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1.
Gd‐DTPA‐Dopamine‐Bisphytanyl Amphiphile: Synthesis,Characterisation and Relaxation Parameters of the Nanoassemblies and Their Potential as MRI Contrast Agents 下载免费PDF全文
Abhishek Gupta Dr. Scott A. Willis Lynne J. Waddington Dr. Tim Stait‐Gardner Dr. Liliana de Campo Prof. Dennis W. Hwang Dr. Nigel Kirby Prof. William S. Price Dr. Minoo J. Moghaddam 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(40):13950-13960
Here, a new amphiphilic magnetic resonance imaging (MRI) contrast agent, a GdIII‐chelated diethylenetriaminepentaacetic acid conjugated to two branched alkyl chains via a dopamine spacer, Gd‐DTPA‐dopamine‐bisphytanyl (Gd‐DTPA‐Dop‐Phy), which is readily capable of self‐assembling into liposomal nanoassemblies upon dispersion in an aqueous solution, is reported. In vitro relaxivities of the dispersions were found to be much higher than Magnevist, a commercially available contrast agent, at 0.47 T but comparable at 9.40 T. Analysis of variable temperature 17O NMR transverse relaxation measurements revealed the water exchange of the nanoassemblies to be faster than that previously reported for paramagnetic liposomes. Molecular reorientation dynamics were probed by 1H NMRD profiles using a classical inner and outer sphere relaxation model and a Lipari–Szabo “model‐free” approach. High payloads of GdIII ions in the liposomal nanoassemblies made solely from the Gd‐DTPA‐Dop‐Phy amphiphiles, in combination with slow molecular reorientation and fast water exchange makes this novel amphiphile a suitable candidate to be investigated as an advanced MRI contrast agent. 相似文献
2.
Frontispiece: Gd‐DTPA‐Dopamine‐Bisphytanyl Amphiphile: Synthesis,Characterisation and Relaxation Parameters of the Nanoassemblies and Their Potential as MRI Contrast Agents 下载免费PDF全文
Abhishek Gupta Dr. Scott A. Willis Lynne J. Waddington Dr. Tim Stait‐Gardner Dr. Liliana de Campo Prof. Dennis W. Hwang Dr. Nigel Kirby Prof. William S. Price Dr. Minoo J. Moghaddam 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(40)
3.
Dr. Fabio Carniato Dr. Lorenzo Tei Dr. Aldo Arrais Prof. Leonardo Marchese Prof. Mauro Botta 《Chemistry (Weinheim an der Bergstrasse, Germany)》2013,19(4):1421-1428
The optimization of the physico‐chemical properties of both GdIII chelates and nanocarriers is of great importance for the development of effective nanosystems for magnetic resonance imaging (MRI) applications. With this aim, macrocyclic GdIII chelates were selectively attached to the pendant amino groups exposed to the external surface of spheroidal mesoporous silica nanoparticles (MSNs). This was achieved by treating the metal complexes with MSNs that contained the templating surfactant molecules confined within the silica channels (hexadecyltrimethylammonium (CTA)/MSN), followed by extraction of the surfactant. The nanoparticles showed greatly improved 1H relaxometric efficiency relative to corresponding systems that also feature GdIII chelates conjugated inside the pores. A further significant relaxivity enhancement was observed after chemical transformation of the free amino groups into amides. The ionic relaxivity of the final nanoparticles (r1p=79.1 mM ?1 s?1; 0.5 T, 310 K) is one of the highest reported so far. 相似文献
4.
Dr. Loredana Leone Luca Guarnieri Dr. Jonathan Martinelli Prof. Massimo Sisti Prof. Andrea Penoni Prof. Mauro Botta Prof. Lorenzo Tei 《Chemistry (Weinheim an der Bergstrasse, Germany)》2021,27(46):11811-11817
The first binuclear Gd-complex of the 12-membered pyridine-based polyaminocarboxylate macrocyclic ligand PCTA was synthesized by C−C connection of the pyridine units through two different synthetic procedures. A dimeric AAZTA-ligand was also synthesized with the aim to compare the relaxometric results or the two ditopic Gd-complexes. Thus, the 1H relaxometric study on [Gd2PCTA2(H2O)4] and on [Gd2AAZTA2(H2O)4]2− highlighted the remarkable rigidity and compactness of the two binuclear complexes, which results in molar relaxivities (per Gd), at 1.5 T and 298 K of ca. 12–12.6 mM−1 s−1 with an increase of ca. 80 % at 1.5 T and 298 K (+70 % at 310 K) with respect to the corresponding mononuclear complexes. 相似文献
5.
