Ultrasound-mediated blood–brain barrier disruption for targeted drug delivery in the central nervous system

Advanced Drug Delivery Reviews - Tập 72 - Trang 94-109 - 2014
Muna Aryal1,2, Costas D. Arvanitis2, Phillip M. Alexander2,3, Nathan McDannold2
1Department of Physics, Boston College, Chestnut Hill, USA
2Department of Radiology, Brigham & Women’s Hospital/Harvard Medical School, Boston, USA
3Institute of Biomedical Engineering, Department of Engineering Science, and Brasenose College, University of Oxford, Oxford, UK

Tài liệu tham khảo

Neuwelt, 2011, Engaging neuroscience to advance translational research in brain barrier biology, Nat. Rev. Neurosci., 12, 169, 10.1038/nrn2995 Abbott, 1996, Transporting therapeutics across the blood–brain barrier, Mol. Med. Today, 2, 106, 10.1016/1357-4310(96)88720-X Pardridge, 2005, Molecular biology of the blood–brain barrier, Mol. Biotechnol., 30, 57, 10.1385/MB:30:1:057 Eichler, 2011, The biology of brain metastases—translation to new therapies, Nat. Rev. Clin. Oncol., 8, 344, 10.1038/nrclinonc.2011.58 Minniti, 2010, Patterns of failure and comparison of different target volume delineations in patients with glioblastoma treated with conformal radiotherapy plus concomitant and adjuvant temozolomide, Radiother. Oncol., 97, 377, 10.1016/j.radonc.2010.08.020 Dobelbower, 2011, Patterns of failure for glioblastoma multiforme following concurrent radiation and temozolomide, J. Med. Imaging Radiat. Oncol., 55, 77, 10.1111/j.1754-9485.2010.02232.x Chamberlain, 2011, Radiographic patterns of relapse in glioblastoma, J. Neurooncol., 101, 319, 10.1007/s11060-010-0251-4 Fukumura, 2007, Tumor microenvironment abnormalities: causes, consequences, and strategies to normalize, J. Cell. Biochem., 101, 937, 10.1002/jcb.21187 Regina, 2001, Multidrug resistance in brain tumors: roles of the blood–brain barrier, Cancer Metastasis Rev., 20, 13, 10.1023/A:1013104423154 Lockman, 2010, Heterogeneous blood–tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer, Clin. Cancer Res., 16, 5664, 10.1158/1078-0432.CCR-10-1564 Groothuis, 2000, The blood–brain and blood–tumor barriers: a review of strategies for increasing drug delivery, Neuro Oncol., 2, 45, 10.1093/neuonc/2.1.45 Pardridge, 2007, Blood–brain barrier delivery, Drug Discov. Today, 12, 54, 10.1016/j.drudis.2006.10.013 Blumling Iii, 2012, Targeting the brain: advances in drug delivery, Curr. Pharm. Biotechnol., 13, 2417, 10.2174/138920112803341833 Tomita, 1991, Interstitial chemotherapy for brain tumors: review, J. Neurooncol., 10, 57, 10.1007/BF00151247 Bobo, 1994, Convection-enhanced delivery of macromolecules in the brain, Proc. Natl. Acad. Sci. U. S. A., 91, 2076, 10.1073/pnas.91.6.2076 Guerin, 2004, Recent advances in brain tumor therapy: local intracerebral drug delivery by polymers, Invest. New Drugs, 22, 27, 10.1023/B:DRUG.0000006172.65135.3e Brem, 2001, Biodegradable polymer implants to treat brain tumors, J. Control. Release, 74, 63, 10.1016/S0168-3659(01)00311-X Fung, 1996, Chemotherapeutic drugs released from polymers: distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea in the rat brain, Pharm. Res., 13, 671, 10.1023/A:1016083113123 Voges, 2003, Imaging-guided convection-enhanced delivery and gene therapy of glioblastoma, Ann. Neurol., 54, 479, 10.1002/ana.10688 Fleischhack, 2005, Pharmacokinetics following intraventricular administration of chemotherapy in patients with neoplastic meningitis, Clin. Pharmacokinet., 44, 1, 10.2165/00003088-200544010-00001 Illum, 2003, Nasal drug delivery—possibilities, problems and solutions, J. Control. Release, 87, 187, 10.1016/S0168-3659(02)00363-2 Illum, 2002, Nasal drug delivery: new developments and strategies, Drug Discov. Today, 7, 1184, 10.1016/S1359-6446(02)02529-1 Ugwoke, 2005, Nasal mucoadhesive drug delivery: background, applications, trends and future perspectives, Adv. Drug Deliv. Rev., 57, 1640, 10.1016/j.addr.2005.07.009 Pires, 2009, Intranasal drug delivery: how, why and what for?, J. Pharm. Pharm. Sci., 12, 288, 10.18433/J3NC79 Oldendorf, 1972, Blood–brain barrier: penetration of morphine, codeine, heroin, and methadone after carotid injection, Science, 178, 984, 10.1126/science.178.4064.984 