A R2p/R1p Ratiometric Procedure to Assess Matrix Metalloproteinase‐2 Activity by Magnetic Resonance Imaging

Catanzaro, Valeria; Gringeri, Concetta V.; Menchise, Valeria; Padovan, Sergio; Boffa, Cinzia; Dastrù, Walter; Chaabane, Linda; Digilio, Giuseppe; Aime, Silvio

doi:10.1002/anie.201209286

Cited by 32 publications

(23 citation statements)

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“…[10] Fort his purpose,aspecific biotinylated MMP-2 responsive molecule (Biot-MMP2-resp) was incorporated in the LipoCEST membrane ( Figure 3B;S upporting Information, Figure S3). This enzyme is known to be able to cleave ap eptide chain containing the NIPVSLYA sequence.…”

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Enzyme‐Responsive LipoCEST Agents: Assessment of MMP‐2 Activity by Measuring the Intra‐liposomal Water¹H NMR Shift

et al. 2017

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Mobile proton-containing solutes can be detected by MRI by the chemical exchange saturation transfer (CEST) method. CEST sensitivity is dramatically enhanced by using, as exchanging protons,t he water molecules confined inside liposomes,s hifted by ap aramagnetic shift reagent. The chemical shift of the intraliposomal water resonance (d IL )i s affected by the overall shape of the supramolecular system. d IL of as pherical LipoCEST acts as as ensitive reporter of the distribution of streptavidin proteins anchored at the liposome surface by biotinylated phospholipids.T his finding prompted the design of aM MP-2 responsive LipoCEST agent as the streptavidin moieties can be released from the liposome surfaces when ap roperly tailored enzyme-cleavable peptide is inserted on the phospholipids before the terminal biotin residues. d IL reports on the overall changes in the supramolecular architecture associated to the cleavage carried out by MMP-2. Nuclearmagneticresonance(NMR)spectroscopyisusuallyconsidered unsuitable for analytical chemistry applications,as the detection threshold is in the range of 10 À4 -10 À5 m.O ne possibility to increase the 1 H-NMR sensitivity relies on the assessment of solute effects on the solvent molecule signal. This approach has been extensively exploited when the solute is ap aramagnetic species and the solvent is represented by water molecules. [1] In fact, the observed water proton relaxation enhancement (longitudinal and transversal relaxivities) may in turn be related to the concentration of the species inducing the paramagnetic perturbation. [2] Another route to pursue solute signal amplification relies on the exploitation of saturation transfer (ST) effects to the water protons resonance once mobile protons on the solute molecules are irradiated with ar adiofrequencyc entered at the NMR absorption frequencyo ft he exchanging proton pool. [3] We have previously shown that the sensitivity of the chemical exchange saturation transfer (CEST) method can be further increased by using the ensemble of water molecules present in the inner cavity of al iposome as an exchangeable proton pool.The 1 HNMR intraliposomal water proton resonance is properly shifted by the interaction with as hift reagent (SR) entrapped in this compartment during LipoCEST liposome preparation; [4] from millions to billion water molecules are usually entrapped inside liposomes,depending on the size of the particles,t hus yielding ad etection threshold per particle in the pm range. [4] Thec hemical shift of the intraliposomal water resonance (d IL )i sd etermined by the sum of two contributions [Equation (1)]:where Hyp and BMS refer to hyperfine and bulk magnetic susceptibility contributions,respectively. [4a,c] It has been shown that the generation of osmotically shrunken LipoCESTs make it possible to increase the attainable shift for the inner water resonance (d IL )u pt o AE 20/25 ppm. [4a,c, 5] Thes hift enhancement relies on the orientation of non-spherical systems when placed inside am agnetic field (B 0 ). Th...

