Environmentally responsive MRI contrast agents

Abstract

Biomedical imaging techniques can provide a vast amount of anatomical information, enabling diagnosis and the monitoring of disease and treatment profile. MRI uniquely offers convenient, non-invasive, high resolution tomographic imaging. A considerable amount of effort has been invested, across several decades, in the design of non toxic paramagnetic contrast agents capable of enhancing positive MRI signal contrast. Recently, focus has shifted towards the development of agents capable of specifically reporting on their local biochemical environment, where a switch in image contrast is triggered by a specific stimulus/biochemical variable. Such an ability would not only strengthen diagnosis but also provide unique disease-specific biochemical insight. This feature article focuses on recent progress in the development of MRI contrast switching with molecular, macromolecular and nanoparticle-based agents.

Fig. 1

Schematic representation of inner, second and outer sphere water interaction with a typical T₁ contrast agent, a Gd–DOTA chelate.

Fig. 2

Schematic representation of Egad MRI contrast agent; galactopyranose groups (red) are removed via β-galactosidase cleavage, resulting in an irreversible transition from a weak to a strong relaxivity state, reproduced with permission from ref. . Copyright 1997 Wiley-VCH Verlag GmbH & Co. KGaA.

Fig. 3

Illustration of the generic association between a Gd³⁺ chelate (brown sphere) and a protein target (purple) resulting in lengthened τ_R and improved MRI contrast.

Fig. 4

A proposed mechanism of MRI relaxivity modulation based on hydration (q) alterations due to pendant acetate coordination in the presence of Zn²⁺ ions, adapted with permission from ref. . Copyright 2008 American Chemical Society.

Fig. 5

Representation of MRI contrast agent species with Cu^+/2+ selectivity, where L is a ligand, such as a thioether-based donor, n = 1, 2; adapted with permission from ref. . Copyright 2009 American Chemical Society.

Fig. 6

Redox-sensitive structural isomerisation of spiropyran–merocyaninetethered GdDOTA, adapted with permission from ref. . Copyright 2009 Wiley-VCH Verlag GmbH & Co. KGaA.

Fig. 7

The relaxivity of a nanoparticulate MRI probe (blue sphere) with conjugated Gd³⁺-complexes (brown spheres) is determined by the local rotational time of the complex around the linker (τ_RL), the global rotational motion (τ_RG), and the coordinated water exchange rate (k_ex = 1/τ_m). Adapted with permission from ref. . Copyright 2012 Wiley-VCH Verlag GmbH & Co. KGaA.

Fig. 8

Schematic representation of local and global mobility processes relevant to Gd³⁺-chelates (brown spheres) in (a) cross-linked polymeric nanoparticles, (b) dendrites, (c) enosomes, and (d) memsomes with τ_RG and τ_RL representing global and local rotational correlation times, respectively. Paramagnetic chelates are covalently bound in (a) and (b); for the paramagnetic chelates encapsulated (in (c) and (d)) in the membrane or aqueous phase of a liposome, τ_io denotes water exchange rate between the interior and exterior and τ_Ri the rotational correlation time of the internalised complex.

Fig. 9

The carboxylic groups of anionic polymeric nanoparticulates are progressively deionised when exposed to an acidic environment resulting in polymer shrinking, restricted side chain mobility, and significantly increasing relaxivity. The blue net represents the polymer and brown spheres the Gd³⁺-chelate groups covalently conjugated to polymer side chains. Picture adapted with permission from ref. .

Fig. 10

NMRD profile showing the pH tuned¹H longitudinal relaxivity of LUV loaded with a Gd³⁺–DO3A derivative (1 mM [Gd]) as a function of applied magnetic field. The colour scale bar in the arrow denotes the signal intensities of T₁-weighted images, and the two red bars represent ¹H relaxivities at two different magnetic fields (8.5 MHz and 40 MHz). Adapted with permission from ref. . Copyright 2012 American Chemical Society.

Fig. 11

Schematic summary of the protein gating of MSNs. Externally biotinylated Gd–DOTA MSNs enjoy good water accessibility and a high relaxivity that can be reversibly capped by the steric bulk of bound streptavidin. In the presence of low μM of biotinylated BSA, the gating protein is competed off the particle surface and relaxivity recovers. Adapted from ref. with permission from The Royal Society of Chemistry.