Akihiko; Kanno, Yuichi; Kondo, Yuya; Sunaga, Yuta; Umezawa, Hatsumi; Okada, Munehiro; Yamada, Hideshi; Iwaki, Ren; Kato, Atsushi; Fukui, Koji

    2017-01-15

    A series of five new fluorescent deoxynojirimycin (DNJ) conjugates were synthesized and evaluated for their inhibitory effect (IC50) on several α- and β-glucosidases. Three of the conjugates showed enhanced activity. The two synthetic conjugates, DNJ-CF31 and DNJ-Me 2, exhibited improved α-glucosidase inhibitory effects compared to DNJ and miglitol. Interestingly, conjugates 1 and 2 showed strong inhibition of almond-derived β-glucosidase, in contrast to the inhibition tendencies of other inhibitors. Conjugate 5 strongly inhibited rat intestinal maltase, even at 0.10μM. A docking study indicated that all five conjugates bind to the active site of α-glucosidase (PDB: 3L4V, derived from Homo sapiens). The DNJ portion of the conjugate fits into the cavity of the enzyme, and the fluorescent part locates randomly on the outside surface. Thus, it is likely that these conjugates can specifically recognize intestinal cells, specifically the α-glucosidase on cell membranes. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Targetable N-(2-hydroxypropyl)methacrylamide copolymer-chlorin e6 conjugates

    Science.gov (United States)

    Kopecek, Jindrich; Krinick, Nancy L.; Rihova, B.; Ulbrich, K.

    1990-07-01

    Two N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-chlorin es-anti-Thy 1.2 antibody conjugates were synthesized. They differ in the method of antibody binding. in conjugate A, the polyclonal anti-Thy 1 .2 antibody was bound via NEamino groups of lysine residues. Conjugate B contained anti-Thy-I .2 antibodies bound via oxidized carbohydrate groups present near the hinge region of the F part of the antibody molecule. The photodynamic activities of these conjugates (and of appropriate controls) were evaluated on mouse splenocytes in vitro. Both conjugates (A and B) were more biologically active compared to the nontargetable conjugate (without antibody). All polymeric chiorin e6 conjugates were less toxic in the dark compared to free chlorin e6. Conjugate B was the most active; its activity at low concentrations was higher compared to free chlorin e6. The results demonstrate the importance of the chemistry of antibody binding on the biological activity of targetable polymeric drugs.

  16. Europium (III) chelate microparticle-based lateral flow immunoassay strips for rapid and quantitative detection of antibody to hepatitis B core antigen.

    Science.gov (United States)

    Liang, Rong-Liang; Deng, Qiao-Ting; Chen, Zhen-Hua; Xu, Xu-Ping; Zhou, Jian-Wei; Liang, Jun-Yu; Dong, Zhi-Ning; Liu, Tian-Cai; Wu, Ying-Song

    2017-10-26

    Quantitative hepatitis B core antigen (anti-HBc) measurements could play an important role in evaluating therapeutic outcomes and optimizing the antiviral therapy of chronic hepatitis B infection. In this study, we have developed a simple and rapid fluorescence point-of-care test based on a lateral flow immunoassay (LFIA) method integrated with Eu (III) chelate microparticles to quantitatively determine anti-HBc concentrations in serum. This assay is based on a direct competitive immunoassay performed on lateral flow test strips with an assay time of 15 min. The Eu (III) chelate microparticle-based LFIA assay could quantitatively detect anti-HBc levels with a limit of detection of 0.31 IU mL -1 , and exhibited a wide linear range (0.63-640 IU mL -1 ). The intra- and inter-assay coefficients of variation for anti-HBc were both less than 10% and a satisfactory dilution test and accuracy were demonstrated. There were no statistically significant differences in sensitivity or specificity in serum samples between the Eu (III) chelate microparticle-based LFIA strips and the Abbott Architect kit. A simple, rapid and effective quantitative detection of anti-HBc was possible using the Eu (III) chelate microparticle-based LFIA strips. The strips will provide diagnostic value for clinical application.

  17. Standardization of methodology to derivatization and radiolabeling of the anti-CD20 monoclonal antibody from bifunctional chelator DOTA-NHS-Ester

    Energy Technology Data Exchange (ETDEWEB)

    Massicano, Adriana V.F.; Akanji, Akinkunmi G.; Santos, Josefina S.; Pujatti, Priscilla B.; Couto, Renata M.; Massicano, Felipe; Araujo, Elaine Bortoleti de [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)], E-mail: adriana.avfernandes@gmail.com

    2009-07-01

    Lymphomas are cancers of the lymphatic system, being the most common the non-Hodgkin lymphoma (NHL). The Radioimmunotherapy (RIT), that increase the cytotoxic effect of monoclonal antibodies (mAb), therefore labeling these Mab with different radioisotopes. RIT combines the specificity of the antibody and the toxicity of the radionuclides. The mAb anti-CD20 is used for treatment of relapse or refractory NHL. The labeling of anti- CD20 with {sup 177}Lu, requires a bifunctional chelating agent that is designed to make a 'connect bridge' between the mAb and the radionuclide. The incorporation of the chelating group in mAb structure is called derivatization. The aim of this work is to study the derivatization of anti-CD20 antibody with DOTA-NHS-ester chelating group and labeling parameters to produce {sup 177}Lu-DOTA-Anti CD20. Five milligrams of anti-CD20 were purified by dialysis against phosphate buffer pH 8.0 and derivatized with DOTA-NHS-ester in 1:250, 1:500 and 1:1000 molar ratios. The reaction was conducted for 1 hour in gently mixing at room temperature and remained under refrigeration for 48 hours. The reaction mixture was purified in gel column Sephadex G-50 ; the aliquots that presented greater protein concentration, were mixed and concentrated. The purified antibody conjugated was added to 111-185MBq (3-5mCi) of {sup 177}LuCl3 diluted in 0.4 M acetate buffer pH 5.5. Radiochemical purity was less than 95% in all the molar ratios, indicating necessity of the purification after the labeling. The mAb derivatized showed stable when stored for to 1 month to 4 deg C and 4 days at -20 deg C. (author)

  18. HPMA copolymer-aminohexylgeldanamycin conjugates targeting cell surface expressed GRP78 in prostate cancer.

    Science.gov (United States)

    Larson, Nate; Ray, Abhijit; Malugin, Alexander; Pike, Daniel B; Ghandehari, Hamidreza

    2010-12-01

    This study focused on the synthesis and in vitro characterization of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates for the delivery of geldanamycin to prostate cancer tumors. Conjugates were modified to incorporate WIFPWIQL peptide, which binds to cell-surface-expressed Glucose-regulated protein 78. HPMA copolymers containing aminohexylgeldanamycin with and without WIFPWIQL peptide were synthesized and characterized, and stability in pH 7.4 and pH 5.0 buffers, complete cell culture medium, and fetal bovine serum was evaluated. The comparative cell surface expression of GRP78 in DU145 and PC3 cell lines was assessed and competitive binding to cell surface expressed GRP78 evaluated. The ability of the conjugates to inhibit cell growth was also evaluated in vitro. HPMA copolymer-aminohexylgeldanamycin conjugates were stable with maximal release observed in fetal bovine serum at 37°C of approximately 10% in 72 h. HPMA copolymers bearing WIFPWIQL peptide bound to cell surface expressed GRP78 with affinities comparable to free WIFPWIQL peptide and demonstrated increased cytotoxicity as compared to untargeted conjugates. HPMA copolymer aminohexylgeldanamycin conjugates bearing WIFPWIQL peptide have the ability to bind to cell-surface-expressed GRP78 and inhibit the growth of human prostate cancer cells, suggesting that the conjugates have the potential to target solid prostate cancer tumors.

  19. Development of iron chelators for Cooley's anemia. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Crosby, W.H.; Green, R.

    1982-01-26

    Iron chelators were screened in an iron-loaded rat model using selective radioiron probes. In all experiments, chelators D and F, in that order, induced significant loss of radioiron compared with controls. However, use of chelator D was associated with side effects, and resulted in the death of some animals. There was some evidence that chelator A also caused iron loss significantly greater than controls. Chelators B, C and E were without apparent enhancing effect on radioiron excretion. This was a blind study and the compounds used were A - 2,3-Dihydroxybenzoic acid; B - N,N1-Dimethyladipohydroxamic acid; C - DL-Phenylalanine hydroxamic acid; D - Ethylenediamine-N,N1-bis(2-hydroxphenylacetic acid); E - Propionohydroxamic acid; and F - Deferrioxamine B.

  20. 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.

  1. Conversion of agonist site to metal-ion chelator site in the beta(2)-adrenergic receptor

    DEFF Research Database (Denmark)

    Elling, C E; Thirstrup, K; Holst, Birgitte

    1999-01-01

    effect of, for example Cu(2+), and in several cases increased the affinity of the ions for the agonistic site. Wash-out experiments and structure-activity analysis indicated, that the high-affinity chelators and the metal ions bind and activate the mutant receptor as metal ion guided ligand complexes...... in the mutant receptors not by normal catecholamine ligands but instead either by free zinc ions or by zinc or copper ions in complex with small hydrophobic metal-ion chelators. Chelation of the metal ions by small hydrophobic chelators such as phenanthroline or bipyridine protected the cells from the toxic....... Because of the well-understood binding geometry of the small metal ions, an important distance constraint has here been imposed between TM-III and -VII in the active, signaling conformation of 7TM receptors. It is suggested that atoxic metal-ion chelator complexes could possibly in the future be used...

  2. Convection-aided collection of metal ions using chelating porous flat-sheet membranes.

    Science.gov (United States)

    Saito, Kaori; Saito, Kyoichi; Sugita, Kazuyuki; Tamada, Masao; Sugo, Takanobu

    2002-04-19

    Chelating porous membranes were prepared by radiation-induced graft polymerization of an epoxy-group-containing monomer onto a polyethylene flat sheet and subsequent conversion of the epoxy group to an iminodiacetate group as a chelate-forming group. The chelating group density on the resultant porous flat-sheet membrane of 1.0 mol/kg was comparable to that of commercially available chelating beads. The pure water permeability of the membrane was 40% that of the trunk porous membrane, which was used for microfiltration. During the permeation of a copper chloride solution through the membrane, diffusional mass-transfer resistance of copper ion was negligible, since the ion was transported by convective flow through the pore. The tensile strength and elongation at break of the membranes were measured as a function of dose of electron-beam irradiation, the degree of grafting, and the chelating group density to determine an applicable range for practical use.

  3. Red Blood Cell Transfusion Independence Following the Initiation of Iron Chelation Therapy in Myelodysplastic Syndrome

    Directory of Open Access Journals (Sweden)

    Maha A. Badawi

    2010-01-01

    Full Text Available Iron chelation therapy is often used to treat iron overload in patients requiring transfusion of red blood cells (RBC. A 76-year-old man with MDS type refractory cytopenia with multilineage dysplasia, intermediate-1 IPSS risk, was referred when he became transfusion dependent. He declined infusional chelation but subsequently accepted oral therapy. Following the initiation of chelation, RBC transfusion requirement ceased and he remained transfusion independent over 40 months later. Over the same time course, ferritin levels decreased but did not normalize. There have been eighteen other MDS patients reported showing improvement in hemoglobin level with iron chelation; nine became transfusion independent, nine had decreased transfusion requirements, and some showed improved trilineage myelopoiesis. The clinical features of these patients are summarized and possible mechanisms for such an effect of iron chelation on cytopenias are discussed.

  4. Chelation and stabilization of berkelium in oxidation state +IV

    Science.gov (United States)

    Deblonde, Gauthier J.-P.; Sturzbecher-Hoehne, Manuel; Rupert, Peter B.; An, Dahlia D.; Illy, Marie-Claire; Ralston, Corie Y.; Brabec, Jiri; de Jong, Wibe A.; Strong, Roland K.; Abergel, Rebecca J.

    2017-09-01

    Berkelium (Bk) has been predicted to be the only transplutonium element able to exhibit both +III and +IV oxidation states in solution, but evidence of a stable oxidized Bk chelate has so far remained elusive. Here we describe the stabilization of the heaviest 4+ ion of the periodic table, under mild aqueous conditions, using a siderophore derivative. The resulting Bk(IV) complex exhibits luminescence via sensitization through an intramolecular antenna effect. This neutral Bk(IV) coordination compound is not sequestered by the protein siderocalin—a mammalian metal transporter—in contrast to the negatively charged species obtained with neighbouring trivalent actinides americium, curium and californium (Cf). The corresponding Cf(III)-ligand-protein ternary adduct was characterized by X-ray diffraction analysis. Combined with theoretical predictions, these data add significant insight to the field of transplutonium chemistry, and may lead to innovative Bk separation and purification processes.

  5. Beryllium Chelation by Dicarboxylic Acids in Aqueous Solution.

    Science.gov (United States)

    Schmidt, Michael; Bauer, Andreas; Schmidbaur, Hubert

    1997-05-07

    Maleic and phthalic acids are found to react with Be(OH)(2), generated in situ from BeSO(4)(aq) and Ba(OH)(2)(aq), in aqueous solution at pH 3.0 or 4.4, respectively (25 degrees C), to give solutions containing the complexes (H(2)O)(2)Be[(OOCCH)(2)] (1) and (H(2)O)(2)Be[(OOC)(2)C(6)H(4)] (3). The products can be isolated in high yield and identified by microanalytical data. With 2 equiv of the dicarboxylic acids and the pH adjusted to 5.5 and 5.9, respectively, by addition of ammonia, the bis-chelate complexes [(NH(4))(+)](2){[Be[(OOCCH)(2)](2)}(2)(-) (2) and [(NH(4))(+)](2){Be[(OOC)(2)C(6)H(4)](2)}(2)(-) (4) are obtained, which can also be isolated. The compounds show distinct (9)Be, (1)H, and (13)C resonances in their NMR spectra in aqueous solutions. Layering of an aqueous solution of compound 4 with acetone at ambient temperature leads to the precipitation of single crystals suitable for an X-ray structure determination. This salt (5) was found to contain the bis-chelated dianion {Be[(OOC)(2)C(6)H(4)](2)}(2)(-) with the beryllium atom in the spiro center of two seven-membered rings and an overall geometry approaching closely C(2) symmetry. These anions are associated with two crystallographically independent but structurally similar counterions [MeC(O)CH(2)CMe(2)NH(3)](+), which are the product of a condensation reaction of the ammonium cation with the acetone solvent. In the crystal the ammonium hydrogen atoms of the cations form N-H.O hydrogen bonds with the oxo functions of the dianion.