Abbott, 2010, Structure and function of the blood–brain barrier, Neurobiol. Dis., 37, 13, 10.1016/j.nbd.2009.07.030 Zhang, 2002, Structural biology and function of solute transporters: implications for identifying and designing substrates, Drug Metab. Rev., 34, 709, 10.1081/DMR-120015692 Pardridge, 2003, Blood–brain barrier drug targeting: the future of brain drug development, Mol. Interv., 3, 90, 10.1124/mi.3.2.90 Pardridge, 2007, Drug targeting to the brain, Pharm. Res., 24, 1733, 10.1007/s11095-007-9324-2 Blasi, 2007, Solid lipid nanoparticles for targeted brain drug delivery, Adv. Drug Deliv. Rev., 59, 454, 10.1016/j.addr.2007.04.011 Olivier, 2005, Drug transport to brain with targeted nanoparticles, NeuroRx, 2, 108, 10.1602/neurorx.2.1.108 Schnyder, 2005, Drug transport to brain with targeted liposomes, NeuroRx, 2, 99, 10.1602/neurorx.2.1.99 Broadwell, 1988, Transcytotic pathway for blood-borne protein through the blood–brain barrier, Proc. Natl. Acad. Sci. U. S. A., 85, 632, 10.1073/pnas.85.2.632 Mellman, 1996, Endocytosis and molecular sorting, Annu. Rev. Cell Dev. Biol., 12, 575, 10.1146/annurev.cellbio.12.1.575 Mukherjee, 1997, Endocytosis, Physiol. Rev., 77, 759, 10.1152/physrev.1997.77.3.759 Rapoport, 1970, Effect of concentrated solutions on blood–brain barrier, Am. J. Physiol., 219, 270, 10.1152/ajplegacy.1970.219.1.270 Rapoport, 2001, Advances in osmotic opening of the blood–brain barrier to enhance CNS chemotherapy, Expert. Opin. Investig. Drugs, 10, 1809, 10.1517/13543784.10.10.1809 Kroll, 1998, Outwitting the blood–brain barrier for therapeutic purposes: osmotic opening and other means, Neurosurgery, 42, 1083, 10.1097/00006123-199805000-00082 Bellavance, 2008, Recent advances in blood–brain barrier disruption as a CNS delivery strategy, AAPS J., 10, 166, 10.1208/s12248-008-9018-7 Doolittle, 2000, Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood–brain barrier for the treatment of patients with malignant brain tumors, Cancer, 88, 637, 10.1002/(SICI)1097-0142(20000201)88:3<637::AID-CNCR22>3.0.CO;2-Y Hall, 2006, Osmotic blood–brain barrier disruption chemotherapy for diffuse pontine gliomas, J. Neurooncol., 77, 279, 10.1007/s11060-005-9038-4 Jahnke, 2008, Intraarterial chemotherapy and osmotic blood–brain barrier disruption for patients with embryonal and germ cell tumors of the central nervous system, Cancer, 112, 581, 10.1002/cncr.23221 Angelov, 2009, Blood–brain barrier disruption and intra-arterial methotrexate-based therapy for newly diagnosed primary CNS lymphoma: a multi-institutional experience, J. Clin. Oncol., 27, 3503, 10.1200/JCO.2008.19.3789 Boockvar, 2011, Safety and maximum tolerated dose of superselective intraarterial cerebral infusion of bevacizumab after osmotic blood–brain barrier disruption for recurrent malignant glioma. Clinical article, J. Neurosurg., 114, 624, 10.3171/2010.9.JNS101223 Guillaume, 2010, Intra-arterial chemotherapy with osmotic blood–brain barrier disruption for aggressive oligodendroglial tumors: results of a phase I study, Neurosurgery, 66, 48 Inamura, 1994, Intracarotid histamine infusion increases blood tumour permeability in RG2 glioma, Neurol. Res., 16, 125, 10.1080/01616412.1994.11740209 Gutman, 1996, Increased microvascular permeability induced by prolonged interleukin-2 administration is attenuated by the oxygen-free-radical scavenger dimethylthiourea, Cancer Immunol. Immunother., 43, 240, 10.1007/s002620050328 Black, 1992, Increased opening of blood–tumour barrier by leukotriene C4 is dependent on size of molecules, Neurol. Res., 14, 402, 10.1080/01616412.1992.11740093 de Vries, 1996, The influence of cytokines on the integrity of the blood–brain barrier in vitro, J. Neuroimmunol., 64, 37, 10.1016/0165-5728(95)00148-4 Lynn, 1944, Histology of cerebral lesions produced by focused ultrasound, Am. J. Pathol., 20, 637 Fry, 1960, Fundamental neurological research and human neurosurgery using intense ultrasound, IRE Trans. Med. Electron., ME-7, 166, 10.1109/IRET-ME.1960.5008041 Ballantine, 1960, Progress and problems in the neurological applications of focused ultrasound, J. Neurosurg., 17, 858, 10.3171/jns.1960.17.5.0858 Lele, 1987, Effects of