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WIREs Nanomed Nanobiotechnol
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Magnetoliposomes as magnetic resonance imaging contrast agents

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Abstract Among the wide variety in iron oxide nanoparticles which are routinely used as magnetic resonance imaging (MRI) contrast agents, magnetoliposomes (MLs) take up a special place. In the present work, the two main types (large and small MLs) are defined and their specific features are commented. For both types of MLs, the flexibility of the lipid coating allows for efficient functionalization, enabling bimodal imaging (e.g., MRI and fluorescence) or the use of MLs as theranostics. These features are especially true for large MLs, where several magnetite cores are encapsulated within a single large liposome, which were found to be highly efficient theranostic agents. By carefully fine‐tuning the number of magnetite cores and attaching Gd3+‐complexes onto the liposomal surface, the large MLs can be efficiently optimized for dynamic MRI. A special type of MLs, biogenic MLs, can also be efficiently used in this regard, with potential applications in cancer treatment and imaging. Small MLs, where the lipid bilayer is immediately attached onto a solid magnetite core, give a very high r2/r1 ratio. The flexibility of the lipid bilayer allows the incorporation of poly(ethylene glycol)–lipid conjugates to increase blood circulation times and be used as bone marrow contrast agents. Cationic lipids can also be incorporated, leading to high cell uptake and associated strong contrast generation in MRI of implanted cells. Unique for these small MLs is the high resistance the particles exhibit against intracellular degradation compared with dextran‐ or citrate‐coated particles. Additionally, intracellular clustering of the iron oxide cores enhances negative contrast generation and enables longer tracking of labeled cells in time. WIREs Nanomed Nanobiotechnol 2011 3 197–211 DOI: 10.1002/wnan.122 This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > In Vivo Nanodiagnostics and Imaging

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Coronal FSE 3000/45 millisecond images before (a, c) and 1 h after (b, d) injection of polyethylene glycolylated small magnetoliposomes (MLs), obtained in 6–8‐week‐old rats. Arrows outline bone marrow uptake. (Reprinted with permission from Ref 66. Copyright 1999 Wiley‐Liss.)

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Morphological characterization of Dictyostelium discoideum‐released vesicles. (a) Electron microscopy image of vesicles secreted by D. discoideum cells and collected on a magnetic column. (b) Apparent size distribution of collected magnetic vesicles. Mean diameter is 380 ± 120 nm. (Reprinted with permission from Ref 58. Copyright 2008 Wiley‐VCH.)

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(a–f) Electron micrographs of crystal morphologies and intracellular organization of magnetosomes found in various magnetotactic bacteria. Shapes of magnetic crystals include cubo‐octahedral (a), elongated hexagonal prismatic (b, d–f), and bullet‐shaped morphologies (c). The particles are arranged in one (a–c), two (e), or multiple chains (d) or irregularly (f). Bar equivalent to 100 nm. (Reprinted with permission from Ref 53. Copyright 1999 Springer‐Verlag.)

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Confocal microscopy images of PC3 cells incubated with polyethylene glycolylated rhodamine‐labeled large magnetoliposomes (MLs) (400 nmol of total lipids per 106 cells; [lipids] = 0.4 mM) in the presence of a 0.4 T magnet attached under the coverslip. Magnetic influence domain (a). Cell cytoplasmic membrane labeled by fluorescent linker FITC‐PKH67 was seen in green while rhodamine‐MLs are seen in red. Images viewed from the top cell surface (921 × 921 µm) of rhodamine fluorescence (b), FITC fluorescence (c), and superimposition of both (d). White bar represents 230 µm. (Reprinted with permission from Ref 38. Copyright 2008 Elsevier.)

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(a) Transmission electron micrograph of small (cationic) magnetoliposomes (MLs) showing the phospholipid bilayer (visualized by negative staining using 2% uranylacetate) surrounding the electron dense iron oxide cores. (b) Cryo‐electron micrograph of a large (cationic) ML showing dispersed nanosized, citrate‐coated iron oxide cores within a unilamellar liposome. Scale bars: 50 nm. (Reprinted with permission from Ref 27. Copyright 2009 Elsevier.)