  6. Optimization, biological evaluation and microPET imaging of copper-64-labeled bombesin agonists, [{sup 64}Cu-NO2A-(X)-BBN(7-14)NH{sub 2}], in a prostate tumor xenografted mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Lane, Stephanie R., E-mail: srlf36@mail.missouri.ed [Department of Radiology, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States); Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201 (United States); Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211 (United States); Nanda, Prasanta [Department of Radiology, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States); Rold, Tammy L. [Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States); Sieckman, Gary L. [Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201 (United States); Figueroa, Said D. [Department of Radiology, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States); Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201 (United States); Hoffman, Timothy J. [Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201 (United States); The Radiopharmaceutical Sciences Institute, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States); Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211 (United States); Jurisson, Silvia S. [Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211 (United States); Smith, Charles J., E-mail: smithcj@health.missouri.ed [Department of Radiology, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States); Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201 (United States); University of Missouri Research Reactor Center, University of Missouri-Columbia, Columbia, MO 65211 (United States); The Radiopharmaceutical Sciences Institute, University of Missouri-Columbia School of Medicine, Columbia, MO 65211 (United States)

    2010-10-15

    Gastrin-releasing peptide receptors (GRPr) are a member of the bombesin (BBN) receptor family. GRPr are expressed in high numbers on specific human cancers, including human prostate cancer. Therefore, copper-64 ({sup 64}Cu) radiolabeled BBN(7-14)NH{sub 2} conjugates could have potential for diagnosis of human prostate cancer via positron-emission tomography (PET). The aim of this study was to produce [{sup 64}Cu-NO2A-(X)-BBN(7-14)NH{sub 2}] conjugates for prostate cancer imaging, where X=pharmacokinetic modifier (beta-alanine, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, 9-aminonanoic acid or para-aminobenzoic acid) and NO2A=1,4,7-triazacyclononane-1,4-diacetic acid [a derivative of NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid)]. Methods: [(X)-BBN(7-14)NH{sub 2}] Conjugates were synthesized by solid-phase peptide synthesis (SPPS), after which NOTA was added via manual conjugation. The new peptide conjugates were radiolabeled with {sup 64}Cu radionuclide. The receptor-binding affinity was determined in human prostate PC-3 cells, and tumor-targeting efficacy was determined in PC-3 tumor-bearing severely combined immunodeficient (SCID) mice. Whole-body maximum intensity microPET/CT images of PC-3 tumor-bearing SCID mice were obtained 18 h postinjection (pi). Results: Competitive binding assays in PC-3 cells indicated high receptor-binding affinity for the [NO2A-(X)-BBN(7-14)NH{sub 2}] and [{sup nat}Cu-NO2A-(X)-BBN(7-14)NH{sub 2}] conjugates. In vivo biodistribution studies of the [{sup 64}Cu-NO2A-(X)-BBN(7-14)NH{sub 2}] conjugates at 1, 4 and 24 h pi showed very high uptake of the tracer in GRPr-positive tissue with little accumulation and retention in nontarget tissues. High-quality, high-contrast microPET images were obtained, with xenografted tumors being clearly visible at 18 h pi. Conclusions: NO2A chelator sufficiently stabilizes copper(II) radiometal under in vivo conditions, producing conjugates with very high uptake and retention in

  7. Green ultrasound-assisted three-component click synthesis of novel 1H-1,2,3-triazole carrying benzothiazoles and fluorinated-1,2,4-triazole conjugates and their antimicrobial evaluation.

    Science.gov (United States)

    Rezki, Nadjet; Aouad, Mohamed Reda

    2017-09-01

    The present study describes an efficient and ecofriendly, ultrasound, one-pot click cycloaddition approach for the construction of a novel series of 1,4-disubstituted-1,2,3-triazoles tethered with fluorinated 1,2,4-triazole-benzothiazole molecular conjugates. It involved three-component condensation of the appropriate bromoacetamide benzothiazole, sodium azide and 4-alkyl/aryl-5-(2-fluorophenyl)-3-(prop-2-ynylthio)-1,2,4-triazoles 4a-e through a Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction. This approach involves in situ generation of azidoacetamide benzothiazole, followed by condensation with terminal alkynes in the presence of CuSO4/Na-ascorbate in aqueous DMSO under both conventional and ultrasound conditions. Some of the designed 1,2,3-triazole conjugates 6a-o were recognized for their antimicrobial activity against some bacterial and fungal pathogenic strains.

  8. Evaluation of a LPS-based glycoconjugate vaccine against bovine Escherichia coli mastitis: Formation of LPS Abs in cows after immunization with E. coli core oligosaccharides conjugated to hemocyanine.

    Science.gov (United States)

    Brade, Lore; Hensen, Selma; Brade, Helmut

    2013-01-01

    The immune response of cows against the core oligosaccharide of Escherichia coli rough mutants (core types R1-R4, K-12 and J-5) was investigated after immunization with a synthetic glycoconjugate composed of deacylated LPS conjugated to hemocyanine (22 animals). Ab formation was measured by ELISA using LPS or deacylated LPS conjugated to BSA as an Ag. The glycoconjugate immunogens were used to vaccinate cows (36 animals), which were then challenged intramammarily with E. coli O 157 (K1 negative, R1 core type). Compared with control groups no protection was observed, although high titers against the R1 core type were detected in vaccinated animals. Western blots using the immune sera showed that the Ab response was directed against the core region and not against the O-antigen, which may explain the failure of the vaccine.

  9. Development of a potent DOTA-conjugated bombesin antagonist for targeting GRPr-positive tumours

    Energy Technology Data Exchange (ETDEWEB)

    Mansi, Rosalba; Maecke, Helmut R. [University Hospital Basel, Division of Radiological Chemistry, Basel (Switzerland); University of Freiburg, Department of Nuclear Medicine, Freiburg (Germany); Wang, Xuejuan [University Hospital Basel, Division of Radiological Chemistry, Basel (Switzerland); Forrer, Flavio [University Hospital Basel, Institute of Nuclear Medicine, Basel (Switzerland); Erasmus Medical Centre, Nuclear Medicine, Rotterdam (Netherlands); Waser, Beatrice; Cescato, Renzo; Reubi, Jean Claude [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, Berne (Switzerland); Graham, Keith; Borkowski, Sandra [Bayer Schering Pharma AG, Global Drug Discovery, Berlin (Germany)

    2011-01-15

    Radiolabelled somatostatin-based antagonists show a higher uptake in tumour-bearing mouse models than agonists of similar or even distinctly higher receptor affinity. Very similar results were obtained with another family of G protein-coupled receptor ligands, the bombesin family. We describe a new conjugate, RM2, with the chelator DOTA coupled to D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH{sub 2} via the cationic spacer 4-amino-1-carboxymethyl-piperidine for labelling with radiometals such as {sup 111}In and {sup 68}Ga. RM2 was synthesized on a solid support and evaluated in vitro in PC-3 cells. IC{sub 50} and K{sub d} values were determined. The antagonist potency was evaluated by immunofluorescence-based internalization and Ca{sup 2+} mobilization assays. Biodistribution studies were performed in PC-3 and LNCaP tumour-bearing mice with {sup 111}In-RM2 and {sup 68}Ga-RM2, respectively. PET/CT studies were performed on PC-3 and LNCaP tumour-bearing nude mice with {sup 68}Ga-RM2. RM2 and {sup 111}In-RM2 are high-affinity and selective ligands for the GRP receptor (7.7{+-}3.3 nmol/l for RM2; 9.3{+-}3.3 nmol/l for {sup nat}In-RM2). The potent antagonistic properties were confirmed by an immunofluorescence-based internalization and Ca{sup 2+} mobilization assays. {sup 68}Ga- and {sup 111}In-RM2 showed high and specific uptake in both the tumour and the pancreas. Uptake in the tumour remained high (15.2{+-}4.8%IA/g at 1 h; 11.7{+-}2.4%IA/g at 4 h), whereas a relatively fast washout from the pancreas and the other abdominal organs was observed. Uptake in the pancreas decreased rapidly from 22.6{+-}4.7%IA/g at 1 h to 1.5{+-}0.5%IA/g at 4 h. RM2 was shown to be a potent GRPr antagonist. Pharmacokinetics and imaging studies indicate that {sup 111}In-RM2 and {sup 68}Ga-RM2 are ideal candidates for clinical SPECT and PET studies. (orig.)

  10. Synthesis and Characterization of BSA Conjugated Silver Nanoparticles (Ag/BSA Nanoparticles) and Evaluation of Biological Properties of Ag/BSA Nanoparticles and Ag/BSA Nanoparticles Loaded Poly(hydroxy butyrate valerate) PHBV Films

    Science.gov (United States)

    Ambaye, Almaz

    Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa are the etiological agents of several infectious diseases. Antibiotic resistance by these three microbes has emerged as a prevalent problem due in part to the misuse of existing antibiotics and the lack of novel antibiotics. Nanoparticles have emerged as an alternative antibacterial agents to conventional antibiotics owing to their high surface area to volume ratio and their unique chemical and physical properties. Among the nanoparticles, silver nanoparticles have gained increasing attention because silver nanoparticles exhibit antibacterial activity against a range of gram positive and gram negative bacteria. Nanoparticles of well-defined chemistry and morphology can be used in broad biomedical applications, especially in bone tissue engineering applications, where bone infection by bacteria can be acute and lethal. It is commonly noted in the literature that the activity of nanoparticles against microorganisms is dependent upon the size and concentration of the nanoparticles as well as the chemistry of stabilizing agent. To the best of our knowledge, a comprehensive study that evaluates the antibacterial activity of well characterized silver nanoparticles in particular Bovine Serum Albumin (BSA) stabilized against S. aureus and E. coli and cytotoxicity level of BSA stabilized silver nanoparticles towards osteoblast cells (MC3T3-E1) is currently lacking. Therefore, the primary objective of this study was to characterize protein conjugated silver nanoparticles prepared by chemical reduction of AgNO3 and BSA mixture. The formation of Ag/BSA nanoparticles was studied by UV-Vis spectroscopy. The molar ratio of silver to BSA in the Ag/BSA nanoparticles was established to be 27+/- 3: 1, based on Thermogravimetric Analysis and Atomic Absorption Spectroscopy. Based on atomic force microscopy, dynamic light scattering,and transmission electron microscopy(TEM) measurements, the particle size (diameter) of

  11. Preparation and assessment cytotoxic and hemolytic activities of Complexes from “Chelating Kojic–Lipid Conjugate”

    Directory of Open Access Journals (Sweden)

    Antônio S. C. Carvalho

    2012-06-01

    Full Text Available Complex bis (2-Oleicoyloxymethyl-5-hydroxy-gamma-pyrone copper (II and tris (2-Oleicoyloxymethyl-5-hydroxy-gamma-pyrone iron (III were prepared in ethanol using the structure "chelator conjugate kojic -lipid". This ester was obtained from kojic acid by improving their lipophilicity of obtaining metalobioactives with application in Medicinal Bioinorganic Chemistry. Through the technique ATR/FTIR, the values ​​of the infrared kojic acid has been updated and it was possible to characterize      the complex 1567m, 1511w (Cu (II←[O=C]2, and 1540m, 1519m (Fe(III←[O=C]3. These compounds no showed cytotoxic potential against B16 (melanoma and ACP02 (gastric adenocarcinoma (IC50> 5 μg mL-1 and low hemolytic activity (EC50> 250 μg mL-1.The preparation of these new molecules by structural modification techniques and these interesting biological results confirm the continuity of this studies related to these coordination complexes to glimpse the possibility of obtaining other derivatives/ analogues with significant biological potential of this metallo-bioactive.

  12. Improved cellular uptake of antisense Peptide nucleic acids by conjugation to a cell-penetrating Peptide and a lipid domain

    DEFF Research Database (Denmark)

    Shiraishi, Takehiko; Nielsen, Peter E

    2011-01-01

    . We have found, however, that this low -bioavailability can be significantly improved by chemical conjugation to a lipid domain ("Lip," such as a fatty acid), thereby creating "CatLip"-conjugates. The cellular uptake of these conjugates is conveniently evaluated using a sensitive cellular assay system...... based on a splicing correction of a mutated luciferase gene in HeLa pLuc705 cells by targeting antisense oligonucleotides to a cryptic splice site. Further improvement in the delivery of CatLip-PNA conjugates is achieved by using auxiliary agents/treatments (e.g., chloroquine, calcium ions...

  13. 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.

  14. Immunochemical parameters of some commercial conjugates for the fluorescent treponemal antibody-absorption test.

    Science.gov (United States)

    Hunter, E F; Smith, J F; Lewis, J S; McGrew, B E; Schmale, J D

    1972-06-01

    Fluorescein-labeled anti-human globulins were examined to determine the need for standardization of conjugates used in the fluorescent treponemal antibody-absorption (FTA-ABS) test. Twenty-one of 33 conjugates submitted by commercial manufacturers to the Reagents Control Activity, Venereal Disease Research Laboratory, for evaluation in the FTA-ABS test were available for study. Conjugates, after evaluation in FTA-ABS performance tests, were examined by immunoelectrophoresis, by titration against immunoglobulins G and M (IgG, IgM) with FTA-ABS techniques, and by the biuret protein and fluorescein diacetate methods for determining fluorescein to protein (F/P) ratios. The conjugates were predominately anti-IgG globulin with anti-light-chain activity. Differences were noted in the ability of some conjugates to detect IgM antibody. The F/P ratios of those conjugates that could be determined varied from 2.6 to 17.8 mug of fluorescein per mg of protein. The need to identify and standardize both the immunologic capabilities and the optimum F/P ratio for FTA-ABS test conjugates is presented.

  15. The Tcp conjugation system of Clostridium perfringens.

    Science.gov (United States)

    Wisniewski, Jessica A; Rood, Julian I

    2017-05-01

    The Gram-positive pathogen Clostridium perfringens possesses a family of large conjugative plasmids that is typified by the tetracycline resistance plasmid pCW3. Since these plasmids may carry antibiotic resistance genes or genes encoding extracellular or sporulation-associated toxins, the conjugative transfer of these plasmids appears to be important for the epidemiology of C. perfringens-mediated diseases. Sequence analysis of members of this plasmid family identified a highly conserved 35kb region that encodes proteins with various functions, including plasmid replication and partitioning. The tcp conjugation locus also was identified in this region, initially based on low-level amino acid sequence identity to conjugation proteins from the integrative conjugative element Tn916. Genetic studies confirmed that the tcp locus is required for conjugative transfer and combined with biochemical and structural analyses have led to the development of a functional model of the Tcp conjugation apparatus. This review summarises our current understanding of the Tcp conjugation system, which is now one of the best-characterized conjugation systems in Gram-positive bacteria. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Designer diatom episomes delivered by bacterial conjugation

    National Research Council Canada - National Science Library

    Karas, Bogumil J; Diner, Rachel E; Lefebvre, Stephane C; McQuaid, Jeff; Phillips, Alex P R; Noddings, Chari M; Brunson, John K; Valas, Ruben E; Deerinck, Thomas J; Jablanovic, Jelena; Gillard, Jeroen T F; Beeri, Karen; Ellisman, Mark H; Glass, John I; Hutchison, 3rd, Clyde A; Smith, Hamilton O; Venter, J Craig; Allen, Andrew E; Dupont, Christopher L; Weyman, Philip D

    2015-01-01

    .... Here we describe the first nuclear episomal vector for diatoms and a plasmid delivery method via conjugation from Escherichia coli to the diatoms Phaeodactylum tricornutum and Thalassiosira pseudonana...