ultrasound on “solid” mammalian tissues and tumors in vivo, 275 Meyers, 1959, Early experiences with ultrasonic irradiation of the pallidfugal and nigral complexes in hyperkinetic and hypertonic disorders, J. Neurosurg., 16, 32, 10.3171/jns.1959.16.1.0032 Heimburger, 1985, Ultrasound augmentation of central nervous system tumor therapy, Indiana Med., 78, 469 Hynynen, 2004, MRI guided and monitored focused ultrasound thermal ablation methods: a review of progress, Int. J. Hyperthermia, 20, 725, 10.1080/02656730410001716597 Clement, 2002, A non-invasive method for focusing ultrasound through the human skull, Phys. Med. Biol., 47, 1219, 10.1088/0031-9155/47/8/301 Aubry, 2003, Experimental demonstration of noninvasive transskull adaptive focusing based on prior computed tomography scans, J. Acoust. Soc. Am., 113, 84, 10.1121/1.1529663 Ishihara, 1995, A precise and fast temperature mapping using water proton chemical shift, Magn. Reson. Med., 34, 814, 10.1002/mrm.1910340606 McDannold, 2010, Transcranial magnetic resonance imaging-guided focused ultrasound surgery of brain tumors: initial findings in 3 patients, Neurosurgery, 66, 323, 10.1227/01.NEU.0000360379.95800.2F Lipsman, 2013, MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study, Lancet Neurol., 12, 462, 10.1016/S1474-4422(13)70048-6 Elias, 2013, A pilot study of focused ultrasound thalamotomy for essential tremor, N. Engl. J. Med., 369, 640, 10.1056/NEJMoa1300962 Martin, 2009, High-intensity focused ultrasound for noninvasive functional neurosurgery, Ann. Neurol., 66, 858, 10.1002/ana.21801 Nyborg, 2002 Leighton, 1994 Dayton, 1999, Acoustic radiation force in vivo: a mechanism to assist targeting of microbubbles, Ultrasound Med. Biol., 25, 1195, 10.1016/S0301-5629(99)00062-9 Miller, 1988, Particle gathering and microstreaming near ultrasonically activated gas-filled micropores, J. Acoust. Soc. Am., 84, 1378, 10.1121/1.396636 Edmonds, 1983, Evidence for free radical production by ultrasonic cavitation in biological media, Ultrasound Med. Biol., 9, 635, 10.1016/0301-5629(83)90009-1 Flynn, 1982, Generation of transient cavities in liquids by microsecond pulses of ultrasound, J. Acoust. Soc. Am., 72, 1926, 10.1121/1.388622 Apfel, 1982, Acoustic cavitation: a possible consequence of biomedical uses of ultrasound, Br. J. Cancer Suppl., 45, 140 Bakay, 1956, Ultrasonically produced changes in the blood–brain barrier, Arch. Neurol., 76, 457, 10.1001/archneurpsyc.1956.02330290001001 Vykhodtseva, 1981, Effects of high intensity pulsed ultrasound on brain tissues, 95 Patrick, 1990, Ultrasound and the blood–brain barrier, Adv. Exp. Med. Biol., 267, 369, 10.1007/978-1-4684-5766-7_36 Vykhodtseva, 1995, Histologic effects of high intensity pulsed ultrasound exposure with subharmonic emission in rabbit brain in vivo, Ultrasound Med. Biol., 21, 969, 10.1016/0301-5629(95)00038-S Mesiwala, 2002, High-intensity focused ultrasound selectively disrupts the blood–brain barrier in vivo, Ultrasound Med. Biol., 28, 389, 10.1016/S0301-5629(01)00521-X McDannold, 2004, MRI investigation of the threshold for thermally induced blood–brain barrier disruption and brain tissue damage in the rabbit brain, Magn. Reson. Med., 51, 913, 10.1002/mrm.20060 Hynynen, 2001, Noninvasive MR imaging-guided focal opening of the blood–brain barrier in rabbits, Radiology, 220, 640, 10.1148/radiol.2202001804 Sheikov, 2004, Cellular mechanisms of the blood–brain barrier opening induced by ultrasound in presence of microbubbles, Ultrasound Med. Biol., 30, 979, 10.1016/j.ultrasmedbio.2004.04.010 McDannold, 2012, Temporary disruption of the blood–brain barrier by use of ultrasound and microbubbles: safety and efficacy evaluation in rhesus macaques, Cancer Res., 72, 3652, 10.1158/0008-5472.CAN-12-0128 Marquet, 2011, Noninvasive, transient and selective blood–brain barrier opening in non-human primates in vivo, PLoS One, 6, e22598, 10.1371/journal.pone.0022598 O'Reilly, 2010, The impact of standing wave effects on transcranial focused ultrasound disruption of the blood–brain barrier in a rat model, Phys. Med. Biol., 55, 5251, 10.1088/0031-9155/55/18/001 Hynynen, 2005, Local and reversible