Ultrasound-mediated targeted microbubbles: a new vehicle for cancer therapy

Abstract

With the hope of overcoming the serious side effects, great endeavor has been made in tumor-targeted chemotherapy, and various drug delivery modalities and drug carriers have been made to decrease systemic toxicity caused by chemotherapeutic agents. Scientists from home and abroad focus on the research of targeted microbubbles contrast agent, and the use of the targeted ultrasound microbubble contrast agent can carry gene drugs and so on to the target tissue, as well as mediated tumor cell apoptosis and tumor microvascular thrombosis block, etc., thus plays the role of targeted therapy. Recent studies have elucidated the mechanisms of drug release and absorption, however, much work remains to be done in order to develop a successful and optimal system. In this review, we summarized the continuing efforts in understanding the usage of the ultrasound triggered target microbubbles in cancer therapy, from release mechanism to preparation methods. The latest applications of ultrasound-triggered targeted microbubbles in cancer therapy, especially in gene therapy and antiangiogenic cancer therapy were discussed. Moreover, we concluded that as a new technology, ultrasound–triggered targeted microbubbles used as drug carriers and imaging agents are still energetic and are very likely to be translated into clinic in the near future.

Key words： ultrasound-mediated; targeted microbubbles; cancer

Acknowledgments

This work was sponsored by Grant R31-2008-000-10103-01 from the World Class University (WCU) project of South Korea. Victor C. Yang is currently a participating faculty member in the Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, South Korea. It was also partially supported by National Key Basic Research Program of China (2013CB932502), School of Pharmacy, Fudan University & The Open Project Program of Key Laboratory of Smart Drug Delivery (Fudan University), MOE & PLA, China (SDD2011-02).

References

1 Rapoport N. Physical stimuli-responsive polymeric micelles for anti-cancer drug delivery. Progress in Polymer Science, 2007, 32(8–9): 962–990

2 Deckers R, Moonen C T W. Ultrasound triggered, image guided, local drug delivery. Journal of Controlled Release, 2010, 148(1): 25–33

3 Heath C H, Sorace A, Knowles J, Rosenthal E, Hoyt K. Microbubble therapy enhances anti-tumor properties of cisplatin and cetuximab in vitro and in vivo. Otolaryngology- Head and Neck Surgery, 2012, 146(6): 938–945

4 Bekeredjian R, Kroll R D, Fein E, Tinkov S, Coester C, Winter G, Katus H A, Kulaksiz H. Ultrasound targeted microbubble destruction increases capillary permeability in hepatomas. Ultrasound in Medicine & Biology, 2007, 33(10): 1592–1598

5 Carson A R, McTiernan C F, Lavery L, Grata M, Leng X, Wang J, Chen X, Villanueva F S. Ultrasound-targeted microbubble destruction to deliver siRNA cancer therapy. Cancer Research, 2012, 72(23): 6191–6199

6 Chang S, Guo J, Sun J, Zhu S, Yan Y, Zhu Y, Li M, Wang Z, Xu R X. Targeted microbubbles for ultrasound mediated gene transfection and apoptosis induction in ovarian cancer cells. Ultrasonics Sonochemistry, 2013, 20(1): 171–179

7 Gao Z, Kennedy A M, Christensen D A, Rapoport N Y. Drug-loaded nano/microbubbles for combining ultrasonography and targeted chemotherapy. Ultrasonics, 2008, 48(4): 260–270

8 Korpanty G, Chen S, Shohet R V, Ding J, Yang B, Frenkel P A, Grayburn P A. Targeting of VEGF-mediated angiogenesis to rat myocardium using ultrasonic destruction of microbubbles. Gene Therapy, 2005, 12(17): 1305–1312

9 Park K. Microbubble ultrasound-guided targeted delivery to tumors. Journal of Controlled Release, 2012, 157(2): 167

10 Korpanty G, Grayburn P A, Shohet R V, Brekken R A. Targeting vascular endothelium with avidin microbubbles. Ultrasound in Medicine & Biology, 2005, 31(9): 1279–1283