  17. Intracellular trafficking of new anticancer therapeutics: antibody–drug conjugates

    Directory of Open Access Journals (Sweden)

    Kalim M

    2017-08-01

    Full Text Available Muhammad Kalim,1 Jie Chen,1 Shenghao Wang,1 Caiyao Lin,1 Saif Ullah,1 Keying Liang,1 Qian Ding,1 Shuqing Chen,2 Jinbiao Zhan1 1Department of Biochemistry and Genetics, School of Medicine, 2Department of Pharmaceutical Analysis, College of Pharmaceutical Science, Zhejiang University, Hangzhou, People’s Republic of China Abstract: Antibody–drug conjugate (ADC is a milestone in targeted cancer therapy that comprises of monoclonal antibodies chemically linked to cytotoxic drugs. Internalization of ADC takes place via clathrin-mediated endocytosis, caveolae-mediated endocytosis, and pinocytosis. Conjugation strategies, endocytosis and intracellular trafficking optimization, linkers, and drugs chemistry present a great challenge for researchers to eradicate tumor cells successfully. This inventiveness of endocytosis and intracellular trafficking has given consi­derable momentum recently to develop specific antibodies and ADCs to treat cancer cells. It is significantly advantageous to emphasize the endocytosis and intracellular trafficking pathways efficiently and to design potent engineered conjugates and biological entities to boost efficient therapies enormously for cancer treatment. Current studies illustrate endocytosis and intracellular trafficking of ADC, protein, and linker strategies in unloading and also concisely evaluate practically applicable ADCs. Keywords: antibody–drug conjugate, antibody, endocytosis, intracellular trafficking, clathrin

  18. Test of charge conjugation invariance.

    Science.gov (United States)

    Nefkens, B M K; Prakhov, S; Gårdestig, A; Allgower, C E; Bekrenev, V; Briscoe, W J; Clajus, M; Comfort, J R; Craig, K; Grosnick, D; Isenhower, D; Knecht, N; Koetke, D; Koulbardis, A; Kozlenko, N; Kruglov, S; Lolos, G; Lopatin, I; Manley, D M; Manweiler, R; Marusić, A; McDonald, S; Olmsted, J; Papandreou, Z; Peaslee, D; Phaisangittisakul, N; Price, J W; Ramirez, A F; Sadler, M; Shafi, A; Spinka, H; Stanislaus, T D S; Starostin, A; Staudenmaier, H M; Supek, I; Tippens, W B

    2005-02-04

    We report on the first determination of upper limits on the branching ratio (BR) of eta decay to pi0pi0gamma and to pi0pi0pi0gamma. Both decay modes are strictly forbidden by charge conjugation (C) invariance. Using the Crystal Ball multiphoton detector, we obtained BR(eta-->pi0pi0gamma)pi0pi0pi0gamma)<6 x 10(-5) at the 90% confidence level, in support of C invariance of isovector electromagnetic interactions.

  19. Economic Evaluation of Immunisation Programme of 23-Valent Pneumococcal Polysaccharide Vaccine and the Inclusion of 13-Valent Pneumococcal Conjugate Vaccine in the List for Single-Dose Subsidy to the Elderly in Japan.

    Science.gov (United States)

    Hoshi, Shu-ling; Kondo, Masahide; Okubo, Ichiro

    2015-01-01

    Currently in Japan, both 23-valent pneumococcal polysaccharide vaccine (PPSV-23) and 13-valent pneumococcal conjugate vaccine (PCV-13) are available for the elderly for the prevention of S. pneumoniae-related diseases. PPSV-23 was approved in 1988, while the extended use of PCV-13 was approved for adults aged 65 and older in June 2014. Despite these two vaccines being available, the recently launched national immunisation programme for the elderly only subsidised PPSV-23. The framework of the current immunisation programme lasts for five years. The elderly population eligible for the subsidised PPSV-23 shot for the 1st year are those aged 65, 70, 75, 80, 85, 90, 95 and ≥ 100. While from the 2nd year to the 5th year, those who will age 65, 70, 75, 80, 85, 90, 95 and 100 will receive the same subsidised shot. We performed economic evaluations to (1) evaluate the efficiency of alternative strategies of PPSV-23 single-dose immunisation programme, and (2) investigate the efficiency of PCV-13 inclusion in the list for single-dose pneumococcal vaccine immunisation programme. Three alternative strategies were created in this study, namely: (1) current PPSV-23 strategy, (2) 65 to 80 (as "65-80 PPSV-23 strategy"), and (3) 65 and older (as "≥ 65 PPSV-23 strategy"). We constructed a Markov model depicting the S. pneumoniae-related disease course pathways. The transition probabilities, utility weights to estimate quality adjusted life year (QALY) and disease treatment costs were either calculated or cited from literature. Cost of per shot of vaccine was ¥ 8,116 (US$74; US$1 = ¥ 110) for PPSV-23 and ¥ 10,776 (US$98) for PCV-13. The model runs for 15 years with one year cycle after immunisation. Discounting was at 3%. Compared to current PPSV-23 strategy, 65-80 PPSV-23 strategy cost less but gained less, while the incremental cost-effectiveness ratios (ICERs) of ≥ 65 PPSV-23 strategy was ¥ 5,025,000 (US$45,682) per QALY gained. PCV-13 inclusion into the list for single

  20. Economic Evaluation of Immunisation Programme of 23-Valent Pneumococcal Polysaccharide Vaccine and the Inclusion of 13-Valent Pneumococcal Conjugate Vaccine in the List for Single-Dose Subsidy to the Elderly in Japan.

    Directory of Open Access Journals (Sweden)

    Shu-ling Hoshi

    Full Text Available Currently in Japan, both 23-valent pneumococcal polysaccharide vaccine (PPSV-23 and 13-valent pneumococcal conjugate vaccine (PCV-13 are available for the elderly for the prevention of S. pneumoniae-related diseases. PPSV-23 was approved in 1988, while the extended use of PCV-13 was approved for adults aged 65 and older in June 2014. Despite these two vaccines being available, the recently launched national immunisation programme for the elderly only subsidised PPSV-23. The framework of the current immunisation programme lasts for five years. The elderly population eligible for the subsidised PPSV-23 shot for the 1st year are those aged 65, 70, 75, 80, 85, 90, 95 and ≥ 100. While from the 2nd year to the 5th year, those who will age 65, 70, 75, 80, 85, 90, 95 and 100 will receive the same subsidised shot.We performed economic evaluations to (1 evaluate the efficiency of alternative strategies of PPSV-23 single-dose immunisation programme, and (2 investigate the efficiency of PCV-13 inclusion in the list for single-dose pneumococcal vaccine immunisation programme. Three alternative strategies were created in this study, namely: (1 current PPSV-23 strategy, (2 65 to 80 (as "65-80 PPSV-23 strategy", and (3 65 and older (as "≥ 65 PPSV-23 strategy". We constructed a Markov model depicting the S. pneumoniae-related disease course pathways. The transition probabilities, utility weights to estimate quality adjusted life year (QALY and disease treatment costs were either calculated or cited from literature. Cost of per shot of vaccine was ¥ 8,116 (US$74; US$1 = ¥ 110 for PPSV-23 and ¥ 10,776 (US$98 for PCV-13. The model runs for 15 years with one year cycle after immunisation. Discounting was at 3%.Compared to current PPSV-23 strategy, 65-80 PPSV-23 strategy cost less but gained less, while the incremental cost-effectiveness ratios (ICERs of ≥ 65 PPSV-23 strategy was ¥ 5,025,000 (US$45,682 per QALY gained. PCV-13 inclusion into the list for

  1. Generation and characterization of phage-GnRH chemical conjugates for potential use in cat and dog immunocontraception.

    Science.gov (United States)

    Samoylov, A; Cox, N; Cochran, A; Wolfe, K; Donovan, C; Kutzler, M; Petrenko, V; Baker, H; Samoylova, T

    2012-12-01

    Overpopulation of cats and dogs is a serious worldwide problem that demands novel, safe and cost-effective solutions. The objective of this study was to generate and characterize phage-peptide conjugates with gonadotropin-releasing hormone (GnRH) for potential use as an immunocontraceptive. A filamentous phage vector f5-8 with wild-type phage coat proteins was used as a carrier for construction of chemical conjugates with GnRH, a peptide that acts as a master reproductive hormone. In such conjugates, the phage body plays the role of a carrier protein, while multiple copies of GnRH peptide stimulate production of neutralizing anti-GnRH antibodies potentially leading to contraceptive effects. To generate the constructs, four different GnRH-based peptides were synthesized and conjugated to phage particles in a two-step procedure: (i) peptides were reacted with phage to form a conjugate using 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride chemistry (EDC) and (ii) the conjugates were separated from remaining free peptides by dialysis. Formation and specificity of phage-GnRH conjugates were confirmed by three independent methods: spectrophotometry, electron microscopy and ELISA. When the conjugates were tested for interaction with sera collected from cats and dogs immunized with GnRH-based vaccines in independent studies, strong specific ELISA signals were obtained, suggesting the potential use of the conjugates for cat and dog immunosterilization. The ability of the conjugates to stimulate production of anti-GnRH antibodies in vivo was evaluated in mice. While optimization of dose, immunization route and adjuvant still requires investigation, our preliminary results demonstrated the presence of anti-GnRH antibodies in sera of mice immunized with such conjugates. Fertility trials in cats and dogs will be needed to evaluate contraceptive potentials of the phage-GnRH peptide chemical conjugates. © 2012 Blackwell Verlag GmbH.

  2. The effect of ferrous-chelating hairtail peptides on iron deficiency and intestinal flora in rats.

    Science.gov (United States)

    Lin, Hui-Min; Deng, Shang-Gui; Huang, Sai-Bo; Li, Ying-Jie; Song, Ru

    2016-06-01

    Chelating agents, such as small peptides, can decrease free iron content and increase iron bioavailability. They may have promising therapeutic potential and may prevent the pro-oxidant effects of low molecular weight iron. Hairtail is a species of fish that is rich in easily digestible proteins. We extended this strategy for iron delivery by using an enzymatic hydrolysate of hairtail as the chelating agent and found that the ferrous-chelating hairtail peptides have anti-anaemic activity in Sprague-Dawley rats with anaemia. The anti-anaemic activity of ferrous-chelating hairtail peptides prepared by enzymatic hydrolysis of the hairtail and ferrous chelation was studied in rat models of iron deficiency anaemia. After the end of the 35 d experiment, we noted significant differences in haemoglobin, mean corpuscular volume, haemoglobin distribution width, and ferritin concentrations between those animals supplemented with ferrous-chelating hairtail peptides and FeSO4 and healthy animals. There were no negative side effects on the animals' growth or behaviour. There was no obvious inflammation in the intestinal mucosa lamina propria and no unbalance of intestinal flora. The novel ferrous-chelating hairtail peptides may be a suitable fortificant for improving iron-deficiency status. Our findings demonstrated that this multi-tracer technique has many applications in nutritional research. © 2015 Society of Chemical Industry. © 2015 Society of Chemical Industry.

  3. Micelles by self-assembling peptide-conjugate amphiphile: synthesis and structural characterization.

    Science.gov (United States)

    Accardo, Antonella; Tesauro, Diego; Del Pozzo, Luigi; Mangiapia, Gaetano; Paduano, Luigi; Morelli, Giancarlo

    2008-08-01

    The chemical synthesis by solid-phase methods of a novel amphiphilic peptide, peptide-conjugate amphiphile (PCA), containing in the same molecule three different functions: (i) the N,N-bis[2-[bis(carboxy-ethyl)amino]ethyl]-L-glutamic acid (DTPAGlu) chelating agent, (ii) the CCK8 bioactive peptide, and (iii) a hydrophobic moiety containing four alkyl chains with 18 carbon atoms each, is reported. In water solution at pH 7.4, PCA self-assembles in very stable micelles at very low concentration [critical micellar concentration (cmc) values of 5 x 10(-7) mol kg(-1)] as confirmed by fluorescence spectroscopy. The structural characterization, obtained with small-angle neutron scattering (SANS) measurements, indicates that the aggregates are substantially represented by ellipsoidal micelles with an aggregation number of 39 +/- 2 and the two micellar axes of about 52 and 26 A. Copyright (c) 2008 European Peptide Society and John Wiley & Sons, Ltd.

  4. Design and development of receptor-avid peptide conjugates for in-vivo targeting of cancer

    Science.gov (United States)

    Volkert, Wynn A.; Hoffman, Timothy J.

    1999-07-01

    Radiometallated peptides that exhibit high specificity for cognate receptors over expressed on cancer cells offer important potential as site-directed diagnostic and therapeutic radiopharmaceutical. The formation of effective radioactive drugs for specific in vivo targeting of cancerous tumors is being facilitated by the integration of novel chelation strategies and receptor-avid derivatives. Significant efforts are being made to design Technetium-99m labeled for diagnostic imaging of cancerous tumors for use in conjunction with Single Photon Emission Tomography instrumentation in nuclear medicine. Receptor avid radiopharmaceutical are also being developed that utilize other radionuclides for imaging and therapeutic applications. Despite the technological challenges that must be overcome, radiolabeled receptor avid peptide conjugates are providing promising site-directed targeting agents for the assessment and treatment of cancerous tumors in humans.