Javier Aríñez‐Soriano Jorge Albalad Arnau Carné‐Sánchez Célia S. Bonnet Prof. Félix Busqué Prof. Julia Lorenzo Jordi Juanhuix Maxwell W. Terban Inhar Imaz Prof. Éva Tóth Prof. Daniel Maspoch 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(37):13162-13170
Lanthanide‐containing nanoscale particles have been widely explored for various biomedical purposes, however, they are often prone to metal leaching. Here we have created a new coordination polymer (CP) by applying, for the first time, a stable GdIII chelate as building block in order to prevent any fortuitous release of free lanthanide(III) ion. The use of the Gd‐DOTA‐4AmP complex as a design element in the CP allows not only for enhanced relaxometric properties (maximum r1=16.4 mm ?1 s?1 at 10 MHz), but also for a pH responsiveness (Δr1=108 % between pH 4 and 6.5), beyond the values obtained for the low molecular weight Gd‐DOTA‐4AmP itself. The CP can be miniaturised to the nanoscale to form colloids that are stable in physiological saline solution and in cell culture media and does not show cytotoxicity. 相似文献
6.
Dr. Mariapina D'Onofrio Dr. Eliana Gianolio Alberto Ceccon Francesca Arena Dr. Serena Zanzoni Prof. David Fushman Prof. Silvio Aime Prof. Henriette Molinari Dr. Michael Assfalg 《Chemistry (Weinheim an der Bergstrasse, Germany)》2012,18(32):9919-9928
Gadolinium complexes linked to an apolar fragment are known to be efficiently internalized into various cell types, including hepatocytes. Two lipid‐functionalized gadolinium chelates have been investigated for the targeting of the human liver fatty acid binding protein (hL‐FABP) as a means of increasing the sensitivity and specificity of intracellular‐directed MRI probes. hL‐FABP, the most abundant cytosolic lipid binding protein in hepatocytes, displays the ability to interact with multiple ligands involved in lipid signaling and is believed to be an obligate carrier to escort lipidic drugs across the cell. The interaction modes of a fatty acid and a bile acid based gadolinium complex with hL‐FABP have been characterized by relaxometric and NMR experiments in solution with close‐to‐physiological protein concentrations. We have introduced the analysis of paramagnetic‐induced protein NMR signal intensity changes as a quantitative tool for the determination of binding stoichiometry and of precise metal‐ion‐center positioning in protein–ligand supramolecular adducts. A few additional NMR‐derived restraints were then sufficient to locate the ligand molecules in the protein binding sites by using a rapid data‐driven docking method. Relaxometric and 13C NMR competition experiments with oleate and the gadolinium complexes revealed the formation of heterotypic adducts, which indicates that the amphiphilic compounds may co‐exist in the protein cavity with physiological ligands. The differences in adduct formation between fatty acid and bile acid based complexes provide the basis for an improved molecular design of intracellular targeted probes. 相似文献
7.
Dr. Martín Regueiro‐Figueroa Dr. Gabriele A. Rolla Dr. David Esteban‐Gómez Dr. Andrés de Blas Dr. Teresa Rodríguez‐Blas Prof. Mauro Botta Dr. Carlos Platas‐Iglesias 《Chemistry (Weinheim an der Bergstrasse, Germany)》2014,20(52):17300-17305
Stable Mn2+ mono‐ and binuclear complexes containing pentadentate 6,6′‐((methylazanediyl)bis(methylene))dipicolinic acid coordinating units give remarkably high relaxivities due to the presence of two inner‐sphere water molecules. The mononuclear derivative binds human serum albumin (HSA) with an association constant of 3372 M ?1, which results in the replacement of the coordinated water molecules by donor atoms of protein residues. The dinuclear analogue also binds HSA while leaving one of the Mn2+ centres exposed to the solvent with two coordinated water molecules. Thus, this complex shows remarkably high relaxivities upon protein binding (39.0 mM ?1 s?1 per Mn, at 20 MHz and 37 °C). 相似文献
8.
