In vivo MRI multicontrast kinetic analysis of the uptake and intracellular trafficking of paramagnetically labeled liposomes.
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.
Department of Chemistry IFM, and Molecular Imaging Center, University of Torino, Via Nizza 52, 10126 Torino, Italy.
Daniela
D
Delli Castelli
Walter
W
Dastrù
Enzo
E
Terreno
Evelina
E
Cittadino
Francesco
F
Mainini
Elena
E
Torres
Michela
M
Spadaro
Silvio
S
Aime
D000818:Animals; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000493:pharmacokinetics*; D005260:Female; D005682:Gadolinium; D006571:Heterocyclic Compounds / Q000493:pharmacokinetics; D008081:Liposomes / Q000493:pharmacokinetics*; D008279:Magnetic Resonance Imaging; D008280:Magnetics; D008546:Melanoma, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage; D009368:Neoplasm Transplantation; D009942:Organometallic Compounds / Q000493:pharmacokinetics; D013194:Staining and Labeling
D003287:Contrast Media; D006571:Heterocyclic Compounds; D008081:Liposomes; D009942:Organometallic Compounds; C550981:thulium(III) 1,4,7,10-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate; C062402:gadoteridol; D005682:Gadolinium