Korean Journal of Radiology

The Korean Society of Radiology (대한영상의학회)
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Therapeutic Effects of Microbubbles Added to Combined High-Intensity Focused Ultrasound and Chemotherapy in a Pancreatic Cancer Xenograft Model

  • Yu, Mi Hye (Department of Radiology, Konkuk University Medical Center) ;
  • Lee, Jae Young (Department of Radiology, Seoul National University Hospital) ;
  • Kim, Hae Ri (Department of Pre-Dentistry, Gangneung-Wonju National University College of Dentistry) ;
  • Kim, Bo Ram (Department of Radiology, Seoul National University Hospital) ;
  • Park, Eun-Joo (Department of Radiology, Seoul National University Hospital) ;
  • Kim, Hoe Suk (Department of Radiology, Seoul National University Hospital) ;
  • Han, Joon Koo (Department of Radiology, Seoul National University Hospital) ;
  • Choi, Byung Ihn (Department of Radiology, Chung-Ang University Hospital)
  • Received : 2016.02.22
  • Accepted : 2016.06.15
  • Published : 2016.09.01
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Abstract

Objective: To investigate whether high-intensity focused ultrasound (HIFU) combined with microbubbles enhances the therapeutic effects of chemotherapy. Materials and Methods: A pancreatic cancer xenograft model was established using BALB/c nude mice and luciferase-expressing human pancreatic cancer cells. Mice were randomly assigned to five groups according to treatment: control (n = 10), gemcitabine alone (GEM; n = 12), HIFU with microbubbles (HIFU + MB, n = 11), combined HIFU and gemcitabine (HIGEM; n = 12), and HIGEM + MB (n = 13). After three weekly treatments, apoptosis rates were evaluated using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay in two mice per group. Tumor volume and bioluminescence were monitored using high-resolution 3D ultrasound imaging and in vivo bioluminescence imaging for eight weeks in the remaining mice. Results: The HIGEM + MB group showed significantly higher apoptosis rates than the other groups (p < 0.05) and exhibited the slowest tumor growth. From week 5, the tumor-volume-ratio relative to the baseline tumor volume was significantly lower in the HIGEM + MB group than in the control, GEM, and HIFU + MB groups (p < 0.05). Despite visible distinction, the HIGEM and HIGEM + MB groups showed no significant differences. Conclusion: High-intensity focused ultrasound combined with microbubbles enhances the therapeutic effects of gemcitabine chemotherapy in a pancreatic cancer xenograft model.

Keywords

Acknowledgement

Supported by : National Research Foundation of Korea (NRF), NIPA (National IT Industry Promotion Agency), SNUH

