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Pharmaceutical Research

, Volume 30, Issue 6, pp 1574–1585 | Cite as

The Antitumor Effect of a New Docetaxel-Loaded Microbubble Combined with Low-Frequency Ultrasound In Vitro: Preparation and Parameter Analysis

  • Shu-Ting Ren
  • Yi-Ran Liao
  • Xiao-Ning Kang
  • Yi-Ping Li
  • Hui Zhang
  • Hong Ai
  • Qiang Sun
  • Jing Jing
  • Xing-Hua Zhao
  • Li-Fang Tan
  • Xin-Liang Shen
  • Bing WangEmail author
Research Paper
First Online:

Abstract

Purpose

To develop a novel docetaxel (DOC)-loaded lipid microbubbles (MBs) for achieving target therapy and overcoming the poor water-solubility drawback of DOC.

Methods

A novel DOC-loaded microbubble (DOC + MB) was prepared by lyophilization and the physicochemical properties including ultrasound contrast imaging of the liver were measured. The anti-tumor effect of the DOC + MBs combined with low-frequency ultrasound (LFUS; 0.8Hz, 2.56 W/cm2, 50% cycle duty) on the DLD-1 cancer cell line was examined using an MTT assay.

Results

The physicochemical properties of the two tested formats of DOC + MBs (1.0 mg and 1.6 mg) was shown: concentration, (6.74 ± 0.02) × 108 bubbles/mL and (8.27 ± 0.15) × 108 bubbles/mL; mean size, 3.296 ± 0.004 μm and 3.387 ± 0.005 μm; pH value, 6.67 ± 0.11 and 6.56 ± 0.05; release rate, 3.41% and 12.50%; Zeta potential, −37.95 ± 7.84 mV and −44.35 ± 8.70 mV; and encapsulation efficiency, 54.9 ± 6.21% and 46.3 ± 5.69%, respectively. Compared with SonoVue, the DOC + MBs similarly enhanced the echo signal of the liver imaging. The anti-tumor effect of the DOC + MBs/LFUS group was significantly better than that of DOC alone and that of the normal MBs/LFUS groups.

Conclusions

The self-made DOC + MBs have potential as a new ultrasound contrast agent and drug-loaded microbubble, and can obviously enhance the antitumor effect of DOC under LFUS exposure.

Key words

docetaxel lipid microbubbles tumor-targeted therapy ultrasound contrast agent 

Abbreviations

DOC

docetaxel

DOC + MB

docetaxel-loaded microbubble

IR

inhibitory rate

LFUS

low-frequency ultrasound

MB

microbubble

NMB

normal microbubble

NS

normal saline

PTX

paclitaxel

PBS

phosphate buffer saline

RP-HPLC

reverse-phase liquid chromatography

TtoPk

time to peak

TIC

time intensity curve

UCA

ultrasound contrast agent

US

ultrasound

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Notes

Acknowledgments and Disclosures

The authors would like to thank Hua-Sheng Liu, Ph.D. and Jiang-Wei Liang for helps in the experiment. The present study was supported by the Scientific Technology Planning Foundation of Shaanxi Province (No.2010K12-01, 2011K12-56), Province Ministry Graveness Engineering Program (No.2009ZDKG-20; No.2008ZDKG-60, 2007ZDKG-290).

