An overview of therapeutic applications of ultrasound based on synergetic effects with gold nanoparticles and laser excitation

Document Type: Review Article


1 Medical Physics Department, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

2 Medical Physics research Center, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Medical Physics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran


Acoustic cavitation which occurs at high intensities of ultrasound waves can be fatal for tumor cells. The existence of dissolved gases and also the presence of nanoparticles (NPs) in a liquid, irradiated by ultrasound, decrease the acoustic cavitation onset threshold and the resulting bubbles collapse. On the other hand, due to unique capabilities and optical properties of gold nanoparticles (GNPs), they have been emphasized as effective NPs in the field of tumor therapy. Absorption of the laser light by GNPs causes the water molecules around the NPs to evaporate and produces vapor cavities. In this paper, we have reviewed published studies in the fields of ultrasound therapy, sonodynamic therapy (SDT) and synergism of low-level ultrasound and also laser radiation in the presence of GNPs.


Main Subjects

1. Warden SJ, Fuchs PK, Kessler CK, Avin KG, Cardinal RE, Stewart RL. Ultrasound produced by a conventional therapeutic ultrasound unit accelerates fracture repair. Phys Ther 2006; 86: 1118–1127.
2. Wu F, Wang ZB, Chen WZ. Extracorporeal focused ultrasound surgery for treatment of human solid carcinomas: early Chinese clinical experience. Ultrasound Med Biol 2004; 30: 245-260.
3. Kennedy JE. High-intensity focused ultrasound in the treatment of solid tumours. Nat Rev Cancer 2005;5:321-327.
4. Lejbkowicz F, Zwiran M, Salzberg S. The response of normal and malignant cells to ultrasound in vitro. Ultrasound Med Biol 1993; 19: 75-82.
5. Yu T, Wang Z, Jiang S. Potentiation of cytotoxicity of adriamycin on human ovarian carcinoma cell line 3AO by low-level ultrasound. Ultrasonics 2001;39:307-309.
6. Yu T, Wang Z, Mason TJ. A review of research into the uses of low level ultrasound in cancer therapy. Ultrason Sonochem 2004;11:95-103.
7. Umemura K, Yumita N, Nishigaki R, Umemura S. Sonodynamically induced antitumor effect of Pheophorbide A. Cancer Lett 1996; 102: 151-157.
8. Yumita N, Sasaki K, Umemura S, Nishigaki R. Sonodynamically induced antitumor effect of a gallium-porphyrin complex, ATX-70. Jpn J Cancer Res 1996; 87: 310-316.
9. Palumbo G. Photodynamic therapy and cancer: a brief sightseeing tour, Expert Opin. Drug Deliv 2007; 4:131-418.
10. Frenkel V. Ultrasound mediated delivery of drugs and genes to solid tumors. Adv Drug Deliv Rev 2008;60:1193-1208.
11. Marmottant P, Hilgenfeldt S. Controlled vesicle deformation and lysis by single oscillating bubbles. Nature 2003;423:153-156.
12. Hodnett M, Zeqiri B. A detector for monitoring the onset of cavitation during therapy-level measurements of ultrasonic power. J Phys Conf Ser 2004; 1: 112-117.
13. Tang H, Wang CC, Blankschtein D, Langer R. An investigation of the role of cavitation in low-frequency ultrasound-mediated transdermal drug transport. Pharm Res 2002;19:1160-1169.
14. Barnett SB. Conclusions and recommendations on thermal and non- thermal mechanisms for biologic effects of ultrasound. Ultrasound Med Biol 1998; 24: 41-49.
15. Barnett S, Ter Haar G, Ziskin M, Nyborg W, Maeda K, Bang J. Current status of research on biophysical effects of ultrasound. Ultrasound Med Biol 1994;20:205-208.
16. Daniels S, Price DJ. Sonoluminescence in water and agar gels during irradiation with 0.75 MHz continuous-wave ultrasound. Ultrasound Med Biol 1991;17:297-308.
17. Bommannan D, Menon GK, Okuyama H, Elias PM, Guy RH. Sonophoresis: II. Examination of the mechanism (s) of ultrasound enhanced transdermal drug delivery. Pharm Res 1992; 9:1043-1047.
18. Tuziuti T, Yasui K, Sivakumar M, Iida Y, Miyoshi N. Correlation between acoustic cavitation noise and yield enhancement of sonochemical reaction by particle addition. J Phys Chem 2005;109:4869-4872.