References

  1. von Wichert G, Seufferlein T, Adler G. Palliative treatment of pancreatic cancer. J Dig Dis 2008;9:1-7 https://doi.org/10.1111/j.1443-9573.2007.00314.x
  2. Hariharan D, Saied A, Kocher HM. Analysis of mortality rates for pancreatic cancer across the world. HPB (Oxford) 2008;10:58-62 https://doi.org/10.1080/13651820701883148
  3. Cardenes HR, Chiorean EG, Dewitt J, Schmidt M, Loehrer P. Locally advanced pancreatic cancer: current therapeutic approach. Oncologist 2006;11:612-623 https://doi.org/10.1634/theoncologist.11-6-612
  4. Marechal R, Bachet JB, Mackey JR, Dalban C, Demetter P, Graham K, et al. Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma. Gastroenterology 2012;143:664-674.e1-e6 https://doi.org/10.1053/j.gastro.2012.06.006
  5. el-Kamar FG, Grossbard ML, Kozuch PS. Metastatic pancreatic cancer: emerging strategies in chemotherapy and palliative care. Oncologist 2003;8:18-34
  6. Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15:2403-2413 https://doi.org/10.1200/JCO.1997.15.6.2403
  7. Mukherjee S, Hudson E, Reza S, Thomas M, Crosby T, Maughan T. Pancreatic cancer within a UK cancer network with special emphasis on locally advanced non-metastatic pancreatic cancer. Clin Oncol (R Coll Radiol) 2008;20:535-540 https://doi.org/10.1016/j.clon.2008.02.003
  8. Orsi F, Arnone P, Chen W, Zhang L. High intensity focused ultrasound ablation: a new therapeutic option for solid tumors. J Cancer Res Ther 2010;6:414-420 https://doi.org/10.4103/0973-1482.77064
  9. Jang HJ, Lee JY, Lee DH, Kim WH, Hwang JH. Current and future clinical applications of high-intensity focused ultrasound (HIFU) for pancreatic cancer. Gut Liver 2010;4 Suppl 1:S57-S61 https://doi.org/10.5009/gnl.2010.4.S1.S57
  10. Wu F, Wang ZB, Zhu H, Chen WZ, Zou JZ, Bai J, et al. Feasibility of US-guided high-intensity focused ultrasound treatment in patients with advanced pancreatic cancer: initial experience. Radiology 2005;236:1034-1040 https://doi.org/10.1148/radiol.2362041105
  11. Xiong LL, Hwang JH, Huang XB, Yao SS, He CJ, Ge XH, et al. Early clinical experience using high intensity focused ultrasound for palliation of inoperable pancreatic cancer. JOP 2009;10:123-129
  12. Sofuni A, Moriyasu F, Sano T, Yamada K, Itokawa F, Tsuchiya T, et al. The current potential of high-intensity focused ultrasound for pancreatic carcinoma. J Hepatobiliary Pancreat Sci 2011;18:295-303 https://doi.org/10.1007/s00534-010-0355-4
  13. Sung HY, Jung SE, Cho SH, Zhou K, Han JY, Han ST, et al. Long-term outcome of high-intensity focused ultrasound in advanced pancreatic cancer. Pancreas 2011;40:1080-1086 https://doi.org/10.1097/MPA.0b013e31821fde24
  14. Li PZ, Zhu SH, He W, Zhu LY, Liu SP, Liu Y, et al. Highintensity focused ultrasound treatment for patients with unresectable pancreatic cancer. Hepatobiliary Pancreat Dis Int 2012;11:655-660 https://doi.org/10.1016/S1499-3872(12)60241-0
  15. Zhao H, Yang G, Wang D, Yu X, Zhang Y, Zhu J, et al. Concurrent gemcitabine and high-intensity focused ultrasound therapy in patients with locally advanced pancreatic cancer. Anticancer Drugs 2010;21:447-452 https://doi.org/10.1097/CAD.0b013e32833641a7
  16. Lee JY, Choi BI, Ryu JK, Kim YT, Hwang JH, Kim SH, et al. Concurrent chemotherapy and pulsed high-intensity focused ultrasound therapy for the treatment of unresectable pancreatic cancer: initial experiences. Korean J Radiol 2011;12:176-186 https://doi.org/10.3348/kjr.2011.12.2.176