References

  1. 1.
    Zhao P, Dai M, Chen W, Li N. Cancer trends in China. Jpn J Clin Oncol. 2010;40(4):281–5.PubMedCrossRefGoogle Scholar
  2. 2.
    Baeuerle PA, Itin C. Clinical experience with gene therapy and bispecific antibodies for T cell-based therapy of cancer. Curr Pharm Biotechnol. 2012;13(8):1399–408.PubMedCrossRefGoogle Scholar
  3. 3.
    Anwer K, Kao G, Proctor B, Anscombe I, Florack V, Earls R, et al. Ultrasound enhancement of cationic lipid-mediated gene transfer to primary tumors following systemic administration. Gene Ther. 2000;7(21):1833–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Yan F, Li X, Jin Q, Jiang C, Zhang Z, Ling T, et al. Therapeutic ultrasonic microbubbles carrying paclitaxel and LyP-1 peptide: preparation, characterization and application to ultrasound-assisted chemotherapy in breast cancer cells. Ultrasound Med Biol. 2011;37(5):768–79.PubMedCrossRefGoogle Scholar
  5. 5.
    Kang J, Wu X, Wang Z, Ran H, Xu C, Wu J, et al. Antitumor effect of docetaxel-loaded lipid microbubbles combined with ultrasound-targeted microbubble activation on VX2 rabbit liver tumors. J Ultrasound Med. 2010;29(1):61–70.PubMedGoogle Scholar
  6. 6.
    Waite CL, Roth CM. Nanoscale drug delivery systems for enhanced drug penetration into solid tumors: current progress and opportunities. Crit Rev Biomed Eng. 2012;40(1):21–41.PubMedCrossRefGoogle Scholar
  7. 7.
    Guarneri V, Dieci MV, Conte P. Enhancing intracellular taxane delivery: current role and perspectives of nanoparticle albumin-bound paclitaxel in the treatment of advanced breast cancer. Expert Opin Pharmacother. 2012;13(3):395–406.PubMedCrossRefGoogle Scholar
  8. 8.
    Collins-Gold L, Lyons R, Bartholow L. Parenteral emulsions for drug delivery. Adv Drug Deliv Rev. 1990;5(3):189–208.CrossRefGoogle Scholar
  9. 9.
    Harris JD, Gutierrez AA, Hurst HC, Sikora K, Lemoine NR. Gene therapy for cancer using tumour-specific prodrug activation. Gene Ther. 1994;1(3):170–5.PubMedGoogle Scholar
  10. 10.
    Kato T, Sato K, Sasaki R, Kakinuma H, Moriyama M. Targeted cancer chemotherapy with arterial microcapsule chemoembolization: review of 1013 patients. Cancer Chemother Pharmacol. 1996;37(4):289–96.PubMedCrossRefGoogle Scholar
  11. 11.
    Luo G, Yu X, Jin C, Yang F, Fu D, Long J, et al. LyP-1-conjugated nanoparticles for targeting drug delivery to lymphatic metastatic tumors. Int J Pharm. 2010;385(1–2):150–6.PubMedCrossRefGoogle Scholar
  12. 12.
    O’Shaughnessy JA. Pegylated liposomal doxorubicin in the treatment of breast cancer. Clin Breast Cancer. 2003;4(5):318–28.PubMedCrossRefGoogle Scholar
  13. 13.
    Park JW. Liposome-based drug delivery in breast cancer treatment. Breast Cancer Res. 2002;4(3):95–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Schutt EG, Klein DH, Mattrey RM, Riess JG. Injectable microbubbles as contrast agents for diagnostic ultrasound imaging: the key role of perfluorochemicals. Angew Chem Int Ed. 2003;42(28):3218–35.CrossRefGoogle Scholar
  15. 15.
    Tartis MS, McCallan J, Lum AFH, LaBell R, Stieger SM, Matsunaga TO, et al. Therapeutic effects of paclitaxel-containing ultrasound contrast agents. Ultrasound Med Biol. 2006;32(11):1771–80.PubMedCrossRefGoogle Scholar
  16. 16.
    Zhou X, Qin H, Li J, Wang B, Wang C, Liu Y, et al. Platelet-targeted microbubbles inhibit re-occlusion after thrombolysis with transcutaneous ultrasound and microbubbles. Ultrasonics. 2011;51(3):270–4.PubMedCrossRefGoogle Scholar
  17. 17.
    Lentacker I, De Smedt SC, Sanders NN. Drug loaded microbubble design for ultrasound triggered delivery. Soft Matter. 2009;5(11):2161–70.CrossRefGoogle Scholar
  18. 18.
    Barnett S. Nonthermal issues: cavitation–its nature, detection and measurement. Ultrasound Med Biol. 1998;24:S11–21.CrossRefGoogle Scholar
  19. 19.
    Liu Y, Miyoshi H, Nakamura M. Encapsulated ultrasound microbubbles: therapeutic application in drug/gene delivery. J Control Release. 2006;114(1):89–99.PubMedCrossRefGoogle Scholar
  20. 20.
    Engels FK, Mathot RAA, Verweij J. Alternative drug formulations of docetaxel: a review. Anti Cancer Drugs. 2007;18(2):95.PubMedCrossRefGoogle Scholar
  21. 21.
    Frenkel PA, Chen S, Thai T, Shohet RV, Grayburn PA. DNA-loaded albumin microbubbles enhance ultrasound-mediated transfection in vitro. Ultrasound Med Biol. 2002;28(6):817–22.PubMedCrossRefGoogle Scholar
  22. 22.
    Michaud LB, Valero V, Hortobagyi G. Risks and benefits of taxanes in breast and ovarian cancer. Drug Saf. 2000;23(5):401–28.PubMedCrossRefGoogle Scholar
  23. 23.
    Rowinsky EK, Donehower RC. Paclitaxel (taxol). N Engl J Med. 1995;332(15):1004.PubMedCrossRefGoogle Scholar
  24. 24.
    Cortes JE, Pazdur R. Docetaxel. J Clin Oncol. 1995;13(10):2643–55.PubMedGoogle Scholar
  25. 25.
