Mn(II)-Based Lipidic Nanovesicles as High-Efficiency MRI Probes

Although nowadays there is a renewed and growing interest in Mn-based contrast agents, there are only few studies dealing with Mn-based lipophilic nanoparticles and how they may be optimized as MRI contrast agents. Three amphiphilic paramagnetic Mn(II) complexes based on derivatives of EDTA and 1,4-DO2A were used for the preparation of lipidic nanoparticles. The length and position of the aliphatic chains were found to control whether either vesicular liposomes, nonvesicular bicelles, or a mixture of both was produced as well as the size and morphology of phospholipid-based self-assembling nanoaggregates. These differences determine whether hydrophilic Gd-based contrast agents or fluorescent dyes can be entrapped in the aqueous core of the nanoaggregate. Structural characterization was performed by cryo-TEM. Detailed ¹H NMR relaxometric analyses were carried out on all systems. The effect of entrapping gadoteridol in the aqueous core (where present) was studied by preparing diamagnetic amphiphilic Zn(II) analogues. In the case of homogeneous systems, the data were also fitted to obtain the relaxometric parameters for comparison with literature data. The results of these studies demonstrate enhanced relaxivity of the nanoaggregates with respect to monomeric analogues. This work allowed us to understand how to control the formation of different types of nanovesicles (liposomes, bicelles, and micelles), optimize their MRI contrast, and provide different in vivo biodistribution characteristics.