  17. Iwanaga K, Tominaga K, Yamamoto K, Habu M, Maeda H, Akifusa S, et al. Local delivery system of cytotoxic agents to tumors by focused sonoporation. Cancer Gene Ther 2007;14:354-363 https://doi.org/10.1038/sj.cgt.7701026
  18. Karshafian R, Bevan PD, Williams R, Samac S, Burns PN. Sonoporation by ultrasound-activated microbubble contrast agents: effect of acoustic exposure parameters on cell membrane permeability and cell viability. Ultrasound Med Biol 2009;35:847-860 https://doi.org/10.1016/j.ultrasmedbio.2008.10.013
  19. Bazan-Peregrino M, Arvanitis CD, Rifai B, Seymour LW, Coussios CC. Ultrasound-induced cavitation enhances the delivery and therapeutic efficacy of an oncolytic virus in an in vitro model. J Control Release 2012;157:235-242 https://doi.org/10.1016/j.jconrel.2011.09.086
  20. Kudo N, Okada K, Yamamoto K. Sonoporation by singleshot pulsed ultrasound with microbubbles adjacent to cells. Biophys J 2009;96:4866-4876 https://doi.org/10.1016/j.bpj.2009.02.072
  21. Tzu-Yin W, Wilson KE, Machtaler S, Willmann JK. Ultrasound and microbubble guided drug delivery: mechanistic understanding and clinical implications. Curr Pharm Biotechnol 2013;14:743-752
  22. Delalande A, Kotopoulis S, Postema M, Midoux P, Pichon C. Sonoporation: mechanistic insights and ongoing challenges for gene transfer. Gene 2013;525:191-199 https://doi.org/10.1016/j.gene.2013.03.095
  23. Ibsen S, Schutt CE, Esener S. Microbubble-mediated ultrasound therapy: a review of its potential in cancer treatment. Drug Des Devel Ther 2013;7:375-388
  24. Lawrie A, Brisken AF, Francis SE, Tayler DI, Chamberlain J, Crossman DC, et al. Ultrasound enhances reporter gene expression after transfection of vascular cells in vitro. Circulation 1999;99:2617-2620 https://doi.org/10.1161/01.CIR.99.20.2617
  25. Lindner JR. Microbubbles in medical imaging: current applications and future directions. Nat Rev Drug Discov 2004;3:527-532 https://doi.org/10.1038/nrd1417
  26. Hernot S, Klibanov AL. Microbubbles in ultrasound-triggered drug and gene delivery. Adv Drug Deliv Rev 2008;60:1153-1166 https://doi.org/10.1016/j.addr.2008.03.005
  27. Suzuki R, Oda Y, Utoguchi N, Maruyama K. Progress in the development of ultrasound-mediated gene delivery systems utilizing nano- and microbubbles. J Control Release 2011;149:36-41 https://doi.org/10.1016/j.jconrel.2010.05.009
  28. Watanabe Y, Aoi A, Horie S, Tomita N, Mori S, Morikawa H, et al. Low-intensity ultrasound and microbubbles enhance the antitumor effect of cisplatin. Cancer Sci 2008;99:2525-2531 https://doi.org/10.1111/j.1349-7006.2008.00989.x
  29. Lee NG, Berry JL, Lee TC, Wang AT, Honowitz S, Murphree AL, et al. Sonoporation enhances chemotherapeutic efficacy in retinoblastoma cells in vitro. Invest Ophthalmol Vis Sci 2011;52:3868-3873 https://doi.org/10.1167/iovs.10-6501
  30. Kotopoulis S, Dimcevski G, Gilja OH, Hoem D, Postema M. Treatment of human pancreatic cancer using combined ultrasound, microbubbles, and gemcitabine: a clinical case study. Med Phys 2013;40:072902 https://doi.org/10.1118/1.4808149
  31. Kotopoulis S, Delalande A, Popa M, Mamaeva V, Dimcevski G, Gilja OH, et al. Sonoporation-enhanced chemotherapy significantly reduces primary tumour burden in an orthotopic pancreatic cancer xenograft. Mol Imaging Biol 2014;16:53-62 https://doi.org/10.1007/s11307-013-0672-5