blood–brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications, Neuroimage, 24, 12, 10.1016/j.neuroimage.2004.06.046 Treat, 2007, Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound, Int. J. Cancer, 121, 901, 10.1002/ijc.22732 Chopra, 2010, Influence of exposure time and pressure amplitude on blood–brain-barrier opening using transcranial ultrasound exposures, ACS Chem. Neurosci., 1, 391, 10.1021/cn9000445 McDannold, 2008, Blood–brain barrier disruption induced by focused ultrasound and circulating preformed microbubbles appears to be characterized by the mechanical index, Ultrasound Med. Biol., 34, 834, 10.1016/j.ultrasmedbio.2007.10.016 McDannold, 2008, Effects of acoustic parameters and ultrasound contrast agent dose on focused-ultrasound induced blood–brain barrier disruption, Ultrasound Med. Biol., 34, 930, 10.1016/j.ultrasmedbio.2007.11.009 Choi, 2010, Microbubble-size dependence of focused ultrasound-induced blood–brain barrier opening in mice in vivo, IEEE Trans. Biomed. Eng., 57, 145, 10.1109/TBME.2009.2034533 Vlachos, 2011, Permeability dependence study of the focused ultrasound-induced blood–brain barrier opening at distinct pressures and microbubble diameters using DCE-MRI, Magn. Reson. Med., 66, 821, 10.1002/mrm.22848 Samiotaki, 2012, A quantitative pressure and microbubble-size dependence study of focused ultrasound-induced blood–brain barrier opening reversibility in vivo using MRI, Magn. Reson. Med., 67, 769, 10.1002/mrm.23063 Choi, 2011, Noninvasive and localized blood–brain barrier disruption using focused ultrasound can be achieved at short pulse lengths and low pulse repetition frequencies, J. Cereb. Blood Flow Metab., 31, 725, 10.1038/jcbfm.2010.155 Choi, 2011, Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles, Proc. Natl. Acad. Sci. U. S. A., 108, 16539, 10.1073/pnas.1105116108 Bing, 2009, Blood–brain barrier (BBB) disruption using a diagnostic ultrasound scanner and Definity in mice, Ultrasound Med. Biol., 35, 1298, 10.1016/j.ultrasmedbio.2009.03.012 Yang, 2007, Quantitative evaluation of focused ultrasound with a contrast agent on blood–brain barrier disruption, Ultrasound Med. Biol., 33, 1421, 10.1016/j.ultrasmedbio.2007.04.006 Weng, 2011, Detecting blood–brain barrier disruption within minimal hemorrhage following transcranial focused ultrasound: a correlation study with contrast-enhanced MRI, Magn. Reson. Med., 65, 802, 10.1002/mrm.22643 Weng, 2010, Pulse sequence and timing of contrast-enhanced MRI for assessing blood–brain barrier disruption after transcranial focused ultrasound in the presence of hemorrhage, J. Magn. Reson. Imaging, 31, 1323, 10.1002/jmri.22174 Park, 2012, The kinetics of blood brain barrier permeability and targeted doxorubicin delivery into brain induced by focused ultrasound, J. Control. Release, 162, 134, 10.1016/j.jconrel.2012.06.012 Yang, 2011, Reversible blood–brain barrier disruption by repeated transcranial focused ultrasound allows enhanced extravasation, J. Control. Release, 150, 111, 10.1016/j.jconrel.2010.10.038 O'Reilly, 2011, Focused-ultrasound disruption of the blood–brain barrier using closely-timed short pulses: influence of sonication parameters and injection rate, Ultrasound Med. Biol., 37, 587, 10.1016/j.ultrasmedbio.2011.01.008 McDannold, 2011, Blood–brain barrier disruption and vascular damage induced by ultrasound bursts combined with microbubbles can be influenced by choice of anesthesia protocol, Ultrasound Med. Biol., 37, 1259, 10.1016/j.ultrasmedbio.2011.04.019 Wang, 2010, Effects of combining low frequency ultrasound irradiation with papaverine on the permeability of the blood–tumor barrier, J. Neurooncol., 102, 213, 10.1007/s11060-010-0321-7 Zhang, 2009, Synergistic effect of low-frequency ultrasound and low-dose bradykinin on increasing permeability of the blood–tumor barrier by opening tight junction, J. Neurosci. Res., 87, 2282, 10.1002/jnr.22061 Zhang, 2010, Additive effect of low-frequency ultrasound and endothelial monocyte-activating polypeptide II on blood–tumor barrier in rats with brain glioma, Neurosci. Lett., 481, 21, 10.1016/j.neulet.2010.06.042 Goertz, 2010, Contrast agent kinetics in the rabbit brain during exposure to therapeutic ultrasound, Ultrasound