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Gold nanoparticles have been shown to enhance local radiation dose due to its high Z value. Ultrasonically-stimulated microbubbles at therapeutic conditions can sensitize cells to ionizing radiation and enhance cell permeability allowing gold nanoparticles to cross the plasma membrane. In this study, ultrasound-microbubble potentiated enhancement of cell death in combination with gold nanoparticles and ionizing radiation is investigated in vitro. A suspension model of breast cancer (MDA-MB-231) cells was exposed to ultrasound and microbubbles (USMB), gold nanoparticles (AuNP) and ionizing radiation (XRT). A 12 nm spherical AuNPs at concentrations of 7.8 x1010 nps/mL and 1.6 x 1011 nps/mL were investigated at fixed USMB conditions of 500 kHz pulse center frequency, 580 kPa peak negative pressure, 10 μs pulse duration, 60s insonation time, Definity® microbubbles at 3.3% (v/v) and XRT dose of 2 Gy. Cell viability post treatment was evaluated using clonogenic assay. The application of AuNP and USMB induced a synergistic increase in cell death when combined with XRT. A 22 fold increase in cell death was observed with the combined treatment (AuNP+USMB+XRT=3±0.4%) compared to radiotherapy only (XRT=65±3%). The combined treatment of ultrasound-microbubbles with gold nanoparticles followed by radiotherapy induced a synergistic effect in cell death.
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 Unger EC, Porter T, Culp W, et al. Therapeutic applications of lipid-coated microbubbles. Adv Drug Deliv Rev. 2004; 56(9):1291-314.
 Goertz DE, Todorova M, Mortazavi O, et al. Antitumor Effects of Combining Docetaxel (Taxotere) with the Antivascular Action of Ultrasound Stimulated Microbubbles. Plos One. 2012; 7(12).
 Yan F, Li X, Jin Q, et al. Therapeutic Ultrasonic Microbubbles Carrying Paclitaxel and LyP-1 Peptide: Preparation, Characterization and Application to Ultrasound-Assisted Chemotherapy in Breast Cancer Cells. Ultrasound in Medicine & Biology. 2011; 37(5):768-79.
 Choijamts B, Naganuma Y, Nakajima K, et al. Metronomic irinotecan chemotherapy combined with ultrasound irradiation for a human uterine sarcoma xenograft. Cancer Science. 2011; 102(2):452-9.
 Nomikou N, Li YS, McHale AP. Ultrasound-enhanced drug dispersion through solid tumours and its possible role in aiding ultrasound-targeted cancer chemotherapy. Cancer Letters. 2010; 288(1):94-8.
 Hernot S, Klibanov A. Microbubbles in ultrasound-triggered drug and gene delivery☆. Advanced Drug Delivery Reviews. 2008; 60(10):1153-66.
 Lee J, Karshafian R, Papanicolau N, et al. QUANTITATIVE ULTRASOUND FOR THE MONITORING OF NOVEL MICROBUBBLE AND ULTRASOUND RADIOSENSITIZATION. Ultrasound in Medicine and Biology. 2012; 38(7):1212-21.
 Czarnota GJ, Karshafian R, Burns PN, et al. Tumor radiation response enhancement by acoustical stimulation of the vasculature. Proc Natl Acad Sci USA. 2012; 109(30):E2033-41.
 Todorova M, Agache V, Mortazavi O, et al. Antitumor effects of combining metronomic chemotherapy with the antivascular action of ultrasound stimulated microbubbles. International Journal of Cancer. 2013; 132(12):2956-66.
 Treat LH, McDannold N, Vykhodtseva N, et al. Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound. Int J Cancer. 2007; 121(4):901-7.
 Zhao Y-Zea. Enhancing chemotherapeutic drug inhibition on tumor growth by ultrasound: an in vivo experiment. Journal of Drug Targeting. 2011; 19(2):154-60.
 Goertz DE, Karshafian R, Hynynen K. Antivascular effects of pulsed low intensity ultrasound and microbubbles in mouse tumors. Ultrasonics Symposium, 2008 IUS 2008 IEEE. 2008:670-3.
 Tarapacki C, Karshafian R. Enhancing laser therapy using PEGylated gold nanoparticles combined with ultrasound and microbubbles. Ultrasonics. 2015; 57:36-43.
