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R2 and R2* Mapping for Sensing Cell-bound Superparamagnetic Nanoparticles: In Vitro and Murine in Vivo Testing¹

¹ From the Department of Clinical Radiology, University Hospital of Muenster, Albert-Schweitzer-Str 33, D-48129 Muenster, Germany (R.K., L.M., T.P., A.v.W., T.A., W.L.H., C.B.); Philips Research Laboratories, Hamburg, Germany (H.D., T.S.); and Interdisciplinary Center for Clinical Research (IZKF Muenster, FG3), University of Muenster, Muenster, Germany (C.B.). Received August 3, 2006; revision requested October 10; revision received December 18; accepted January 6, 2007; final version accepted March 14. C.B. supported in part by the Deutsche Forschungsgemeinschaft (BR 1653/2-1) and the Bundesministerium für Bildung und Forschung (13N8896). Address correspondence to C.B. (e-mail: bremerc{at}uni-muenster.de).

Purpose: To prospectively determine the cellular iron uptake by using R2 and R2* mapping with multiecho readout gradient-echo and spin-echo sequences.

Materials and Methods: All experiments were approved by the institutional animal care committee. Lung carcinoma cells were lipofected with superparamagnetic iron oxides (SPIOs). Agarose gel phantoms containing (a) 1 x 10⁵ CCL-185 cells per milliliter of agarose gel with increasing SPIO load (0.01–5.00 mg of iron per milliliter in the medium), (b) different amounts (5.0 x 10³ to 2.5 x 10⁵ cells per milliliter of agarose gel) of identically loaded cells, and (c) free (non–cell-bound) SPIOs at the iron concentrations described for (b) were analyzed with 3.0-T R2 and R2* relaxometry. Iron uptake was analyzed with light microscopy, quantified with atomic emission spectroscopy (AES), and compared with MR data. For in vivo relaxometry, agarose gel pellets containing SPIO-labeled cells, free SPIO, unlabeled control cells, and pure agarose gel were injected into three nude mice each. Linear and nonlinear regression analyses were performed.

Results: Light microscopy and AES revealed efficient SPIO particle uptake (mean uptake: 0.22 pg of iron per cell ± 0.1 [standard deviation] for unlabeled cells, 31.17 pg of iron per cell ± 4.63 for cells incubated with 0.5 mg/mL iron). R2 and R2* values were linearly correlated with cellular iron load, number of iron-loaded cells, and content of freely dissolved iron (r² range, 0.92–0.99; P < .001). For cell-bound SPIO, R2* effects were significantly greater than R2 effects (P < .01); for free SPIO, R2 and R2* effects were similar. In vivo relaxometry enabled accurate prediction of the number of labeled cells. R2' (R2* – R2) mapping enabled differentiation between cell-bound and free iron in vitro and in vivo.

Conclusion: Quantitative R2 and R2* mapping enables noninvasive estimations of cellular iron load and number of iron-labeled cells. Cell-bound SPIOs can be differentiated from free SPIOs with R2' imaging.

© RSNA, 2007