Breaking free from vascular confinement: status and prospects for submicron ultrasound contrast agents

Opinion

Carly Pellow, David E. Goertz, Gang Zheng

Published Online: Nov 17 2017

DOI: 10.1002/wnan.1502

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

The development of encapsulated microbubbles (~1–6 μm) has expanded the utility of ultrasound from soft tissue anatomical imaging to not only functional intravascular imaging, but therapeutic interventions, with compelling studies of elicited biological effects. The large diameter of these bubbles has confined their utility to the vasculature, but converging interdisciplinary research pathways are giving rise to new submicron ultrasound contrast agents capable of extending their effects beyond the vascular compartment. This article reviews the status and prospects of exogenous agents including nanobubbles, echogenic liposomes, gas vesicles, cavitation seeds, and nanodroplets, and assesses outstanding criticisms preventing their advance. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Emerging Technologies

Schematic of ultrasound‐stimulated microbubble behaviors and biophysical effects. (a) Mechanical stresses of bubble oscillation cause overexpansion and contraction of the vessel walls, and (b) circulating fluid flow patterns or acoustic streaming around the bubble give rise to shear stress at the lumen surface of endothelial cells. Larger oscillation amplitudes can lead to inertial cavitation and bubble collapse, with (c) microjetting capable of perforating the vessel wall, and (d) violent shock waves with accompanying temperature and pressure elevations and the release of reactive oxygen species.

[ Normal View | Magnified View ]

Classes of submicron ultrasound contrast agents, including nanobubbles, echogenic liposomes, gas vesicles, cavitation seeds, and nanodroplets. Various encapsulating shells have been reported, including lipids, polymers, and proteins, and perfluorocarbon cores. These exogenous agents vary in size from 20 nm to several microns.

[ Normal View | Magnified View ]

In contrast to healthy tissue, tumors demand a high supply of nutrients and oxygen, and will invade existing vessels and develop new ones to meet these demands. However, uneven angiogenic signaling from the tumor results in vessels abnormal in form and architecture, characterized by haphazard dilated, tortuous channels lacking the organization and hierarchy of healthy blood vessels. This vascular heterogeneity is coupled with structural abnormalities; a defective endothelium barrier, with larger gaps and poorly adherent pericytes. While microbubbles are confined to remain in the vasculature, physiological consequences of tumor microvasculature afford opportunities for nanoscale agents to escape the intravascular space and expand bubble‐mediated potential.

[ Normal View | Magnified View ]

