Generation of superparamagnetic liposomes revealed as highly efficient MRI contrast agents for in vivo imaging.
Maghemite (gamma-Fe2O3) nanocrystals stable at neutral pH and in isotonic aqueous media were synthesized and encapsulated within large unilamellar vesicles of egg phosphatidylcholine (EPC) and distearoyl-SN-glycero-3-phosphoethanolamine-N-[methoxy(poly(ethylene glycol))-2000] (DSPE-PEG(2000), 5 mol %), formed by film hydration coupled with sequential extrusion. The nonentrapped particles were removed by flash gel exclusion chromatography. The magnetic-fluid-loaded liposomes (MFLs) were homogeneous in size (195 +/- 33 hydrodynamic diameters from quasi-elastic light scattering). Iron loading was varied from 35 up to 167 Fe(III)/lipid mol %. Physical and superparamagnetic characteristics of the iron oxide particles were preserved after liposome encapsulation as shown by cryogenic transmission electron microscopy and magnetization curve recording. In biological media, MFLs were highly stable and avoided ferrofluid flocculation while being nontoxic toward the J774 macrophage cell line. Moreover, steric stabilization ensured by PEG-surface-grafting significantly reduced liposome association with the macrophages. The ratios of the transversal (r2) and longitudinal (r1) magnetic resonance (MR) relaxivities of water protons in MFL dispersions (6 < r2/r1 < 18) ranked them among the best T2 contrast agents, the higher iron loading the better the T2 contrast enhancement. Magnetophoresis demonstrated the possible guidance of MFLs by applying a magnetic field gradient. Mouse MR imaging assessed MFLs efficiency as contrast agents in vivo: MR angiography performed 24 h after intravenous injection of the contrast agent provided the first direct evidence of the stealthiness of PEG-ylated magnetic-fluid-loaded liposomes.
Martina
Marie-Sophie
MS
Laboratoire de Physico-Chimie des Systèmes Polyphasés, UMR CNRS 8612, Université Paris-Sud, Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, F-92296 Châtenay-Malabry Cedex, France.
Fortin
Jean-Paul
JP
Ménager
Christine
C
Clément
Olivier
O
Barratt
Gillian
G
Grabielle-Madelmont
Cécile
C
Gazeau
Florence
F
Cabuil
Valérie
V
Lesieur
Sylviane
S
D000818:Animals; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry*; D004355:Drug Stability; D052203:Ferrosoferric Oxide; D007501:Iron / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry*; D008264:Macrophages; D018810:Magnetic Resonance Angiography / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008280:Magnetics; D051379:Mice; D049329:Nanostructures / Q000737:chemistry*; D010087:Oxides / Q000737:chemistry*; D010713:Phosphatidylcholines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry
D003287:Contrast Media; D008081:Liposomes; D010087:Oxides; D010713:Phosphatidylcholines; D011092:Polyethylene Glycols; D007501:Iron; D052203:Ferrosoferric Oxide