19. Farny CH, Wu T, Holt RG, Murray TW, Roy RA. Nucleating cavitation from laser-illuminated nano-particles. Acoust Res Lett Online 2005;6:138-143.
20. Izadifar Z, Babyn P, Chapman D. Mechanical and biological effects of ultrasound: A review of present knowledge. Ultrasound Med Biol 2017;43:1085-1104.
21. Kim YS, Rhim H, Choi MJ, Lim HK, Choi D. High-Intensity Focused Ultrasound Therapy: an Overview for Radiologists. Korean J Radiol. 2008; 9:291-302.
22. Clement G. Perspectives in clinical uses of high-intensity focused ultrasound. Ultrasonics 2004;42:1087-1093.
23. Wood RW, Loomis AL. The physical and biological effects of high frequency sound waves of great intensity. Philos Mag 1927; 4: 417-423.
24. Lynn JG, Zwemer RL, Chick AJ, Miller AF. A new method for the generation and use of focused ultrasound in experimental biology. J Gen Physiol 1942; 26: 179 193.
25. Fry WJ, Fry FJ. Fundamental neurological research and human neurosurgery using intense ultrasound. IRE Trans Med Electron ME-7 1960: 166-181.
26. Madersbacher S, Pedevilla M, Vingers L, Susani M, Marberger M. Effect of high-intensity focused ultrasound on human prostate cancer in vivo. Cancer Res 1995;55:3346-3351.
27. Ng KKC, Poon RTP, Chan SC, Chok KSH, Cheung TT, Tung H, et al. High-intensity focused ultrasound for hepatocellular carcinoma. Ann Surg 2011; 253;981-987.
28. Champlin V, Kaskey CF. Multi-focal HIFU reduces cavitation in mild-hyperthermia. J Ther Ultrasound 2017;5:12-18.
29. Sazgarnia A, Shanei A, Shanei MM. Monitoring of transient cavitation induced by ultrasound and intense pulsed light in presence of gold nanoparticles. Ultrason Sonochem 2014;21:268-274.
30. Flannigan DJ, Suslick KS. Inertially confined plasma in an imploding bubble. Nature Phys 2010;6:598-601.
31. May DJ, Allen JS, Ferrara KW. Dynamics and fragmentation of thick-shelled microbubbles. IEEE Trans Ultrason Ferroelectr Frequ Control 2002;49:1400-1410.
32. Miller MW, Miller DL, Brayman AA. A review of in vitro bioeffects of inertial ultrasonic cavitation from a mechanistic perspective. Ultrasound  Med Biol 1996;22:1131-1154.
33. Price GJ, Duck FA, Digby M, Holland W, Berryman T. Measurement of radical production as a result of cavitation in medical ultrasound fields. Ultrason Sonochem 1997;4:165-171.
34. Sazgarnia A, Shanei A, Eshghi H, Hassanzadeh-Khayyat M, Esmaily H, Shanei MM. Detection of sonoluminescence signals in a gel phantom in the presence of Protoporphyrin IX conjugated to gold nanoparticles. Ultrasonics 2013;53:29-35.
35. Fang X, Mark G, von Sonntag C. OH radical formation by ultrasound in aqueous solutions Part I: the chemistry underlying the terephthalate dosimeter. Ultrason Sonochem 1996;3:57-63.
36. Sazgarnia A, Shanei A. Evaluation of acoustic cavitation in terephthalic acid solutions containing gold nanoparticles by the spectrofluorometry method. Int J Photoenergy 2012; Article ID 376047:5 pages.
37. Mark G, Tauber A, Laupert R, Schuchmann HP, Schulz D, Mues A, et al. OH-radical formation by ultrasound in aqueous solution–Part II: Terephthalate and Fricke dosimetry and the influence of various conditions on the sonolytic yield. Ultrason Sonochem 1998;5:41-52.
38. Haosheng C, Jiadao W, Darong C. Cavitation damages on solid surfaces in suspensions containing spherical and irregular microparticles. Wear 2009;266:345-348.
39. Simonin J-P. On the mechanisms of in vitro and in vivo phonophoresis. J Control Release 1995;33:125-141.
40. Kimmel E. Cavitation bioeffects. Crit Rev Biomed Eng 2006; 34: 105–161.
41. Tran BC, Seo J, Hall TL, Fowlkes JB, Cain CA. Microbubble-enhanced cavitation for noninvasive ultrasound surgery. IEEE Trans Ultrason Ferroelectr Frequ Control 2003;50:1296-1304.