  5. Physiological Responses of Some Iranian Grape Cultivars to Iron Chelate Application in Calcareous Soil

    Directory of Open Access Journals (Sweden)

    H. Doulati Baneh

    2016-07-01

    Full Text Available Introduction: Iron chlorosis is considered to be one of the most important nutritional disorders in grapevines, particularly in calcareous soils that under these conditions fruit yield and quality is depressed in the current year and fruit buds poorly develop for following year. Symptoms of iron chlorosis in orchards and vineyards are usually more frequent in spring when shoot growth is rapid and bicarbonate concentration in the soil solution buffers soil pH in the rhizosphere and root apoplast. Several native grapevine (Vitis vinifera L. genotypes, highly appreciated for their organoleptic characteristics and commercial potential, are widely cultivated in Iran. Cultivated plants differ as to their susceptibility to Fe deficiency in calcareous soils, some being poorly affected while others showing severe leaf chlorotic symptoms. Selection and the use of Fe-efficient genotypes is one of the important approaches to prevent this nutritional problem. In this research the response of three local grapevine cultivars was evaluated to iron chelate consumption in a calcareous soil (26% T.N.V. Materials and Methods: Well rooted woody cuttings of three autochthonous varieties (Rasha, Qezel uzum, Keshmeshi Qermez were cultivated in pots filled with a calcareous soil with iron chelate consumption at three rates (0, 7.5 and 15 mg Fe/ Kg soil. The study was conducted with two factors (cultivar and iron chelate and 3 replicates in a factorial arrangement based on randomized complete block design. Plant parameters including vegetative growth, chlorophyll index and leaf area were monitored during the growth period. At the end of the treatment, fresh and dry weight of shoots and roots were determined. The concentrations of macro and micro elements in the leaves were assayed using an atomic absorption and spectrophotometer. One-way-ANOVA was applied comparing the behavior of the cultivars growing. Results and Discussion: Analysis of variance showed that chlorophyll

  6. Excited state evolution towards ligand loss and ligand chelation at group 6 metal carbonyl centres.

    Science.gov (United States)

    Manton, Jennifer C; Amirjalayer, Saeed; Coleman, Anthony C; McMahon, Suzanne; Harvey, Emma C; Greetham, Gregory M; Clark, Ian P; Buma, Wybren Jan; Woutersen, Sander; Pryce, Mary T; Long, Conor

    2014-12-21

    The photochemistry and photophysics of three model "half-sandwich" complexes (η(6)-benzophenone)Cr(CO)3, (η(6)-styrene)Cr(CO)3, and (η(6)-allylbenzene)Cr(CO)3 were investigated using pico-second time-resolved infrared spectroscopy and time-dependent density functional theory methods. The (η(6)-benzophenone)Cr(CO)3 complex was studied using two excitation wavelengths (470 and 320 nm) while the remaining complexes were irradiated using 400 nm light. Two independent excited states were detected spectroscopically for each complex, one an unreactive excited state of metal-to-arene charge-transfer character and the other with metal-to-carbonyl charge transfer character. This second excited state leads to an arrested release of CO on the pico-second time-scale. Low-energy excitation (470 nm) of (η(6)-benzophenone)Cr(CO)3 populated only the unreactive excited state which simply relaxes to the parent complex. Higher energy irradiation (320 nm) induced CO-loss. Irradiation of (η(6)-styrene)Cr(CO)3, or (η(6)-allylbenzene)Cr(CO)3 at 400 nm provided evidence for the simultaneous population of both the reactive and unreactive excited states. The efficiency at which the unreactive excited state is populated depends on the degree of conjugation of the substituent with the arene π-system and this affects the efficiency of the CO-loss process. The quantum yield of CO-loss is 0.50 for (η(6)-allylbenzene)Cr(CO)3 and 0.43 for (η(6)-styrene)Cr(CO)3. These studies provide evidence for the existence of two photophysical routes to CO loss, a minor ultrafast route and an arrested mechanism involving the intermediate population of a reactive excited state. This reactive excited state either relaxes to reform the parent species or eject CO. Thus the quantum yield of the CO-loss is strongly dependent on the excitation wavelength. Time-dependent density functional theory calculations confirm that the state responsible for ultrafast CO-loss has significant metal-centred character while

  7. Gastrin Receptor-Avid Peptide Conjugates

    Energy Technology Data Exchange (ETDEWEB)

    Hoffman, Timothy J. (Columbia, MO); Volkert, Wynn A. (Columbia, MO); Li, Ning (Baltimore, MD); Sieckman, Gary (Ashland, MO); Higginbotham, Chrys-Ann (Columbia, MO)

    2005-07-26

    A compound for use as a therapeutic or diagnostic radiopharmaceutical includes a group capable of complexing a medically useful metal attached to a moiety which is capable of binding to a gastrin releasing peptide receptor. A method for treating a subject having a neoplastic disease includes administering to the subject an effective amount of a radiopharmaceutical having a metal chelated with a chelating group attached to a moiety capable of binding to a gastrin releasing peptide receptor expressed on tumor cells with subsequent internalization inside of the cell. A method of forming a therapeutic or diagnostic compound includes reacting a metal synthon with a chelating group covalently linked with a moiety capable of binding a gastrin releasing peptide receptor.

  8. Gastrin receptor-avid peptide conjugates

    Energy Technology Data Exchange (ETDEWEB)

    Hoffman, Timothy J.; Volkert, Wynn A.; Sieckman, Gary; Smith, Charles J.; Gali, Hariprasad

    2006-06-13

    A compound for use as a therapeutic or diagnostic radiopharmaceutical includes a group capable of complexing a medically useful metal attached to a moiety which is capable of binding to a gastrin releasing peptide receptor. A method for treating a subject having a neoplastic disease includes administering to the subject an effective amount of a radiopharmaceutical having a metal chelated with a chelating group attached to a-moiety capable of binding to a gastrin releasing peptide receptor expressed on tumor cells with subsequent internalization inside of the cell. A method of forming a therapeutic or diagnostic compound includes reacting a metal synthon with a chelating group covalently linked with a moiety capable of binding a gastrin releasing peptide receptor.

  9. Gastrin receptor-avid peptide conjugates

    Energy Technology Data Exchange (ETDEWEB)

    Hoffman, Timothy J.; Volkert, Wynn A.; Li, Ning; Sieckman, Gary; Higginbotham, Chrys-Ann

    2006-12-12

    A compound for use as a therapeutic or diagnostic radiopharmaceutical includes a group capable of complexing a medically useful metal attached to a moiety which is capable of binding to a gastrin releasing peptide receptor. A method for treating a subject having a neoplastic disease includes administering to the subject an effective amount of a radiopharmaceutical having a metal chelated with a chelating group attached to a moiety capable of binding to a gastrin releasing peptide receptor expressed on tumor cells with subsequent internalization inside of the cell. A method of forming a therapeutic or diagnostic compound includes reacting a metal synthon with a chelating group covalently linked with a moiety capable of binding a gastrin releasing peptide receptor.

  10. Photoluminescence of Conjugated Star Polymers

    Science.gov (United States)

    Ferguson, J. B.; Prigodin, N. V.; Epstein, A. J.; Wang, F.

    2000-10-01

    Higher dimensionality "star" polymers provide new properties beyond those found in their linear analogs. They have been used to improving electronic properties for nonlinear optics through exciton transfer and molecular antenna structures for example (M. Kawa, J. M. J. Frechet, Chem. Mater. 10, 286 (1998).). We report on photoluminescence properties of star polymers with a hyperbranched core (both hyperbranched phenlyene and hyperbranched triphenylamine) and polyhexylthiophene arms. The arm is a conjugated oligomer of polythiophene that has been investigated extensively for metallic like conductivity when doped as well as utilized in field effect transistors in its undoped form (A. Tsumara, H. Koezuka, T. Ando, Appl. Phys. Lett. 49, 1210 (1986).). The cores are respectively, a nonconjugated polymer in the case of hyperbranched phenlyene and a conjugated polymer in the case of hyperbranched triphenylamine. The photoluminesce spectrum (λ_max at 575 nm) is identical for both star polymers with the two electronically different hyperbranched cores and for linear polythiophene alone. We conclude the wave functions of the core and arms do not strongly interact to form states different from their individual states and excitons formed on the hyperbranched cores migrate to the lower bandgap polythiophene before recombining.

  11. Chelating properties of alpha-oximinocarboxamides-I alpha-Oximinophenylacetamide isomers.

    Science.gov (United States)

    Coviello, D A; El-Fatatry, H M

    1971-06-01

    Various polyfunctional oximes chelate with metals pro vided that the other functional group is proximal to the oxime and contains a good donor atom or is a good donor itself. Thus alpha-oximinocarboxamides are potential chelating agents of analytical value since the amide function attached to the carbon atom bearing the oxime has two groups capable of functioning as donors (ketone and amine). Two isomers of alpha-oximinophenylacetamide (AOPA) were obtained by two different synthetic routes, and structures were assigned by spectrometric methods. syn-AOPA was found to have chelating properties, but the anti-isomer did not. The synthesis and details of structure assignments are reported here.

  12. Inhibitor Ranking Through QM based Chelation Calculations for Virtual Screening of HIV-1 RNase H inhibition

    DEFF Research Database (Denmark)

    Poongavanam, Vasanthanathan; Svendsen, Casper Steinmann; Kongsted, Jacob

    2014-01-01

    Quantum mechanical (QM) calculations have been used to predict the binding affinity of a set of ligands towards HIV-1 RT associated RNase H (RNH). The QM based chelation calculations show improved binding affinity prediction for the inhibitors compared to using an empirical scoring function...... of the methods based on the use of a training set of molecules, QM based chelation calculations were used as filter in virtual screening of compounds in the ZINC database. By this, we find, compared to regular docking, QM based chelation calculations to significantly reduce the large number of false positives...

  13. Radiolabeled technetium chelates for use in renal function determinations

    Science.gov (United States)

    Fritzberg, Alan; Kasina, Sudhakar; Johnson, Dennis L.

    1990-01-01

    The present invention is directed to novel radiopharmaceutical imaging agents incorporating Tc-99m as a radiolabel. In particular, the novel imaging agents disclosed herein have relatively high renal extraction efficiencies, and hence are useful for conducting renal function imaging procedures. The novel Tc-99m compounds of a present invention have the following general formula: ##STR1## wherein X is S or N; and wherein Y is--H or wherein Y is ##STR2## and where R.sub.1 is --H, --CH.sub.3, or --CH.sub.2 CH.sub.3 ; R.sub.2 is --H, --CH.sub.2 CO.sub.2 H, --CH.sub.2 CONH.sub.2, --CH.sub.2 CH.sub.2 CO.sub.2 H, --CH.sub.2 CH.sub.2 CONH.sub.2, --CH.sub.3, --CH.sub.2 CH.sub.3, CH.sub.2 C.sub.6 H.sub.5, or --CH.sub.2 OH; and Z is --H, --CO.sub.2 H, --CONH.sub.2, --SO.sub.3 H, --SO.sub.2 NH.sub.2, or --CONHCH.sub.2 CO.sub.2 H; and the Tc is Tc-99m; and water-soluble salts thereof. Of the foregoing, the presently preferred Tc-99m compound of the present invention is Tc-99m-mercaptoacetylglycylglycylglycine (Tc-99m-MAGGG). The present invention is also directed to novel chelating agents that may be reacted with Tc-99m to form the foregoing compounds. Such novel chelating agents have the following general formula. ##STR3## where X and Y have the same definitions as above, and wherein Y' is --H.sub.2 when X is N, or wherein Y' is --H, or a suitable protective group such as --COCH.sub.3, --COC.sub.6 H.sub.5, --CH.sub.2 NHCOCH.sub.3, --COCF.sub.3, or --COCH.sub.2 OH when X is S. The present invention also provides methods for preparing and using the novel Tc-99m compounds.

  14. Garlic's ability to prevent in vitro Cu2+-induced lipoprotein oxidation in human serum is preserved in heated garlic: effect unrelated to Cu2+-chelation

    Directory of Open Access Journals (Sweden)

    Menjívar Marta

    2004-09-01

    Full Text Available Abstract Background It has been shown that several extracts and compounds derived from garlic are able to inhibit Cu2+-induced low density lipoprotein oxidation. In this work we explored if the ability of aqueous garlic extract to prevent in vitro Cu2+-induced lipoprotein oxidation in human serum is affected by heating (a aqueous garlic extracts or (b garlic cloves. In the first case, aqueous extract of raw garlic and garlic powder were studied. In the second case, aqueous extract of boiled garlic cloves, microwave-treated garlic cloves, and pickled garlic were studied. It was also studied if the above mentioned preparations were able to chelate Cu2+. Methods Cu2+-induced lipoprotein oxidation in human serum was followed by the formation of conjugated dienes at 234 nm and 37°C by 240 min in a phosphate buffer 20 mM, pH 7.4. Blood serum and CuSO4 were added to a final concentration of 0.67% and 0.0125 mM, respectively. The lag time and the area under the curve from the oxidation curves were obtained. The Cu2+-chelating properties of garlic extracts were assessed using an approach based upon restoring the activity of xanthine oxidase inhibited in the presence of 0.050 mM Cu2+. The activity of xanthine oxidase was assessed by monitoring the production of superoxide anion at 560 nm and the formation of uric acid at 295 nm. Data were compared by parametric or non-parametric analysis of variance followed by a post hoc test. Results Extracts from garlic powder and raw garlic inhibited in a dose-dependent way Cu2+-induced lipoprotein oxidation. The heating of garlic extracts or garlic cloves was unable to alter significantly the increase in lag time and the decrease in the area under the curve observed with the unheated garlic extracts or raw garlic. In addition, it was found that the garlic extracts were unable to chelate Cu2+. Conclusions (a the heating of aqueous extracts of raw garlic or garlic powder or the heating of garlic cloves by boiling

  15. Evaluation of iron fortified Gouda cheese for sensory and physicochemical attributes

    National Research Council Canada - National Science Library

    Indumathi, K P; Kaushik, R; Arora, S; Wadhwa, B K

    2015-01-01

    .... Physicochemical attributes evaluation demonstrated higher moisture content in whey protein chelated iron fortified Gouda cheese and hence lower ash, protein and fat content in comparison with control...

  16. 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.

  17. Determinants of pneumococcal conjugate vaccine uptake among ...

    African Journals Online (AJOL)

    Determinants of pneumococcal conjugate vaccine uptake among children attending immunisation services at Kenyatta National Hospital, Nairobi, Kenya. ... Results: The study established that the determinants of uptake of Pneumococcal Conjugate Vaccine are age(OR 5.8, CI 1.4-23.4, p=0.014), level of education (OR 5.8, ...

  18. Preconditioning the modified conjugate gradient method ...

    African Journals Online (AJOL)

    In this paper, the convergence analysis of the conventional conjugate Gradient method was reviewed. And the convergence analysis of the modified conjugate Gradient method was analysed with our extension on preconditioning the algorithm. Convergence of the algorithm is a function of the condition number of M-1A.

