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This work aims at developing a MRI method that allows to get more insight into the understanding of the in vivo fate of liposomes and their payload. The method relies on the temporal assessment of the contrast changes induced by the presence of a classical relaxation agent versus the effect induced by a CEST (chemical exchange saturation transfer) agent. Liposomes were loaded with the paramagnetic complexes, Gd-HPDO3A and [Tm-DOTMA](-) [Na](+), in order to endow the nanovesicles with the characteristic properties of T(1)/T(2) and CEST/T(2) MRI agents, respectively. The paramagnetically loaded liposomes were injected directly into the tumor (B16 melanoma xenograft in mice) where they generate T(1), T(2), and CEST MR contrasts that were quantitatively monitored over time (0-48h). The kinetic of each contrast enhancement reports about peculiar properties relative to the fate of the liposomes in the tumor environment. A kinetic model has been set-up to fit the experimental multicontrast data in order to extract the relevant information about the cellular uptake of the liposomes and the release of their payload. Upon comparing conventional stealth liposomes with pH-sensitive ones, it has been shown that the latter ones differ essentially in the step associated with the release of the drug that is likely occurring in the endosomal acidic vesicles., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

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. [ABSTRACT FROM AUTHOR]

Abstract: The design of long circulating liposomes co-loaded with the glucocorticoid prednisolone phosphate (PLP) and the amphiphilic paramagnetic contrast agent Gd-DOTAMA(C18)2 allowed the MRI-guided in vivo visualization of the delivery and biodistribution of PLP, as well as the monitoring of drug efficacy. The performance of this theranostic probe was investigated in a mouse model bearing a melanoma B16 syngeneic tumor. The release kinetics of the drug were evaluated in vitro where it displayed a peculiar behavior characterized by a fast process (completed in few hours) involving only a small portion (<5%) of the drug. Interestingly, the incorporation of the amphiphilic imaging reporter in the liposomal bilayer slightly increased the amount of the fast-release portion (<10%), thus suggesting that it could be attributed to a drug fraction embedded in the liposomal bilayer. In fact, the release of a hydrophilic imaging probe encapsulated in the inner core of the same long circulating liposomes formulated for carrying the drug, displayed different, single-step, kinetics. The in vivo monitoring of the antitumor activity of the nanomedicine revealed that the incorporation of the MRI probe into the liposome bilayer did not significantly affect the drug efficacy. The in vivo experiments also indicated a relevant and fast liposome uptake from macrophage-rich organs like spleen and liver, which reduced the tumor accumulation of the liposomes. The accumulation of the amphipatic MRI label caused the occurrence of a long-term residual T1 contrast still detectable 1week after injection. [Copyright &y& Elsevier]