42. Skyba DM, Price RJ, Linka AZ, Skalak TC, Kaul S. Direct in vivo visualization of intravascular destruction of microbubbles by ultrasound and its local effects on tissue. Circulation 1998;98:290-293.
43. Poliachik SL, Chandler WL, Mourad PD, Bailey  MR, Bloch S, Cleveland RO, et al. Effect of high-intensity focused ultrasound on whole blood with and without microbubble contrast agent. Ultrasound Med Biol 1999;25:991-998.
44. Umemura S, Kawabata K, Sasaki K. Utilizing nonlinear behavior of microbubbles in medical ultrasound. Electr Commun Jpn (Part III: Fundam Electron Sci) 2007; 8: 1-6.
45. Roy RA, Madanshetty SI, Apfel RE. An acoustic back scattering technique for the detection of transient cavitation produced by microsecond pulses of ultrasound. J Acoust Soc Am 1991;87:2451–2458.
46. Chen H, Wang J, Chen D. Cavitation damages on solid surfaces in suspensions containing spherical and irregular microparticles. Wear 2009;266:345–348.
47. Sazgarnia A, Shanei A, Taheri AR, Tayyebi Meibodi N, Eshghi H, Attaran N, et al. Therapeutic effects of acoustic cavitation in the presence of gold nanoparticles on a colon tumor model. J Ultrasound Med 2013;32:475-483.
48. De Jong WH, Hagens WI, Krystek P, Burger MC, Sips AJ, Geertsma RE. Particle size-dependent organ distribution of gold nanoparticles after intravenous administration. Biomaterials 2008;29:1912-1919.
49. Balasubramanian SK, Jittiwat J, Manikandan J, Ong C-N, Liya EY, Ong W-Y. Biodistribution of gold nanoparticles and gene expression changes in the liver and spleen after intravenous administration in rats. Biomaterials 2010;31:2034-2042.
50. Shanei A, Shanei MM. Effect of gold nanoparticle size on acoustic cavitation using chemical dosimetry method. Ultrason sonochem 2017;34:45-50.
51. Tang W, Liu Q, Wang X, Zhang J, Wang P, Mi N. Ultrasound exposure in the presence of hematoporphyrin induced loss of membrane integral proteins and inactivity of cell proliferation associated enzymes in sarcoma 180 cells in vitro. Ultrason sonochem 2008;15:747-754.
52. Yumita N, Kawabata K-i, Sasaki K, Umemura S-i. Sonodynamic effect of erythrosin B on sarcoma 180 cells in vitro. Ultrason sonochem 2002;9:259-265.
53. Yumita N, Umemura S. Sonodynamic therapy with photofrin II on AH130 solid tumor. Cancer Chemother Pharmacol 2003;51:174-178.
54.  Tachibana K, Tachibana S. Application of ultrasound energy as a new drug delivery system. Jpn J Appl phys 1999;38:3014-3019.
55. Kessel D, Jeffers R, Fowlkes J, Cain C. Porphyrin-induced enhancement of ultrasound cytotoxicity. Int J Radiat Biol 1994;66:221-228.
56. Worthington A, Thompson J, Rauth A, Hunt J. Mechanism of ultrasound enhanced porphyrin cytotoxicity. Part I: a search for free radical effects. Ultrasound Med Biol 1997;23:1095-1105.
57. Mišík V, Riesz P. Recent applications of EPR and spin trapping to sonochemical studies of organic liquids and aqueous solutions. Ultrason Sonochem 1996;3:173-186.
58. Valko M, Rhodes C, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol  Interact 2006;160:1-40.
69. Nordberg J, Arnér ES. Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radical Bio Med 2001;31:1287-1312.
60. Kuroki M, Hachimine K, Abe H, Shibaquchi H, Kuroki M, Maekawa S, et al. Sonodynamic therapy of cancer using novel sonosensitizers. Anticancer Res 2007;27:3673-3677.
61. Abe H, Kuroki M, Tachibana K, Li T, Awasthi A, Ueno A, et al. Targeted sonodynamic therapy of cancer using a photosensitizer conjugated with antibody against carcinoembryonic antigen. Anticancer Res 2002;22:1575-1580.