  32. Kim JH, Kim H, Kim YJ, Lee JY, Han JK, Choi BI. Dynamic contrast-enhanced ultrasonographic (DCE-US) assessment of the early response after combined gemcitabine and HIFU with low-power treatment for the mouse xenograft model of human pancreatic cancer. Eur Radiol 2014;24:2059-2068 https://doi.org/10.1007/s00330-014-3260-4
  33. Lee ES, Lee JY, Kim H, Choi Y, Park J, Han JK, et al. Pulsed high-intensity focused ultrasound enhances apoptosis of pancreatic cancer xenograft with gemcitabine. Ultrasound Med Biol 2013;39:1991-2000 https://doi.org/10.1016/j.ultrasmedbio.2013.06.004
  34. Greis C. Technology overview: SonoVue (Bracco, Milan). Eur Radiol 2004;14 Suppl 8:P11-P15 https://doi.org/10.1007/s10406-004-0076-3
  35. He W, Wang W, Zhou P, Wang YX, Zhou P, Li RZ, et al. Enhanced ablation of high intensity focused ultrasound with microbubbles: an experimental study on rabbit hepatic VX2 tumors. Cardiovasc Intervent Radiol 2011;34:1050-1057 https://doi.org/10.1007/s00270-010-0052-3
  36. Chung DJ, Cho SH, Lee JM, Hahn ST. Effect of microbubble contrast agent during high intensity focused ultrasound ablation on rabbit liver in vivo. Eur J Radiol 2012;81:e519-e523 https://doi.org/10.1016/j.ejrad.2011.06.002
  37. Poff JA, Allen CT, Traughber B, Colunga A, Xie J, Chen Z, et al. Pulsed high-intensity focused ultrasound enhances apoptosis and growth inhibition of squamous cell carcinoma xenografts with proteasome inhibitor bortezomib. Radiology 2008;248:485-491 https://doi.org/10.1148/radiol.2482071674
  38. Yu T, Wang G, Hu K, Ma P, Bai J, Wang Z. A microbubble agent improves the therapeutic efficiency of high intensity focused ultrasound: a rabbit kidney study. Urol Res 2004;32:14-19 https://doi.org/10.1007/s00240-003-0362-x
  39. Kaneko Y, Maruyama T, Takegami K, Watanabe T, Mitsui H, Hanajiri K, et al. Use of a microbubble agent to increase the effects of high intensity focused ultrasound on liver tissue. Eur Radiol 2005;15:1415-1420 https://doi.org/10.1007/s00330-005-2663-7
  40. Luo W, Zhou X, Ren X, Zheng M, Zhang J, He G. Enhancing effects of SonoVue, a microbubble sonographic contrast agent, on high-intensity focused ultrasound ablation in rabbit livers in vivo. J Ultrasound Med 2007;26:469-476 https://doi.org/10.7863/jum.2007.26.4.469
  41. Luo W, Zhou X, Zhang J, Qian Y, Zheng M, Yu M, et al. Analysis of apoptosis and cell proliferation after high intensityfocused ultrasound ablation combined with microbubbles in rabbit livers. Eur J Gastroenterol Hepatol 2007;19:962-968 https://doi.org/10.1097/MEG.0b013e3282cfb6f0
  42. Vykhodtseva N, McDannold N, Martin H, Bronson RT, Hynynen K. Apoptosis in ultrasound-produced threshold lesions in the rabbit brain. Ultrasound Med Biol 2001;27:111-117 https://doi.org/10.1016/S0301-5629(00)00275-1
  43. Kennedy JE, Ter Haar GR, Cranston D. High intensity focused ultrasound: surgery of the future? Br J Radiol 2003;76:590- 599 https://doi.org/10.1259/bjr/17150274
  44. Hilger I, Rapp A, Greulich KO, Kaiser WA. Assessment of DNA damage in target tumor cells after thermoablation in mice. Radiology 2005;237:500-506 https://doi.org/10.1148/radiol.2372041451
  45. Casey G, Cashman JP, Morrissey D, Whelan MC, Larkin JO, Soden DM, et al. Sonoporation mediated immunogene therapy of solid tumors. Ultrasound Med Biol 2010;36:430-440 https://doi.org/10.1016/j.ultrasmedbio.2009.11.005
  46. Jiang L, Hu B, Guo Q, Chen L. Treatment of pancreatic cancer in a nude mouse model using high-intensity focused ultrasound. Exp Ther Med 2013;5:39-44 https://doi.org/10.3892/etm.2012.744

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