Mauro Vaccaro Dr. Gaetano Mangiapia Dr. Luigi Paduano Prof. Eliana Gianolio Dr. Antonella Accardo Dr. Diego Tesauro Dr. Giancarlo Morelli Prof. 《Chemphyschem》2007,8(17):2526-2538
The structural and relaxometric characterization of a novel class of supramolecular aggregates, as potential tumor‐specific contrast agents in magnetic resonance imaging (MRI), is reported. The aggregates are based on a new monomer with an upsilon shape (MonY) that contains, in the same molecule, all three fundamental tasks that are required: 1) a hydrophobic moiety that allows the formation of supramolecular aggregates; 2) the bioactive CCK8 peptide for target recognition; and 3) a chelating agent able to give stable gadolinium complexes. As indicated by dynamic light scattering and small‐angle neutron scattering (SANS) measurements, MonY and its gadolinium complex MonY(Gd) aggregate in aqueous solution to give ellipsoidal micelles with a ratio between the micellar axes of ≈1.7 and an aggregation number Nagg of ≈30. There are no differences in the aggregation behavior of MonY and MonY(Gd), which indicates that the presence of metal ions, and therefore the reduction of the net charge, does not influence the aggregation behavior. When MonY or MonY(Gd) are blended with dioleoyl phosphatidylcholine (DOPC), the aggregation behavior is dictated by the tendency of DOPC to give liposomes. Only when the amount of MonY or MonY(Gd) is higher than 20 % is the coexistence of liposomes and micelles observed. The thickness d of the bilayer is estimated by SANS to be ≈35–40 Å, whereas cryogenic transmission electron microscopy images show that the diameter of the liposomes ranges from ≈50 to 150 nm. Self‐assembling micelles of MonY(Gd) present high relaxivity values (r1p=15.03 mM ?1 s?1) for each gadolinium complex in the aggregate. Liposomes containing MonY(Gd) inserted in the DOPC bilayer at a molar ratio of 20:80 present slightly lower relaxivity values (r1p=12.7 mM ?1 s?1), independently of their internal or external position in the liposome. 相似文献
9.
Rachele Stefania Dr. Lorenzo Tei Dr. Alessandro Barge Dr. Simonetta Geninatti Crich Dr. Ibolya Szabo Dr. Claudia Cabella Dr. Giancarlo Cravotto Prof. Silvio Aime Prof. 《Chemistry (Weinheim an der Bergstrasse, Germany)》2009,15(1):76-85
Three new magnetic resonance imaging probes that target glutamine transporters have been synthesized. They consist of a Gd‐DOTA‐monoamide moiety (DOTA=1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid) linked through a six carbon atom chain to a vector represented by a glutamine residue bound through α‐carboxylic, γ‐carboxamidic, or α‐amino functionalities. Their uptake by HTC (rat hepatocarcinoma) and healthy rat hepatocytes has shown that the system containing the glutamine vector bound through the α‐carboxylic group displays a markedly higher affinity for tumor cells. The observed behavior is rationalized in terms of the exploitation of an additional glutamine transporter active in hepatic tumor cells. 相似文献
10.
《中国化学会会志》2018,65(5):561-566
A novel methodology involving the use of Gd3+–Xylenol Orange (Gd–XO), a solution colorimetric probe, was used to determine the conditional relative rates of complex formation between the Gd3+ ion and polyamino carboxylate ligands used in MRI contrast agent development. Among the ligands tested, the order of rate of Gd‐complex formation was found to be DTPA ≈ DOTP > DOTA > DO3A > DOTAM. The observed rates are an effect of ligand denticity, backbone structure, and nature of the ligand donor groups. 相似文献
11.