62. Umemura Si, Yumita N, Nishigaki R. Enhancement of Ultrasonically Induced Cell Damage by a Gallium‐Porphyrin Complex, ATX‐70. Cancer Sci 1993;84:582-588.
63. MišÍk V, Riesz P. Free radical intermediates in sonodynamic therapy. Ann NY Acad Sci 2000;899:335-348.
64. Nomura H, Koda S, Yasuda K, Kojima Y. Ultrasonic irradiation effect on porphyrin and its application for quantification of ultrasonic intensity. Ultrasonics 1996;34:555-557.
65. Wang X, Xiong D, Wang J, Chen D, Zhang L, Zhang Y, et al. Investigation on damage of DNA molecules under irradiation of low frequency ultrasound in the presence of hematoporphyrin–gallium (HP–Ga) complex. Ultrason Sonochem 2008;15:761-767.
66. Suzuki N, Okada K, Chida S, Komori C, Shimada Y, Suzuki T. Antitumor effect of acridine orange under ultrasonic irradiation in vitro. Anticancer Res 2007;27:4179-4184.
67. Yamashita Y, Kai Y, Shirakusa T. Clinical use of photodynamic therapy for patients with cancer. International Congress Series: Elsevier 2004:169-174.
68. Liu Q, Wang X, Wang P, Xiao L. Sonodynamic antitumor effect of protoporphyrin IX disodium salt on S180 solid tumor. Chemotherapy 2007;53:429-436.
69. Sazgarnia A, Shanei A, Meibodi NT, Eshghi H, Nassirli H. A Novel Nanosonosensitizer for Sonodynamic Therapy. J Ultrasound Med 2011;30:1321-1329.
70. Clement G. Perspectives in clinical uses of high-intensity focused ultrasound. Ultrasonics 2004;42:1087-1093.
71. Wang S, Gao R, Zhou F, Selke M. Nanomaterials and singlet oxygen photosensitizers: potential applications in photodynamic therapy. J Mater Chem 2004;14:487-493.
72. Perez JLJ, Orea AC, Gallegos ER, Fuentes RG. Photoacoustic spectroscopy to determine in vitro the nonradiative relaxation time of porotoporphyrin IX solution containing gold metallic nanoparticles. Eur Phys Spec Top 2008;152:353–356.
73. Shanei A, Sazgarnia A, Tayyebi Meibodi N, Eshghi H, Hassanzadeh-Khayyat M, Esmaily H, et al. Sonodynamic therapy using protoporphyrin IX conjugated to gold nanoparticles: an in vivo study on a colon tumor model. Iran J Basic Med Sci 2012;15:759-767.
74. Eshghi H, Attaran N, Sazgarnia A, Mirzaie N, Shanei A. Synthesis and characterisation of new designed protoporphyrin-stabilised gold nanoparticles for cancer cells nanotechnology-based targeting. Int J Nanotechnol 2011;8:700-711.
75. Paciotti GF, Myer L, Weinreich D, Goia D, Pavel N, Mclaughlin RE, et al. Colloidal gold: a novel nanoparticle vector for tumor directed drug delivery. Drug deliv 2004;11:169-183.
76. Li B, Moriyama EH, Li F, Jarvi MT, Allen C, Wilson BC. Diblock copolymer micelles deliver hydrophobic protoporphyrin IX for photodynamic therapy. Photochem Photobiol 2007;83:1505-1512.
77. Shanei A, Sazgarnia A, Hassanzadeh-Kayyat M, Eshghi H, Soudmand S, Attaran Kakhki N. Evaluation of Sonochemiluminescence in a Phantom in the Presence of Protoporphyrin IX Conjugated to Nanoparticles. Iran J Med Phys 2012;9:41-50.
78. Pustovalov V, Babenko V. Optical properties of gold nanoparticles at laser radiation wavelengths for laser applications in nanotechnology and medicine. Laser Phys Lett 2004;1:516-520.
79. Miller DL. Frequency relationships for ultrasonic activation of free microbubbles, encapsulated microbubbles, and gas-filled micropores. J Acoust Soc Am 1998;104:2498-2505.
80. Barati AH, Mokhtari-Dizaji M, Mozdarani H, Bathaie SZ, Hassan ZM. Treatment of murine tumors using dual-frequency ultrasound in an experimental in vivo model. Ultrasound Med Biol 2009;35:756-763.