Skip to main content

Advertisement

SpringerLink
Log in

Dual-frequency ultrasound activation of nanomicellar doxorubicin in targeted tumor chemotherapy

  • Original Article
  • Published:
Journal of Medical Ultrasonics Aims and scope Submit manuscript

Abstract

Introduction

This study investigated the therapeutic effect of dual-frequency sonication (3 MHz and 28 kHz) at low intensity levels in combination with micellar doxorubicin in the treatment of a tumor model of spontaneous breast adenocarcinoma in Balb/c mice.

Methods

We used sonication frequencies 28 kHz and 3 MHz and their dual combinations in the progressive wave mode to enhance acoustic cavitation. Then, the antitumor effect of the simultaneous dual-frequency ultrasound (28 kHz and 3 MHz) at low intensity levels in combination with doxorubicin and micellar doxorubicin injection was investigated in a spontaneous model of breast adenocarcinoma in Balb/c mice. Sixty-three tumor-bearing mice were randomly divided into seven groups: control, sham, sonication with dual frequency, doxorubicin without sonication, doxorubicin with dual-frequency sonication, micellar doxorubicin without sonication, and micellar doxorubicin with dual-frequency sonication. The tumor volume change relative to the initial volume, tumor growth inhibition ratio, the required times for each tumor to reach two (T 2) and five (T 5) times its initial volume, and survival period were the tumor growth delay parameters which were calculated and recorded at various times after treatment.

Results

The results of the combination of frequencies 28 kHz (0.04 W/cm2) and 3 MHz (2.00 W/cm2) showed remarkable enhancement of the cavitation activity compared with single-frequency sonication (P < 0.05). The micellar doxorubicin injection with sonication group showed a significant difference in the relative volume percent parameter compared with the other groups (P < 0.05). Additionally, the T 2 and T 5 times in the micellar doxorubicin with sonication group were significantly higher than in the other groups (P < 0.05). Also, the survival period of the mice in the micellar doxorubicin with sonication group was significantly longer than in the other groups (P < 0.05). These findings were verified histopathologically.

Conclusion

This study shows that simultaneous combined dual-frequency ultrasound sonication in continuous mode is effective in producing cavitation activity at low intensity. We conclude that dual-frequency sonication with micellar doxorubicin injection extends survival in a murine breast adenocarcinoma model.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  1. Barati AH, Mokhtari-Dizaji M, Mozdarani H, et al. Treatment of murine tumors using dual-frequency ultrasound in an experimental in vivo model. Ultrasound Med Biol. 2009;35:756–63.

    Article  PubMed  Google Scholar 

  2. Gao Z, Fain H, Rapoporrt N. Controlled and targeted tumor chemotherapy by micellar encapsulated drug and ultrasound. J Control Release. 2005;102:203–22.

    Article  CAS  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. Leighton TG. The acoustic bubble. London: Academic Press; 1994. p. 67–93.

    Book  Google Scholar 

  5. Bailey M, Halaas D, Reed J, et al. Dual frequency high intensity focused ultrasound to control bubbles. In: Proceedings of the 2nd international symposium on therapeutic ultrasound. 2002. p. 51.

  6. Barati AH, Mokhtari-Dizaji M, Mozdarani H, et al. Effect of exposure parameters on cavitation induced by low level dual frequency ultrasound. Ultrason Sonochem. 2007;14:783–9.

    Article  CAS  PubMed  Google Scholar 

  7. Feng R, Zhao Y, Zhu C, et al. Enhancement of ultrasonic cavitation yield by multi-frequency sonication. Ultrason Sonochem. 2002;9:231–6.

    Article  CAS  PubMed  Google Scholar 

  8. Hasanzadeh H, Mokhtari-Dizaji M, Bathaie SZ, et al. Enhancement and control of acoustic cavitation yield by low-level dual frequency sonication: a subharmonic analysis. Ultrason Sonochem. 2011;18:394–400.

    Article  CAS  PubMed  Google Scholar 

  9. Husseini G, Myrup G, Pitt W, et al. Factors affecting acoustically triggered release of drugs from polymeric micelles. J Control Release. 2000;69:43–52.

    Article  CAS  PubMed  Google Scholar 

  10. Husseini G, Christensen D, Rapoport N, et al. Ultrasonic release of Doxorubicin from Pluronic P105 micelles stabilized with an interpenetrating network of N,N-diethylacrylamide. J Control Release. 2002;83:303–5.