 Tarapacki C, Kumaradas C, Karshafian R. Enhancing laser thermal-therapy using ultrasound-microbubbles and gold nanorods of in vitro cells. Ultrasonics. 2013; 53(3):793-8.
 Karshafian R, Bevan P, Williams R, et al. Sonoporation by Ultrasound-Activated Microbubble Contrast Agents: Effect of Acoustic Exposure Parameters on Cell Membrane Permeability and Cell Viability. Ultrasound in medicine & biology. 2009; 35(5):847-60.
 Karshafian R, Samac S, Bevan P, et al. Microbubble mediated sonoporation of cells in suspension: Clonogenic viability and influence of molecular size on uptake. Ultrasonics. 2010.
 Chen W-S, Brayman AA, Matula TJ, et al. The pulse length-dependence of inertial cavitation dose and hemolysis. Ultrasound in medicine & biology. 2003; 29(5):739-48.
 Hu YX, Wan JMF, Yu ACH. Membrane Perforation and Recovery Dynamics in Microbubble-Mediated Sonoporation. Ultrasound in Medicine and Biology. 2013; 39(12):2393-405.
 Kumon R, Aehle M, Sabens D, et al. Spatiotemporal Effects of Sonoporation Measured by Real-Time Calcium Imaging. Ultrasound in medicine & biology. 2008:13.
 Deng CX, Sieling F, Pan H, et al. Ultrasound-induced cell membrane porosity. Ultrasound in medicine & biology. 2004; 30(4):519-26.
 Nofiele JIT, Karshafian R, Furukawa M, et al. Ultrasound-Activated Microbubble Cancer Therapy: Ceramide Production Leading to Enhanced Radiation Effect in vitro. Technology in Cancer Research & Treatment. 2013; 12(1):53-60.
 Al-Mahrouki AA, Karshafian R, Giles A, et al. Bioeffects of Ultrasound-Stimulated Microbubbles on Endothelial Cells: Gene Expression Changes Associated with Radiation Enhancement in Vitro. Ultrasound in Medicine and Biology. 2012; 38(11):1958-69.
 Kim HC, Al-Mahrouki A, Gorjizadeh A, et al. Quantitative Ultrasound Characterization of Tumor Cell Death: Ultrasound-Stimulated Microbubbles for Radiation Enhancement. Plos One. 2014; 9(7).
 Duvshani-Eshet M, Benny O, Morgenstern A. Therapeutic ultrasound facilitates antiangiogenic gene delivery and inhibits prostate tumor growth. Molecular Cancer Therapeutics. 2007.
 Wood AK, Ansaloni S, Ziemer LS, et al. The antivascular action of physiotherapy ultrasound on murine tumors. Ultrasound in medicine & biology. 2005; 31(10):1403-10.
 Hwang JH, Brayman AA, Reidy MA, et al. Vascular effects induced by combined 1-MHz ultrasound and microbubble contrast agent treatments in vivo. Ultrasound in medicine & biology. 2005; 31(4):553-64.
 Bing KF, Howles GP, Qi Y, et al. Blood-Brain Barrier (BBB) Disruption Using a Diagnostic Ultrasound Scanner and Definity® in Mice. Ultrasound in medicine & biology. 2009; 35(8):1298-308.
 Kong T, Zeng J, Wang XP, et al. Enhancement of radiation cytotoxicity in breast-cancer cells by localized attachment of gold nanoparticles. Small. 2008; 4(9):1537-43.
 Zhang XJ, Xing JZ, Chen J, et al. Enhanced radiation sensitivity in prostate cancer by gold-nanoparticles. Clinical and Investigative Medicine. 2008; 31(3):E160-E7.
 Pignol JP, Rakovitch E, Beachey D, et al. Clinical significance of atomic inner shell ionization (ISI) and Auger cascade for radiosensitization using IUdR, BUdR, platinum salts, or gadolinium porphyrin compounds. International Journal of Radiation Oncology Biology Physics. 2003; 55(4):1082-91.
 Hainfeld JF, Slatkin DN, Focella TM, et al. Gold nanoparticles: a new X-ray contrast agent. British Journal of Radiology. 2006; 79(939):248-53.