Zuzana Kotková Dr. Jan Kotek Dr. Daniel Jirák Dr. Pavla Jendelová Dr. Vít Herynek Dr. Zuzana Berková Dr. Petr Hermann Dr. Ivan Lukeš Prof. 《Chemistry (Weinheim an der Bergstrasse, Germany)》2010,16(33):10094-10102
A novel bimodal fluorescence/MRI probe based on a cyclodextrin scaffold has been synthesized and characterized. The final agent employs the fluorescein (F) functionality as a fluorescence marker and the GdIII complex of a macrocyclic DOTA‐based ligand (GdL) having one aminobenzyl‐phosphinic acid pendant arm as an MRI probe, and has a statistical composition of (GdL)6.9‐F0.1‐β‐CD. Slow rotational dynamics (governed by a very rigid cyclodextrin scaffold) combined with fast water exchange (ensured by the chosen macrocyclic ligand) resulted in a high relaxivity of ~22 s?1 mM ?1 per GdIII or ~150 s?1 mM ?1 per molecule of the final conjugate (20 MHz, 25 °C). In vitro labelling of pancreatic islets (PIs) and rat mesenchymal stem cells has been successfully performed. The agent is not cytotoxic and is easily internalized into cells. The labelled cells can be visualized by MRI, as proved by the detection of individual labelled PIs. A fluorescence study performed on mesenchymal stem cells showed that the agent stays in the intracellular space for a long time. 相似文献
12.
Dr. Gyula Tircsó Dr. Martín Regueiro‐Figueroa Viktória Nagy Zoltán Garda Tamás Garai Dr. Ferenc Krisztián Kálmán Dr. David Esteban‐Gómez Dr. Éva Tóth Dr. Carlos Platas‐Iglesias 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(3):896-901
A highly rigid open‐chain octadentate ligand (H4cddadpa) containing a diaminocylohexane unit to replace the ethylenediamine bridge of 6,6′‐[(ethane‐1,2 diylbis{(carboxymethyl)azanediyl})bis(methylene)]dipicolinic acid (H4octapa) was synthesized. This structural modification improves the thermodynamic stability of the Gd3+ complex slightly (log KGdL=20.68 vs. 20.23 for [Gd(octapa)]?) while other MRI‐relevant parameters remain unaffected (one coordinated water molecule; relaxivity r1=5.73 mm ?1 s?1 at 20 MHz and 295 K). Kinetic inertness is improved by the rigidifying effect of the diaminocylohexane unit in the ligand skeleton (half‐life of dissociation for physiological conditions is 6 orders of magnitude higher for [Gd(cddadpa)]? (t1/2=1.49×105 h) than for [Gd(octapa)]?. The kinetic inertness of this novel chelate is superior by 2–3 orders of magnitude compared to non‐macrocyclic MRI contrast agents approved for clinical use. 相似文献
13.
《Magnetic resonance in chemistry : MRC》2003,41(8):585-588
A novel, radical responsive MRI contrast agent based on a gadolinium chelate conjugated to a liposome through a disulfide linker was synthesized, with the aim of pursuing the in vivo mapping of radicals. The liposome was prepared by incorporating a thiol‐activated phospholipid, which was subsequently reacted with a gadolinium chelate containing a free thiol group. The long reorientational motion of the supramolecular adduct endows the paramagnetic agent with a relaxivity significantly higher than that of the free complex. The disulfide bond represents a radical‐sensitive moiety and a large decrease in contrast efficacy (T1 relaxivity) is shown upon its cleavage. A preliminary assessment of the system was made by means of in vitro gamma‐irradiation and thiol–disulfide bond exchange with dithiothreitol. Both methods showed a clear dose‐dependent decrease in T1‐relaxivity. Copyright © 2003 John Wiley & Sons, Ltd. 相似文献
14.