    Article  CAS  PubMed  Google Scholar 

  11. Husseini G, de la Rosa MA, Gabuji T, et al. Release of Doxorubicine from unstablized and stabilized micelles under the action of ultrasound. J Nanosci Nanotechnol. 2007;7:1028–33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Larina I, Evers B, Ashitkov T, et al. Enhancement of drug delivery in tumors by using interaction of nanoparticles with ultrasound radiation. Technol Cancer Res Treat. 2005;4:217–26.

    PubMed  Google Scholar 

  13. Marine A, Muniruzzaman M, Rapoport N. Acoustic activation of drug delivery from polymeric micelles: effect of pulsed ultrasound. J Control Release. 2001;71:239–49.

    Article  Google Scholar 

  14. Nelson J, Roeder B, Carmen J, et al. Ultrasonically activated chemotherapeutic drug delivery in a rat model. Cancer Res. 2002;62:7280–3.

    CAS  PubMed  Google Scholar 

  15. Alakhov V, Klinski E, Li S, et al. Block copolymer-based formulation of doxorubicin. From cell screen to clinical trials. Colloids Surf B Biointerfaces. 1999;16:113–34.

    Article  CAS  Google Scholar 

  16. Colombo PE, Boustta M, Poujol S, et al. Biodistribution of doxorubicin-alkylated poly (l-lysine citramide imide) conjugates in an experimental model of peritoneal carcinomatosis after intraperitoneal administration. Eur J Pharm Sci. 2007;31:43–52.

    Article  CAS  PubMed  Google Scholar 

  17. Fundar A, Cavalli R, Bargoni A, et al. Non-stealth and stealth solid lipid nanoparticles (SLN) carrying doxorubicin: pharmacokinetics and tissue distribution after i.v. administration to rats. Pharmacol Res. 2000;42:337–43.

    Article  Google Scholar 

  18. Kümmerle A, Krueger T, Dusmet M, et al. A validated assay for measuring doxorubicin in biological fluids and tissues in an isolated lung perfusion model: matrix effect and heparin interference strongly influence doxorubicin measurements. J Pharm Biomed Anal. 2003;33:475–94.

    Article  PubMed  Google Scholar 

  19. Osman AMM, Nemnem MM, Abou-Bakr AA, et al. Effect of methimazole treatment on doxorubicin-induced cardiotoxicity in mice. Food Chem Toxicol. 2009;47:2425–30.

    Article  CAS  PubMed  Google Scholar 

  20. Yokoyama M, Miyauchi M, Yamada N, et al. Characterization and anticancer activity of the micelle-forming polymeric anticancer drug adriamycin-conjugated poly(ethylene glycol)-poly(aspartic acid) block copolymer. Cancer Res. 1990;50:1693–700.

    CAS  PubMed  Google Scholar 

  21. Yokoyama M, Miyauchi M, Yamada N, et al. Polymer micelles as novel drug carrier: adriamycin-conjugated poly (ethylene glycol)-poly (aspartic acid) block copolymer. J Control Release. 1990;11:269–78.

    Article  CAS  Google Scholar 

  22. Kazunori K, Glenn SK, Masayuki Y, et al. Block copolymer micelles as vehicles for drug delivery. J Control Release. 1993;24:119–32.

    Article  Google Scholar 

  23. Miwa A, Ishibe A, Nakano M, et al. Development of novel chitosan derivatives as micellar carriers of taxol. Pharm Res. 1998;15:1844–50.

    Article  CAS  PubMed  Google Scholar 

  24. Son YJ, Jang JS, Cho YW, et al. Biodistribution and anti-tumor efficacy of doxorubicin loaded glycol–chitosan nanoaggregates by EPR effect. J Control Release. 2003;91:135–45.

    Article  CAS  PubMed  Google Scholar 

  25. Yokoyama M, Okano T, Sakurai Y, et al. Toxicity and antitumor activity against solid tumors of micelle-forming polymeric anticancer drug and its extremely long circulation in blood. Cancer Res. 1991;51:3229–36.

    CAS  PubMed  Google Scholar 

  26. Yoo HS, Park TG. Biodegradable polymeric micelles composed of doxorubicin conjugated PLGA–PEG block copolymer. J Control Release. 2001;70:63–70.

    Article  CAS  PubMed  Google Scholar 

  27. Hasanzadeh H, Mokhtari-Dizaji M, Bathaie SZ, et al. Effect of local dual frequency sonication on drug distribution from polymeric nanomicelles. Ultrason Sonochem. 2011;18:1165–71.

    Article  CAS  PubMed  Google Scholar 

  28. Pruitt JD, Husseini G, Rapoport N, et al. Stabilization of Pluronic P-105 micelles with an interpenetrating network of N,N-diethylacrylamide. Macromolecules. 2000;33:9306–9.