 Popovtzer R, Agrawal A, Kotov NA, et al. Targeted Gold Nanoparticles Enable Molecular CT Imaging of Cancer. Nano Letters. 2008; 8(12):4593-6.
 Torchilin VP. Targeted pharmaceutical nanocarriers for cancer therapy and Imaging. Aaps Journal. 2007; 9(2):E128-E47.
 Hainfeld JF, Dilmanian FA, Slatkin DN, et al. Radiotherapy enhancement with gold nanoparticles. Journal of Pharmacy and Pharmacology. 2008; 60(8):977-85.
 Kennedy LC, Bear AS, Young JK, et al. T cells enhance gold nanoparticle delivery to tumors in vivo. Nanoscale Research Letters. 2011; 6.
 Chithrani BD, Ghazani AA, Chan WCW. Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano Letters. 2006; 6(4):662-8.
 Trono JD, Mizuno K, Yusa N, et al. Size, Concentration and Incubation Time Dependence of Gold Nanoparticle Uptake into Pancreas Cancer Cells and its Future Application to X-ray Drug Delivery System. Journal of Radiation Research. 2011; 52(1):103-9.
 Chithrani DB, Dunne M, Stewart J, et al. Cellular uptake and transport of gold nanoparticles incorporated in a liposomal carrier'. Nanomedicine-Nanotechnology Biology and Medicine. 2010; 6(1):161-9.
 Pan Y, Neuss S, Leifert A, et al. Size-dependent cytotoxicity of gold nanoparticles. Small. 2007; 3(11):1941-9.
 Hauck TS, Ghazani AA, Chan WCW. Assessing the effect of surface chemistry on gold nanorod uptake, toxicity, and gene expression in mammalian cells. Small. 2008; 4(1):153-9.
 Chattopadhyay N, Cai ZL, Pignol JP, et al. Design and Characterization of HER-2-Targeted Gold Nanoparticles for Enhanced X-radiation Treatment of Locally Advanced Breast Cancer. Molecular Pharmaceutics. 2010; 7(6):2194-206.
 Bliss CI. The toxicity of poisons applied jointly. Annals of Applied Biology. 1939; 26(3):585-615.
 Lechtman E, Chattopadhyay N, Cai Z, et al. Implications on clinical scenario of gold nanoparticle radiosensitization in regards to photon energy, nanoparticle size, concentration and location. Physics in medicine and biology. 2011; 56(15):4631-47.
 Hao YZ, Yang XY, Song S, et al. Exploring the cell uptake mechanism of phospholipid and polyethylene glycol coated gold nanoparticles. Nanotechnology. 2012; 23(4).
 Kumar R, Roy I, Ohulchanskky TY, et al. In Vivo Biodistribution and Clearance Studies Using Multimodal Organically Modified Silica Nanoparticles. Acs Nano. 2010; 4(2):699-708.
 Wang C, Jiang Y, Li X, et al. Thioglucose-bound gold nanoparticles increase the radiosensitivity of a triple-negative breast cancer cell line (MDA-MB-231). Breast Cancer.
 Wang CH, Li XH, Wang Y, et al. Enhancement of radiation effect and increase of apoptosis in lung cancer cells by thio-glucose-bound gold nanoparticles at megavoltage radiation energies. Journal of Nanoparticle Research. 2013; 15(5).
 Zhang XD, Guo ML, Wu HY, et al. Irradiation stability and cytotoxicity of gold nanoparticles for radiotherapy. International Journal of Nanomedicine. 2009; 4:165-73.
 Feril LB, Tachibana K, Ikeda-Dantsuji Y, et al. Therapeutic potential of low-intensity ultrasound (part 2): biomolecular effects, sonotransfection, and sonopermeabilization. Journal of Medical Ultrasonics. 2008; 35(4):161-7.
 Stieger SM, Caskey CF, Adamson RH, et al. Enhancement of vascular permeability with low-frequency contrast-enhanced ultrasound in the chorioallantoic membrane model. Radiology. 2007; 243(1):112-21.
 Schlicher RK, Radhakrishna H, Tolentino TP, et al. Mechanism of intracellular delivery by acoustic cavitation. Ultrasound in medicine & biology. 2006; 32(6):915-24.