A Eu<sup>II</sup>‐Containing Cryptate as a Redox Sensor in Magnetic Resonance Imaging of Living Tissue

Ekanger, Levi A.; Polin, Lisa; Shen, Yimin; Haacke, E. Mark; Martin, Philip D.; Allen, Matthew J.

doi:10.1002/ange.201507227

Cited by 18 publications

(36 citation statements)

References 26 publications

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“…[5,6] Additionally, 1 -Eu II , EuCl 2 (aq), and 2 -Eu II encompass a relatively wide range in reduction potentials (Table 1) with 1 -Eu II being 374 mV more negative than EuCl 2 (aq) [7] and 2 -Eu II being 547 mV more positive than EuCl 2 (aq). [17] Although we have observed rapid oxidation of Eu II by gaseous diatomic molecules, such as O 2 and NO, we elected to study reaction kinetics with non-gaseous oxidants for the ease of quantifying and handling in an inert atmosphere.…”

Section: Resultsmentioning

confidence: 99%

“…This observation can be explained by the cryptand of 2 -Eu II inhibiting access to the metal center by decreasing available coordination sites from 9 or 10 in EuCl 2 (aq) to 1 or 2 in 2 -Eu II . [5] A similar explanation was used to rationalize the decreased rate of Eu II oxidation by hydrogen peroxide upon chelation in crown ethers and cryptands. [13] In that study, the decreased oxidation rate was attributed to the steric protection of Eu II ions within appropriately sized ligands.…”

Section: Resultsmentioning

confidence: 99%

“…Unlike 1 -Eu II and EuCl 2 (aq), the lack of reactivity between 2 -Eu II and GSSG can be explained by positive Gibbs free energies at pH 5 and 7 (Table 1), indicating that spontaneous reactions should not be observed. Altogether, the GSSG data and in vivo imaging experiments [5,6] indicate that, from a biological standpoint, bulky disulfide bonds or other bulky oxidizing agents are likely minor contributors at most to Eu II oxidation in vivo for imaging experiments shorter than four hours.…”

Section: Resultsmentioning

confidence: 99%

“…[4–7] Out of the lanthanide ions, Eu II is uniquely poised for oxidation-responsive MRI because (1) some Eu II -containing complexes are stable in aqueous media, (2) Eu II provides positive (bright or T 1 -shortening) contrast enhancement in MRI, (3) the E 1/2 of Eu II/III can be tuned over a physiologically relevant range, and (4) the +2 and +3 oxidation states of Eu exhibit different magnetic and spectroscopic characteristics making responsive imaging feasible. [7,8] The oxidation-responsive behavior of Eu II -containing complexes has been documented in vivo, [5,6] making the kinetics of oxidation under physiological conditions important to understand for the rational design of new complexes. Accordingly, there is a need for kinetic and thermodynamic analyses to enable a detailed understanding of Eu II -containing complexes for responsive MRI.…”

Section: Introductionmentioning

confidence: 99%

“…Before performing kinetic measurements, we studied a fundamental reaction between EuCl 2 and O 2 to determine if an oxygen-containing product could be identified. Given the in vivo correlation between tissue p O 2 and the persistence of Eu II -based positive contrast enhancement, [5,6] these studies are important for rationalizing Eu II oxidation-responses.…”

Section: Introductionmentioning

confidence: 99%

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The Role of Coordination Environment and pH in Tuning the Oxidation Rate of Europium(II)

Ekanger

Basal

Allen

2016

Chemistry A European J

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The EuII/III redox couple offers metal-based oxidation-sensing with magnetic resonance imaging making the study of EuII oxidation chemistry important in the design of new probes. Accordingly, we explored oxidation reactions with a set of EuII-containing complexes. We report the observation of superoxide formation from the reaction between EuII and dioxygen using electron paramagnetic resonance spectroscopy. Additionally, we report oxidation kinetics of three EuII-containing complexes with bromate and glutathione disulfide at pH values including 5 and 7. In the reaction with bromate, the oxidation rate of two of the complexes increased by 7.3 and 6.7× upon decreasing pH from 7 to 5, but the rate increased by 17× for a complex containing amide functional groups over the same pH range. The oxidation rate of a fluorobenzo-functionalized cryptate was relatively slow, indicating that the ligand used to impart thermodynamic oxidative stability might also be useful for controlling oxidation kinetics.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Role of Coordination Environment and pH in Tuning the Oxidation Rate of Europium(II)

Ekanger

Basal

Allen

2016

Chemistry A European J

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Outersphere Approach to Increasing the Persistance of Oxygen‐Sensitive Europium(II)‐Containing Contrast Agents for Magnetic Resonance Imaging with Perfluorocarbon Nanoemulsions toward Imaging of Hypoxia

Lutter

Batchev

Ortiz

et al. 2023

Adv Healthcare Materials

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Radiographic mapping of hypoxia is needed to study a wide range of diseases. Complexes of Eu(II) are a promising class of molecules to fit this need, but they are generally limited by their rapid oxidation rates in vivo. Here, a perfluorocarbon-nanoemulsion perfused with N 2 , forms an interface with aqueous layers to hinder oxidation of a new perfluorocarbon-soluble complex of Eu(II). Conversion of the perfluorocarbon solution of Eu(II) into nanoemulsions results in observable differences between reduced and oxidized forms by magnetic resonance imaging both in vitro and in vivo. Oxidation in vivo occurrs over a period of ≈30 min compared to <5 min for a comparable Eu(II)-containing complex without nanoparticle interfaces. These results represent a critical step toward delivery of Eu(II)-containing complexes in vivo for the study of hypoxia.

