A cell-permeable gadolinium contrast agent for magnetic resonance imaging of copper in a Menkes disease model

Que, Emily L.; New, Elizabeth J.; Chang, Christopher J.

doi:10.1039/c2sc20273e

Cited by 45 publications

(38 citation statements)

References 66 publications

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“…To circumvent this issue, we introduced a polyarginine tag on the CG2 scaffold to improve cellular uptake of the probe. Synthesis of Arg 8 CG2 resulted in a cell‐permeable copper‐responsive MR‐based probe with comparable spectroscopic properties and response to Cu + that allowed for the visualization of biological perturbations of copper levels in a murine Menkes disease model cell line . Indeed, Arg 8 CG2 showed greater cellular uptake compared with CG2 in HEK 293T cells as confirmed by ICP‐MS studies of the lysed cells.…”

Section: Magnetic Resonance‐based Copper‐sensing Probesmentioning

confidence: 87%

Thioether Coordination Chemistry for Molecular Imaging of Copper in Biological Systems

Ramos-Torres

Kölemen

Chang

2016

Israel Journal of Chemistry

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Copper is an essential element in biological systems. Its potent redox activity renders it necessary for life, but at the same time, misregulation of its cellular pools can lead to oxidative stress implicated in aging and various disease states. Copper is commonly thought of as a static cofactor buried in protein active sites; however, evidence of a more loosely bound, labile pool of copper has emerged. To help identify and understand new roles for dynamic copper pools in biology, we have developed selective molecular imaging agents for this metal, drawing inspiration from both biological binding motifs and synthetic model complexes that reveal thioether coordination as a general design strategy for selective and sensitive copper recognition. In this review, we summarize some contributions, primarily from our own laboratory, on fluorescence- and magnetic resonance-based molecular-imaging probes for studying copper in living systems using thioether coordination chemistry.

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Section: Magnetic Resonance‐based Copper‐sensing Probesmentioning

confidence: 87%

Thioether Coordination Chemistry for Molecular Imaging of Copper in Biological Systems

Ramos-Torres

Kölemen

Chang

2016

Israel Journal of Chemistry

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“…In order to target the in cellulo Cu + , it was modified with an octaarginine (Arg 8 ) tail to afford 15 for improved cellular uptake and retention. It is also worth noting that 15 exhibits cytotoxicity with an IC 50 value of 295 M in HEK293 cells after a 24 h incubation, compared with >2000 M for the extracellular parent compound 10 [38]. This encouraging progress may shed light on the in vivo application of 15 as a copper sensor to report on biological regulation of exchangeable copper pools [38].…”

Section: Copper Sensingmentioning

confidence: 85%

“…Derivative 15 accumulates in live cells at concentrations 9-fold greater than the parent sensor 10, and was able to discriminate copper levels between a wildtype and a Menkes disease model cell line with a mutant copper efflux protein [38]. In order to target the in cellulo Cu + , it was modified with an octaarginine (Arg 8 ) tail to afford 15 for improved cellular uptake and retention.…”

Section: Copper Sensingmentioning

confidence: 99%

Detection of Metal Ions, Anions and Small Molecules Using Metal Complexes

Wang

Franz

2014

Inorganic Chemical Biology

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Biology is a complex network of molecules that interact, organize, and communicate. We cannot readily visualize most of these species, and yet we are interested in tracking their presence within cells, tissues, or biological fluids in order to provide a deeper understanding of their physiological significance. There has been considerable effort, therefore, to develop chemical sensors that can "see" specific analytes in biological systems.A chemical sensor reports the presence of an analyte by converting a recognition event (usually, but not always, a binding event) into a spectroscopic signal. The analytes of interest include a broad swath of molecule types, including anions, reactive small molecules, proteins, nucleic acids, metal ions, or any other biological or foreign molecule. The spectroscopic signals can be colorimetric, luminescent, magnetic, electrochemical, or radioactive. Currently used sensors largely rely on organic dyes, fluorescent proteins, nanoparticles, and metal complexes for responsive signal transduction. In this chapter, we focus exclusively on the use of metal complexes as design features for chemical sensors. Subsets of this category include radiometals and electroactive metals, which are not covered further here. Instead, we direct interested readers to a recent comprehensive review of the coordination chemistry of radiometals and their application as probes in PET and SPECT imaging [1], as well as reviews on the use of electroactive transition metal receptors for electrochemical sensing applications [2,3].

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“…Progress in the field of cell-penetrating, lanthanide-based contrast agents has been reviewed 8,33 and includes the use of polyarginine 34 and Tat-based peptides. 35 This technique has also been applied to luminescent metal complexes 36 and dual imaging agents.…”

Section: Resultsmentioning

confidence: 99%

Effect of Lanthanide Complex Structure on Cell Viability and Association

et al. 2014

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A systematic study of the effect of hydrophobicity and charge on the cell viability and cell association of lanthanide metal complexes is presented. The terbium luminescent probes feature a macrocyclic polyaminocarboxylate ligand (DOTA) in which the hydrophobicity of the antenna and that of the carboxyamide pendant arms are independently varied. Three sensitizing antennas were investigated in terms of their function in vitro: 2-methoxyisophthalamide (IAM(OMe)), 2-hydroxyisophthalamide (IAM), and 6-methylphenanthridine (Phen). Of these complexes, Tb-DOTA-IAM exhibited the highest quantum yield, although the higher cell viability and more facile synthesis of the structurally related Tb-DOTA-IAM(OMe) platform renders it more attractive. Further modification of this latter core structure with carboxyamide arms featuring hydrophobic benzyl, hexyl, and trifluoro groups as well as hydrophilic amino acid based moieties generated a family of complexes that exhibit high cell viability (ED50 > 300 μM) regardless of the lipophilicity or the overall complex charge. Only the hexyl-substituted complex reduced cell viability to 60% in the presence of 100 μM complex. Additionally, cellular association was investigated by ICP-MS and fluorescence microscopy. Surprisingly, the hydrophobic moieties did not increase cell association in comparison to the hydrophilic amino acid derivatives. It is thus postulated that the hydrophilic nature of the 2-methoxyisophthalamide antenna (IAM(OMe)) disfavors the cellular association of these complexes. As such, responsive luminescent probes based on this scaffold would be appropriate for the detection of extracellular species.

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A cell-permeable gadolinium contrast agent for magnetic resonance imaging of copper in a Menkes disease model

Cited by 45 publications

References 66 publications

Thioether Coordination Chemistry for Molecular Imaging of Copper in Biological Systems

Thioether Coordination Chemistry for Molecular Imaging of Copper in Biological Systems

Detection of Metal Ions, Anions and Small Molecules Using Metal Complexes

Effect of Lanthanide Complex Structure on Cell Viability and Association

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