Med. Biol., 36, 916, 10.1016/j.ultrasmedbio.2010.03.005 Liu, 2010, Opening of the blood–brain barrier by low-frequency (28-kHz) ultrasound: a novel pinhole-assisted mechanical scanning device, Ultrasound Med. Biol., 36, 325, 10.1016/j.ultrasmedbio.2009.10.004 McDannold, 2006, Targeted disruption of the blood–brain barrier with focused ultrasound: association with cavitation activity, Phys. Med. Biol., 51, 793, 10.1088/0031-9155/51/4/003 Tung, 2010, In vivo transcranial cavitation threshold detection during ultrasound-induced blood–brain barrier opening in mice, Phys. Med. Biol., 55, 6141, 10.1088/0031-9155/55/20/007 Arvanitis, 2012, Controlled ultrasound-induced blood–brain barrier disruption using passive acoustic emissions monitoring, PLoS One, 7, e45783, 10.1371/journal.pone.0045783 Deng, 2004, Ultrasound-induced cell membrane porosity, Ultrasound Med. Biol., 30, 519, 10.1016/j.ultrasmedbio.2004.01.005 Sheikov, 2008, Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium, Ultrasound Med. Biol., 34, 1093, 10.1016/j.ultrasmedbio.2007.12.015 Sheikov, 2006, Brain arterioles show more active vesicular transport of blood-borne tracer molecules than capillaries and venules after focused ultrasound-evoked opening of the blood–brain barrier, Ultrasound Med. Biol., 32, 1399, 10.1016/j.ultrasmedbio.2006.05.015 Raymond, 2007, Multiphoton imaging of ultrasound/Optison mediated cerebrovascular effects in vivo, J. Cereb. Blood Flow Metab., 27, 393, 10.1038/sj.jcbfm.9600336 Cho, 2011, Two-photon fluorescence microscopy study of cerebrovascular dynamics in ultrasound-induced blood–brain barrier opening, J. Cereb. Blood Flow Metab., 31, 1852, 10.1038/jcbfm.2011.59 Chen, 2011, Blood vessel deformations on microsecond time scales by ultrasonic cavitation, Phys. Rev. Lett., 106, 034301, 10.1103/PhysRevLett.106.034301 Sassaroli, 2005, Resonance frequency of microbubbles in small blood vessels: a numerical study, Phys. Med. Biol., 50, 5293, 10.1088/0031-9155/50/22/006 Marty, 2012, Dynamic study of blood–brain barrier closure after its disruption using ultrasound: a quantitative analysis, J. Cereb. Blood Flow Metab., 32, 1948, 10.1038/jcbfm.2012.100 Howles, 2010, Contrast-enhanced in vivo magnetic resonance microscopy of the mouse brain enabled by noninvasive opening of the blood–brain barrier with ultrasound, Magn. Reson. Med., 64, 995, 10.1002/mrm.22411 Baseri, 2010, Multi-modality safety assessment of blood–brain barrier opening using focused ultrasound and Definity microbubbles: a short-term study, Ultrasound Med. Biol., 36, 1445, 10.1016/j.ultrasmedbio.2010.06.005 McDannold, 2005, MRI-guided targeted blood–brain barrier disruption with focused ultrasound: histological findings in rabbits, Ultrasound Med. Biol., 31, 1527, 10.1016/j.ultrasmedbio.2005.07.010 Liu, 2008, Hemorrhage detection during focused-ultrasound induced blood–brain-barrier opening by using susceptibility-weighted magnetic resonance imaging, Ultrasound Med. Biol., 34, 598, 10.1016/j.ultrasmedbio.2008.01.011 Hynynen, 2006, Focal disruption of the blood–brain barrier due to 260-kHz ultrasound bursts: a method for molecular imaging and targeted drug delivery, J. Neurosurg., 105, 445, 10.3171/jns.2006.105.3.445 Liu, 2010, In vivo assessment of macrophage CNS infiltration during disruption of the blood–brain barrier with focused ultrasound: a magnetic resonance imaging study, J. Cereb. Blood Flow Metab., 30, 674, 10.1038/jcbfm.2009.251 Shang, 2011, Mechanism of low-frequency ultrasound in opening blood–tumor barrier by tight junction, J. Mol. Neurosci., 43, 364, 10.1007/s12031-010-9451-9 Alonso, 2010, Reorganization of gap junctions after focused ultrasound blood–brain barrier opening in the rat brain, J. Cereb. Blood Flow Metab., 30, 1394, 10.1038/jcbfm.2010.41 Deng, 2012, The role of caveolin-1 in blood–brain barrier disruption induced by focused ultrasound combined with microbubbles, J. Mol. Neurosci., 46, 677, 10.1007/s12031-011-9629-9 Xia, 2012, Low-frequency ultrasound irradiation increases blood–tumor barrier permeability by transcellular pathway in a rat glioma model, J. Mol. Neurosci., 48, 281, 10.1007/s12031-012-9770-0 Shajahan, 2004, Gbetagamma activation of