References

Gramiak, R, Shah, PM. Echocardiography of the aortic root. Invest Radiol 1968, 3:356–366.
Nanda, NC. History of echocardiographic contrast agents. Clin Cardiol 1997, 20:7–11.
Quaia, E. Microbubble ultrasound contrast agents: an update. Eur Radiol 2007, 17:1995–2008.
Medwin, H. Counting bubbles acoustically: a review. Ultrasonics 1977, 15:7–13.
Leighton, TG. The Acoustic Bubble. San Diego: Academic Press; 1994.
Appis, AW, Tracy, MJ, Feinstein, SB. Update on the safety and efficacy of commercial ultrasound contrast agents in cardiac applications. Echo Res Practice 2015, 2:R55–R62.
Sidhu, PS, Choi, BI, Nielsen, MB. The EFSUMB guidelines on the non‐hepatic clinical applications of contrast enhanced ultrasound (CEUS): a new dawn for the escalating use of this ubiquitous technique. Ultraschall Medizin 2012, 33:5–7.
Goertz, DE. An overview of the influence of therapeutic ultrasound exposures on the vasculature: high intensity ultrasound and microbubble‐mediated bioeffects. Int J Hyperthermia 2015, 31:134–144.
Lentacker, I, De Cock, I, Deckers, R, De Smedt, SC, Moonen, CTW. Understanding ultrasound induced sonoporation: definitions and underlying mechanisms. Adv Drug Deliv Rev 2014, 72:49–64.
Lentacker, I, De Smedt, SC, Sanders, NN. Drug loaded microbubble design for ultrasound triggered delivery. Soft Matter 2009, 5:2161–2170.
Unger, EC, Porter, T, Culp, W, Labell, R, Matsunaga, T, Zutshi, R. Therapeutic applications of lipid‐coated microbubbles. Adv Drug Deliv Rev 2004, 56:1291–1314.
Kooiman, K, Vos, HJ, Versluis, M, de Jong, N. Acoustic behaviour of microbubbles and implications for drug delivery. Adv Drug Deliv Rev 2014, 72:28–48.
Miller, DL, Dou, C, Armstrong, WF. The influence of agent delivery mode on cardiomyocyte injury induced by myocardial contrast echocardiography in rats. Ultrasound Med Biol 2005, 31:1257–1263.
Hwang, JH, Tu, J, Brayman, AA, Matula, TJ, Crum, LA. Correlation between inertial cavitation dose and endothelial cell damage in vivo. Ultrasound Med Biol 2006, 32:1611–1619.
Hwang, JH, Zhou, Y, Warren, C, Brayman, AA, Crum, LA. Targeted venous occlusion using pulsed high‐intensity focused ultrasound. IEEE Trans Biomed Eng 2010, 57:37–40.
Molina, C, Ribo, M, Rubiera, M, Montaner, J, Santamarina, E, Delgado‐Mederos, R, Arenillas, J, Huertas, R, Purroy, F, Delgado, P, et al. Microbubble administration accelerates clot lysis during continuous 2‐MHz ultrasound monitoring in stroke patients treated with intravenous tissue plasminogen activator. Stroke 2006, 37:425–429.
Datta, S, Coussios, CC, McAdory, LE, Tan, J, Porter, T, De Courten‐Myers, G, Holland, C k. Correlation of cavitation with ultrasound enhancement of thrombolysis. Ultrasound Med Biol 2006, 32:1257–1267.
Song, J, Qi, M, Kaul, S, Price, RJ. Stimulation of arteriogenesis in skeletal muscle by microbubble destruction with ultrasound. Circulation 2002, 106:1550–1555.
Song, J, Cottler, PS, Klibanov, AL, Kaul, S, Price, RJ. Microvascular remodeling and accelerated hyperemia blood flow restoration in arterially occluded skeletal muscle exposed to ultrasonic microbubble destruction. Am J Physiol 2004, 287:2754–2761.
Wood, AKW, Ansaloni, S, Ziemer, LS, Lee, WM‐F, Feldman, MD, Sehgal, CM. The antivascular action of physiotherapy ultrasound on murine tumors. Ultrasound Med Biol 2005, 31:1403–1410.
Goertz, DE, Todorova, M, Mortazavi, O, Agache, V, Chen, B, Karshafian, R, Hynynen, K. Antitumor effects of combining docetaxel (Taxotere) with the antivascular action of ultrasound stimulated microbubbles. PLoS One 2012, 7:e52307.
