Gold nanoparticles functionalised with stable, fast water exchanging Gd3+ chelates as high relaxivity contrast agents for MRI

Ferreira, Miguel; Mousavi, Bibimaryam; Ferreira, Paula M. T.; Martins, Catarina; Helm, Lothar; Martins, José A.; Geraldes, Carlos F. G. C.

doi:10.1039/c2dt30388d

Cited by 58 publications

(74 citation statements)

References 27 publications

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“…It should be noted that NMRD profiles for slowly rotating systems are shown and fitted herein only in the high field region because of the known limitations of SBM theory in the slowly rotating regime that render it unable to completely account for the behaviour of more slowly rotating chelates at very low magnetic field strengths. 65 These profiles are notable because the high field relaxivity enhancement arising when molecular tumbling is slow (longer τ R ) is greater for S-RRR -Gd 4, the isomer (SAP) with the more slowly exchanging water molecule. This is in direct contrast to the general expectation that more rapid water exchange kinetics (up to an optimal value of about 6 ns at 1.5 T) 7,34 will afford higher relaxivities.…”

Section: Resultsmentioning

confidence: 99%

Coupling Fast Water Exchange to Slow Molecular Tumbling in Gd³⁺ Chelates: Why Faster Is Not Always Better

et al. 2013

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The influence of dynamics on solution state structure is a widely overlooked consideration in chemistry. Variations in Gd3+ chelate hydration with changing coordination geometry and dissociative water exchange kinetics substantially impact the effectiveness (or relaxivity) of mono-hydrated Gd3+ chelates as T1-shortening contrast agents for MRI. Theory shows that relaxivity is highly dependent upon the Gd3+-water proton distance (rGdH) and yet this distance is almost never considered as a variable in assessing the relaxivity of a Gd3+ chelate as a potential contrast agent. The consequence of this omission can be seen when considering the relaxivity of isomeric Gd3+ chelates that exhibit different dissociative water exchange kinetics. The results described herein show that the relaxivity of a chelate with ‘optimal’ dissociative water exchange kinetics is actually lower than that of an isomeric chelate with ‘sub-optimal’ dissociative water exchange. When the rate of molecular tumbling of these chelates is slowed, an approach that has long been understood to increase relaxivity, the observed difference in relaxivity is increased with the more rapidly exchanging (‘optimal’) chelate exhibiting lower relaxivity than the ‘sub-optimally’ exchanging isomer. The difference between the chelates arises from a non-field dependent parameter: either the hydration number (q) or rGdH. For solution state Gd3+ chelates, changes in the values of q and rGdH are indistinguishable. These parametric expressions simply describe the hydration state of the chelate – i.e. the number and position of closely associating water molecules. The hydration state (q/rGdH6) of a chelate is intrinsically linked to its dissociative water exchange rate kex and the interrelation of these parameters must be considered when examining the relaxivity of Gd3+ chelates. The data presented herein indicates that the changes in the hydration parameter (q/rGdH6) associated with changing dissociative water exchange kinetics has a profound effect on relaxivity and suggest that achieving the highest relaxivities in monohydrated Gd3+ chelates is more complicated than simply “optimizing” dissociative water exchange kinetics.

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Section: Resultsmentioning

confidence: 99%

Coupling Fast Water Exchange to Slow Molecular Tumbling in Gd³⁺ Chelates: Why Faster Is Not Always Better

et al. 2013

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“…Further efforts include the application of alternative chelators. For example, immobilization of 70 Gd-DO3A molecules on a 4.8 nm-sized gold nanoparticles led to I-N-V relaxivities of 20.0 mM −1 s −1 – 1,400 mM −1 s −1 – 24.17 mM −1 s −1 nm −3 at 30 MHz (Ferreira et al, 2012). The increased water exchange rate of the DO3A chelator led to an increase in ionic relaxivity in this case.…”

Section: Nanoparticle-based Mr Contrast Agents In Developmentmentioning

confidence: 99%

Engineering Gd-loaded nanoparticles to enhance MRI sensitivity viaT₁shortening

Bruckman

Steinmetz

2013

Nanotechnology

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Magnetic resonance imaging (MRI) is a noninvasive imaging technique capable of obtaining highresolution anatomical images of the body. Major drawbacks of MRI are the low contrast agent sensitivity and inability to distinguish healthy tissue from diseased tissue, making early detection challenging. To address this technological hurdle, paramagnetic contrast agents have been developed to increase the longitudinal relaxivity (R 1 ), leading to an increased signal-to-noise ratio. This review focuses on methods and principles that enabled the design and engineering of nanoparticles to deliver contrast agents with enhanced ionic relaxivities. Different engineering strategies and nanoparticle platforms will be compared in terms of their manufacturability, biocompatibility properties, and their overall potential to make an impact in clinical MR imaging.

