Relaxivity enhancement in macromolecular and nanosized Gd ^III-based MRI contrast agents

In recent years, novel, better, and more complex systems have been developed in which Gd^III chelates are attached to macromolecular substrates or incorporated into nanoparticles. These magnetic resonance imaging (MRI) nanoprobes make it possible to deliver to the site of interest a large number of Gd³⁺ ions, thus increasing the sensitivity of the technique. In this paper, we review the most important systems developed, the conjugation methods, and the procedures devised to optimize the relaxivity. These involve the use of Gd^III complexes with higher hydration number, the control of the rate of exchange of the bound water molecule(s), and the reduction of the local rotational motions of the conjugated complexes. The increase in relaxivity of the individual Gd chelates leads to significant relaxivity enhancement of the nanosized systems. The development of more effective nanosystems for magnetic resonance imaging (MRI) applications, ranging from protein-based to silica nanoparticles, has scarcely been combined with an attempt at enhancing the relaxivity of the individual Gd chelate. Optimization of the physicochemical properties of the chelate and its conjugation mode enables large increases in relaxivity.