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Oxidative Conversion of a Europium(II)‐Based T₁ Agent into a Europium(III)‐Based paraCEST Agent that can be Detected In Vivo by Magnetic Resonance Imaging

et al. 2016

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The Eu II complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)t etra(glycinate) has ah igher reduction potential than most Eu II chelates reported to date.The reduced Eu II form acts as an efficient water proton T 1 relaxation reagent, while the Eu III form acts as awater-based chemical exchange saturation transfer (CEST) agent. The complex has extremely fast water exchange rate.O xidation to the corresponding Eu III complex yields aw ell-defined signal from the paraCEST agent. The time course of oxidation was studied in vitro and in vivo by T 1 -weighted and CEST imaging.Gadolinium complexes are commonly used as contrast agents in magnetic resonance imaging (MRI). They generate image contrast by shortening the longitudinal (T 1 )relaxation time of bulk water protons.T he efficiencyo faT 1 agent is defined by r 1 relaxivity,w hich is dependent on several parameters,i ncluding the metal bound water exchange rate, rotational correlation time of the complex, and the electronic relaxation time of the metal ion. [1] An alternative to the Gd 3+based contrast agents is the isoelectronic Eu 2+ ion. [2] Both ions have a4f 7 electron configuration and asymmetric 8 S 7/2 ground state but Eu 2+ complexes in general display much faster water exchange rates and faster electronic relaxation times. [2] Analogous complexes of Eu 2+ and Gd 3+ can produce similar relaxivity values at lower fields while at higher fields the Eu 2+ complexes tend to be more efficient. [3] TheE u 2+ aqua ion is extremely sensitive to oxidation as demonstrated by its strongly negative reduction potential (À585 mV vs.A g + /AgCl). Eu 2+ poly(amino carboxylate) chelates usually have lower reduction potential, although some Eu 2+ cryptates have been reported to be more stable towards oxidation. [4,5] Eu 2+ complexes have been proposed as redox sensitive T 1 agents, [3,5,6] because oxidation of Eu 2+ leads to the formation of weakly paramagnetic Eu 3+ ,w hich has little impact on water proton T 1 .T he Eu 3+ ion however generates am oderately strong magnetic dipolar field that produces large hyperfine shifts of NMR signals of nearby ligand protons.W hile Eu 3+ complexes are very poor T 1shortening agents,E u 3+ DOTAt etra(amides) (Figure 1) belong to ac onceptually different class of MRI contrast agents,k nown as paraCEST agents that alter image contrast by transferring selectively saturated spins from ah ighly shifted small pool of proton spins (metal-bound water) to the bulk water pool. [7] Chemical exchange saturation transfer (CEST) occurs when the proton exchange rate between the two pools (k ex )isinthe slow-to-intermediate exchange regime (k ex Dw,where Dw is the chemical shift difference between the two pools). Ar edox responsive liposomal Eu 2+ /Eu 3+ system was recently reported that showed T 1 shortening effect and lipoCEST effect (Dw % 1ppm) originating from the exchange between the water protons inside the liposomes and the bulk water protons not associated with the liposomes. Upon oxidation, the T 1 enhancement disappeare...

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A Eu^II‐Containing Cryptate as a Redox Sensor in Magnetic Resonance Imaging of Living Tissue

Cited by 18 publications

References 26 publications

The Role of Coordination Environment and pH in Tuning the Oxidation Rate of Europium(II)

The Role of Coordination Environment and pH in Tuning the Oxidation Rate of Europium(II)

Outersphere Approach to Increasing the Persistance of Oxygen‐Sensitive Europium(II)‐Containing Contrast Agents for Magnetic Resonance Imaging with Perfluorocarbon Nanoemulsions toward Imaging of Hypoxia

Oxidative Conversion of a Europium(II)‐Based T₁ Agent into a Europium(III)‐Based paraCEST Agent that can be Detected In Vivo by Magnetic Resonance Imaging

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A EuII‐Containing Cryptate as a Redox Sensor in Magnetic Resonance Imaging of Living Tissue

Cited by 18 publications

References 26 publications

The Role of Coordination Environment and pH in Tuning the Oxidation Rate of Europium(II)

The Role of Coordination Environment and pH in Tuning the Oxidation Rate of Europium(II)

Outersphere Approach to Increasing the Persistance of Oxygen‐Sensitive Europium(II)‐Containing Contrast Agents for Magnetic Resonance Imaging with Perfluorocarbon Nanoemulsions toward Imaging of Hypoxia

Oxidative Conversion of a Europium(II)‐Based T1 Agent into a Europium(III)‐Based paraCEST Agent that can be Detected In Vivo by Magnetic Resonance Imaging

Contact Info

Product

Resources

About

A Eu^II‐Containing Cryptate as a Redox Sensor in Magnetic Resonance Imaging of Living Tissue

Oxidative Conversion of a Europium(II)‐Based T₁ Agent into a Europium(III)‐Based paraCEST Agent that can be Detected In Vivo by Magnetic Resonance Imaging