Src induces caveolae-mediated endocytosis in endothelial cells, J. Biol. Chem., 279, 48055, 10.1074/jbc.M405837200 Jalali, 2010, Focused ultrasound-mediated BBB disruption is associated with an increase in activation of Akt: experimental study in rats, BMC Neurol., 10, 114, 10.1186/1471-2377-10-114 Zhao, 2006, Phosphoinositide-3-kinase/Akt survival signal pathways are implicated in neuronal survival after stroke, Mol. Neurobiol., 34, 249, 10.1385/MN:34:3:249 Nath, 2001, Inhibition of p38 kinase mimics survival signal-linked protection against apoptosis in rat cerebellar granule neurons, Cell. Mol. Biol. Lett., 6, 173 Harada, 1999, An inhibitor of p38 and JNK MAP kinases prevents activation of caspase and apoptosis of cultured cerebellar granule neurons, Jpn. J. Pharmacol., 79, 369, 10.1254/jjp.79.369 Alonso, 2010, Neurons but not glial cells overexpress ubiquitin in the rat brain following focused ultrasound-induced opening of the blood–brain barrier, Neuroscience, 169, 116, 10.1016/j.neuroscience.2010.04.001 Park, 2010, Modulation of intracellular Ca2+ concentration in brain microvascular endothelial cells in vitro by acoustic cavitation, Ultrasound Med. Biol., 36, 1176, 10.1016/j.ultrasmedbio.2010.04.006 Park, 2011, Effects of shear stress cultivation on cell membrane disruption and intracellular calcium concentration in sonoporation of endothelial cells, J. Biomech., 44, 164, 10.1016/j.jbiomech.2010.09.003 Ayata, 2004, Pronounced hypoperfusion during spreading depression in mouse cortex, J. Cereb. Blood Flow Metab., 24, 1172, 10.1097/01.WCB.0000137057.92786.F3 Burgess, 2012, Focused ultrasound for targeted delivery of siRNA and efficient knockdown of Htt expression, J. Control. Release, 163, 125, 10.1016/j.jconrel.2012.08.012 Choi, 2010, Molecules of various pharmacologically-relevant sizes can cross the ultrasound-induced blood–brain barrier opening in vivo, Ultrasound Med. Biol., 36, 58, 10.1016/j.ultrasmedbio.2009.08.006 Muldoon, 1999, A physiological barrier distal to the anatomic blood–brain barrier in a model of transvascular delivery, AJNR Am. J. Neuroradiol., 20, 217 Liu, 2010, Blood–brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment, Radiology, 255, 415, 10.1148/radiol.10090699 Mei, 2009, Experimental study on targeted methotrexate delivery to the rabbit brain via magnetic resonance imaging-guided focused ultrasound, J. Ultrasound Med., 28, 871, 10.7863/jum.2009.28.7.871 Zeng, 2012, Focused ultrasound-induced blood–brain barrier disruption enhances the delivery of cytarabine to the rat brain, J. Chemother., 24, 358, 10.1179/1973947812Y.0000000043 Wei, 2013, Focused ultrasound-induced blood–brain barrier opening to enhance temozolomide delivery for glioblastoma treatment: a preclinical study, PLoS One, 8, e58995, 10.1371/journal.pone.0058995 Aryal, 2013, Multiple treatments with liposomal doxorubicin and ultrasound-induced disruption of blood–tumor and blood–brain barriers improve outcomes in a rat glioma model, J. Control. Release, 169, 103, 10.1016/j.jconrel.2013.04.007 Yang, 2012, Focused ultrasound and interleukin-4 receptor-targeted liposomal doxorubicin for enhanced targeted drug delivery and antitumor effect in glioblastoma multiforme, J. Control. Release, 160, 652, 10.1016/j.jconrel.2012.02.023 Liu, 2010, Magnetic resonance monitoring of focused ultrasound/magnetic nanoparticle targeting delivery of therapeutic agents to the brain, Proc. Natl. Acad. Sci. U. S. A., 107, 15205, 10.1073/pnas.1003388107 Chen, 2010, Novel magnetic/ultrasound focusing system enhances nanoparticle drug delivery for glioma treatment, Neuro Oncol., 12, 1050, 10.1093/neuonc/noq054 Fan, 2013, SPIO-conjugated, doxorubicin-loaded microbubbles for concurrent MRI and focused-ultrasound enhanced brain-tumor drug delivery, Biomaterials, 34, 3706, 10.1016/j.biomaterials.2013.01.099 Kinoshita, 2006, Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood–brain barrier disruption, Proc. Natl. Acad. Sci. U. S. A., 103, 11719, 10.1073/pnas.0604318103 Park, 2012, Ultrasound-mediated blood–brain/blood–tumor barrier disruption improves outcomes with trastuzumab in a breast cancer brain metastasis model, J. Control. Release, 