Mainprize, DT. Blood‐brain barrier disruption using transcranial MRI‐guided focused ultrasound. ClinicalTrials.gov, 12 January 2015. [Online]. Available at: https://clinicaltrials.gov/ct2/show/NCT02343991.
Burgess, A, Hynynen, K. Noninvasive and targeted drug delivery to the brain using focused ultrasound. ACS Chem Nerosci 2013, 4:519–526.
Dimcevski, G, Kotopoulis, S, Bjanes, T, Hoem, D, Schjott, J, Gjertsen, BT, Biermann, M, Molven, A, Sorbye, H, McCormack, E, et al. A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer. J Control Release 2016, 243:172–181.
Goertz, DE, de Jong, N, van der Steen, AFW. Attenuation and size distribution measurements of definity and manipulated definity populations. Ultrasound Med Biol 2007, 33:1376–1388.
Goertz, DE, Wong, SWS, Cherin, E, Chin, CT, Burns, PN, Foster, FS. Nonlinear scattering properties of microbubble contrast agents at high frequencies. In: Proceedings of IEEE Ultrasonics Symposium; 2001.
Goertz, DE, Frijlink, M, Bouakaz, A, Chin, CT, de Jong, N, van der Steen, AWF. The effect of bubble size on nonlinear scattering at high frequencies. In: Proceedings of IEEE Ultrasonics Symposium; 2003.
Alheshibri, M, Qian, J, Jehannin, M, Craig, VSJ. A history of nanobubbles. Langmuir 2016, 32:11086–11100.
Faez, T, Emmer, M, Kooiman, K, Versluis, M, van der Steen, AFW, de Jong, N. 20 years of ultrasound contrast agent modeling. IEEE Trans Ultrason Ferroelectr Freq Control 2013, 60:7–20.
Krupka, TM, Solorio, L, Wilson, RE, Wu, H, Azar, N, Exner, AA. Formulation and characterization of echogenic lipid‐pluronic nanobubbles. Mol Pharm 2009, 7:49–59.
Jong, N d, Emmer, M, van Wamel, A, Versluis, M. Ultrasonic characterization of ultrasound contrast agents. Med Biol Eng Comput 2009, 47:861–873.
Goertz, DE, Frijlink, ME, De Jong, N, van der Steen, AFW. High frequency nonlinear scattering from a micrometer to submicrometer sized lipid encapsulated contrast agent. Ultrasound Med Biol 2006, 32:569–577.
Wang, Y, Liu, G, Hu, H, Li, TY, Johri, AM, Li, X, Wang, J. Stable encapsulated air nanobubbles in water. Angew Chem Int Ed 2015, 54:14291–14294.
Wu, H, Rognin, NG, Krupka, TM, Solorio, L, Yoshiara, H, Guenette, G, Sanders, C, Kamiyama, N, Exner, AA. Acoustic characterization and pharmacokinetic analyses of new nanobubble ultrasound contrast agents. Ultrasound Med Biol 2013, 39:2137–2146.
Perera, RH, Wu, H, Peiris, P, Hernandez, C, Burke, A, Zhang, H, Exner, AA. Improving performance of nanoscale ultrasound contrast agents using N,N‐diethylacrylamide stabilization. Nanomed Nanotechnol Biol Med 2017, 13:59–67.
Dube, NK, Oeffinger, BE, Wheatley, MA. Development and characterization of a nano‐sized surfactant stabilized contrast agent for diagnostic ultrasound. In: IEEE, pp. 102–103; 2003.
Xing, Z, Wang, J, Ke, H, Zhao, B, Yue, X, Dai, Z, Liu, J. The fabrication of novel nanobubble ultrasound contrast agent for potential tumor imaging. Nanotechnology 2010, 21:145607.
Wheatley, MA, Lewandowski, J. Nano‐sized ultrasound contrast agent: salting‐out method. Mol Imaging 2010, 9:96–107.
Cavalli, R, Bisazza, A, Giustetto, P, Civra, A, Lembo, D, Trotta, G, Guiot, C, Trotta, M. Preparation and characterization of dextran nanobubbles for oxygen delivery. Int J Pharm 2009, 381:160–165.
Cai, WB, Yang, HL, Zhang, J, Yin, JK, Yang, YL, Yuan, LJ, Zhang, L, Duan, YY. The optimized fabrication of nanobubbles as ultrasound contrast agents for tumor imaging. Sci Rep 2015, 5:13725.
Yin, T, Wang, P, Zheng, R, Zheng, B, Cheng, D, Zhang, X, Shuai, X. Nanobubbles for enhanced ultrasound imaging of tumors. Int J Nanomedicine 2012, 7:895–904.