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“…Various groups have explored dendrimers [14], liposomes [15, 16], protein cages [17, 18], and gold nanoparticles [19] as potential platforms for conjugation of small-molecule contrast agents. Virus-like particles (VLPs) derived from virus particles but devoid of their nucleic acid have an advantage over other systems because of their large macromolecular size and control over assembly, which allows high loading density of desired cargo molecules.…”

Section: Introductionmentioning

confidence: 99%

Manganese(III) porphyrins complexed with P22 virus-like particles as T 1-enhanced contrast agents for magnetic resonance imaging

et al. 2013

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Virus-like particles are powerful platforms for the development of functional hybrid materials. Here, we have grown a cross-linked polymer (cross-linked aminoethyl methacrylate) within the confines of the bacteriophage P22 capsid (P22-xAEMA) and functionalized the polymer with various loadings of paramagnetic manganese(III) protoporphyrin IX (MnPP) complexes for evaluation as a macromolecular magnetic resonance imaging contrast agent. The resulting construct (P22-xAEMA-MnPP) has r1,particle = 7,098 mM−1 s−1 at 298 K and 2.1 T (90 MHz) for a loading of 3,646 MnPP molecules per capsid. The Solomon-Bloembergen-Morgan theory for paramagnetic relaxivity predicts conjugating MnPP to P22, a supramolecular structure, would result in an enhancement in ionic relaxivity; however, all loadings experienced low ionic relaxivities, r1,ionic, ranging from 1.45 to 3.66 mM−1 s−1, similar to the ionic relaxivity of free MnPP. We hypothesize that intermolecular interactions between neighboring MnPP molecules block access of water to the metal site, resulting in low r1,ionic relaxivities. We investigated the effect of MnPP interactions on relaxivity further by either blocking or exposing water binding sites on MnPP. On the basis of these results, future design strategies for enhanced r1,ionic relaxivity are suggested. The measured r2,ionic relaxivities demonstrated an inverse relationship between loading and relaxivity. This results in a loading-dependent r2/r1 behavior of these materials indicating synthetic control over the relaxivity properties, making them interesting alternatives to current magnetic resonance imaging contrast agents.

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Gold nanoparticles functionalised with stable, fast water exchanging Gd3+ chelates as high relaxivity contrast agents for MRI

Cited by 58 publications

References 27 publications

Coupling Fast Water Exchange to Slow Molecular Tumbling in Gd³⁺ Chelates: Why Faster Is Not Always Better

Coupling Fast Water Exchange to Slow Molecular Tumbling in Gd³⁺ Chelates: Why Faster Is Not Always Better

Engineering Gd-loaded nanoparticles to enhance MRI sensitivity viaT₁shortening

Manganese(III) porphyrins complexed with P22 virus-like particles as T 1-enhanced contrast agents for magnetic resonance imaging

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Gold nanoparticles functionalised with stable, fast water exchanging Gd3+ chelates as high relaxivity contrast agents for MRI

Cited by 58 publications

References 27 publications

Coupling Fast Water Exchange to Slow Molecular Tumbling in Gd3+ Chelates: Why Faster Is Not Always Better

Coupling Fast Water Exchange to Slow Molecular Tumbling in Gd3+ Chelates: Why Faster Is Not Always Better

Engineering Gd-loaded nanoparticles to enhance MRI sensitivity viaT1shortening

Manganese(III) porphyrins complexed with P22 virus-like particles as T 1-enhanced contrast agents for magnetic resonance imaging

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Coupling Fast Water Exchange to Slow Molecular Tumbling in Gd³⁺ Chelates: Why Faster Is Not Always Better

Coupling Fast Water Exchange to Slow Molecular Tumbling in Gd³⁺ Chelates: Why Faster Is Not Always Better

Engineering Gd-loaded nanoparticles to enhance MRI sensitivity viaT₁shortening