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Delivery of Systemic Chemotherapeutic Agent to Tumors by Using Focused Ultrasound: Study in a Murine Model¹

¹ From the Lucas Magnetic Resonance Imaging and Sprectroscopy Research Center, Department of Radiology, Stanford University School of Medicine, Stanford, Calif (E.L.Y., L.C., M.D.B.); and Department of Radiology, Warren Grant Magnuson Clinical Center, National Institutes of Health, 10 Center Dr, Bldg 10, Room 1C657, Bethesda, MD 20892 (S.G.S., S.A.M., J.X., V.F., M.D.B., K.C.P.L.). Received June 5, 2003; revision requested August 18; final revision received May 3, 2004; accepted June 17. Supported in part by the Lucas Foundation, the Phil Allen Trust, and the National Institutes of Health. E.L.Y. supported by the National Cancer Institute, Lucas Center for Magnetic Resonance Imaging and Spectroscopy Research Center, Cancer Imaging Fellowship, and Stanford Medical Student Scholars Program. S.G.S. supported by the National Institutes of Health Intramural Research Training Award. Address correspondence to V.F. (e-mail: vfrenkel@cc.nih.gov).

PURPOSE: To quantitatively determine the delivery of systemic liposomal doxorubicin to tumors treated with pulsed high-intensity focused ultrasound and to study the mechanism underlying this delivery in a murine model.

MATERIALS AND METHODS: All animal work was performed in compliance with guidelines and approval of institutional animal care committee. C3H mice received subcutaneous injections in the flank of a cell suspension of SCC7, a murine squamous cell carcinoma cell line; mice (n = 32) in drug delivery study received unilateral injections, whereas mice (n = 10) in mechanistic study received bilateral injections. Tumors were treated when they reached 1 cm³ in volume. In the drug delivery study, doxorubicin hydrochloride liposomes were injected into the tail vein: Mice received therapy with doxorubicin injections and high-intensity focused ultrasound, doxorubicin injections alone, or neither form of therapy (controls). Tumors were removed, and the doxorubicin content was assayed with fluorescent spectrophotometry. In the mechanistic study, all mice received an injection of 500-kDa dextran–fluorescein isothyocyanate into the tail vein, and half of them were exposed to high-intensity focused ultrasound prior to injection. Contralateral tumors served as controls for each group. Extravasation of dextran–fluorescein isothyocyanate was observed by using in vivo confocal microscopy.

RESULTS: Mean doxorubicin concentration in tumors treated with pulsed high-intensity focused ultrasound was 9.4 µg · g^–1 ± 2.1 (standard deviation), and it was significantly higher (124% [9.4 µg · g^–1/4.2 µg · g^–1]) than in those that were not treated with high-intensity focused ultrasound (4.2 µg · g^–1 ± 0.95) (P < .001, unpaired two-tailed Student t test). Extravasation of dextran–fluorescein isothyocyanate was observed in the vasculature of tumors treated with high-intensity focused ultrasound but not in that of untreated tumors.

CONCLUSION: Pulsed high-intensity focused ultrasound is an effective method of targeting systemic drug delivery to tumor tissue. Potential mechanisms for producing the observed enhancement are discussed.

© RSNA, 2005

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