Sirsi, SR, Borden, MA. State‐of‐the‐art materials for ultrasound‐triggered drug delivery. Adv Drug Deliv Rev 2014, 72:3–14.
Helfield, B, Cherin, E, Foster, FS, Goertz, DE. Investigating the subharmonic response of individual phospholipid encapsulated microbubbles at high frequencies: a comparative study of five agents. Ultrasound Med Biol 2012, 38:846–863.
Alkan‐Onyuksel, H, Demos, SM, Lanza, GM, Vonesh, MJ, Klegerman, ME, Kane, BJ, Kuszak, J, McPherson, DD. Development of inherently echogenic liposomes as an ultrasonic contrast agent. J Pharm Sci 1996, 85:486–490.
Huang, S‐L. Liposomes in ultrasonic drug and gene delivery. Adv Drug Deliv Rev 2008, 60:1167–1176.
Huang, S‐L, McPherson, DD, MacDonald, RC. A method to co‐encapsulate gas and drugs in liposomes for ultrasound‐controlled drug delivery. Ultrasound Med Biol 2008, 34:1272–1280.
Huang, S‐L, MacDonald, RC. Acoustically active liposomes for drug encapsulation and ultrasound‐triggered release. Biochim Biophys Acta Biomembr 2004, 1665:134–141.
Coussios, CC, Holland, CK, Jakubowska, L, Huang, S‐L, MacDonald, RC, Nagaraj, A, McPherson, DD. In vitro characterization of liposomes and optison by acoustic scattering at 3.5 MHz. Ultrasound Med Biol 2004, 30:181–190.
Radhakrishnan, K, Haworth, KJ, Huang, S‐L, Klegerman, ME, McPherson, DD, Holland, CK. Stability of echogenic liposomes as a blood pool ultrasound contrast agent in a physiologic flow phantom. Ultrasound Med Biol 2012, 38:1970–1981.
Huang, S, Hamilton, AJ, Tiukinhoy, SD, Nagaraj, A, Kane, BJ, Klegerman, M, McPherson, DD, MacDonald, RC. Liposomes as ultrasound imaging contrast agents and as utlrasound‐sensitive drug delivery agents. Cell Mol Biol Lett 2002, 7:233–235.
Kopechek, J, Abruzzo, T, Wang, B, Chrzanowski, S, Smith, D, Kee, PH, Huang, S‐L, Collier, J, McPherson, DD, Holland, CK. Ultrasound‐mediated release of hydrophilic and lipophilic agents from echogenic liposomes. J Ultrasound Med 2008, 27:1597–1606.
Klegerman, ME, Wassler, M, Huang, S‐L, Zhou, Y, Kim, H, Shelat, HS, Holland, CK, Geng, Y‐J, McPherson, DD. Liposomal modular complexes for simultaneous delivery of bioactive gases and therapeutics. J Control Release 2010, 142:326–331.
Fix, SM, Borden, MA, Dayton, PA. Therapeutic gas delivery via microbubbles and liposomes. J Control Release 2015, 209:139–149.
Bouakaz, A, De Jong, N, Cachard, C. Standard properties of ultrasound contrast agents. Ultrasound Med Biol 1998, 24:469–472.
Walsby, AE. Gas Vesicles. Microbiol Rev 1994, 58:94–144.
Shapiro, MG, Goodwill, PW, Neogy, A, Yin, M, Foster, FS, Schaffer, DV, Conolly, SM. Biogenic gas nanostructures as ultrasonic molecular reporters. Nat Nanotechnol 2014, 9:311–316.
Lakshmanan, A, Farhadi, A, Nety, SP, Lee‐Gosselin, A, Bourdeau, RW, Maresca, D, Shapiro, MG. Molecular engineering of acoustic protein nanostructures. ACS Nano 2016, 10:7314–7322.
Cherin, E, Melis, JM, Bourdeau, RW, Yin, M, Kochmann, DM, Foster, SF, Shapiro, MG. Acoustic behaviour of Halobacterium salinarium gas vesicles in the high‐frequency range: experiments and modeling. Ultrasound Med Biol 2017, 43:1016–1030.
Maresca, D, Lakshmanan, A, Lee‐Gosselin, A, Melis, JM, Ni, Y‐L, Bourdeau, RW, Kochmann, DM, Shapiro, MG. Nonlinear ultrasound imaging of nanoscale acoustic biomolecules. Appl Phys Lett 2017, 110:073704.
Yang, Y, Qiu, Z, Liu, C, Huang, Y, Sun, L. Acoustic characterization of nano gas vesicles. In: IEEE International Ultrasonics Symposium Proceedings, 2015.
Pfeifer, F. Distribution, formation and regulation of gas vesicles. Nat Rev Microbiol 2012, 10:705–715.
Borkent, BM, Gekle, S, Prosperetti, A, Lohse, D. Nucleation threshold and deactivation mechanisms of nanoscopic cavitation nuclei. Phys Fluids 2009, 21:102003.
