n-(1-(2-3-dioleyloxy)propyl)-n-n-n-trimethylammonium-chloride and Fibrosarcoma

To explore the feasibility of tracking thulium (Tm)-1,4,7,10-tetraazacyclododecane-α,α',α'',α'''-tetramethyl-1,4,7,10-tetraacetic acid (DOTMA)-labeled cells in vivo by means of highly shifted proton magnetic resonance (MR) imaging as a potential alternative to established cell-tracking methods.. All animal experiments were approved by the local ethics committee for animal experiments. Highly shifted proton MR imaging is based on the principle that the shifted resonances on Tm and dysprosium (Dy)-DOTMA can be detected separately from the tissue water signal at MR imaging with very short echo time and radial center-out readout (UTE, or "ultrashort echo time"). MR imaging of aqueous solutions and in mice in vivo was performed at 9.4 T. Human fibrosarcoma cells (HT-1080) and murine macrophages were labeled with different amounts of Tm-DOTMA. Labeled fibrosarcoma cells were injected subcutaneously into three mice. For cell tracking, labeled macrophages were administered intravenously into eight mice bearing local granulomatous inflammation. Three-dimensional UTE MR imaging was performed during 1 week. Macrophage viability and activity and fibrosarcoma cell viability were statistically analyzed by performing an unpaired two-tailed t test for labeled versus unlabeled cells by using data of at least six independent experiments.. The strongly shifted MR lines of Tm- and Dy-DOTMA can be separated from the tissue water signal and from each other. A detection limit of about 25 µmol/L of Tm-DOTMA was calculated from in vitro MR measurements. A mean ± standard error of the mean intracellular uptake of (4.19 ± 0.88) × 10(9) (HT-1080) and (10.1 ± 3.0) × 10(10) (macrophages) of Tm-DOTMA molecules per cell was achieved. In vivo, Tm-DOTMA signal was detectable for 1 week in both tumors and macrophages, with a detection limit of approximately 10(4) HT-1080 and 600 macrophages. Histologic examination results and elemental bioimaging confirmed labeled cells as source of MR signal.. Strongly shifted proton three-dimensional UTE MR imaging of Tm-DOTMA-labeled cells is a highly specific and sensitive tool for in vivo cell tracking.

Topics: Animals; Cell Line, Tumor; Cell Tracking; Contrast Media; Female; Fibrosarcoma; Granuloma; Humans; Image Enhancement; Macrophages; Magnetic Resonance Imaging; Mice; Mice, Nude; Protons; Quaternary Ammonium Compounds; Reproducibility of Results; Sensitivity and Specificity

Summary A "hot spot" magnetic resonance (MR) imaging cell tracking technique has been developed that allows direct detection of dysprosium- or thulium-1,4,7,10-tetraazacyclododecane-α,α',α'',α'''-tetramethyl-1,4,7,10-tetraacetic acid (DOTMA)-labeled protons inside cells. These highly shifted protons may allow specific detection of multiple cell types because it does not rely on acquiring the proton signal from bulk water.

Topics: Animals; Cell Tracking; Female; Fibrosarcoma; Granuloma; Humans; Image Enhancement; Macrophages; Magnetic Resonance Imaging; Quaternary Ammonium Compounds

Noninvasive techniques to monitor temperature have numerous useful biomedical applications. However, MR thermometry techniques based on the chemical shift, relaxation rates, and molecular diffusion rate of the water 1H signal suffer from poor thermal resolution. The feasibility of MR thermometry based on the strong temperature dependence of the hyperfine-shifted 1H signal from the paramagnetic lanthanide complex thulium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (TmDOTA-) was recently demonstrated. The use of paramagnetic lanthanide complexes for MR thermometry can be further enhanced by improving the signal-to-noise ratio (SNR) of the observed signal. In this study, the use of lanthanide complexes of a methyl-substituted analog of DOTA4-, 1,4,7,10-tetramethyl 1,4,7,10-tetra azacyclodoecane-1,4,7,10-tetraacetic acetate (DOTMA4-) was evaluated. DOTMA4- complexes have 12 magnetically equivalent methyl protons, which provide an intense and sharper resonance compared to the corresponding DOTA- complexes. Experiments with paramagnetic Pr3+, Yb3+, Tb3+, Dy3+, and Tm3+ complexes of DOTMA4- showed that the Tm3+ complex is most favorable for MR thermometery because of the high temperature dependence of its chemical shift and its relatively narrow linewidth. The chemical shift of the methyl 1H signal from TmDOTMA- was approximately 60 times more sensitive to temperature than the water 1H shift and was insensitive to changes in concentration, pH, [Ca2+], or the presence of other ions and macromolecules. The application of TmDOTMA- for measuring temperature in a subcutaneously implanted tumor model was demonstrated. Lastly, the feasibility of obtaining 3D images from the methyl 1H resonance of TmDOTMA- was demonstrated in phantom and live animal experiments. Overall, TmDOTMA- appears to be a promising probe for MR thermometry in vivo.

Topics: Algorithms; Animals; Cell Line, Tumor; Feasibility Studies; Fibrosarcoma; Image Interpretation, Computer-Assisted; Lanthanoid Series Elements; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Magnetics; Mice; Mice, Inbred C3H; Phantoms, Imaging; Protons; Quaternary Ammonium Compounds; Rats; Rats, Inbred F344; Reproducibility of Results; Sensitivity and Specificity; Thermography