Matthias Brendel Carolin Braun Dr. Frank Rominger Prof. Dr. Peter Hofmann 《Angewandte Chemie (International ed. in English)》2014,53(33):8741-8745
For a long time d10‐ML2 fragments have been known for their potential to activate unreactive bonds by oxidative addition. In the development of more active species, two approaches have proven successful: the use of strong σ‐donating ligands leading to electron‐rich metal centers and the employment of chelating ligands resulting in a bent coordination geometry. Combining these two strategies, we synthesized bis‐NHC chelate complexes of nickel(0) and platinum(0). Bis(1,5‐cyclooctadiene)nickel(0) and ‐platinum(0) react with bisimidazolium salts, deprotonated in situ at room temperature, to yield tetrahedral or trigonal‐planar bis‐NHC chelate olefin complexes. The synthesis and characterization of these complexes as well as a first example of C? C bond activation with these systems are reported. Due to the enforced cis arrangement of two NHCs, these compounds should open interesting perspectives for bond‐activation chemistry and catalysis. 相似文献
15.
André Boltjes Dr. Annadka Shrinidhi Kees van de Kolk Dr. Eberhardt Herdtweck Prof. Dr. Alexander Dömling 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(22):7352-7356
A simple Ugi tetrazole multicomponent reaction allows the synthesis of a novel macrocyclic cyclen derivative with four appendant tetrazole arms in just two steps in excellent yields. This ligand, called TEMDO, turns out to have a high complexation affinity with lanthanoid metals. Here we describe the design, synthesis, solid‐state structure, binding constant, and some MRI applications of the Gd‐TEMDO complex as the first example of a congeneric family of oligo‐amino tetrazoles. 相似文献
16.
Lorenzo Tei Dr. Alessandro Barge Dr. Simonetta Geninatti Crich Dr. Roberto Pagliarin Dr. Viviana Negri Dr. Daniela Ramella Dr. Giancarlo Cravotto Prof. Silvio Aime Prof. 《Chemistry (Weinheim an der Bergstrasse, Germany)》2010,16(27):8080-8087
To design efficient targeting strategies in magnetic resonance (MR) molecular imaging applications, the formation of supramolecular adducts between (strept)avidin ((S)Av) and tribiotinylated Gd‐DOTA‐monoamide complexes (DOTA=1,4,7,10‐tetraazacyclododecane‐N,N′,N′′,N′′′‐tetraacetic acid) was explored. Two compounds based on the trivalent core of tris(2‐aminoethyl)amine each containing three biotin molecules and one ( L1 ) or three ( L2 ) DOTA‐monoamide (DOTAMA) ligands were synthesized. In these tribiotinylated derivatives the biotins are spaced far enough apart to allow the formation of the supramolecular adduct with the protein and to host the chelating units in between the (S)Av layers. Size exclusion HPLC analyses indicated complete formation of very high molecular weight polymers (>2 MDa) with (S)Av in solution. A 1H NMR spectroscopy relaxometric study on the obtained polymeric adducts showed a marked increase of the relaxivity at 35–40 MHz as a consequence of the lengthening of the tumbling time due to the formation of Gd‐chelates/(S)Av polymers. The most efficient Gd3 L2 /(S)Av polymeric system was used for a test in cell cultures. The target is represented by a neural cell adhesion molecule (NCAM), which is overexpressed in Kaposi’s sarcoma cells and tumor endothelial cells (TEC) and that is efficiently recognized by a biotinylated tetrameric peptide (C3d‐Bio). In vitro experiments showed that only cells incubated with both C3d‐Bio and Gd3 L2 /SAv polymer were hyperintense with respect to the control. Relaxation rates of cell pellets incubated with Gd3 L2 /SAv alone were not significantly different from the untreated cells demonstrating the absence of a specific binding. 相似文献
17.
Six linear oligo‐DTPA‐ester Gd(III) complexes being used for potential MRI contrast agents were synthesized from amino adds and characterized. Their longitudinal relaxation rates were measured. One of them, die phenylalanine derivative, with high relaxivity, was chosen for the acute toxicity and T1,‐weighted imaging test. The results indicated that there was no obvious toxicity for this new oligomeric Gd(III) complex, and it exhibits the highly enhanced MRI signal intensity and the increasing signal duration in the liver tissue compared to Gd‐DTPA. 相似文献
18.