Harvey, EN, Barnes, KK, McElroy, WD, Whitely, AH, Pease, DC, Cooper, KW. Bubble formation in animals. I. Physical factors. J Cell Comp Physiol 1944, 24:1–22.
Apfel, RE. The role of impurities in cavitation‐threshold determination. J Acoust Soc Am 1970, 48:1179–1186.
Atchley, AA, Prosperetti, A. The crevice model of bubble nucleation. J Acoust Soc Am 1989, 86:1065–1084.
Crum, LA. Tensile strength of water. Nature 1979, 278:148–149.
Zhao, Y, Zhu, Y. Synergistic cytotoxicity of low‐energy ultrasound and innovative mesoporous silica‐based sensitive nanoagents. J Mater Sci 2014, 49:3665–3673.
Yildirim, A, Chattaraj, R, Blum, NT, Goldscheitter, GM, Goodwin, AP. Stable encapsulation of air in mesoporous silica nanoparticles: fluorocarbon‐free nanoscale ultrasound contrast agents. Adv Healthc Mater 2016, 5:1290–1298.
Yildirim, A, Chattaraj, R, Blum, NT, Goodwin, AP. Understanding acoustic cavitation initiation by porous nanoparticles: toward nanoscale agents for ultrasound imaging and therapy. Chem Mater 2016, 28:5962–5972.
Jin, Q, Kang, S‐T, Chang, Y‐C, Zheng, H, Yeh, C‐K. Inertial cavitation initiated by polytetrafluoroethylene nanoparticles under pulsed ultrasound stimulation. Ultrason Sonochem 2016, 32:1–7.
Kwan, JJ, Myers, R, Coviello, CM, Grahan, SM, Shah, AR, Stride, E, Carlisle, RC, Coussios, CC. Ultrasound‐propelled nanocups for drug delivery. Small 2015, 11:5305–5314.
Kwan, JJ, Lajoinie, G, de Jong, N, Stride, E, Versluis, M, Coussios, CC. Ultrahigh‐speed dynamics of micrometer‐scale inertial cavitation from nanoparticles. Phys Rev Appl 2016, 6:044004.
Rapoport, N, Gao, Z, Kennedy, A. Multifunctional nanoparticles for combining ultrasonic tumor imaging and targeted chemotherapy. J Natl Cancer Inst 2007, 99:1095–1106.
Ho, Y‐J, Chang, Y‐C, Yeh, C‐K. Improving nanoparticle penetration in tumors by vascular disruption with acoustic droplet vaporization. Theranostics 2016, 6:392–403.
Couture, O, Bevan, PD, Cherin, E, Cheung, K, Burns, PN, Foster, FS. Investigating perfluorohexane particles with high‐frequency ultrasound. Ultrasound Med Biol 2006, 32:73–82.
Lanza, GM, Wallace, KD, Scott, MJ, Chacheris, WP, Abendschein, DR, Christy, DH, Sharkey, AM, Miller, JG, Gaffney, PJ, Wickline, SA. A novel site‐targeted ultrasonic contrast agent with broad biomedical applications. Circulation 1996, 94:3334–3340.
Sheeran, P, Matsuura, N, Borden, MA, Williams, R, Matsunaga, TO, Burns, PN, Dayton, PA. Methods of generating submicrometer phase‐shift perfluorocarbon droplets for applications in medical ultrasonography. IEEE Trans Ultrason Ferroelectr Freq Control 2017, 64:252–263.
Tran, TD, Caruthers, SD, Hughes, M, Marsh, JN, Cyrus, T, Winter, PM, Neubauer, AM, Wickline, SA, Lanza, GM. Clinical applications of perfluorocarbon nanoparticles for molecular imaging and targeted therapeutics. Int J Nanomedicine 2007, 2:515–526.
Lanza, GM, Trousil, RL, Wallace, KD, Rose, JH, Hall, CS, Scott, MJ, Miller, JG, Eisenberg, PR, Gaffney, PJ, Wickline, SA. In vitro characterization of a novel, tissue‐targeted ultrasonic contrast system with acoustic microscopy. J Acoust Soc Am 1998, 104:3665–3672.
Paproski, RJ, Forbich, A, Huynh, E, Chen, J, Lewis, JD, Zheng, G, Zemp, RJ. Porphyrin nanodroplets: sub‐micrometer ultrasound and photoacoustic contrast imaging agents. Small 2016, 12:371–380, 2–5.
Martin, KH, Dayton, PA. Current status and prospects for microbubbles in ultrasound and theranostics. WIREs Nanomed Nanobiotechnol 2013, 5:329–345.
