Large Relaxivity Enhancement of Paramagnetic Lipid Nanoparticles by Restricting the Local Motions of the Gd^III Chelates

Abstract

A Gd(III)-DOTA-like complex bearing two aliphatic chains on adjacent acetic arms was designed, synthesized, and compared with its analogous monofunctionalized complex. A 1/T(1) NMR relaxometric study of the two amphiphilic complexes incorporated into micelles and liposomes showed an unprecedented relaxivity enhancement for the complex with two lipophilic side arms. This remarkable result, which is attributed to a favorable water exchange rate and increased rigidity of the system resulting from limiting of the local motion of the gadolinium center, represents an important advance in the development of highly efficient nanosystems for MRI applications.

GdDOTAGA(C18)2: an efficient amphiphilic Gd(iii) chelate for the preparation of self-assembled high relaxivity MRI nanoprobes

“…We have recently addressed the problem of the simultaneous optimization of k ex and τ RL using a GdDOTA-like complex (GdDOTA(GAC 12 ) 2 ) functionalized with two hydrophobic chains on adjacent pendant arms that serve to rigidify the incorporated chelate. 20 The high relaxivity found in liposomes loaded with this complex was also confirmed in vivo at 1 T on a melanoma tumour model in mice. 21 Remarkably, the Gd-probe is rapidly cleared from the organs due to the presence of the two dodecyl chains.…”

“…Assuming that the τ M value of the incorporated GdDOTAGA(C 18 ) 2 is identical to that reported for the water soluble precursor GdDOTAGA, 20 [a] The parameters for electronic relaxation were used as empirical fitting parameters and have no real physical meaning for nanosized systems. Hence, the data at magnetic field < 3 MHz, which are the most affected by electronic relaxation, were not included in data analysis, in accordance with a wellestablished approach.…”

Innovative Design of Ca-Sensitive Paramagnetic Liposomes Results in an Unprecedented Increase in Longitudinal Relaxivity

“…However, the r 1 values measured for both the formulations were lower than the relaxivities typically displayed by liposomes incorporated with macrocyclic Gd(III) complexes (>10 s −1 mM −1 ). 23,24 This observation is not surprising because a deep structural investigation performed on a very close analogue of L outlined that this class of Gd-based SCA displays the isomerism commonly observed for macrocyclic lanthanide complexes, for which the coordination cage adopts two interconverting conformations based on square-or twisted-square antiprismatic structures (SAP and TSAP, respectively). 21,25 The peculiarity of this class of Ca-sensing SCAs is that the Gd(III) ion in the SAP isomer is fully coordinated by the ligand with seven donor atoms from the DO3A cage plus two donor groups (one amide and one carboxylate) from the EGTA-like cage.…”

In Vivo Magnetic Resonance Imaging Detection of Paramagnetic Liposomes Loaded with Amphiphilic Gadolinium(III) Complexes: Impact of Molecular Structure on Relaxivity and Excretion Efficiency

“…[3,5] We can distinguish: 1) a region of constant relaxivity at low fields ( % 0.01-0.5 MHz); 2) a dispersion around 1-3 MHz; 3) a peak centred about 20-30 MHz; and 4) a steep decrease of r 1 at higher fields. However, although for LIPO-GdDOTAMA(C 18 ) 2 the r 1 peak (r 1 [14] and approximately 20 mm À1 s…”

“…From this perspective, a reduced rotational flexibility is expected for GdDOTA(GAC 12 ) 2 in which the two aliphatic chains are positioned on two adjacent acetic arms, therefore achieving the so-called multisite attachment. [14,16] For a more accurate and quantitative interpretation aimed at identifying in detail the reasons for the different relaxivity of the two systems, we need to analyse the observed NMRD profiles in terms of the paramagnetic relaxation theory. Typically, the data are fitted by using the equations for the inner (IS) and outer hydration sphere (OS) contributions to relaxivity.…”