11 Villanueva F S. Ultrasound mediated destruction of DNA-loaded microbubbles for enhancement of cell-based therapies. JACC: Cardiovascular Imaging, 2009, 2(7): 880–882

12 Gao Z G, Fain H D, Rapoport N. Controlled and targeted tumor chemotherapy by micellar-encapsulated drug and ultrasound. Journal of Controlled Release, 2005, 102(1): 203–222

13 Rapoport N, Gao Z, Kennedy A. Multifunctional nanoparticles for combining ultrasonic tumor imaging and targeted chemotherapy. Journal of the National Cancer Institute, 2007, 99(14): 1095–1106

14 Gao Z, Fain H D, Rapoport N. Ultrasound-enhanced tumor targeting of polymeric micellar drug carriers. Molecular Pharmaceutics, 2004, 1(4): 317–330

15 Dijkmans P, Juffermans L, Musters R, Vanwamel A, Tencate F, Vangilst W, Visser C, Dejong N, Kamp O. Microbubbles and ultrasound: from diagnosis to therapy. European Journal of Echocardiography, 2004, 5(4): 245–256

16 Stride E, Saffari N. On the destruction of microbubble ultrasound contrast agents. Ultrasound in Medicine & Biology, 2003, 29(4): 563–573

17 Basta G, Venneri L, Lazzerini G, Pasanisi E, Pianelli M, Vesentini N, Del Turco S, Kusmic C, Picano E. In vitro modulation of intracellular oxidative stress of endothelial cells by diagnostic cardiac ultrasound. Cardiovascular Research, 2003, 58(1): 156–161

18 Wu J. Temperature rise generated by ultrasound in the presence of contrast agent. Ultrasound in Medicine & Biology, 1998, 24(2): 267–274

19 Unger E C, Hersh E, Vannan M, Matsunaga T O, McCreery T. Local drug and gene delivery through microbubbles. Progress in Cardiovascular Diseases, 2001, 44(1): 45–54

20 Liu Y, Miyoshi H, Nakamura M. Encapsulated ultrasound microbubbles: therapeutic application in drug/gene delivery. Journal of Controlled Release, 2006, 114(1): 89–99

21 Klibanov A L. Targeted delivery of gas-filled microspheres, contrast agents for ultrasound imaging. Advanced Drug Delivery Reviews, 1999, 37(1-3): 139–157

22 Fokong S, Theek B, Wu Z, Koczera P, Appold L, Jorge S, Resch-Genger U, van Zandvoort M, Storm G, Kiessling F, Lammers T. Image-guided, targeted and triggered drug delivery to tumors using polymer-based microbubbles. Journal of Controlled Release, 2012, 163(1): 75–81

23 Zhao Y Z, Lu C T, Mei X G. Optimization of the preparation of sonogenic phospholipids-based microbubbles by using central composite experimental design and response surface methodology. Acta pharmaceutica Sinica, 2008, 43(8): 862–867 (in Chinese)

24 Wang D S, Panje C, Pysz M A, Paulmurugan R, Rosenberg J, Gambhir S S, Schneider M, Willmann J K. Cationic versus neutral microbubbles for ultrasound-mediated gene delivery in cancer. Radiology, 2012, 264(3): 721–732

25 Higuchi Y, Kawakami S, Hashida M. Strategies for in vivo delivery of siRNAs: recent progress. BioDrugs, 2010, 24(3): 195–205

26 Carson A R, McTiernan C F, Lavery L, Hodnick A, Grata M, Leng X, Wang J, Chen X, Modzelewski R A, Villanueva F S. Gene therapy of carcinoma using ultrasound-targeted microbubble destruction. Ultrasound in Medicine & Biology, 2011, 37(3): 393–402

27 Feril L B Jr. Ultrasound-mediated gene transfection. Methods in Molecular Biology (Clifton, N.J.), 2009, 542: 179–194

28 Unger E C, Hersh E, Vannan M, Matsunaga T O, McCreery T. Local drug and gene delivery through microbubbles. Progress in Cardiovascular Diseases, 2001, 44(1): 45–54

