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Magnetic Resonance Guided High-Intensity Focused Ultrasound Mediated Hyperthermia Improves the Intratumoral Distribution of Temperature-Sensitive Liposomal Doxorubicin

de Smet, Mariska MSc*; Hijnen, Nicole M. MSc*; Langereis, Sander PhD; Elevelt, Aaldert MSc; Heijman, Edwin PhD; Dubois, Ludwig PhD; Lambin, Philippe MD, PhD; Grüll, Holger PhD*†

doi: 10.1097/RLI.0b013e3182806940
Original Articles

Objectives The aim of this study was to investigate the intratumoral distribution of a temperature-sensitive liposomal carrier and its encapsulated compounds, doxorubicin, and a magnetic resonance (MR) imaging contrast agent after high-intensity focused ultrasound (HIFU)–mediated hyperthermia-induced local drug release.

Materials and Methods 111In-labeled temperature-sensitive liposomes encapsulating doxorubicin and [Gd(HPDO3A) (H2O)] were injected intravenously in the tail vein of rats (n = 12) bearing a subcutaneous rhabdomyosarcoma tumor on the hind leg. Immediately after the injection, local tumor hyperthermia (2 × 15 minutes) was applied using a clinical 3 T MR-HIFU system. Release of [Gd(HPDO3A)(H2O)] was studied in vivo by measuring the longitudinal relaxation rate R1 with MR imaging. The presence of the liposomal carriers and the intratumoral distribution of doxorubicin were imaged ex vivo with autoradiography and fluorescence microscopy, respectively, for 2 different time points after injection (90 minutes and 48 hours).

Results In hyperthermia-treated tumors, radiolabeled liposomes were distributed more homogeneously across the tumor than in the control tumors (coefficient of variationhyp, 90 min = 0.7 ± 0.2; coefficient of variationcntrl, 90 min = 1.1 ± 0.2). At 48 hours after injection, the liposomal accumulation in the tumor was enhanced in the hyperthermia group in comparison with the controls. A change in R1 was observed in the HIFU-treated tumors, suggesting release of the contrast agent. Fluorescence images showed perivascular doxorubicin in control tumors, whereas in the HIFU-treated tumors, the delivered drug was spread over a much larger area and also taken up by tumor cells at a larger distance from blood vessels.

Conclusions Treatment with HIFU hyperthermia not only improved the immediate drug delivery, bioavailability, and intratumoral distribution but also enhanced liposomal accumulation over time. The sum of these effects may have a significant contribution to the therapeutic outcome.

Supplemental digital content is available in the text.

From the *Department of Biomedical Engineering, Biomedical NMR, Eindhoven University of Technology; †Department of Minimally Invasive Healthcare, Philips Research Eindhoven, Eindhoven; and ‡Department of Radiation Oncology (Maastro), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.

Received for publication July 5, 2012; and accepted for publication, after revision, November 27, 2012.

Conflicts of interest and source of funding: Sander Langereis, Aaldert Elevelt, Edwin Heijman, and Holger Grüll are employed by Philips. Mariska de Smet is currently receiving a grant from the EU FP7 project Sonodrugs (NMP4-LA-2008-213706). Nicole M. Hijnen is currently receiving a grant (05T-201) from the Center for Translational Molecular Medicine project VOLTA (CTMM;; Sander Langereis and Aaldert Elevelt, from CTMM project HIFUChem (grant 030-301); and Ludwig Dubois, from CTMM project AIRFORCE (grant 030-103).

M. de Smet and N.M. Hijnen contributed equally to this work.

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Reprints: Holger Grüll, PhD, Eindhoven University of Technology, Department of Biomedical Engineering, Biomedical NMR, High Tech Campus 11.p 261, 5656 AE Eindhoven, the Netherlands. E-mail:

© 2013 by Lippincott Williams & Wilkins