    Article  CAS  Google Scholar 

  29. Bloom HJ, Richardson WW. Histological grading and prognosis in breast cancer: a study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer. 1957;11:359–77.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Spiegel MR. Mathematical handbook of formulas and tables. New York: McGraw-Hill; 1990. p. 134–9.

    Google Scholar 

  31. Tomayko MM, Reynolds CP. Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother Pharmacol. 1989;24:148–54.

    Article  CAS  PubMed  Google Scholar 

  32. Zhao L, Ma J, Zhai X. Enhanced mechanism of catalytic ozonation by ultrasound with orthogonal dual frequencies for the degradation of nitrobenzene in aqueous solution. Ultrason Sonochem. 2010;17:84–91.

    Article  CAS  PubMed  Google Scholar 

  33. Servant G, Laborde JL, Hita A, et al. On the interaction between ultrasound waves and bubble clouds in mono- and dual-frequency sonoreactors. Ultrason Sonochem. 2003;10:347–55.

    Article  CAS  PubMed  Google Scholar 

  34. Tatake PA, Pandit AB. Modelling and experimental investigation into cavity dynamics and cavitational yield: influence of dual frequency ultrasound sources. Chem Eng Sci. 2002;57:4987–95.

    Article  CAS  Google Scholar 

  35. Iernetti G, Ciuti P, Dezhkunov NV, et al. Enhancement of high-frequency acoustic cavitation effects by a low-frequency stimulation. Ultrason Sonochem. 1997;4:263–8.

    Article  Google Scholar 

  36. Ciuti P, Dezkkunov NV, Francescutto A, et al. Study into mechanisms of the enhancement of multibubble sonoluminscence emission in interacting fields of different frequencies. Ultrason Sonochem. 2003;10:337–41.

    Article  CAS  PubMed  Google Scholar 

  37. Carpenedo L, Ciuti P, Francescutto A, et al. Space–time interaction of two ultrasound fields and sonoluminescence during transient cavitation in distilled water. Acoust Lett. 1987;10:178–81.

    Google Scholar 

  38. Kanthale PM, Brotchie A, Ashokkumar M, et al. Experimental and theoretical investigations on sonoluminescence under dual frequency conditions. Ultrason Sonochem. 2008;15:629–35.

    Article  CAS  PubMed  Google Scholar 

  39. Jeong YI, Na HS, Cho KO, et al. Antitumor activity of adriamycin-incorporated polymeric micelles of poly([gamma]-benzyl l-glutamate)/poly(ethylene oxide). Int J Pharm. 2009;365:150–6.

    Article  CAS  PubMed  Google Scholar 

  40. Kwon GS, Naito M, Yokoyama M, et al. Physical entrapment of adriamycin in AB block copolymer micelles. Pharm Res. 1995;12:192–5.

    Article  CAS  PubMed  Google Scholar 

  41. Rapoport N, Pitt WG, Sun H, et al. Drug delivery in polymeric micelles: from in vitro to in vivo. J Control Release. 2003;91:85–95.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Mr. S. Pour-Beiranvand and Mrs. S. Ebrahimi for the preparation of pathological sections, and Mrs. M. Alamolhoda and Mr. H.R. Miri from Tarbiat Modares University for the animal handling and treatment protocol. We would also like to thank Mr. V. Nilchiani from Pars Nahand Engineering Company for providing assistance in designing the sonication system. This work was supported in part by the Iran National Science Foundation (INSF).

Conflict of interest

None.

Author information

Author notes

  1. Hadi Hasanzadeh

    Present address: Department of Medical Physics, Semnan University of Medical Sciences, Semnan, Iran

Authors and Affiliations

  1. Department of Medical Physics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    Hadi Hasanzadeh & Manijhe Mokhtari-Dizaji

  2. Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    S. Zahra Bathaie

  3. Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    Zuhair M. Hassan

  4. Department of Pathobiology, Faculty of Veterinary Medicine, Tabriz University, Tabriz, Iran

    Amir Ali Shahbazfar

Authors
  1. Hadi Hasanzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manijhe Mokhtari-Dizaji
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Zahra Bathaie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zuhair M. Hassan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Amir Ali Shahbazfar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Manijhe Mokhtari-Dizaji.

About this article

Cite this article

Hasanzadeh, H., Mokhtari-Dizaji, M., Zahra Bathaie, S. et al. Dual-frequency ultrasound activation of nanomicellar doxorubicin in targeted tumor chemotherapy. J Med Ultrasonics 41, 139–150 (2014). https://doi.org/10.1007/s10396-013-0484-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10396-013-0484-x

Keywords

Search

Navigation