  19. DENDRIMER CONJUGATES FOR SELECTIVE OF PROTEIN AGGREGATES

    DEFF Research Database (Denmark)

    2004-01-01

    Dendrimer conjugates are presented, which are formed between a dendrimer and a protein solubilising substance. Such dendrimer conjugates are effective in the treatment of protein aggregate-related diseases (e.g. prion-related diseases). The protein solubilising substance and the dendrimer together...

  20. CONJUGATED BLOCK-COPOLYMERS FOR ELECTROLUMINESCENT DIODES

    NARCIS (Netherlands)

    Hilberer, A; Gill, R.E; Herrema, J.K; Malliaras, G.G; Wildeman, J.; Hadziioannou, G

    In this article we review results obtained in our laboratory on the design and study of new light-emitting polymers. We are interested in the synthesis and characterisation of block copolymers with regularly alternating conjugated and non conjugated sequences. The blocks giving rise to luminescence

  1. Bio-Conjugates for Nanoscale Applications

    DEFF Research Database (Denmark)

    Villadsen, Klaus

    Bio-conjugates for Nanoscale Applications is the title of this thesis, which covers three different projects in chemical bio-conjugation research, namely synthesis and applications of: Lipidated fluorescent peptides, carbohydrate oxime-azide linkers and N-aryl O-R2 oxyamine derivatives. Lipidated...

  2. Catalytic enantioselective conjugate addition with Grignard reagents

    NARCIS (Netherlands)

    Lopez, Fernando; Minnaard, Adriaan J.; Feringa, Ben L.

    In this Account, recent advances in catalytic asymmetric conjugate addition of Grignard reagents are discussed. Synthetic methodology to perform highly enantioselective Cu-catalyzed conjugate addition of Grignard reagents to cyclic enones with ee's up to 96% was reported in 2004 from our

  3. Supplementary Information DA conjugated polymers containing ...

    Indian Academy of Sciences (India)

    D-A conjugated polymers containing substituted thiophene, 1,3,4-oxadiazole and non-conjugation linkers: Synthesis and study of optical and electrochemical properties. PRASHANTH KUMAR K Ra, UDAYAKUMAR Da,*, SIJI NARENDRAN N Kb, CHANDRASEKHARAN Kb and RITU SRIVASTAVAc. aDepartment of ...

  4. Ferrocene-pyrimidine conjugates: Synthesis, electrochemistry, physicochemical properties and antiplasmodial activities.

    Science.gov (United States)

    Chopra, Rakesh; de Kock, Carmen; Smith, Peter; Chibale, Kelly; Singh, Kamaljit

    2015-07-15

    The promise of hybrid antimalarial agents and the precedence set by the antimalarial drug ferroquine prompted us to design ferrocene-pyrimidine conjugates. Herein, we report the synthesis, electrochemistry and anti-plasmodial evaluation of ferrocenyl-pyrimidine conjugates against chloroquine susceptible NF54 strain of the malaria parasite Plasmodium falciparum. Also their physicochemical properties have been studied. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  5. Cellular delivery and antisense effects of peptide nucleic acid conjugated to polyethyleneimine via disulfide linkers

    DEFF Research Database (Denmark)

    Berthold, Peter R; Shiraishi, Takehiko; Nielsen, Peter E

    2010-01-01

    moiety) and further reacted this with a cysteine PNA. The level of modification was determined spectrophotometrically with high accuracy, and the PNA transfection efficiency of the conjugates was evaluated in an antisense luciferase splice-correction assay using HeLa pLuc705 cells. We find that PEI....... Finally, the method can be easily modified to allow for co-conjugation of other small molecules in a high-throughput screening assay that does not require a purification step....

  6. Effect of chelating agent acetylacetone on corrosion protection properties of silane-zirconium sol–gel coatings

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Mei, E-mail: yumei@buaa.edu.cn; Liang, Min; Liu, Jianhua; Li, Songmei; Xue, Bing; Zhao, Hao

    2016-02-15

    Graphical abstract: - Highlights: • AcAc was employed as a chelating agent in order to form stable sols. • The sol particle size depends on the concentration of AcAc. • AFM results indicate that AcAc content affects the morphology of the coatings. • Coating AcAc3 shows the optimal corrosion protection. - Abstract: The hybrid sol–gel coatings on AA2024-T3 were prepared with a silane coupling agent 3-glycidoxypropyltrimethoxysilane (GPTMS) and a metal alkoxide tetra-n-propoxyzirconium (TPOZ) as precursors. The effect of acetylacetone (AcAc) as a chelating agent on the corrosion protection properties of sol–gel coatings were evaluated and the optimal AcAc/TPOZ molar ratio was obtained. The sol–gel coatings were characterized by atomic force microscopy (AFM), scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS). The corrosion protection properties of the coatings were evaluated by means of potentiodynamic polarization study (PDS) and electrochemical impedance spectroscopy (EIS). It is demonstrated that AcAc avoids fast hydrolysis of TPOZ and benefits to form stable sols. The coating with AcAc/TPOZ molar ratio of 3 shows the best corrosion protection performance in 0.05 M NaCl solution.

  7. In Vitro and In Vivo Evaluation of Alexa Fluor 680-Bombesin[7–14]NH2 Peptide Conjugate, a High-Affinity Fluorescent Probe with High Selectivity for the Gastrin-Releasing Peptide Receptor

    Directory of Open Access Journals (Sweden)

    Lixin Ma

    2007-05-01

    Full Text Available Gastrin-releasing peptide (GRP receptors are overexpressed on several types of human cancer cells, including breast, prostate, small cell lung, and pancreatic cancers. Bombesin (BBN, a 14–amino acid peptide that is an analogue of human GRP, binds to GRP receptors with very high affinity and specificity. The aim of this study was to develop a new fluorescent probe based on BBN having high tumor uptake and optimal pharmacokinetics for specific targeting and optical imaging of human breast cancer tissue. In this study, solid-phase peptide synthesis was used to produce H2N-glycylglycylglycine-BBN[7–14]NH2 peptide with the following general sequence: H2N-G-G-G-Q-W-A-V-G-H-L-M-(NH2. This conjugate was purified by reversed-phase high-performance liquid chromatography and characterized by electrospray-ionization mass spectra. The fluorescent probe Alexa Fluor 680-G-G-G-BBN[7–14]NH2 conjugate was prepared by reaction of Alexa Fluor 680 succinimidyl ester to H2N-G-G-G-BBN[7–14]NH2 in dimethylformamide (DMF. In vitro competitive binding assays, using 125I-Tyr4-BBN as the radiolabeling gold standard, demonstrated an inhibitory concentration 50% value of 7.7 ± 1.4 nM in human T-47D breast cancer cells. Confocal fluorescence microscopy images of Alexa Fluor 680-G-G-G-BBN[7–14]NH2 in human T-47D breast cancer cells indicated specific uptake, internalization, and receptor blocking of the fluorescent bioprobe in vitro. In vivo investigations in SCID mice bearing xenografted T-47D breast cancer lesions demonstrated the ability of this new conjugate to specifically target tumor tissue with high selectivity and affinity.

  8. In vitro and in vivo evaluation of Alexa Fluor 680-bombesin[7-14]NH2 peptide conjugate, a high-affinity fluorescent probe with high selectivity for the gastrin-releasing peptide receptor.

    Science.gov (United States)

    Ma, Lixin; Yu, Ping; Veerendra, Bhadrasetty; Rold, Tammy L; Retzloff, Lauren; Prasanphanich, Adam; Sieckman, Gary; Hoffman, Timothy J; Volkert, Wynn A; Smith, Charles J

    2007-01-01

    Gastrin-releasing peptide (GRP) receptors are overexpressed on several types of human cancer cells, including breast, prostate, small cell lung, and pancreatic cancers. Bombesin (BBN), a 14-amino acid peptide that is an analogue of human GRP, binds to GRP receptors with very high affinity and specificity. The aim of this study was to develop a new fluorescent probe based on BBN having high tumor uptake and optimal pharmacokinetics for specific targeting and optical imaging of human breast cancer tissue. In this study, solid-phase peptide synthesis was used to produce H(2)N-glycylglycylglycine-BBN[7-14]NH(2) peptide with the following general sequence: H(2)N-G-G-G-Q-W-A-V-G-H-L-M-(NH(2)). This conjugate was purified by reversed-phase high-performance liquid chromatography and characterized by electrospray-ionization mass spectra. The fluorescent probe Alexa Fluor 680-G-G-G-BBN[7-14]NH(2) conjugate was prepared by reaction of Alexa Fluor 680 succinimidyl ester to H(2)N-G-G-G-BBN[7-14]NH(2) in dimethylformamide (DMF). In vitro competitive binding assays, using (125)I-Tyr(4)-BBN as the radiolabeling gold standard, demonstrated an inhibitory concentration 50% value of 7.7 +/- 1.4 nM in human T-47D breast cancer cells. Confocal fluorescence microscopy images of Alexa Fluor 680-G-G-G-BBN[7-14]NH(2) in human T-47D breast cancer cells indicated specific uptake, internalization, and receptor blocking of the fluorescent bioprobe in vitro. In vivo investigations in SCID mice bearing xenografted T-47D breast cancer lesions demonstrated the ability of this new conjugate to specifically target tumor tissue with high selectivity and affinity.

  9. Phthalocyanine-Peptide Conjugates for Epidermal Growth Factor Receptor Targeting1

    Science.gov (United States)

    Ongarora, Benson G.; Fontenot, Krystal R.; Hu, Xiaoke; Sehgal, Inder; Satyanarayana-Jois, Seetharama D.; Vicente, M. Graça H.

    2012-01-01

    Four phthalocyanine (Pc)-peptide conjugates designed to target the epidermal growth factor receptor (EGFR) were synthesized and evaluated in vitro using four cell lines: human carcinoma A431 and HEp2, human colorectal HT-29, and kidney Vero (negative control) cells. Two peptide ligands for EGFR were investigated: EGFR-L1 and -L2, bearing 6 and 13 amino acid residues, respectively. The peptides and Pc-conjugates were shown to bind to EGFR using both theoretical (Autodock) and experimental (SPR) investigations. The Pc-EGFR-L1 conjugates 5a and 5b efficiently targeted EGFR and were internalized, in part due to their cationic charge, whereas the uncharged Pc-EGFR-L2 conjugates 4b and 6a poorly targeted EGFR maybe due to their low aqueous solubility. All conjugates were non-toxic (IC50 > 100 µM) to HT-29 cells, both in the dark and upon light activation (1 J/cm2). Intravenous (iv) administration of conjugate 5b into nude mice bearing A431 and HT-29 human tumor xenografts resulted in a near-IR fluorescence signal at ca. 700 nm, 24 h after administration. Our studies show that Pc-EGFR-L1 conjugates are promising near-IR fluorescent contrast agents for CRC, and potentially other EGFR over-expressing cancers. PMID:22468711

  10. The Hermitian -Conjugate Generalized Procrustes Problem

    Directory of Open Access Journals (Sweden)

    Hai-Xia Chang

    2013-01-01

    Full Text Available We consider the Hermitian -conjugate generalized Procrustes problem to find Hermitian -conjugate matrix such that is minimum, where , , , and (, are given complex matrices, and and are positive integers. The expression of the solution to Hermitian -conjugate generalized Procrustes problem is derived. And the optimal approximation solution in the solution set for Hermitian -conjugate generalized Procrustes problem to a given matrix is also obtained. Furthermore, we establish necessary and sufficient conditions for the existence and the formula for Hermitian -conjugate solution to the linear system of complex matrix equations , , ( and are positive integers. The representation of the corresponding optimal approximation problem is presented. Finally, an algorithm for solving two problems above is proposed, and the numerical examples show its feasibility.

  11. Approximate error conjugation gradient minimization methods

    Science.gov (United States)

    Kallman, Jeffrey S

    2013-05-21

    In one embodiment, a method includes selecting a subset of rays from a set of all rays to use in an error calculation for a constrained conjugate gradient minimization problem, calculating an approximate error using the subset of rays, and calculating a minimum in a conjugate gradient direction based on the approximate error. In another embodiment, a system includes a processor for executing logic, logic for selecting a subset of rays from a set of all rays to use in an error calculation for a constrained conjugate gradient minimization problem, logic for calculating an approximate error using the subset of rays, and logic for calculating a minimum in a conjugate gradient direction based on the approximate error. In other embodiments, computer program products, methods, and systems are described capable of using approximate error in constrained conjugate gradient minimization problems.

  12. Model-Based Optimisation of Deferoxamine Chelation Therapy.

    Science.gov (United States)

    Bellanti, Francesco; Del Vecchio, Giovanni C; Putti, Maria C; Cosmi, Carlo; Fotzi, Ilaria; Bakshi, Suruchi D; Danhof, Meindert; Della Pasqua, Oscar

    2016-02-01

    Here we show how a model-based approach may be used to provide further insight into the role of clinical and demographic covariates on the progression of iron overload. The therapeutic effect of deferoxamine is used to illustrate the application of disease modelling as a means to characterising treatment response in individual patients. Serum ferritin, demographic characteristics and individual treatment data from clinical routine practice on 27 patients affected by β-thalassaemia major were used for the purposes of this analysis. The time course of serum ferritin was described by a hierarchical nonlinear mixed effects model, in which compliance was parameterised as a covariate factor. Modelling and simulation procedures were implemented in NONMEM (7.2.0). A turnover model best described serum ferritin changes over time, with the effect of blood transfusions introduced on the ferritin conversion rate and the effect of deferoxamine on the elimination parameter (Kout) in a proportional manner. The results of the simulations showed that poor quality of execution is preferable over drug holidays; and that independently of the compliance pattern, the therapeutic intervention is not effective if >60% of the doses are missed. Modelling of ferritin response enables characterisation of the dynamics of iron overload due to chronic transfusion. The approach can be used to support decision making in clinical practice, including personalisation of the dose for existing and novel chelating agents.

  13. Bifunctional chelates of RH-105 and AU199 as potential radiotherapeutic agents

    Energy Technology Data Exchange (ETDEWEB)

    Droege, P.

    1997-03-01

    Research is presented on new bifunctional chelating ligand systems with stability on the macroscopic and radiochemical levels. The synthesis of the following complexes are described: rhodium 105, palladium 109, and gold 198.

  14. A Zinc Chelator TPEN Attenuates Airway Hyperresponsiveness Airway Inflammation in Mice In Vivo

    Directory of Open Access Journals (Sweden)

    Satoru Fukuyama

    2011-01-01

    Conclusions: In pulmonary allergic inflammation induced in mice immunized with antigen without alum, zinc chelator inhibits airway inflammation and hyperresponsiveness. These findings suggest that zinc may be a therapeutic target of allergic asthma.