Erika Cerutti Annelaure Damont Frédéric Dollé Simona Baroni Silvio Aime 《Magnetic resonance in chemistry : MRC》2013,51(2):116-122
DPA‐713 is the lead compound of a recently reported pyrazolo[1,5‐a]pyrimidineacetamide series, targeting the translocator protein (TSPO 18 kDa), and as such, this structure, as well as closely related derivatives, have been already successfully used as positron emission tomography radioligands. On the basis of the pharmacological core of this ligands series, a new magnetic resonance imaging probe, coded DPA‐C6‐(Gd)DOTAMA was designed and successfully synthesized in six steps and 13% overall yield from DPA‐713. The Gd‐DOTA monoamide cage (DOTA = 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid) represents the magnetic resonance imaging reporter, which is spaced from the phenylpyrazolo[1,5‐a]pyrimidineacetamide moiety (DPA‐713 motif) by a six carbon‐atom chain. DPA‐C6‐(Gd)DOTAMA relaxometric characterization showed the typical behavior of a small‐sized molecule (relaxivity value: 6.02 mM?1 s?1 at 20 MHz). The good hydrophilicity of the metal chelate makes DPA‐C6‐(Gd)DOTAMA soluble in water, affecting thus its biodistribution with respect to the parent lipophilic DPA‐713 molecule. For this reason, it was deemed of interest to load the probe to a large carrier in order to increase its residence lifetime in blood. Whereas DPA‐C6‐(Gd)DOTAMA binds to serum albumin with a low affinity constant, it can be entrapped into liposomes (both in the membrane and in the inner aqueous cavity). The stability of the supramolecular adduct formed by the Gd‐complex and liposomes was assessed by a competition test with albumin. Copyright © 2013 John Wiley & Sons, Ltd. 相似文献
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20.
Dr. Zsolt Baranyai Zoltán Pálinkás Dr. Fulvio Uggeri Dr. Alessandro Maiocchi Prof. Silvio Aime Prof. Ernő Brücher 《Chemistry (Weinheim an der Bergstrasse, Germany)》2012,18(51):16426-16435
The kinetics of the metal exchange reactions between open‐chain Gd(DTPA)2? and Gd(DTPA‐BMA), macrocyclic Gd(DOTA)? and Gd(HP‐DO3A) complexes, and Cu2+ ions were investigated in the presence of endogenous citrate, phosphate, carbonate and histidinate ligands in the pH range 6–8 in NaCl (0.15 M ) at 25 °C. The rates of the exchange reactions of Gd(DTPA)2? and Gd(DTPA‐BMA) are independent of the Cu2+ concentration in the presence of citrate and the reactions occur via the dissociation of Gd3+ complexes catalyzed by the citrate ions. The HCO3?/CO32? and H2PO4? ions also catalyze the dissociation of complexes. The rates of the dissociation of Gd(DTPA‐BMA), catalyzed by the endogenous ligands, are about two orders of magnitude higher than those of the Gd(DTPA)2?. In fact near to physiological conditions the bicarbonate and carbonate ions show the largest catalytic effect, that significantly increase the dissociation rate of Gd(DTPA‐BMA) and make the higher pH values (when the carbonate ion concentration is higher) a risk‐factor for the dissociation of complexes in body fluids. The exchange reactions of Gd(DOTA)? and Gd(HP‐DO3A) with Cu2+ occur through the proton assisted dissociation of complexes in the pH range 3.5–5 and the endogenous ligands do not affect the dissociation rates of complexes. More insights into the interaction scheme between Gd(DTPA‐BMA) and Gd(DTPA)2? and endogenous ligands have been obtained by acquiring the 13C NMR spectra of the corresponding diamagnetic Y(III)‐complexes, indicating the increase of the rates of the intramolecular rearrangements in the presence of carbonate and citrate ions. The herein reported results may have implications in the understanding of the etiology of nephrogenic systemic fibrosis, a rare disease that has been associated to the administration of Gd‐containing agents to patients with impaired renal function. 相似文献