The use of dendritic structures to incorporate an increasing number of Gd-chelates at the periphery for enhancing the relaxivity (r1) has been largely explored in the last two decades. This is because dendrimeric scaffolds offer favourable properties such as extremely low polydispersity, well-defined size and shape characteristics, non-toxicity and ease of chemical modification.
Monomeric and dimeric AAZTA-based bifunctional chelators (AAZTA = 6-amino-6-methylperhydro-1,4-diazepine tetraacetic acid) were attached to different generations (G0, G1 and G2) of ethylenediamine-cored PAMAM dendrimers (PAMAM = polyamidoamine) to obtain a series of six dendrimeric systems with 4 to 32 chelates at the periphery. These GdIII-loaded dendrimers have molecular weight ranging from 3.5 to 25 kDa, thus allowing a systematic investigation on the changes in relaxivity with the variation of the rotational dynamics following the increase in molecular size. Variable-temperature 17O NMR (the dimeric building block Gd2L2) and 1H Nuclear Magnetic Relaxation Dispersion (Fast Field Cycling NMR relaxometry) measurements at different temperatures indicate that the water exchange lifetime (tM ~ 90 ns) of the two inner sphere water molecules does not represent a limiting factor to r1 of the systems. The r1 values at 1.5 T and 298 K increases from 10.2 mM-1 s-1 for the monomer GdL1 to 31.4 mM-1 s-1 for the dendrimer Gd32G2-32 (+ 308%). However, the relaxivity (per Gd) does not show a linear dependence on the molecular mass, but rather the enhancement tends to attenuate markedly for larger systems. This effect is attributed to the growing decrease in correlation between local rotational motions and global molecular tumbling.
These experimental results confirm the published theoretical predictions and simulations. With the increase of the magnetic field, r1 no longer scales with tR and relatively simple systems (dimer-tetramers) afford optimal results, provided they are compact and characterized by predominantly isotropic rotation motion.