Kripfgans, OD, Fowlkes, JB, Miller, DL, Eldevik, OP, Carson, PL. Acoustic droplet vaporization for therapeutic and diagnostic applications. Ultrasound Med Biol 2000, 26:1177–1189.
Schad, KC, Hynynen, K. In vitro characterization of perfluorocarbon droplets for focused ultrasound therapy. Phys Med Biol 2010, 55:4933–4947.
Giesecke, T, Hynynen, K. Ultrasound‐mediated cavitation thresholds of liquid perfluorocarbon droplets in vitro. Ultrasound Med Biol 2003, 29:1359–1365.
Sheeran, PS, Matsunaga, TO, Dayton, PA. Phase‐transition thresholds and vaporization phenomena for ultrasound phase‐change nanoemulsions assessed via high speed optical microscopy. Phys Med Biol 2013, 58:4513–4534.
Shpak, O, Verweij, M, Vos, HJ, de Jong, N, Lohse, D, Versluis, M. Acoustic droplet vaporization is initiated by superharmonic focusing. Proc Natl Acad Sci U S A 2013, 111:1697–1702.
Samuel, S, Duprey, A, Fabiilli, ML, Bull, JL, Fowlkes, BJ. In vivo microscopy of targeted vessel occlusion employing acoustic droplet vaporization. Microcirculation 2012, 19:501–509.
Sheeran, PS, Dayton, PA. Phase‐change contrast agents for imaging and therapy. Curr Pharm Des 2012, 18:2152–2165.
Haworth, KJ, Fowlkes, JB, Carson, PL, Kripfgans, OD. Towards aberration correction of transcranial ultrasound using acoustic droplet vaporization. Ultrasound Med Biol 2008, 34:435–445.
Sheeran, PS, Streeter, JE, Mullin, LB, Matsunaga, TO, Dayton, PA. Toward ultrasound molecular imaging with phase‐change contrast agents: an in vitro proof of principle. Ultrasound Med Biol 2013, 39:893–902.
Sheeran, PS, Rojas, JD, Puett, C, Hjelmquist, J, Arena, CB, Dayton, PA. Contrast‐enhanced ultrasound imaging and in vivo circulatory kinetics with low‐boiling‐point nanoscale phase‐change perfluorocarbon agents. Ultrasound Med Biol 2015, 41:814–831.
Rapoport, NY, Kennedy, AM, Shea, JE, Scaife, CL, Nam, K‐H. Controlled and targeted tumor chemotherapy by ultrasound‐activated nanoemulsions/microbubbles. J Control Release 2009, 138:268–276.
Sheeran, PS, Wong, VP, Luois, S, McFarland, RJ, Ross, WD, Feingold, S, Matsunaga, TO, Dayton, PA. Decafluorobutane as a phase‐change contrast agent for low‐energy extravascular ultrasonic imaging. Ultrasound Med Biol 2011, 37:1518–1530.
Reznik, N, Williams, R, Burns, PN. Investigation of vaporized submicron perfluorocarbon droplets as an ultrasound contrast agent. Ultrasound Med Biol 2011, 37:1271–1279.
Zhang, P, Porter, T. An in vitro study of a phase‐shift nanoemulsion: a potential nucleation agent for bubble‐enhanced HIFU tumor ablation. Ultrasound Med Biol 2010, 36:1856–1866.
Moyer, LC, Timbie, KF, Sheeran, PS, Price, RJ, Miller, GW, Dayton, PA. High‐intensity focused ultrasound ablation enhancement in vivo via phase‐shift nanodroplets compared to microbubbles. J Therap Ultrasound 2015, 3:7.
Seo, M, Williams, R, Matsuura, N. Size reduction of cosolvent‐infused microbubbles to form acoustically responsive monodisperse perfluorocarbon nanodroplets. Lab Chip 2015, 15:3581–3590.
Anderson, W, Kozak, D, Coleman, VA, Jamting, AK, Trau, M. A comparative study of submicron particle sizing platforms: accuracy, precision and resolution analysis of polydisperse particle size distributions. J Colloid Interface Sci 2013, 405:322–330.
de Jong, N, Hoff, L, Skotland, T, Bom, N. Absorption and scatter of encapsulated gas filled microspheres: theoretical considerations and some measurements. Ultrasonics 1992, 30:95–103.
van der Meer, SM, Dollet, B, Voormolen, MM, Chin, CT, Bouakaz, A, de Jong, N, Versluis, M, Lohse, D. Microbubble spectroscopy of ultrasound contrast agents. J Acoust Soc Am 2007, 121:648–656.