    Sanli UA, Uslu R, Karabulut B, Sezgin C, Saydam G, Omay SB, et al. Which dosing scheme is suitable for the taxanes? An in vitro model. Arch Pharm Res. 2002;25(4):550–5.PubMedCrossRefGoogle Scholar
  26. 26.
    Ren ST, Zhang H, Wang YW, Jing BB, Li YX, Liao YR, et al. The preparation of a new self-made microbubble-loading urokinase and its thrombolysis combined with low-frequency ultrasound in vitro. Ultrasound Med Biol. 2011;37(11):1828–37.PubMedCrossRefGoogle Scholar
  27. 27.
    Schneider M. Characteristics of SonoVuetrade mark. Echocardiography. 1999;16(7, Pt 2):743–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Sirsi S, Borden M. Microbubble compositions, properties and biomedical applications. Bubble Sci Eng Technol. 2009;1(1–2):3–17.PubMedCrossRefGoogle Scholar
  29. 29.
    Duncan PB, Needham D. Test of the Epstein-Plesset model for gas microparticle dissolution in aqueous media: effect of surface tension and gas undersaturation in solution. Langmuir. 2004;20(7):2567–78.PubMedCrossRefGoogle Scholar
  30. 30.
    Unger EC, McCreery TP, Sweitzer RH, Caldwell VE, Wu Y. Acoustically active lipospheres containing paclitaxel: a new therapeutic ultrasound contrast agent. Invest Radiol. 1998;33(12):886–92.PubMedCrossRefGoogle Scholar
  31. 31.
    Cochran MC, Eisenbrey J, Ouma RO, Soulen M, Wheatley MA. Doxorubicin and paclitaxel loaded microbubbles for ultrasound triggered drug delivery. Int J Pharm. 2011;414(1–2):161–70.PubMedCrossRefGoogle Scholar
  32. 32.
    Tinkov S, Bekeredjian R, Winter G, Coester C. Microbubbles as ultrasound triggered drug carriers. J Pharm Sci. 2009;98(6):1935–61.PubMedCrossRefGoogle Scholar
  33. 33.
    Talu E, Hettiarachchi K, Zhao S, Powell RL, Lee AP, Longo ML, et al. Tailoring the size distribution of ultrasound contrast agents: possible method for improving sensitivity in molecular imaging. Mol Imaging. 2007;6(6):384–92.PubMedGoogle Scholar
  34. 34.
    Phillips LC, Klibanov AL, Wamhoff BR, Hossack JA, editors. Ultrasound-microbubble-mediated drug delivery efficacy and cell viability depend on microbubble radius and ultrasound frequency 2010: IEEE International Ultrasonics Symposium Proceedings.Google Scholar
  35. 35.
    Klibanov AL. Preparation of targeted microbubbles: ultrasound contrast agents for molecular imaging. Med Biol Eng Comput. 2009;47(8):875–82.PubMedCrossRefGoogle Scholar
  36. 36.
    Fisher NG, Christiansen JP, Klibanov A, Taylor RP, Kaul S, Lindner JR. Influence of microbubble surface charge on capillary transit and myocardial contrast enhancement. J Am Coll Cardiol. 2002;40(4):811–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Wang B, Wang L, Zhou XB, Liu YM, Wang M, Qin H, et al. Thrombolysis effect of a novel targeted microbubble with low-frequency ultrasound in vivo. Thromb Haemost. 2008;100(2):356–61.PubMedGoogle Scholar
  38. 38.
    Daffertshofer M, Gass A, Ringleb P, Sitzer M, Sliwka U, Els T, et al. Transcranial low-frequency ultrasound-mediated thrombolysis in brain ischemia: increased risk of hemorrhage with combined ultrasound and tissue plasminogen activator: results of a phase II clinical trial. Stroke. 2005;36(7):1441–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Jenne JW, Preusser T, Gunther M. High-intensity focused ultrasound: principles, therapy guidance, simulations and applications. Z Med Phys. 2012 Aug 9.Google Scholar
  40. 40.
    Feril Jr LB, Kondo T. Biological effects of low intensity ultrasound: the mechanism involved, and its implications on therapy and on biosafety of ultrasound. J Radiat Res. 2004;45(4):479–89.PubMedCrossRefGoogle Scholar
  41. 41.
    Feril Jr LB, Kondo T. Major factors involved in the inhibition of ultrasound-induced free radical production and cell killing by pre-sonication incubation or by high cell density. Ultrason Sonochem. 2005;12(5):353–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Tachibana K, Feril Jr LB, Ikeda-Dantsuji Y. Sonodynamic therapy. Ultrasonics. 2008;48(4):253–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Shu-Ting Ren
    • 1
  • Yi-Ran Liao
    • 2
  • Xiao-Ning Kang
    • 1
  • Yi-Ping Li
    • 2
  • Hui Zhang
    • 2
  • Hong Ai
    • 3
  • Qiang Sun
    • 2
  • Jing Jing
    • 1
  • Xing-Hua Zhao
    • 2
  • Li-Fang Tan
    • 3
  • Xin-Liang Shen
    • 4
  • Bing Wang
    • 1
    Email author
  1. 1.Department of Pathology and Therapeutic Vaccines Engineering Center of Shaanxi Province, School of MedicineXi’an Jiaotong UniversityXi’anChina
  2. 2.Department of Pharmacology and Therapeutic Vaccines Engineering Center of Shaanxi Province, School of MedicineXi’an Jiaotong UniversityXi’anChina
  3. 3.Department of Ultrasound Imaging, First Affiliated Hospital of Medical CollegeXi’an Jiaotong UniversityXi’anChina
  4. 4.China National Biotechnology GroupBeijingChina

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