From polyamines to nanogels: a supramolecular approach for boosting relaxivity of [Gd(DOTP)]⁵

Supramolecular chemistry has played a central role in advancing the development of more effective contrast agents (CAs) for magnetic resonance imaging (MRI). By incorporating Gd(III) complexes into larger supramolecular architectures, host-guest interactions can be exploited to enhance both performance and targeting. Optimizing these interactions has the potential to substantially increase relaxivity (r₁), thereby improving MRI signal enhancement and enabling lower administered doses without compromising image quality. In this work, we investigated the formation of ion pairs between the anionic complex [Gd(DOTP)]^5-, which lacks an inner-sphere water molecule, and cationic polyamine substrates such as cyclen, octaazacryptand, and low-molecular-weight polyethyleneimine. Our approach combines ¹H NMR relaxometric techniques with DFT calculations. Relaxometric titrations of dilute [Gd(DOTP)]^5- solutions with increasing amounts of the cationic substrates allow determination of the ion-pair binding constants as well as the relaxivity of the resulting supramolecular adducts. The strength of these interactions increases with the number of positive charges on the polyamine and depends strongly on pH, reflecting the optimal balance of charges between anion and cation. A further and remarkable enhancement in relaxivity is observed when the metal complex is confined within nanogels. Analysis of the corresponding NMRD (Nuclear Magnetic Relaxation Dispersion) profiles highlights the essential contribution of well-organized second-sphere water molecules with restricted mobility, which are responsible for the unusually high relaxivity values at magnetic fields relevant for MRI.