Insights into the use of paramagnetic Gd(III) complexes in MR‐molecular imaging investigations

Abstract

Can gadolinium III [Gd(III)] complexes be considered good candidates for magnetic resonance (MR)-molecular imaging studies? In this review article, we examine the principal issues that are the basis of successful use of Gd-based protocols in molecular imaging applications. High relaxivity is the primary requisite. Therefore, the design of such paramagnetic probes has to be pursued keeping in mind the relationships between structure, dynamics, and the relevant parameters involved in paramagnetic relaxation processes. Moreover, the limited number of target molecules on cellular membranes makes it necessary to define strategies aimed at delivering many Gd-containing moieties to the sites of interest. Examples are reported for the attainment of very high relaxivities for the design of new routes for pursuing the accumulation of small sized Gd(III) complexes at the targeting sites. An efficient cellular uptake of Gd-containing probes is the key step for attaining the visualization of targeted cells by MR imaging, and selected examples are reported. In this context, the problem of the assessment of the minimum amount of Gd(III) complexes necessary for the MR imaging-visualization of cells has been addressed by reporting the authors' observations on the cell-internalization of Gd(III) complexes. A particularly efficient delivery system is represented by Gd-loaded apoferritin, which allows the MR visualization of hepatocytes when the number of Gd-complexes per cell is 4 Ϯ 1 ϫ 10 7 . Finally, the potential of responsive systems is considered by outlining the exploitation of the amplification effect brought about by the action of a specific enzymatic activity on the relaxivity of a suitably functionalized Gd(III) complex. IT IS NOW WELL ESTABLISHED that magnetic resonance imaging (MRI) is the pre-eminent methodology among the various diagnostic modalities currently available, as it offers a powerful way to map structure and function in soft tissues by sampling the amount, flow, and environment of water protons in vivo. The intrinsic contrast can be augmented by the use of contrast agents (CA) in both clinical and experimental settings. Thus, the use of CA adds highly relevant physiological information to the superb anatomical resolution obtained in MR images. Most of the work with CAs has dealt with the use of gadolinium (III) [Gd(III)] complexes, because this metal ion couples a large magnetic moment with a long electron spin relaxation time.The new scenery of molecular imaging applications requires the development of a novel class of CAs characterized by a higher contrasting ability and improved targeting capabilities (1). In this survey, we intend to tackle some basic issues that are of fundamental importance for the use of Gd(III)-based systems in molecular imaging applications, namely: 1) actual understanding of the determinants of T 1 -relaxivity of Gd(III) complexes, and how to proceed to attain very high relaxivities; 2) how one may envisage efficient routes for the delivery of a high number of Gd(III) complexes a...

Development of Contrast Agents Targeted to Macrophage Scavenger Receptors for MRI of Vascular Inflammation

“…(52)(53)(54)(55)(56) There are number of examples in the literature of efficient cellular uptake of Gd(III) complexes using Gd-DOTA derived molecules (57)(58)(59)(60). More recent efforts have sought to maximize the load of Gd delivered per receptor by tethering carrier molecules to dendridic polymers containing high numbers of Gd(III)(61), uptake through the folate receptor has been demonstrated by this means as has avidin-biotin antibody-based targeting (59,62,63). Again, definitive measurement of the amount of Gd required to produce contrast depends upon the imaging parameters employed and these must also be evaluated when testing the new contrast agents.…”

Discrepancies between the fate of myoblast xenograft in mouse leg muscle and NMR label persistency after loading with Gd-DTPA or SPIOs

“…20,23,24 Grafted on Matrigel structures and subcutaneously implanted, endothelial progenitor cells labeled with Gd-HPDO3A were identified as hyperintensities 14 days after injection. 20 Plugged in mouse kidney, they were visible 24 h after injection.…”

Cellular labeling with Gd(III) chelates: only high thermodynamic stabilities prevent the cells acting as ‘sponges’ of Gd3+ ions

“…In vivo MRI tracking of labeled cells is currently a topic of huge interest (1,2). In most cases the label is represented by iron-oxide based agents that enable the visualization of the labeled cells as dark spots in the MR images as a consequence of the largely dominant T 2 Ã effects induced by the presence of the magnetic particles (3)(4)(5)(6).…”

“…By this process the cells internalize solutes that are dissolved in the extracellular medium together with molecules that are bound to the external membrane surface (10). In order to internalize a number of Gd(III) chelates sufficient for MRI visualization [of the order of 10 7 -10 8 gadolinium per cell (2)], the cells have to be incubated for several hours (6-12 h) in media that have been added to the Gd(III) chelate at relatively high concentration (typically 15-25 mM). The commercially available Gd-HPDO3A (ProHance 1 ) has been proven to be a particularly suitable agent as it is neutral, highly hydrophilic and very well tolerated by the cellular machinery (7).…”