10.1016/j.jconrel.2012.09.007 Yang, 2012, Boron neutron capture therapy for glioblastoma multiforme: enhanced drug delivery and antitumor effect following blood–brain barrier disruption induced by focused ultrasound, Future Oncol., 8, 1361, 10.2217/fon.12.118 Alkins, 2013, Enhancing drug delivery for boron neutron capture therapy of brain tumors with focused ultrasound, Neuro Oncol., 15, 1225, 10.1093/neuonc/not052 Alkins, 2013, Focused ultrasound delivers targeted immune cells to metastatic brain tumors, Cancer Res., 73, 1892, 10.1158/0008-5472.CAN-12-2609 Ting, 2012, Concurrent blood–brain barrier opening and local drug delivery using drug-carrying microbubbles and focused ultrasound for brain glioma treatment, Biomaterials, 33, 704, 10.1016/j.biomaterials.2011.09.096 Wang, 2012, Targeted delivery of GDNF through the blood–brain barrier by MRI-guided focused ultrasound, PLoS One, 7, e52925, 10.1371/journal.pone.0052925 Huang, 2012, Targeted gene delivery to the mouse brain by MRI-guided focused ultrasound-induced blood–brain barrier disruption, Exp. Neurol., 233, 350, 10.1016/j.expneurol.2011.10.027 Fan, 2013, Antiangiogenic-targeting drug-loaded microbubbles combined with focused ultrasound for glioma treatment, Biomaterials, 34, 2142, 10.1016/j.biomaterials.2012.11.048 Baseri, 2012, Activation of signaling pathways following localized delivery of systemically administered neurotrophic factors across the blood–brain barrier using focused ultrasound and microbubbles, Phys. Med. Biol., 57, N65, 10.1088/0031-9155/57/7/N65 Raymond, 2008, Ultrasound enhanced delivery of molecular imaging and therapeutic agents in Alzheimer's disease mouse models, PLoS One, 3, e2175, 10.1371/journal.pone.0002175 Jordao, 2010, Antibodies targeted to the brain with image-guided focused ultrasound reduces amyloid-beta plaque load in the TgCRND8 mouse model of Alzheimer's disease, PLoS One, 5, e10549, 10.1371/journal.pone.0010549 Burgess, 2011, Targeted delivery of neural stem cells to the brain using MRI-guided focused ultrasound to disrupt the blood–brain barrier, PLoS One, 6, e27877, 10.1371/journal.pone.0027877 Thevenot, 2012, Targeted delivery of self-complementary adeno-associated virus serotype 9 to the brain, using magnetic resonance imaging-guided focused ultrasound, Hum. Gene Ther., 23, 1144, 10.1089/hum.2012.013 Alonso, 2013, Focal delivery of AAV2/1-transgenes into the rat brain by localized ultrasound-induced BBB opening, Mol. Ther. Nucleic Acids, 2, e73, 10.1038/mtna.2012.64 Hsu, 2013, Noninvasive and targeted gene delivery into the brain using microbubble-facilitated focused ultrasound, PLoS One, 8, e57682, 10.1371/journal.pone.0057682 Treat, 2012, Improved anti-tumor effect of liposomal doxorubicin after targeted blood–brain barrier disruption by MRI-guided focused ultrasound in rat glioma, Ultrasound Med. Biol., 38, 1716, 10.1016/j.ultrasmedbio.2012.04.015 Jordao, 2013, Amyloid-beta plaque reduction, endogenous antibody delivery and glial activation by brain-targeted, transcranial focused ultrasound, Exp. Neurol., 248, 16, 10.1016/j.expneurol.2013.05.008 Choi, 2007, Noninvasive, transcranial and localized opening of the blood–brain barrier using focused ultrasound in mice, Ultrasound Med. Biol., 33, 95, 10.1016/j.ultrasmedbio.2006.07.018 O'Reilly, 2011, Ultrasound insertion loss of rat parietal bone appears to be proportional to animal mass at submegahertz frequencies, Ultrasound Med. Biol., 37, 1930, 10.1016/j.ultrasmedbio.2011.08.001 Pichardo, 2011, Multi-frequency characterization of the speed of sound and attenuation coefficient for longitudinal transmission of freshly excised human skulls, Phys. Med. Biol., 56, 219, 10.1088/0031-9155/56/1/014 White, 2006, Longitudinal and shear mode ultrasound propagation in human skull bone, Ultrasound Med. Biol., 32, 1085, 10.1016/j.ultrasmedbio.2006.03.015 Hynynen, 1997, Thermal effects of focused ultrasound on the brain: determination with MR imaging, Radiology, 204, 247, 10.1148/radiology.204.1.9205255 McDannold, 2008, Magnetic resonance acoustic radiation force imaging, Med. Phys., 35, 3748, 10.1118/1.2956712 Hosseinkhah, 2012, A three-dimensional model of an ultrasound contrast agent gas bubble