Effects of low-intensity focused ultrasound on the mouse submandibular gland


      Ultrasound is expected to make a considerable contribution to drug delivery systems (DDSs). We tested the hypothesis that low-intensity focused ultrasound (LIFU) increases vessel permeability in the mouse submandibular gland without causing parenchymal damage. In a preliminary study, LIFU at 3 W/cm2 with a 50% duty cycle for 2 minutes did not cause histologic damage. We therefore applied LIFU to mouse submandibular gland at these conditions before and after injecting horseradish peroxidase. Single labeling laser scanning confocal microscopy revealed positive horseradish peroxidase staining around the excretory ducts in the mucous-producing part of the gland, but absence of staining in control glands. Immunostaining for fibrinogen was positive in the same region. Fibrinogen is an intravascular protein that does not pass through intact vessels. These findings suggest that LIFU increases vessel permeability and disruption without destruction. It is anticipated that this process will be useful in establishing a DDS that uses LIFU. (E-mail: [email protected])

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        • Adams J.C.
        Biotin amplification of biotin and horseradish peroxidase signals in histochemical stains.
        J Histochem Cytochem. 1992; 40: 1457-1463
        • Chang C.J.
        • Hsu S.H.
        The effects of low intensity ultrasound on peripheral nerve regeneration in poly(DL-lactic acid-co-glycolic acid) conduits seeded with Schwann cells.
        Ultrasound Med Biol. 2004; 30: 1079-1084
        • Claes L.
        • Ruter A.
        • Mayr E.
        Low-intensity ultrasound enhances maturation of callus after segmental transport.
        Clin Orthop Relat Res. 2005; 430: 189-194
        • Crisci A.R.
        • Ferreira A.L.
        Low-intensity pulsed ultrasound accelerates the regeneration of the sciatic nerve after neurotomy in rats.
        Ultrasound Med Biol. 2002; 28: 1335-1341
        • Deng C.X.
        • Sieling F.
        • Pan H.
        • Cui J.
        Ultrasound-induced cell membrane porosity.
        Ultrasound Med Biol. 2004; 30: 519-526
        • Daffertshofer M.
        • Hennerici M.
        Ultrasound in the treatment of ischaemic stroke.
        Lancet Neurol. 2003; 2: 283-290
        • Dinno M.A.
        • Crum L.A.
        • Wu J.
        The effect of therapeutic ultrasound on electrophysiological parameters of frog skin.
        Ultrasound Med Biol. 1989; 15: 461-470
        • Francis C.W.
        • Blinc A.
        • Lee S.
        • Cox C.
        Ultrasound accelerates transport of recombinant tissue plasminogen activator into clots.
        Ultrasound Med Biol. 1995; 21: 419-424
        • Harrison G.H.
        • Balcer-Kubiczek E.K.
        • Eddy H.A.
        Potentiation of chemotherapy by low-level ultrasound.
        Int J Radiat Biol. 1991; 59: 1453-1466
        • Hashizume A.
        • Ueno T.
        • Furuse M.
        • et al.
        Expression patterns of claudin family of tight junction membrane proteins in developing mouse submandibular gland.
        Dev Dyn. 2004; 231: 425-431
        • Hippius M.
        • Smolenski U.
        • Uhlemann C.
        • Schreiber U.
        • Hoffmann A.
        In vitro investigations of drug release and penetration_enhancing effect of ultrasound on transmembrane transport of flufenamic acid.
        Exp Toxicol Pathol. 1998; 50: 450-452
        • Hsu S.H.
        • Huang T.B.
        Bioeffect of ultrasound on endothelial cells in vitro.
        Biomol Eng. 2004; 21: 99-104
        • Huang S.L.
        • MacDonald R.C.
        Acoustically active liposomes for drug encapsulation and ultrasound-triggered release.
        Biochim Biophys Acta. 2004; 1665: 134-141
        • Hynynen K.
        • McDannold N.
        • Sheikov N.A.
        • Jolesz F.A.
        • Vykhodtseva N.
        Local and reversible blood-brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications.
        Neuroimage. 2005; 24: 12-20
        • Ichimiya I.
        • Suzuki M.
        • Hirano T.