  15. Absorption of nitric oxide into aqueous solutions of ferrous chelates accompanied by instantaneous reaction

    NARCIS (Netherlands)

    Demmink, J.F; vanGils, I.C.F.; Beenackers, A.A C M

    1997-01-01

    The absorption of nitric oxide (NO) into aqueous solutions of ferrous chelates of nitrilotriacetic acid (NTA), ethylene diaminetetraacetic acid (EDTA), hydroxyethylenediaminetriacetic acid (HEDTA), and diethylenetriaminepentaacetic acid (DTPA) was studied in a stirred cell reactor. Experimental

  16. Influence of chelation ratio of metal alkoxides on aging of PZT 53/47 ...

    Indian Academy of Sciences (India)

    Administrator

    gel-based synthesis routes, generally demands the use of chelating agents in order to avoid fast hydrolysis and also to allow an easier manipulation of intermediates as well as final solutions. Under these conditions, stability issues sometimes ...

  17. Effect of calcium chelators on physical changes in casein micelles in concentrated micellar casein solutions

    NARCIS (Netherlands)

    Kort, de E.J.P.; Minor, M.; Snoeren, T.H.M.; Hooijdonk, van A.C.M.; Linden, van der E.

    2011-01-01

    The effect of calcium chelators on physical changes of casein micelles in concentrated micellar casein solutions was investigated by measuring calcium-ion activity, viscosity and turbidity, and performing ultracentrifugation. The highest viscosities were measured on addition of sodium

  18. Combined therapy of iron chelator and antioxidant completely restores brain dysfunction induced by iron toxicity

    National Research Council Canada - National Science Library

    Sripetchwandee, Jirapas; Pipatpiboon, Noppamas; Chattipakorn, Nipon; Chattipakorn, Siriporn

    2014-01-01

    .... We investigated the effects of iron overload induced by high iron-diet consumption on brain mitochondrial function, brain synaptic plasticity and learning and memory. Iron chelator (deferiprone) and antioxidant (n-acetyl cysteine...

  19. Effect of chelate dynamics on water exchange reactions of paramagnetic aminopolycarboxylate complexes.

    Science.gov (United States)

    Maigut, Joachim; Meier, Roland; Zahl, Achim; van Eldik, Rudi

    2008-07-07

    Because of our interest in evaluating a possible relationship between complex dynamics and water exchange reactivity, we performed (1)H NMR studies on the paramagnetic aminopolycarboxylate complexes Fe (II)-TMDTA and Fe (II)-CyDTA and their diamagnetic analogues Zn (II)-TMDTA and Zn (II)-CyDTA. Whereas a fast Delta-Lambda isomerization was observed for the TMDTA species, no acetate scrambling between in-plane and out-of-plane positions is accessible for any of the CyDTA complexes because the rigid ligand backbone prevents any configurational changes in the chelate system. In variable-temperature (1)H NMR studies, no evidence of spectral coalescence due to nitrogen inversion was found for any of the complexes in the available temperature range. The TMDTA complexes exhibit the known solution behavior of EDTA, whereas the CyDTA complexes adopt static solution structures. Comparing the exchange kinetics of flexible EDTA-type complexes and static CyDTA complexes appears to be a suitable method for evaluating the effect of ligand dynamics on the overall reactivity. In order to assess information concerning the rates and mechanism of water exchange, we performed variable-temperature and -pressure (17)O NMR studies of Ni (II)-CyDTA, Fe (II)-CyDTA, and Mn (II)-CyDTA. For Ni (II)-CyDTA, no significant effects on line widths or chemical shifts were apparent, indicating either the absence of any chemical exchange or the existence of a very small amount of the water-coordinated complex in solution. For [Fe (II)(CyDTA)(H 2O)] (2-) and [Mn (II)(CyDTA)(H 2O)] (2-), exchange rate constant values of (1.1 +/- 0.3) x 10 (6) and (1.4 +/- 0.2) x 10 (8) s (-1), respectively, at 298 K were determined from fits to resonance-shift and line-broadening data. A relationship between chelate dynamics and reactivity seems to be operative, since the CyDTA complexes exhibited significantly slower reactions than their EDTA counterparts. The variable-pressure (17)O NMR measurements for [Mn (II

  20. Peptide-LNA oligonucleotide conjugates

    DEFF Research Database (Denmark)

    Astakhova, I Kira; Hansen, Lykke Haastrup; Vester, Birte

    2013-01-01

    Although peptide-oligonucleotide conjugates (POCs) are well-known for nucleic acids delivery and therapy, reports on internal attachment of peptides to oligonucleotides are limited in number. To develop a convenient route for preparation of internally labeled POCs with improved biomedical...... properties, peptides were introduced into oligonucleotides via a 2'-alkyne-2'-amino-LNA scaffold. Derivatives of methionine- and leucine-enkephalins were chosen as model peptides of mixed amino acid content, which were singly and doubly incorporated into LNA/DNA strands using highly efficient copper......(i)-catalyzed azide-alkyne cycloaddition (CuAAC) "click" chemistry. DNA/RNA target binding affinity and selectivity of the resulting POCs were improved in comparison to LNA/DNA mixmers and unmodified DNA controls. This clearly demonstrates that internal attachment of peptides to oligonucleotides can significantly...

  1. Photoconductive properties of conjugated polymers

    CERN Document Server

    Halls, J J M

    1997-01-01

    The research described in my dissertation has involved the fabrication and characterisation of photovoltaic cells based on conjugated polymers, including the widely studied polymer poly(p-phenylenevinylene). These materials have semiconducting properties which arise from the delocalisation of electrons along the pi-electron systems of the polymer chains. Research into these materials is motivated both by their novel electronic properties, and also their potential for use in a wide range of applications including light-emitting diodes (LEDs), thin-film transistors, and photovoltaic cells (solar cells and light detectors). Light absorbed in a photovoltaic cell generates opposite charges which are collected at two different electrodes, giving rise to an electric current

  2. A physico-chemical assessment of the thermal stability of pneumococcal conjugate vaccine components.

    Science.gov (United States)

    Gao, Fang; Lockyer, Kay; Burkin, Karena; Crane, Dennis T; Bolgiano, Barbara

    2014-01-01

    Physico-chemical analysis of pneumococcal polysaccharide (PS)-protein conjugate vaccine components used for two commercially licensed vaccines was performed to compare the serotype- and carrier protein-specific stabilities of these vaccines. Nineteen different monovalent pneumococcal conjugates from commercial vaccines utilizing CRM197, diphtheria toxoid (DT), Protein D (PD) or tetanus toxoid (TT) as carrier proteins were incubated at temperatures up to 56°C for up to eight weeks or were subjected to freeze-thawing (F/T). Structural stability was evaluated by monitoring their size, integrity and carrier protein conformation. The molecular size of the vaccine components was well maintained for Protein D, TT and DT conjugates at -20°C, 4°C and F/T, and for CRM197 conjugates at 4°C and F/T. It was observed that four of the eight serotypes of Protein D conjugates tended to form high molecular weight complexes at 37°C or above. The other conjugated carrier proteins also appeared to form oligomers or 'aggregates' at elevated temperatures, but rarely when frozen and thawed. There was evidence of degradation in some of the conjugates as evidenced by the formation of lower molecular weight materials which correlated with measured free saccharide. In conclusion, pneumococcal-Protein D/TT/DT and most CRM197 bulk conjugate vaccines were stable when stored at 2-8°C, the recommended temperature. In common between the conjugates produced by the two manufacturers, serotypes 1, 5, and 19F were relatively less stable and 6B was the most stable, with types 7F and 23F also showing good stability.

  3. Intracellular reduction/activation of a disulfide switch in thiosemicarbazone iron chelators

    OpenAIRE

    Akam, Eman A.; Chang, Tsuhen M.; Astashkin, Andrei V.; Tomat, Elisa

    2014-01-01

    Iron scavengers (chelators) offer therapeutic opportunities in anticancer drug design by targeting the increased demand for iron in cancer cells as compared to normal cells. Prochelation approaches are expected to avoid systemic iron depletion as chelators are liberated under specific intracellular conditions. In the strategy described herein, a disulfide linkage is employed as a redox-directed switch within the binding unit of an antiproliferative thiosemicarbazone prochelator, which is acti...

  4. Synthesis, Characterization and Chelating Properties of 4-Butyrylsemicarbazone-1-phenyl-3-methyl-2-pyrazolin-5-one

    Directory of Open Access Journals (Sweden)

    J. D. Patel

    2010-01-01

    Full Text Available 4-Butyrylsemicarbazone-1-phenyl-3-methyl-2-pyrazolin-5-one (BUMP-SC was prepared and its metal chelates of Cu2+, Ni2+, Co2+, Mn2+, Fe2+, Fe3+, Cr3+, UO2 and OV were prepared. The ligands and its chelates were characterized by elemental analysis, metal:ligand (M:L stoichiometry, IR-electronic spectral studies and magnetic properties. The compounds also were screened for their antimicrobial activity.

  5. Rapid anaerobic benzene oxidation with a variety of chelated Fe(III) forms

    Science.gov (United States)

    Lovley, D.R.; Woodward, J.C.; Chapelle, F.H.

    1996-01-01

    Fe(III) chelated to such compounds as EDTA, N-methyliminodiacetie acid, ethanol diglycine, humic acids, and phosphates stimulated benzene oxidation coupled to Fe(III) reduction in anaerobic sediments from a petroleum- contaminated aquifer as effectively as or more effectively than nitrilotriacetic acid did in a previously demonstrated stimulation experiment. These results indicate that many forms of chelated Fe(III) might be applicable to aquifer remediation.

  6. Influence of chelation ratio of metal alkoxides on aging of PZT 53/47 ...

    Indian Academy of Sciences (India)

    In this work, we explore the sol–gel-based synthesis route of lead zirconate titanate (Pb(Zr0.53Ti0.47)O3 or PZT 53/47) using acetylacetone-chelated propoxides as intermediate reactants. Our main purpose here is to analyse the influence of the alkoxides:acetylacetone chelation ratio on the time evolution of mean particle ...

  7. Comparative Evaluation of Anti-HER2 Affibody Molecules Labeled with 64Cu Using NOTA and NODAGA

    Directory of Open Access Journals (Sweden)

    Vladimir Tolmachev

    2017-01-01

    Full Text Available Imaging using affibody molecules enables discrimination between breast cancer metastases with high and low expression of HER2, making appropriate therapy selection possible. This study aimed to evaluate if the longer half-life of 64Cu (T1/2 = 12.7 h would make 64Cu a superior nuclide compared to 68Ga for PET imaging of HER2 expression using affibody molecules. The synthetic ZHER2:S1 affibody molecule was conjugated with the chelators NOTA or NODAGA and labeled with 64Cu. The tumor-targeting properties of 64Cu-NOTA-ZHER2:S1 and 64Cu-NODAGA-ZHER2:S1 were evaluated and compared with the targeting properties of 68Ga-NODAGA-ZHER2:S1 in mice. Both 64Cu-NOTA-ZHER2:S1 and 64Cu-NODAGA-ZHER2:S1 demonstrated specific targeting of HER2-expressing xenografts. At 2 h after injection of 64Cu-NOTA-ZHER2:S1, 64Cu-NODAGA-ZHER2:S1, and 68Ga-NODAGA-ZHER2:S1, tumor uptakes did not differ significantly. Renal uptake of 64Cu-labeled conjugates was dramatically reduced at 6 and 24 h after injection. Notably, radioactivity uptake concomitantly increased in blood, lung, liver, spleen, and intestines, which resulted in decreased tumor-to-organ ratios compared to 2 h postinjection. Organ uptake was lower for 64Cu-NODAGA-ZHER2:S1. The most probable explanation for this biodistribution pattern was the release and redistribution of renal radiometabolites. In conclusion, monoamide derivatives of NOTA and NODAGA may be suboptimal chelators for radiocopper labeling of anti-HER2 affibody molecules and, possibly, other scaffold proteins with high renal uptake.

  8. Response of soybean plants to the application of synthetic and biodegradable Fe chelates and Fe complexes.

    Science.gov (United States)

    Martín-Fernández, Clara; Solti, Ádám; Czech, Viktória; Kovács, Krisztina; Fodor, Ferenc; Gárate, Agustín; Hernández-Apaolaza, Lourdes; Lucena, Juan J

    2017-09-01

    The growing concern over the environmental risk of synthetic chelate application promotes the search for alternatives in Fe fertilization, such as biodegradable chelating agents and natural complexing agents. In this work, plant responses to the application of several Fe treatments (chelates and complexes) was analyzed to study their potential use in Fe fertilization under calcareous conditions. Thus, the root ferric chelate reductase (FCR) activity of soybean (Glycine max cv. Klaxon) plants was determined, and the effectiveness of the Fe chelates and complexes assessed in a pot experiment, by SPAD and fluorescence induction measurements, and the determination of Fe distribution in plant and soil. Additionally, (57)Fe Mössbauer spectroscopy was conducted to identify the Fe forms present in the soybean roots. The highest FCR activity was observed for the chelates EDDS/Fe(3+) and IDHA/Fe(3+); while no activity was observed when using complexes as Fe substrates. In contrast to the FCR data, the pot experiment confirmed that the o,oEDDHA/Fe(3+) is the most effective treatment, and the complexes LS/Fe(3+) and GA/Fe(3+) are able to alleviate Fe chlorosis, also indicated by SPAD data and the maximal quantum efficiency of photosystem II reaction centers as vitality parameters, and the enhanced plant uptake of Fe from natural sources. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  9. ELECTED PROBLEMS RELATED TO ENVIRONMENTAL HEAVY METALS EXPOSURE AND CHELATION THERAPY

    Directory of Open Access Journals (Sweden)

    Anna Skoczyńska

    2010-09-01

    Full Text Available Background: Exposure to heavy metals leads to functional and metabolic disturbances and many of them are included in pathogenesis of common diseases (arterial hypertension, atherosclerosis, neurodegenerative processes. In this context new therapeutic and prophylactic strategies are necessary. Patients diagnosed with chronic heavy metals intoxication usually require chelation to increase mobilisation of metals from tissues and elimination of them via urine. Acute poisoning with toxic metal may be difficult to diagnosis, especially in case of accidental intoxication or suicidal intention. Patients also require chelation after causative factor is identified. Objectives: To describe some problems connected with toxicity of metals poisoning and to review pharmacologic therapies that could have a role in poisoning with metals. Methods: A review of the literature was carried out and expert opinion expressed. Results/conclusion: Chelation is a common therapy in case of poisoning with toxic metals but it is satisfied only partially. A combined therapy with structurally different chelators or long-term acting chelators could become viable alternatives in the future. A combined therapy with an antioxidant plus chelator may be a good choice in patients chronically poisoned with metals. Exposure to lead should be taken into account during estimation of global cardiovascular risk.

