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

Abstract

The magnetic resonance imaging (MRI) performance of two liposome formulations incorporating amphiphilic 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA)‐like GdIII complexes has been investigated both in vitro and in vivo. The complexes differ in one donor group of the coordination cage (carboxylate versus carboxoamide), and in the length (C12 versus C18) and the point of attachment of the aliphatic chains to the chelators. The in vitro 1H relaxometric characterisation of the systems, performed with a newly developed relaxation model that takes into account the contributions of the GdIII chelates pointing in‐ and outwards of the liposome, indicates that their efficacy is optimal in the range 0.5–1.5 T. The tetracarboxylic C12‐containing liposomes (LIPO‐GdDOTA(GAC12)2; GA=glutaric acid) are four‐fold more efficient than the monoamide C18‐based analogue (LIPO‐GdDOTAMA(C18)2). Such a difference is also found in vivo at 1 T in a melanoma tumour model on mice. A few hours after intravenous injection, the T1 contrast enhancement in the organs where the nanovesicles typically distribute (liver, spleen, kidneys and tumour) is much higher for LIPO‐GdDOTA(GAC12)2. Interestingly, after about 7 h post‐injection the contrast enhancement observed for the more efficient liposomes decreases rapidly and becomes lower than for LIPO‐GdDOTAMA(C18)2. The relaxometric data and the quantification of the GdIII complexes in the organs, determined ex vivo by inductively coupled plasma mass spectrometry, indicate that: 1) the differences in the contrast enhancement can be attributed to the different rate of water exchange and rotational dynamics of the Gd complexes, and 2) the rapid contrast decrease is caused by a faster clearance of GdDOTA(GAC12)2 from the organs. This is also confirmed by using a newly synthesised amphiphilic cyanine‐based fluorescent probe (Cy5‐(C16)2). As one of the main limitations for the clinical translation of liposomes incorporating amphiphilic imaging agents is related to their very long persistence in the body, the results reported herein suggest that the clearance of the probes can be accelerated, without compromising their role, by a proper selection of the lipophilic portion of the incorporated compound as well as of the ligand site at which the aliphatic tails are linked. Then, GdDOTA(GAC12)2 complex may represent a good candidate for the development of improved MRI protocols based on paramagnetically labelled lipidic nanoparticles.

Paramagnetic Phospholipid-Based Micelles Targeting VCAM-1 Receptors for MRI Visualization of Inflammation

“…[35][36][37] Though the presence of an amidic coordinating group does not guarantee an optimal exchange rate of the water molecule bound to the metal, the thermodynamic and kinetic stabilities of the complex, as well as the efficiency and stability of the loading to lipid-based particles, are very good, thus making this agent an excellent option for the preparation of MRI detectable nanocarriers.…”

Paramagnetic Solid Lipid Nanoparticles as a Novel Platform for the Development of Molecular MRI Probes

“…The former is a GdDOTA-monoamide derivative bearing two C 18 chains that is widely used for the preparation of liposome-or micelle-based MRI probes; [10,13] the latter is a GdDOTA-like complex recently employed in the preparation of high relaxivity lipidic nanoparticles due to a restricted local rotation along the two C 12 aliphatic chains. [14,15] Particle size distribution and surface charge were evaluated by analysis of the hydrodynamic average diameter (zaverage), Polydispersity Index (PdI), and z-potential. The diameter range was also confirmed by direct observation of nanoparticles with transmission electron microscopy (TEM), as shown in Figure 2.…”

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

“…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. Although a rapid excretion of the agent is in many cases favourable, in other applications it is preferable that the complex remains embedded in the nanoparticle for longer times.…”