        • Mogi G.
        The influence of pneumococcal otitis media on the cochlear lateral wall.
        Hear Res. 1999; 131: 128-134
        • Koeke P.U.
        • Parizotto N.A.
        • Carrinho A.M.
        • Salate A.C.
        Comparative study of the efficacy of the topical application of hydrocortisone, therapeutic ultrasound and phonophoresis on the tissue repair process in rat tendons.
        Ultrasound Med Biol. 2005; 31: 345-350
        • Loverock P.
        • ter Haar G.
        • Ormerod M.G.
        • Imrie P.R.
        The effect of ultrasound on the cytoxicity of adriamycin.
        Br J Radiol. 1990; 63: 542-546
        • Mesiwala A.H.
        • Farrell L.
        • Wenzel H.J.
        • et al.
        High-intensity focused ultrasound selectively disrupts the blood-brain barrier in vivo.
        Ultrasound Med Biol. 2002; 28: 389-400
        • Nelson J.L.
        • Roeder B.L.
        • Carmen J.C.
        • Roloff F.
        • Pitt W.G.
        Ultrasonically activated chemotherapeutic drug delivery in a rat model.
        Cancer Res. 2002; 62: 7280-7283
        • Ohta S.
        • Suzuki K.
        • Tachibana K.
        • Yamada G.
        Microbubble-enhanced sonoporation.
        Genesis. 2003; 37: 91-101
        • Saad A.H.
        • Hahn G.M.
        Ultrasound-enhanced effects of adriamycin against murine tumors.
        Ultrasound Med Biol. 1992; 18: 715-723
        • Stanley A.V.
        Assessment of blood-retinal barrier integrity.
        Histol Histopath. 1995; 10: 141-154
        • Tachibana K.
        Enhancement of fibrinolysis with ultrasound energy.
        J. Vasc Interv Radiol. 1992; 3: 299-303
        • Tachibana K.
        • Kimura N.
        • Okumura M.
        • Eguchi H.
        • Tachibana S.
        Enhancement of cell killing of HL-60 cells by ultrasound in the presence of the photosensitizing drug Photofrin II.
        Cancer Lett. 1993; 72: 195-199
        • Tachibana K.
        • Uchida T.
        • Hisano S.
        • Morioka E.
        Eliminating adult T-cell leukemia cells with ultrasound.
        Lancet. 1997; 349: 325
        • Tachibana K.
        • Uchida T.
        • Ogawa K.
        • et al.
        Induction of cell-membrane porosity by ultrasound.
        Lancet. 1999; 353: 1409
        • Tachibana K.
        • Uchida T.
        • Tamura K.
        • et al.
        Enhanced cytotoxic effect of Ara-C by low intensity ultrasound to HL-60 cells.
        Canser Lett. 2000; 149: 189-194
        • Taniyama Y.
        • Tachibana K.
        • Hiraoka K.
        • et al.
        Local delivery of plasmid DNA into rat carotid artery using ultrasound.
        Circulation. 2002; 105: 1233-1239
        • Tiwari S.B.
        • Pai R.M.
        • Udupa N.
        Influence of ultrasound on the percutaneous absorption of ketorolac tromethamine in vitro across rat skin.
        Drug Deliv. 2004; 11: 47-51
        • Weimann L.J.
        • Wu J.
        Transdermal delivery of poly-l-lysine by sonomacroporation.
        Ultrasound Med Biol. 2002; 28: 1173-1180
        • Willis C.L.
        • Leach L.
        • Clarke G.J.
        • Nolan C.C.
        • Ray D.E.
        Reversible disruption of tight junction complexes in the rat blood-brain barrier, following transitory focal astrocyte loss.
        Glia. 2004; 48: 1-13
        • Yang R.S.
        • Chen Y.Z.
        • Huang T.H.
        • et al.
        The effects of low-intensity ultrasound on growing bone after sciatic neurectomy.
        Ultrasound Med Biol. 2005; 31: 431-437
        • Yumita N.
        • Nishigaki R.
        • Umemura K.
        • Umemura S.
        Hematoporphyrin as a sensitizer of cell-damaging effect of ultrasound.
        Jpn J Cancer Res. 1989; 80: 219-222