  10. The role of chelation in the treatment of arsenic and mercury poisoning.

    Science.gov (United States)

    Kosnett, Michael J

    2013-12-01

    Chelation for heavy metal intoxication began more than 70 years ago with the development of British anti-lewisite (BAL; dimercaprol) in wartime Britain as a potential antidote the arsenical warfare agent lewisite (dichloro[2-chlorovinyl]arsine). DMPS (unithiol) and DMSA (succimer), dithiol water-soluble analogs of BAL, were developed in the Soviet Union and China in the late 1950s. These three agents have remained the mainstay of chelation treatment of arsenic and mercury intoxication for more than half a century. Animal experiments and in some instances human data indicate that the dithiol chelators enhance arsenic and mercury excretion. Controlled animal experiments support a therapeutic role for these chelators in the prompt treatment of acute poisoning by arsenic and inorganic mercury salts. Treatment should be initiated as rapidly as possible (within minutes to a few hours), as efficacy declines or disappears as the time interval between metal exposure and onset of chelation increases. DMPS and DMSA, which have a higher therapeutic index than BAL and do not redistribute arsenic or mercury to the brain, offer advantages in clinical practice. Although chelation following chronic exposure to inorganic arsenic and inorganic mercury may accelerate metal excretion and diminish metal burden in some organs, potential therapeutic efficacy in terms of decreased morbidity and mortality is largely unestablished in cases of chronic metal intoxication.

  11. Chelating effect of silver nitrate by chitosan on its toxicity and growth performance in broiler chickens

    Directory of Open Access Journals (Sweden)

    Yemdjie Mane Divine Doriane

    2017-06-01

    Full Text Available Objective: This study was conducted to investigate the chelating effect of silver nitrate (AgNO3 by chitosan on growth performances, hematological and biochemical parameters, and the histopathological structure of the liver and the kidney in broiler chicken. Materials and methods: A total of 192 day-old Cobb 500 strain chicks were randomly assigned to 3 treatments of 64 chicks each. Control group was fed on basal diet without supplement (R0 and the two others groups were fed on rations supplemented with 10 mg of unchelated (RAg or chelated (RCs-Ag AgNO3 per Kg of feed, respectively. Parameters that have been studied consisted of feed intake, weight gain, blood and serum biochemical, and histopathological analyses of liver and kidney. Results: Results revealed that chelation of AgNO3 by chitosan did not have any effect on growth performances and hematological parameters in chicken. However, chelated and unchelated AgNO3 increased the serum content in triglyceride, and cholesterol and decreased the serum content in creatinin, albumin and alanine aminotransferase (ALAT. Chelating AgNO3 with chitosan prevented and corrected the toxicity induced on the histological structure of liver and kidney. Conclusion: Chitosan can be used as a chelating agent to alleviate the harmful effects of AgNO3 as silver ion for poultry. [J Adv Vet Anim Res 2017; 4(2.000: 187-193

  12. Detection of biothiols in cells by a terbium chelate-Hg (II) system

    Science.gov (United States)

    Tan, Hongliang; Chen, Yang

    2012-01-01

    Great efforts have been devoted to the development of sensitive and specific analysis methods for biothiols because of their important roles in biological systems. We present a new detection system for biothiols that is based on the reversible quenching and restoration of fluorescence of terbium chelate caused by Hg2+ and thiol species. In the presence of biothiols, a restoration of fluorescence of terbium chelate after quenching by Hg2+ was observed due to the interaction of Hg2+ with thiol groups, and the restored fluorescence increased with the concentration of biothiols. This method was sensitive and selective for biothiols. The detection limit was 80 nM for glutathione, 100 nM for Hcy, and 400 nM for Cysteine, respectively. The terbium chelate-Hg (II) system was successfully applied to determine the levels of biothiols in cancer cells and urine samples. Further, it was also shown to be comparable to Ellman's assay. Compared to other fluorescence methods, the terbium chelate probe is advantageous because interference from short-lived nonspecific fluorescence can be efficiently eliminated due to the long fluorescence lifetime of terbium chelate, which allows for detection by time-resolved fluorescence. The terbium chelate probe can serve as a diagnostic tool for the detection of abnormal levels of biothiols in disease.

  13. Advances in iron chelation therapy: transitioning to a new oral formulation

    Directory of Open Access Journals (Sweden)

    Nirmish R Shah

    2017-06-01

    Full Text Available Iron overload is a concern for patients who require repeated red-blood-cell transfusions due to conditions such as sickle cell disease, thalassemia, or myelodysplastic syndromes. The recommended treatment for removing excess iron in these patients is iron chelation therapy. Currently available iron chelators include deferoxamine, which is administered by injection, and deferasirox and deferiprone, both of which are administered orally. Adherence to iron chelator therapy is an important consideration and may be affected by side effects. A new formulation of deferasirox, a film-coated tablet (FCT, has the potential to improve adherence by offering greater flexibility in administration compared with the original formulation of deferasirox, a dispersible tablet (DT for oral suspension. This review provides an overview of the currently available iron chelator formulations, with a focus on a comparison between deferasirox DT for oral suspension and deferasirox FCT. The new formulation may be associated with fewer side effects and has increased bioavailability. In addition, alternative strategies for iron chelation, such as combining two different iron chelators, will be discussed.

  14. Enhanced conjugation stability and blood circulation time of macromolecular gadolinium-DTPA contrast agent

    Energy Technology Data Exchange (ETDEWEB)

    Jenjob, Ratchapol [Department of New Drug Development, School of Medicine, Inha University, 2F A-dong, Jeongseok Bldg., Sinheung-dong 3-ga, Jung-gu, Incheon 400-712 (Korea, Republic of); Kun, Na [Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743 (Korea, Republic of); Ghee, Jung Yeon [Utah-Inha DDS and Advanced Therapeutics, B-403 Meet-You-All Tower, SongdoTechnopark, 7–50, Songdo-dong, Yeonsu-gu, Incheon 406-840 (Korea, Republic of); Shen, Zheyu; Wu, Xiaoxia [Division of Functional Materials and Nano-Devices, Ningbo Institute of Materials Technology & Engineering (NIMTE), Chinese Academy of Sciences, 519 Zhuangshi Street, Zhenhai District, Ningbo, Zhejiang 315201 (China); Cho, Steve K., E-mail: scho@gist.ac.kr [Division of Liberal Arts and Science, GIST College, Gwangju Institute of Science and Technology, Gwangju 500-712 (Korea, Republic of); Lee, Don Haeng [Utah-Inha DDS and Advanced Therapeutics, B-403 Meet-You-All Tower, SongdoTechnopark, 7–50, Songdo-dong, Yeonsu-gu, Incheon 406-840 (Korea, Republic of); Department of Internal Medicine, School of Medicine, Inha University Hospital, Incheon 420-751 (Korea, Republic of); Yang, Su-Geun, E-mail: Sugeun.Yang@Inha.ac.kr [Department of New Drug Development, School of Medicine, Inha University, 2F A-dong, Jeongseok Bldg., Sinheung-dong 3-ga, Jung-gu, Incheon 400-712 (Korea, Republic of)

    2016-04-01

    In this study, we prepared macromolecular MR T1 contrast agent: pullulan-conjugated Gd diethylene triamine pentaacetate (Gd-DTPA-Pullulan) and estimated residual free Gd{sup 3+}, chelation stability in competition with metal ions, plasma and tissue pharmacokinetics, and abdominal MR contrast on rats. Residual free Gd{sup 3+} in Gd-DTPA-Pullulan was measured using colorimetric spectroscopy. The transmetalation of Gd{sup 3+} incubated with Ca{sup 2+} was performed by using a dialysis membrane (MWCO 100–500 Da) and investigated by ICP-OES. The plasma concentration profiles of Gd-DTPA-Pullulan were estimated after intravenous injection at a dose 0.1 mmol/kg of Gd. The coronal-plane abdominal images of normal rats were observed by MR imaging. The content of free Gd{sup 3+}, the toxic residual form, was less than 0.01%. Chelation stability of Gd-DTPA-Pullulan was estimated, and only 0.2% and 0.00045% of Gd{sup 3+} were released from Gd-DTPA-Pullulan after 2 h incubation with Ca{sup 2+} and Fe{sup 2+}, respectively. Gd-DTPA-Pullulan displayed the extended plasma half-life (t{sub 1/2,α} = 0.43 h, t{sub 1/2,β} = 2.32 h), much longer than 0.11 h and 0.79 h of Gd-EOB-DTPA. Abdominal MR imaging showed Gd-DTPA-Pullulan maintained initial MR contrast for 30 min. The extended plasma half-life of Gd-DTPA-Pullulan probably allows the prolonged MR acquisition time in clinic with enhanced MR contrast. - Highlights: • Macromolecule (pullulan) conjugated Gd contrast agent (Gd-DTPA-Pullulan) showed the extended plasma half-life (t{sub 1/2,α} = 0.43 h, t{sub 1/2,β} = 2.32 h) in comparison with Gd-EOB-DTPA • Gd-DTPA-pullulan T1 contrast agent exhibited strong chelation stability against Gd. • The extended blood circulation attributed the enhanced and prolonged MR contrast on abdominal region of rats. • The extended blood circulation may provide prolonged MR acquisition time window in clinics.

  15. Two New PRP Conjugate Gradient Algorithms for Minimization Optimization Models.

    Science.gov (United States)

    Yuan, Gonglin; Duan, Xiabin; Liu, Wenjie; Wang, Xiaoliang; Cui, Zengru; Sheng, Zhou

    2015-01-01

    Two new PRP conjugate Algorithms are proposed in this paper based on two modified PRP conjugate gradient methods: the first algorithm is proposed for solving unconstrained optimization problems, and the second algorithm is proposed for solving nonlinear equations. The first method contains two aspects of information: function value and gradient value. The two methods both possess some good properties, as follows: 1) βk ≥ 0 2) the search direction has the trust region property without the use of any line search method 3) the search direction has sufficient descent property without the use of any line search method. Under some suitable conditions, we establish the global convergence of the two algorithms. We conduct numerical experiments to evaluate our algorithms. The numerical results indicate that the first algorithm is effective and competitive for solving unconstrained optimization problems and that the second algorithm is effective for solving large-scale nonlinear equations.

  16. Application of Conjugate Gradient methods to tidal simulation

    Science.gov (United States)

    Barragy, E.; Carey, G.F.; Walters, R.A.

    1993-01-01

    A harmonic decomposition technique is applied to the shallow water equations to yield a complex, nonsymmetric, nonlinear, Helmholtz type problem for the sea surface and an accompanying complex, nonlinear diagonal problem for the velocities. The equation for the sea surface is linearized using successive approximation and then discretized with linear, triangular finite elements. The study focuses on applying iterative methods to solve the resulting complex linear systems. The comparative evaluation includes both standard iterative methods for the real subsystems and complex versions of the well known Bi-Conjugate Gradient and Bi-Conjugate Gradient Squared methods. Several Incomplete LU type preconditioners are discussed, and the effects of node ordering, rejection strategy, domain geometry and Coriolis parameter (affecting asymmetry) are investigated. Implementation details for the complex case are discussed. Performance studies are presented and comparisons made with a frontal solver. ?? 1993.

  17. Two New PRP Conjugate Gradient Algorithms for Minimization Optimization Models.

    Directory of Open Access Journals (Sweden)

    Gonglin Yuan

    Full Text Available Two new PRP conjugate Algorithms are proposed in this paper based on two modified PRP conjugate gradient methods: the first algorithm is proposed for solving unconstrained optimization problems, and the second algorithm is proposed for solving nonlinear equations. The first method contains two aspects of information: function value and gradient value. The two methods both possess some good properties, as follows: 1 βk ≥ 0 2 the search direction has the trust region property without the use of any line search method 3 the search direction has sufficient descent property without the use of any line search method. Under some suitable conditions, we establish the global convergence of the two algorithms. We conduct numerical experiments to evaluate our algorithms. The numerical results indicate that the first algorithm is effective and competitive for solving unconstrained optimization problems and that the second algorithm is effective for solving large-scale nonlinear equations.

  18. Helical peptide-polyamine and -polyether conjugates as synthetic ionophores.

    Science.gov (United States)

    Benincasa, Monica; Francescon, Marco; Fregonese, Massimo; Gennaro, Renato; Pengo, Paolo; Rossi, Paola; Scrimin, Paolo; Tecilla, Paolo

    2015-12-01

    Two new synthetic ionophores in which the hydrophobic portion is represented by a short helical Aib-peptide (Aib=α-amino-isobutyric acid) and the hydrophilic one is a poly-amino (1a) or a polyether (1b) chain have been prepared. The two conjugates show a high ionophoric activity in phospholipid membranes being able to efficiently dissipate a pH gradient and, in the case of 1b, to transport Na(+) across the membrane. Bioactivity evaluation of the two conjugates shows that 1a has a moderate antimicrobial activity against a broad spectrum of microorganisms and it is able to permeabilize the inner and the outer membrane of Escherichia coli cells. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. TAT peptide and its conjugates: proteolytic stability.

    Science.gov (United States)

    Grunwald, Jacob; Rejtar, Tomas; Sawant, Rupa; Wang, Zhouxi; Torchilin, Vladimir P

    2009-08-19

    The proteolytic cleavage of TATp, TATp-PEG(1000)-PE conjugate (TATp-conjugate), and TATp as TATp-conjugate in mixed micelles made of TATp-conjugate and PEG(5000)-PE (2.5% mol of TATp-conjugate, TATp-Mic) were studied by HPLC with fluorescent detection using fluorenylmethyl chloroformate (FMOC) labeling and by MALDI-TOF MS analysis. The cleavage kinetics were analyzed in human blood plasma and in trypsin-containing phosphate buffered saline (PBS), pH 7.4, to simulate the proteolytic activity of human plasma. The trypsinolysis of free TATp, TATp-conjugate, and TATp-Mic revealed that the main initial fragmentation is an endocleavage at the carboxyl terminus resulting in an Arg-Arg (RR) dimer. The trypsinolysis followed pseudo-first-order kinetics. The cleavage of the free TATp was relatively fast with a half-life of a few minutes (t(1/2) ∼ 3.5 min). The TATp-conjugate showed more stability with about a 3-fold increase in half-life (t(1/2) ∼ 10 min). TATp in TATp-Mic was highly protected against proteolysis with an over 100-fold increase in half-life (t(1/2) ∼ 430 min). The shielding of TATp by PEG moieties in the proposed TATp-Mic is of great importance for its potential use as a cell-penetrating moiety for multifunctional "smart" drug delivery systems with detachable PEG.