and its mechanical effects on microvessels, Phys. Med. Biol., 57, 785, 10.1088/0031-9155/57/3/785 Tung, 2011, Feasibility of noninvasive cavitation-guided blood–brain barrier opening using focused ultrasound and microbubbles in nonhuman primates, Appl. Phys. Lett., 98, 163704, 10.1063/1.3580763 O'Reilly, 2012, Blood–brain barrier: real-time feedback-controlled focused ultrasound disruption by using an acoustic emissions-based controller, Radiology, 263, 96, 10.1148/radiol.11111417 Salgaonkar, 2009, Passive cavitation imaging with ultrasound arrays, J. Acoust. Soc. Am., 126, 3071, 10.1121/1.3238260 Gyongy, 2010, Passive cavitation mapping for localization and tracking of bubble dynamics, J. Acoust. Soc. Am., 128, EL175, 10.1121/1.3467491 Arvanitis, 2013, Combined ultrasound and MR imaging to guide focused ultrasound therapies in the brain, Phys. Med. Biol., 58, 4749, 10.1088/0031-9155/58/14/4749 Yang, 2011, Micro-SPECT/CT-based pharmacokinetic analysis of 99mTc-diethylenetriaminepentaacetic acid in rats with blood–brain barrier disruption induced by focused ultrasound, J. Nucl. Med., 52, 478, 10.2967/jnumed.110.083071 Yang, 2010, Association between contrast-enhanced MR images and blood–brain barrier disruption following transcranial focused ultrasound, J. Magn. Reson. Imaging, 32, 593, 10.1002/jmri.22297 Chu, 2013, Pharmacodynamic analysis of magnetic resonance imaging-monitored focused ultrasound-induced blood–brain barrier opening for drug delivery to brain tumors, Biomed. Res. Int., 2013, 627496, 10.1155/2013/627496 Vlachos, 2010, Permeability assessment of the focused ultrasound-induced blood–brain barrier opening using dynamic contrast-enhanced MRI, Phys. Med. Biol., 55, 5451, 10.1088/0031-9155/55/18/012 Raymond, 2005, Acoustic transmission losses and field alterations due to human scalp hair, IEEE Trans. Ultrason. Ferroelectr. Freq. Control, 52, 1415, 10.1109/TUFFC.2005.1509801 Park, 2012, Targeted and reversible blood–retinal barrier disruption via focused ultrasound and microbubbles, PLoS One, 7, e42754, 10.1371/journal.pone.0042754 Wachsmuth, 2008, Feasibility of transient image-guided blood–spinal cord barrier disruption, 1113, 256 Fischer, 2009, Renal ultrafiltration changes induced by focused US, Radiology, 253, 697, 10.1148/radiol.2532082100 McDannold, 2006, Microbubble contrast agent with focused ultrasound to create brain lesions at low power levels: MR imaging and histologic study in rabbits, Radiology, 241, 95, 10.1148/radiol.2411051170 Borrelli, 2012, Influences of microbubble diameter and ultrasonic parameters on in vitro sonothrombolysis efficacy, J. Vasc. Interv. Radiol., 23, 1677, 10.1016/j.jvir.2012.08.019 Czarnota, 2012, Tumor radiation response enhancement by acoustical stimulation of the vasculature, Proc. Natl. Acad. Sci. U. S. A., 109, E2033, 10.1073/pnas.1200053109 Yang, 2008, Quantitative evaluation of the use of microbubbles with transcranial focused ultrasound on blood–brain-barrier disruption, Ultrason. Sonochem., 15, 636, 10.1016/j.ultsonch.2007.08.003 McDannold, 2007, Use of ultrasound pulses combined with Definity for targeted blood–brain barrier disruption: a feasibility study, Ultrasound Med. Biol., 33, 584, 10.1016/j.ultrasmedbio.2006.10.004 Lin, 2009, Quantitative micro-SPECT/CT for detecting focused ultrasound-induced blood–brain barrier opening in the rat, Nucl. Med. Biol., 36, 853, 10.1016/j.nucmedbio.2009.04.011 Yang, 2012, Evaluation of the increase in permeability of the blood–brain barrier during tumor progression after pulsed focused ultrasound, Int. J. Nanomedicine, 7, 723, 10.2147/IJN.S28503 Huang, 2012, Effective gene transfer into central nervous system following ultrasound-microbubbles-induced opening of the blood–brain barrier, Ultrasound Med. Biol., 38, 1234, 10.1016/j.ultrasmedbio.2012.02.019 Etame, 2012, Enhanced delivery of gold nanoparticles with therapeutic potential into the brain using MRI-guided focused ultrasound, Nanomedicine, 8, 1133, 10.1016/j.nano.2012.02.003 Wang, 2012, Gold-nanorod contrast-enhanced photoacoustic micro-imaging of focused-ultrasound induced blood–brain-barrier opening in a rat model, J. Biomed. Opt., 17, 061222, 10.1117/1.JBO.17.6.061222