29 Guo D P, Li X Y, Sun P, Tang Y B, Chen X Y, Chen Q, Fan L M, Zang B, Shao L Z, Li X R. Ultrasound-targeted microbubble destruction improves the low density lipoprotein receptor gene expression in HepG2 cells. Biochemical and Biophysical Research Communications, 2006, 343(2): 470–474

30 Unger E C, Matsunaga T O, McCreery T, Schumann P, Sweitzer R, Quigley R. Therapeutic applications of microbubbles. European Journal of Radiology, 2002, 42(2): 160–168

31 Liu Y, Yang H, Sakanishi A. Ultrasound: mechanical gene transfer into plant cells by sonoporation. Biotechnology Advances, 2006, 24(1): 1–16

32 Sirsi S R, Hernandez S L, Zielinski L, Blomback H, Koubaa A, Synder M, Homma S, Kandel J J, Yamashiro D J, Borden M A. Polyplex-microbubble hybrids for ultrasound-guided plasmid DNA delivery to solid tumors. Journal of Controlled Release, 2012, 157(2): 224–234

33 Li X H, Zhou P, Wang L H, Tian S M, Qian Y, Chen L R, Zhang P. The targeted gene (KDRP-CD/TK) therapy of breast cancer mediated by SonoVue and ultrasound irradiation in vitro. Ultrasonics, 2012, 52(1): 186–191

34 Li Y S, Davidson E, Reid C N, McHale A P. Optimising ultrasound-mediated gene transfer (sonoporation) in vitro and prolonged expression of a transgene in vivo: potential applications for gene therapy of cancer. Cancer Letters, 2009, 273(1): 62–69

35 Luo J, Zhou X, Diao L, Wang Z. Experimental research on wild-type p53 plasmid transfected into retinoblastoma cells and tissues using an ultrasound microbubble intensifier. Journal of International Medical Research, 2010, 38(3): 1005–1015

36 Tang Q, He X, Liao H, He L, Wang Y, Zhou D, Ye S, Chen Q. Ultrasound microbubble contrast agent-mediated suicide gene transfection in the treatment of hepatic cancer. Oncology Letters, 2012, 4(5): 970–972

37 Wang J F, Wang J B, Chen H, Zhang C M, Liu L, Pan S H, Wu C J. Ultrasound-mediated microbubble destruction enhances gene transfection in pancreatic cancer cells. Advances in Therapy, 2008, 25(5): 412–421

38 Watanabe A, Otake R, Nozaki T, Morii A, Ogawa R, Fujimoto S, Nakamura S, Fuse H, Kondo T. Effects of microbubbles on ultrasound-mediated gene transfer in human prostate cancer PC3 cells: comparison among Levovist, YM454, and MRX-815H. Cancer Letters, 2008, 265(1): 107–112

39 Chen Z Y, Liang K, Qiu R X. Targeted gene delivery in tumor xenografts by the combination of ultrasound-targeted microbubble destruction and polyethylenimine to inhibit survivin gene expression and induce apoptosis. Journal of Experimental & Clinical Cancer Research, 2010, 29(1): 152–160

40 Rahim A A, Taylor S L, Bush N L, ter Haar G R, Bamber J C, Porter C D. Spatial and acoustic pressure dependence of microbubble-mediated gene delivery targeted using focused ultrasound. Journal of Gene Medicine, 2006, 8(11): 1347–1357

41 Rahim A, Taylor S L, Bush N L, ter Haar G R, Bamber J C, Porter C D. Physical parameters affecting ultrasound/microbubble-mediated gene delivery efficiency in vitro. Ultrasound in Medicine & Biology, 2006, 32(8): 1269–1279

42 Bazan-Peregrino M, Arvanitis C D, Rifai B, Seymour L W, Coussios C C. Ultrasound-induced cavitation enhances the delivery and therapeutic efficacy of an oncolytic virus in an in vitro model. Journal of Controlled Release, 2012, 157(2): 235–242