  20. TCE degradation in groundwater by chelators-assisted Fenton-like reaction of magnetite: Sand columns demonstration.

    Science.gov (United States)

    Jia, Daqing; Sun, Sheng-Peng; Wu, Zhangxiong; Wang, Na; Jin, Yaoyao; Dong, Weiyang; Chen, Xiao Dong; Ke, Qiang

    2018-03-15

    Trichloroethylene (TCE) degradation in sand columns has been investigated to evaluate the potential of chelates-enhanced Fenton-like reaction with magnetite as iron source for in situ treatment of TCE-contaminated groundwater. The results showed that successful degradation of TCE in sand columns was obtained by nitrilotriacetic acid (NTA)-assisted Fenton-like reaction of magnetite. Addition of ethylenediaminedisuccinic acid (EDDS) resulted in an inhibitory effect on TCE degradation in sand columns. Similar to EDDS, addition of ethylenediaminetetraacetic acid (EDTA) also led to an inhibition of TCE degradation in sand column with small content of magnetite (0.5 w.t.%), but enhanced TCE degradation in sand column with high content of magnetite (7.0 w.t.%). Additionally, the presence of NTA, EDDS and EDTA greatly decreased H 2 O 2 uptake in sand columns due to the competition between chelates and H 2 O 2 for surface sites on magnetite (and sand). Furthermore, the presented results show that magnetite in sand columns remained stable in a long period operation of 230 days without significant loss of performance in terms of TCE degradation and H 2 O 2 uptake. Moreover, it was found that TCE was degraded mainly to formic acid and chloride ion, and the formation of chlorinated organic intermediates was minimal by this process. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Biological behavior of {sup 188}Re-biotin chelate for multistep therapy with the avidin-biotin system

    Energy Technology Data Exchange (ETDEWEB)

    Choi, T. H.; Ahn, S. H.; Choi, C. W.; Woo, K. S.; Jung, W. S.; Lim, S. J.; Lim, S. M. [KCCH, Seoul (Korea, Republic of)

    1999-05-01

    The purpose of this study was to test the three-step targeting of tumors in mice using biotinylated antibody, streptavidin and radiolabeled biotin for radioimmunotherapy (RAIT). Three-step pretargetting can potentially decreases harmful radiation to normal tissues in radioimmunotherapy. {sup 188}Re from {sup 188}W-{sup 188}Re generator, is recently introduced in therapeutic nuclear medicine and made it possible to use whenever needed. We studied biotin-chelates MGB for use in the avidin/biotin pretargetting system. Chelates that hold radiometals with high stability under physiological conditions are essential to avoid excessive radiation damage to non-target cells. We synthesized MAG{sub 2}GABA-Biocytin (MGB), labeled with {sup 188}Re and evaluated biological behavior of {sup 188}Re-MGB. biotinyl MAG{sub 2}GABA bind the therapeutic radiometal {sup 188}Re with excellent in vitro stability and have the required physiological properties for pretargetted therapy. In normal mice, {sup 188}Re-MGB was excreted via hepatobiliary pathway, %ID/g of GI tract was 52.1 at 120min. In Raji cells tumor bearing nude mice, liver and colon were higher than those of normal mouse. Tumor uptake at 120min was 0.05%ID/g. {sup 188}Re-MGB may have a role in pretargetted radioimmunotherapy.

  2. [Conjugal violence during pregnancy: a literature review.].

    Science.gov (United States)

    Séguin, L; Pimont, M; Rinfret-Raynor, M; Cantin, S

    2000-01-01

    Conjugal violence is a complicated issue which scope and consequences are increasingly documented. Among the many facets of the phenomenon, its occurrence during pregnancy is particularly worrisome. This article reviews the scientific literature pertaining to this issue. After establishing the prevalence of conjugal violence during pregnancy, the authors examine the major studies analyzing factors associated with this violence as well as its consequences for the mother and the infant. The article concludes that the current informations, although partial, are sufficient to justify early detection of conjugal violence in order to help future mothers efficiently.

  3. Modelling conjugation with stochastic differential equations

    DEFF Research Database (Denmark)

    Philipsen, Kirsten Riber; Christiansen, Lasse Engbo; Hasman, Henrik

    2010-01-01

    Conjugation is an important mechanism involved in the transfer of resistance between bacteria. In this article a stochastic differential equation based model consisting of a continuous time state equation and a discrete time measurement equation is introduced to model growth and conjugation of two...... Enterococcus faecium strains in a rich exhaustible media. The model contains a new expression for a substrate dependent conjugation rate. A maximum likelihood based method is used to estimate the model parameters. Different models including different noise structure for the system and observations are compared...

  4. Xenobiotic conjugation with phosphate - a metabolic rarity.

    Science.gov (United States)

    Mitchell, Stephen C

    2016-08-01

    1. Although not unknown, the conjugation of a xenobiotic with phosphate appears a rarity amongst the routes available for foreign compound metabolism. This is especially true in mammals and may be somewhat surprising as conjugation with sulphate, a seemingly similar moiety, is commonplace. 2. Information from the literature, where xenobiotic phosphate conjugates have been described or suggested, has been collated and presented in this article. By bringing together this diverse material, hopefully interest will be generated in this unusual xenobiotic reaction, and perhaps further research undertaken to better understand and delineate the reasons for its relative absence from the xenobiotic scene.

  5. Chitosan-Fe (III) Complex as a Phosphate Chelator in Uraemic Rats: A Novel Treatment Option.

    Science.gov (United States)

    do Carmo, Wander Barros; Castro, Bárbara Bruna Abreu; Rodrigues, Clóvis Antônio; Custódio, Melani Ribeiro; Sanders-Pinheiro, Helady

    2017-07-20

    Phosphate retention and hyperphosphataemia are associated with increased mortality in patients with chronic kidney disease (CKD). We tested the use of cross-linked iron chitosan III (CH-FeCl) as a potential phosphate chelator in rats with CKD. We evaluated 96 animals, divided equally into four groups (control, CKD, CH-FeCl and CKD/CH-FeCl), over 7 weeks. We induced CKD by feeding animals an adenine-enriched diet (0.75% in the first 4 weeks and 0.1% in the following 3 weeks). We administered 30 mg/kg daily of the test polymer, by gavage, from the third week until the end of the study. All animals received a diet supplemented with 1% phosphorus. Uraemia was confirmed by the increase in serum creatinine in week 4 (36.24 ± 18.56 versus 144.98 ± 22.1 μmol/L; p = 0.0001) and week 7 (41.55 ± 22.1 versus 83.98 ± 18.56 μmol/L; p = 0.001) in CKD animals. Rats from the CKD group treated with CH-FeCl had a 54.5% reduction in serum phosphate (6.10 ± 2.23 versus 2.78 ± 0.55 mmol/L) compared to a reduction of 25.6% in the untreated CKD group (4.75 ± 1.45 versus 3.52 ± 0.74 mmol/L, p = 0.021), between week 4 and week 7. At week 7, renal function in both CKD groups was similar (serum creatinine: 83.98 ± 18.56 versus 83.10 ± 23.87 μmol/L, p = 0.888); however, the CH-FeCl-treated rats had a reduction in phosphate overload measured by fractional phosphate excretion (FEPi) (0.71 ± 0.2 versus 0.4 ± 0.16, p = 0.006) compared to the untreated CKD group. Our study demonstrated that CH-FeCl had an efficient chelating action on phosphate. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  6. The effect of an EDTA-based chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the Trial to Assess Chelation Therapy (TACT).

    Science.gov (United States)

    Escolar, Esteban; Lamas, Gervasio A; Mark, Daniel B; Boineau, Robin; Goertz, Christine; Rosenberg, Yves; Nahin, Richard L; Ouyang, Pamela; Rozema, Theodore; Magaziner, Allan; Nahas, Richard; Lewis, Eldrin F; Lindblad, Lauren; Lee, Kerry L

    2014-01-01

    The Trial to Assess Chelation Therapy (TACT) showed clinical benefit of an EDTA-based infusion regimen in patients aged ≥50 years with prior myocardial infarction. Diabetes mellitus before enrollment was a prespecified subgroup. Patients received 40 infusions of EDTA chelation or placebo. A total of 633 (37%) patients had diabetes mellitus (322 EDTA and 311 placebo). EDTA reduced the primary end point (death, reinfarction, stroke, coronary revascularization, or hospitalization for angina; 25% versus 38%; hazard ratio, 0.59; 95% confidence interval [CI], 0.44-0.79; Pdiabetes mellitus (n=1075; P=0.877), resulting in a treatment by diabetes mellitus interaction (P=0.004). Post-myocardial infarction patients with diabetes mellitus aged ≥50 demonstrated a marked reduction in cardiovascular events with EDTA chelation. These findings support efforts to replicate these findings and define the mechanisms of benefit. However, they do not constitute sufficient evidence to indicate the routine use of chelation therapy for all post-myocardial infarction patients with diabetes mellitus. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00044213.

  7. Characterization of the Conjugation Pattern in Large Polysaccharide-Protein Conjugates by NMR Spectroscopy.

    Science.gov (United States)

    Giuntini, Stefano; Balducci, Evita; Cerofolini, Linda; Ravera, Enrico; Fragai, Marco; Berti, Francesco; Luchinat, Claudio

    2017-10-10

    Carbohydrate-based vaccines are among the safest and most effective vaccines and represent potent tools for prevention of life-threatening bacterial infectious diseases, like meningitis and pneumonia. The chemical conjugation of a weak antigen to protein as a source of T-cell epitopes generates a glycoconjugate vaccine that results more immunogenic. Several methods have been used so far to characterize the resulting polysaccharide-protein conjugates. However, a reduced number of methodologies has been proposed for measuring the degree of saccharide conjugation at the possible protein sites. Here we show that detailed information on large proteins conjugated with large polysaccharides can be achieved by a combination of solution and solid-state NMR spectroscopy. As a test case, a large protein assembly, l-asparaginase II, has been conjugated with Neisseria meningitidis serogroup C capsular polysaccharide and the pattern and degree of conjugation were determined. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. CARDIAC FUNCTION AND IRON CHELATION IN THALASSEMIA MAJOR AND INTERMEDIA: A REVIEW OF THE UNDERLYING PATHOPHYSIOLOGY AND APPROACH TO CHELATION MANAGEMENT

    Directory of Open Access Journals (Sweden)

    Athanasios Aessopos

    2009-07-01

    Full Text Available Heart disease is the leading cause of mortality and one of the main causes of morbidity in beta-thalassemia. Patients with homozygous thalassemia may have either a severe phenotype which is usually transfusion dependent or a milder form that is thalassemia intermedia.  The two main factors that determine cardiac disease in homozygous β thalassemia are the high output state that results from chronic tissue hypoxia, hypoxia-induced compensatory reactions and iron overload.  The high output state playing a major role in thalassaemia intermedia and the iron load being more significant in the major form. Arrhythmias, vascular involvement that leads to an increased pulmonary vascular resistance and an increased systemic vascular stiffness and valvular abnormalities also contribute to the cardiac dysfunction in varying degrees according to the severity of the phenotype.  Endocrine abnormalities, infections, renal function and medications can also play a role in the overall cardiac function.  For thalassaemia major, regular and adequate blood transfusions and iron chelation therapy are the mainstays of management. The approach to thalassaemia intermedia, today, is aimed at monitoring for complications and initiating, timely, regular transfusions and/or iron chelation therapy.  Once the patients are on transfusions, then they should be managed in the same way as the thalassaemia major patients.  If cardiac manifestations of dysfunction are present in either form of thalassaemia, high pre transfusion Hb levels need to be maintained in order to reduce cardiac output and appropriate intensive chelation therapy needs to be instituted.  In general recommendations on chelation, today, are usually made according to the Cardiac Magnetic Resonance findings, if available.  With the advances in the latter technology and the ability to tailor chelation therapy according to the MRI findings as well as the availability of three iron chelators, together with

  9. Iron chelation therapy with deferasirox in patients with aplastic anemia: a subgroup analysis of 116 patients from the EPIC trial

    DEFF Research Database (Denmark)

    Lee, Jong Wook; Yoon, Sung-Soo; Shen, Zhi Xiang

    2010-01-01

    The prospective 1-year Evaluation of Patients' Iron Chelation with Exjade (EPIC) study enrolled a large cohort of 116 patients with aplastic anemia; the present analyses evaluated the efficacy and safety of deferasirox in this patient population. After 1 year, median serum ferritin decreased...... adjustments and ongoing iron intake. Baseline labile plasma iron levels were within normal range despite high serum ferritin levels. The most common drug-related adverse events were nausea (22%) and diarrhea (16%). Serum creatinine increases more than 33% above baseline and the upper limit of normal occurred...... neutrophil and platelet counts remained stable during treatment, and there were no drug-related cytopenias. This prospective dataset confirms the efficacy and well characterizes the tolerability profile of deferasirox in a large population of patients with aplastic anemia. This study was registered at www...

  10. A new chelating reagent and application for coprecipitation of some metals in food samples by FAAS.

    Science.gov (United States)

    Yıldız, Esra; Saçmacı, Şerife; Kartal, Şenol; Saçmacı, Mustafa

    2016-03-01

    A new, simple and rapid coprecipitation method has been developed to separate and preconcentrate traces of Co(II), Cu(II), Fe(III), Pb(II) and Mn(II) in different samples prior to their determinations by flame atomic absorption spectrometry (FAAS). 2-[(E)-(8-hydroxy-2-methylquinolin-5-yl) diazenyl] benzoic acid (QAN) was firstly synthesized and characterized as a new chelating reagent for determination of some metals. IR spectra, (1)H-NMR spectrum and elemental analysis were evaluated for the characterization of the reagent. These metals were quantitatively recovered with Ni(II)/QAN precipitate in pH range of 8-10. Different factors such as sample volume, amount of QAN, and Ni(II) as carrier element, sample volume, and matrix effects for improving the quality of the preconcentration procedure were optimized. Under optimized experimentally established conditions, analytical detection limits were in the range of 0.03-0.83μgL(-1), while precision (RSD) was coprecipitation method was verified by the analysis of certified reference materials. The method was applied to the determination of the analytes in real samples such as food samples and make up products, and accuracy was found high (recoveries >95%). Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Preparation of Amidoxime Polyacrylonitrile Chelating Nanofibers and Their Application for Adsorption of Metal Ions

    Directory of Open Access Journals (Sweden)

    You-Lo Hsieh

    2013-03-01

    Full Text Available Polyacrylonitrile (PAN nanofibers were prepared by electrospinning and they were modified with hydroxylamine to synthesize amidoxime polyacrylonitrile (AOPAN chelating nanofibers, which were applied to adsorb copper and iron