Generation of Superparamagnetic Liposomes Revealed as Highly Efficient MRI Contrast Agents for in Vivo Imaging

• Published in: Journal of the American Chemical Society 2005-08, Vol.127 (30), p.10676-10685
• Main Authors: Martina, Marie-Sophie, Fortin, Jean-Paul, Ménager, Christine, Clément, Olivier, Barratt, Gillian, Grabielle-Madelmont, Cécile, Gazeau, Florence, Cabuil, Valérie, Lesieur, Sylviane
• Format: Article
• Language: English
• Subjects: Animals; Bioengineering; Biological and medical sciences; Biomechanics; Cell Line, Tumor; Chemical Sciences; Condensed Matter; Contrast Media - chemistry; Contrast media. Radiopharmaceuticals; Disperse state. Micelles; Drug Stability; Ferrosoferric Oxide; Fundamental and applied biological sciences. Psychology; Imaging; Inorganic chemistry; Iron - chemistry; Life Sciences; Liposomes - chemistry; Macrophages; Magnetic Resonance Angiography - methods; Magnetic Resonance Imaging - methods; Magnetics; Mechanics; Medical sciences; Mice; Molecular biophysics; Nanostructures - chemistry; Oxides - chemistry; Pharmacology. Drug treatments; Phosphatidylcholines - chemistry; Physico-chemical properties of biomolecules; Physics; Polyethylene Glycols - chemistry; Soft Condensed Matter
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja0516460

Maghemite (γ-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-PEG2000, 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 (r 2) and longitudinal (r 1) magnetic resonance (MR) relaxivities of water protons in MFL dispersions (6 < r 2/r 1 < 18) ranked them among the best T 2 contrast agents, the higher iron loading the better the T 2 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.