Jong, N d, Emmer, M, Chin, CT, Bouakaz, A, Mastik, F, Lohse, D, Versluis, M. “Compression‐only” behaviour of phospholipid‐coated contrast bubbles. Ultrasound Med Biol 2007, 33:653–656.
Helfield, BL, Goertz, DE. Nonlinear resonance behaviour and linear shell estimates for Definity and MicroMarker assessed with acoustic microbubble spectroscopy. J Acoust Soc Am 2013, 133:1158–1168.
Fan, C‐H, Liu, H‐L, Ting, C‐Y, Lee, Y‐H, Huang, C‐Y, Ma, Y‐J, Wei, K‐C, Yen, T‐C, Yeh, C‐K. Submicron‐bubble‐enhanced focused ultrasound for blood brain barrier disruption and improved CNS drug delivery. PLoS One 2014, 5:9.
Matsuura, N, Koonar, E, Zhu, S, Leung, BY, Seo, M, Sivapalan, N, Goertz, DE. Inducing antivascular effects in tumors with ultrasound stimulated micron‐sized bubbles. In: IEEE International Ultrasonics Symposium; 2015.
Helfield, BL, Leung, BYC, Goertz, DE. The effect of boundary proximity on the response of individual ultrasound contrast agent microbubbles. Phys Med Biol 2014, 59:1721–1745.
Blake, J, Gibson, D. Cavitation bubbles near boundaries. Annu Rev Fluid Mech 1987, 19:99–123.
Kobayashi, H, Watanabe, R, Choyke, PL. Improving conventional enhanced permeability and retention (EPR) effects; what is the appropriate target? Theranostics 2014, 4:81–89.
Heneweer, C, Holland, JP, Divilov, V, Carlin, S, Lewis, JS. Magnitude of enhanced permeability and retention effect in tumors with different phenotypes: 89‐Zr‐albumin as a model system. J Nucl Med 2011, 52:625–633.
Wilhelm, S, Tavares, AJ, Dai, Q, Ohta, S, Audet, J, Dvorak, HF, Chan, WCW. Analysis of nanoparticle delivery to tumours. Nat Rev Mater 2016, 1:1–12.
Lanza, GM, Moonen, C, Baker, JRJ, Chang, E, Cheng, Z, Grodzinski, P, Ferrara, K, Hynynen, K, Kelloff, G, Lee, Y‐EK, et al. Assessing the barriers to image‐guided drug delivery. WIREs Nanomed Nanobiotechnol 2014, 6:1–14.
Huynh, E, Leung, BYC, Helfield, BL, Shakiba, M, Gandier, J‐A, Jin, CS, Master, ER, Wilson, BC, Goertz, DE, Zheng, G. In situ conversion of porphyrin microbubbles to nanoparticles for multimodality imaging. Nat Nanotechnol 2015, 2:325–332.
Huynh, E, Jin, CS, Wilson, BC, Zheng, G. Aggregate enhanced trimodal porphyrin shell microbubbles for ultrasound, photoacoustic, and fluorescence imaging. Bioconjug Chem 2014, 25:796–801.
Huynh, E, Lovell, JF, Helfield, BL, Jeon, M, Kim, C, Goertz, DE, Wilson, BC, Zheng, G. Porphyrin shell microbubbles with intrinsic ultrasound and photoacoustic properties. J Am Chem Soc 2012, 134:16464–16467.
Blum, NT, Yildirim, A, Chattaraj, R, Goodwin, AP. Nanoparticles formed by acoustic destruction of microbubbles and their utilization for imaging effects on therapy by high intensity focused ultrasound. Theranostics 2017, 7:694–702.
Lajoinie, G, De Cock, I, Coussios, CC, Lentacker, I, Le Gac, S, Stride, E, Versluis, M. In vitro methods to study bubble‐cell interactions: fundamentals and therapeutic applications. Biomicrofluidics 2016, 10:011501.
Nhan, T, Burgess, A, Hynynen, K. Transducer design and characterization for dorsal based ultrasound exposure and two photon imaging of in vivo blood‐brain barrier disruption in a rat model. IEEE Trans Ultrason Ferroelectr Freq Control 2013, 60:1376–1385.
Burgess, A, Cho, EE, Shaffaf, L, Nhan, T, Poon, C, Hynynen, K. The use of two‐photon microscopy to study the biological effects of focused ultrasound on the brain. In: Proc SPIE 8226; 2012.

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

Breaking free from vascular confinement: status and prospects for submicron ultrasound contrast agents

Browse by Topic

Access to this WIREs title is by subscription only.

The latest WIREs articles in your inbox