43 O Boussif F L h, M A Zanta, M D Mergny, D Scherman, B Demeneix, J PBehr. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Proceedings of the National Academy of Sciences of the United States of America, 1995, 92(16): 7297–7301

44 Cochran M C, Eisenbrey J, Ouma R O, Soulen M, Wheatley M A. Doxorubicin and paclitaxel loaded microbubbles for ultrasound triggered drug delivery. International Journal of Pharmaceutics, 2011, 414(1-2): 161–170

45 Hobbs S K, Monsky W L, Yuan F, Roberts W G, Griffith L, Torchilin V P, Jain R K. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proceedings of the National Academy of Sciences of the United States of America, 1998, 95(8): 4607–4612

46 Maeda H, Wu J, Sawa T, Matsumura Y, Hori K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. Journal of Controlled Release, 2000, 65(1-2): 271–284

47 Ferrara K W, Borden M A, Zhang H. Lipid-shelled vehicles: engineering for ultrasound molecular imaging and drug delivery. Accounts of Chemical Research, 2009, 42(7): 881–892

48 Eisenbrey J R, Burstein O M, Kambhampati R, Forsberg F, Liu J B, Wheatley M A. Development and optimization of a doxorubicin loaded poly(lactic acid) contrast agent for ultrasound directed drug delivery. Journal of Controlled Release, 2010, 143(1): 38–44

49 Mohan P, Rapoport N. Doxorubicin as a molecular nanotheranostic agent: effect of doxorubicin encapsulation in micelles or nanoemulsions on the ultrasound-mediated intracellular delivery and nuclear trafficking. Molecular Pharmaceutics, 2010, 7(6): 1959–1973

50 Eisenbrey J R, Soulen M C, Wheatley M A. Delivery of encapsulated Doxorubicin by ultrasound-mediated size reduction of drug-loaded polymer contrast agents. IEEE Transactions on Bio-Medical Engineering, 2010, 57(1): 24–28

51 Lum A F, Borden M A, Dayton P A, Kruse D E, Simon S I, Ferrara K W. Ultrasound radiation force enables targeted deposition of model drug carriers loaded on microbubbles. Journal of Controlled Release, 2006, 111(1-2): 128–134

52 Ferrara K W B M, Zhang H. Lipid-shelled vehicles engineering for ultrasound molecular imaging and drug delivery. Accounts of Chemical Research, 2009, 42(7): 881–892

53 Guibal A, Taillade L, Mule S, Comperat E, Badachi Y, Golmard J L, Le Guillou-Buffello D, Rixe O, Bridal S L, Lucidarme O. Noninvasive contrast-enhanced US quantitative assessment of tumor microcirculation in a murine model: effect of discontinuing anti-VEGF therapy. Radiology, 2010, 254(2): 420–429

54 Leong-Poi H, Christiansen J, Klibanov A L, Kaul S, Lindner J R. Noninvasive assessment of angiogenesis by ultrasound and microbubbles targeted to alpha(v)-integrins. Circulation, 2003, 107(3): 455–460

55 Hu G Q, Yang L, Xiao Y B, Xie J J, Wu J F, Cai J J, Liu J, Liao W J, Bin J P. Evaluation of tumor angiogenesis using microbubbles conjugated with RGD peptides and contrast enhanced ultrasound. Zhonghua Zhong Liu Za Zhi, 2010, 32(9): 655–658 (in Chinese)

56 Warram J M, Sorace A G, Saini R, Borovjagin A V, Hoyt K, Zinn K R. Systemic delivery of a breast cancer-detecting adenovirus using targeted microbubbles. Cancer Gene Therapy, 2012, 19(8): 545–552

57 Warram J M, Sorace A G, Saini R, Umphrey H R, Zinn K R, Hoyt K. A triple-targeted ultrasound contrast agent provides improved localization to tumor vasculature. Journal of Ultrasound in Medicine, 2011, 30(7): 921–931