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Clustering of magnetoliposomes. (a–e) Effect of PLA2 activity on MLs as indicated by (a) a decrease in pH of PLA2‐treated samples (gray) compared with control samples (black). (b) The ratio of phosphate over magnetite for PLA2‐treated samples (gray) and control samples (black). (c) Hydrodynamic diameters of PLA2‐treated samples (gray) and control samples (black). (d) Optical micrograph of control particles and PLA2‐treated particles upon exposure to a 1‐T magnetic field for 30 min. (e) T2* relaxation times for PLA2‐treated samples (gray) and control samples (black) indicating the enhanced effect of induced clustering of the MLs on MR contrast generation. All data are expressed as mean ± standard deviation (n = 3). When appropriate, the degree of significance is indicated (*P < 0.05; **P < 0.01; ***P < 0.001). (f) Representative optical micrographs of C17.2 NPCs labeled with Endorem (top row) or MLs (bottom row) during 24 h, finally reaching similar average intracellular iron content. Media were removed and cells were kept in culture for the duration indicated. Cells were stained for iron oxide using DAB‐enhanced Prussian Blue reagent and imaged 24 h (left column), 1 week (middle column), and 2 weeks (right column) post‐nanoparticle incubation. Scale bars: 75 µm. The inset is an enlarged view of a single cell displayed in the main image. (Reprinted with permission from Ref 72. Copyright 2010 Wiley‐VCH.)

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pH effect on particle degradation and magnetic resonance (MR) signal intensities. (a–c) The amount of free ferric iron as a function of time for the four NPs (MLs, Endorem, VSOP, and Resovist) incubated at 200 µg Fe/mL in 20 mM sodium citrate containing cell culture medium at different pH (a: pH 7.0; b: pH 5.5; c: pH 4.5; n = 4). (d–g) Representative T2* maps obtained for the various particles (d: ML; e: Endorem; f: VSOP; g: Resovist) in the above‐described medium at pH 4.5. The samples were collected at different time points after addition of the NPs to the acidic culture medium and are represented clockwise in terms of increasing incubation times, going from (a): pure agar to 12 h; 24 h; 48 h; 72 h; 1 week, and 2 weeks. (h–k) T2* values obtained when calculating the respective T2* maps of the four NPs (h: ML; i: Endorem; j: VSOP; k: Resovist) at pH 7.0, 5.5, and 4.5 as a function of different incubation times. Significant increases of T2* relaxation times of NPs treated at pH 5.5 or pH 4.5 compared with the values obtained at pH 7.0 are indicated (*P < 0.05; **P < 0.01; ***P < 0.001). (Reprinted with permission from Ref 72. Copyright 2010 Wiley‐VCH.)

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Cell uptake and magnetic resonance (MR) contrast generation by magnetoliposomes evaluated. (a) Magnetoliposome uptake by stem cells and MR contrast generation were evaluated and compared to Endorem by incubating mouse mesenchymal stem cells (mMSCs) for 24 h with magnetoliposomes (MLs) or Endorem suspensions at different Fe concentrations (50, 100, 200, and 0 µg Fe/mL as indicated on the figures). One lakh mMSCs were harvested, washed, suspended in 1.5% agarose, and collected in 0.2 mL microcentrifuge tubes, held together in a plastic container containing 1.5% agarose. Three‐dimensional T2*‐weighted MR images (panel a, first row; TR/TE/θ = 200 milliseconds/15 milliseconds/27°, 234 µm3 isotropic resolution) and quantitative T2‐maps (6 slices of 0.35 mm, TR = 3000 milliseconds, 16 echoes, TE = 10.098 milliseconds, spatial resolution = 215 µm) were acquired on a Bruker 9.4 T small animal scanner. Relative T2‐values were 0.67 (50 µg Fe/mL), 0.64 (100 µg Fe/mL), and 0.53 (200 µg Fe/mL) for ML‐labeled stem cells, and 0.85 (50 µg Fe/mL) and 0.53 (200 µg Fe/mL) for Endorem‐labeled cells, relative to unlabeled cells (T2 = 1.00). (b) To evaluate in vivo the ML‐mediated MR contrast distribution and contrast generation compared to Endorem, mice (C57Bl/6, n = 2) were stereotactically injected in the striatum with MLs (panel b, first row) or Endorem (panel b, second row) (2.5 µg of total Fe in 3 µL). Representative 3D T2*‐weighted MR images (TR/TE/θ = 100 milliseconds/12 milliseconds/20°) at 1, 3, and 4 weeks post‐injection are shown. After the last time point, mice were sacrificed and processed for histology. The fourth image shows light microscopy photographs of Prussian Blue staining at the vibratome section (50 µm) corresponding to the MR image, visualizing the distribution of Fe(III) around the injection site (scalebars = 1000 µm). The inset shows the site of injection at a higher magnification (scalebar = 200 µm). (c) MLs were evaluated as an MR contrast agent for cell labeling, compared to Endorem. mMSCs were labeled in cell culture with optimized concentrations of MLs (100 µg Fe/mL) and Endorem (250 µg Fe/mL). Subsequently, the labeled stem cells were stereotactically injected in mouse striatum (C57Bl/6, n = 2, 10,000 cells in 3 µL). Mice were MR imaged at 1, 3, and 4 weeks post‐injection with the same scanning parameter set. The first three images show representative 3D T2* MR images of the three consecutive time points. Prussian Blue staining reveals the distribution of Fe(III)‐labeled stem cells.

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