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Enzyme‐Responsive LipoCEST Agents: Assessment of MMP‐2 Activity by Measuring the Intra‐liposomal Water¹H NMR Shift

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“…After air exposure we observed an 86% decrease in T 1 (0.4 and 2.8 s for the same sample before and after air exposure, respectively, at 24 °C, 11.7 T, and 45 mM in Eu), which is a response similar to or greater than other reported contrast agents. 25 A rationale for the large change in T 1 is that Eu 2+ is isoelectronic with Gd 3+ , but Eu 3+ is diamagnetic in its ground state and is not expected to dramatically influence T 1 . The observation of T 1 changing upon air exposure is in good agreement with the T 1 -shortening nature of Eu(2.2.2) 2+ (relaxivity was 3.99 mM −1 s −1 outside of liposomes and 0.2 mM −1 s −1 inside of liposomes at 20 °C and 11.7 T. The lower relaxivity is expected for T 1 -shortening contrast agents encapsulated in spherical liposomes).…”

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Oxidation-responsive Eu^2+/3+-liposomal contrast agent for dual-mode magnetic resonance imaging

2014

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“…79 Instead of relying on reversible changes to molecular conformation, an irreversible reaction was used to change R 2p / R 1p by an enzyme-catalyzed cleavage of a peptide. Before enzyme cleavage, 22a (Figure 23) remained embedded within a liposome membrane, which forced the complex to have a relatively long τ R because of the slow molecular reorientation of liposomes compared to small molecules.…”

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Overcoming the concentration-dependence of responsive probes for magnetic resonance imaging

Ekanger

Allen

2015

Metallomics

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In magnetic resonance imaging, contrast agents are molecules that increase the contrast-to-noise ratio of non-invasively acquired images. The information gained from magnetic resonance imaging can be increased using responsive contrast agents that undergo chemical changes, and consequently changes to contrast enhancement, for example in response to specific biomarkers that are indicative of diseases. A major limitation with modern responsive contrast agents is concentration-dependence that requires the concentration of contrast agent to be known: an extremely challenging task in vivo. Here, we review advances in several strategies aimed at overcoming the concentration-dependent nature of responsive contrast agents.

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A R_2p/R_1p Ratiometric Procedure to Assess Matrix Metalloproteinase‐2 Activity by Magnetic Resonance Imaging

Cited by 32 publications

References 21 publications

Enzyme‐Responsive LipoCEST Agents: Assessment of MMP‐2 Activity by Measuring the Intra‐liposomal Water¹H NMR Shift

Enzyme‐Responsive LipoCEST Agents: Assessment of MMP‐2 Activity by Measuring the Intra‐liposomal Water¹H NMR Shift

Oxidation-responsive Eu^2+/3+-liposomal contrast agent for dual-mode magnetic resonance imaging

Overcoming the concentration-dependence of responsive probes for magnetic resonance imaging

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A R2p/R1p Ratiometric Procedure to Assess Matrix Metalloproteinase‐2 Activity by Magnetic Resonance Imaging

Cited by 32 publications

References 21 publications

Enzyme‐Responsive LipoCEST Agents: Assessment of MMP‐2 Activity by Measuring the Intra‐liposomal Water1H NMR Shift

Enzyme‐Responsive LipoCEST Agents: Assessment of MMP‐2 Activity by Measuring the Intra‐liposomal Water1H NMR Shift

Oxidation-responsive Eu2+/3+-liposomal contrast agent for dual-mode magnetic resonance imaging

Overcoming the concentration-dependence of responsive probes for magnetic resonance imaging

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Product

Resources

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A R_2p/R_1p Ratiometric Procedure to Assess Matrix Metalloproteinase‐2 Activity by Magnetic Resonance Imaging

Enzyme‐Responsive LipoCEST Agents: Assessment of MMP‐2 Activity by Measuring the Intra‐liposomal Water¹H NMR Shift

Enzyme‐Responsive LipoCEST Agents: Assessment of MMP‐2 Activity by Measuring the Intra‐liposomal Water¹H NMR Shift

Oxidation-responsive Eu^2+/3+-liposomal contrast agent for dual-mode magnetic resonance imaging