58 Patan S. Vasculogenesis and angiogenesis as mechanisms of vascular network formation, growth and remodeling. Journal of Neuro-Oncology, 2000, 50(1-2): 1–15

59 Patan S. Vasculogenesis and angiogenesis. Cancer Treatment and Research, 2004, 117: 3–32

60 Price R J, Skyba D M, Kaul S, Skalak T C. Delivery of colloidal particles and red blood cells to tissue through microvessel ruptures created by targeted microbubble destruction with ultrasound. Circulation, 1998, 98(13): 1264–1267

61 Skyba D M, Price R J, Linka A Z, Skalak T C, Kaul S. Direct in vivo visualization of intravascular destruction of microbubbles by ultrasound and its local effects on tissue. Circulation, 1998, 98(4): 290–293

62 Tammela T, Zarkada G, Wallgard E, Murtomaki A, Suchting S, Wirzenius M, Waltari M, Hellstrom M, Schomber T, Peltonen R, Freitas C, Duarte A, Isoniemi H, Laakkonen P, Christofori G, Ylä-Herttuala S, Shibuya M, Pytowski B, Eichmann A, Betsholtz C, Alitalo K. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature, 2008, 454(7204): 656–660

63 Pysz M A, Foygel K, Rosenberg J, Gambhir S S, Schneider M, Willmann J K. Antiangiogenic cancer therapy: monitoring with molecular US and a clinically translatable contrast agent (BR55). Radiology, 2010, 256(2): 519–527

64 Palmowski M, Huppert J, Ladewig G, Hauff P, Reinhardt M, Mueller M M, Woenne E C, Jenne J W, Maurer M, Kauffmann G, Semmler W, Kiessling F. Molecular profiling of angiogenesis with targeted ultrasound imaging: early assessment of antiangiogenic therapy effects. Molecular Cancer Therapeutics, 2008, 7(1): 101–109

65 Anderson C R, Hu X, Zhang H, Tlaxca J, Decleves A E, Houghtaling R, Sharma K, Lawrence M, Ferrara K W, Rychak J J. Ultrasound molecular imaging of tumor angiogenesis with an integrin targeted microbubble contrast agent. Investigative Radiology, 2011, 46(4): 215–224

66 Palmowski M, Huppert J, Ladewig G, Hauff P, Reinhardt M, Mueller M M, Woenne E C, Jenne J W, Maurer M, Kauffmann G W, Semmler W, Kiessling F. Molecular profiling of angiogenesis with targeted ultrasound imaging: early assessment of antiangiogenic therapy effects. Molecular Cancer Therapeutics, 2008, 7(1): 101–109

67 Fan C H, Ting C Y, Liu H L, Huang C Y, Hsieh H Y, Yen T C, Wei K C, Yeh C K. Antiangiogenic-targeting drug-loaded microbubbles combined with focused ultrasound for glioma treatment. Biomaterials, 2013, 34(8): 2142–2155

68 Williams R, Hudson J M, Lloyd B A, Sureshkumar A R, Lueck G, Milot L, Atri M, Bjarnason G A, Burns P N. Dynamic microbubble contrast-enhanced US to measure tumor response to targeted therapy: a proposed clinical protocol with results from renal cell carcinoma patients receiving antiangiogenic therapy. Radiology, 2011, 260(2): 581–590

69 Sirsi S R, Flexman M L, Vlachos F, Huang J, Hernandez S L, Kim H K, Johung T B, Gander J W, Reichstein A R, Lampl B, Wang A, Hielscher A H, Kandel J J, Yamashiro D J, Borden M A. Contrast ultrasound imaging for identification of early responder tumor models to anti-angiogenic therapy. Ultrasound in Medicine & Biology, 2012, 38(6): 1019–1029

70 Rix A, Lederle W, Siepmann M, Fokong S, Behrendt F F, Bzyl J, Grouls C, Kiessling F, Palmowski M. Evaluation of high frequency ultrasound methods and contrast agents for characterising tumor response to anti-angiogenic treatment. European Journal of Radiology, 2012, 81(10): 2710–2716