Commenced in January 2007
Frequency: Monthly
Edition: International
Paper Count: 32119
Effect of Local Dual Frequency Sonication on Drug Distribution from Nanomicelles

Authors: Hadi Hasanzadeh, Manijhe Mokhtari-Dizaji, S.Zahra Bathaie, Zuhair M. Hassan, Hamid R. Miri, Mahbobe Alamolhoda, Vahid Nilchiani, Hamid Goudarzi


The nanosized polymeric micelles release the drug due to acoustic cavitation, which is enhanced in dual frequency ultrasonic fields. In this study, adult female Balb/C mice were transplanted with spontaneous breast adenocarcinoma tumors and were injected with a dose of 1.3 mg/kg doxorubicin in one of three forms: free doxorubicin, micellar doxorubicin without sonication and micellar doxorubicin with sonication. To increase cavitation yield, the tumor region was sonicated with low level dual frequency of 3 MHz and 28 kHz. The animals were sacrificed 24 h after injection, and their tumor, heart, spleen, liver, kidneys and plasma were separated and homogenized. The drug content in their tumor, heart, spleen, liver, kidneys and plasma was determined using tissue fluorimetry. The results show that in the group that received micellar doxorubicin with sonication, the drug concentration in the tumor tissue was nine and three times higher than in the free doxorubicin group and the micellar doxorubicin without sonication group, respectively. In the micellar doxorubicin with sonication group, the drug concentration in other tissues was lower than other groups (p<0.05). We conclude that dual frequency sonication improves drug release from micelles and increases the drug uptake by tumors due to sonoporation.

Keywords: Nanomicelles, Dual frequency ultrasound, Drug delivery

Digital Object Identifier (DOI):

Procedia APA BibTeX Chicago EndNote Harvard JSON MLA RIS XML ISO 690 PDF Downloads 1632


[1] A. K├╝mmerle, T. Krueger, M. Dusmet, C. Vallet, Y. Pan., H.B. Ris and L.A. Decosterd, "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., vol. 33, 2003, pp. 475-494.
[2] P. E. Colombo, M. Boustta, S. Poujol, F. Pinguet, P. Rouanet, F. Bressolle, M. Vert,"Biodistribution of doxorubicin-alkylated poly(llysine citramide imide) conjugates in an experimental model of peritoneal carcinomatosis after intraperitoneal administration," Eur. J. Pharm. Sci. vol. 31, 2007, pp. 43-52.
[3] V. Alakhov, E. Klinski, S. Li, G. Pietrzynski, A. Venne, E. Batrakova, T. Bronitch and A. Kabanov,"Block copolymer-based formulation of doxorubicin. From cell screen to clinical trials,"Colloids Surf. B. Biointerfaces, vol. 16, 1999, pp.113-134.
[4] A. M. M. Osman, M. M. Nemnem, A. A. Abou-Bakr, O. A. Nassier and M. T. Khayyal,"Effect of methimazole treatment on doxorubicin- Tissue Linear regression function Correlati on of coefficien t P-value Spleen Y = 0.2X - 2.6 0.98 <0.01 Heart Y = 0.1X - 1.6 0.98 <0.01 Liver Y = 0.07X - 3.6 0.96 <0.01 Kidney Y = 0.2X - 4.8 0.98 <0.01 Tumor Y = 0.2X - 4.5 0.99 <0.01 Plasma Y = 0.1X - 1.0 0.99 <0.01 Group Splee n Liver Kidney Heart Tumor Plas ma Doxorubicin 2.50 (0.09) 1.13 (0.09) 1.90 (0.21) 2.49 (0.09) 1.50 (0.41) 0.82 (0.12) Micellar Doxorubicin 2.28 (0.26) 0.94 (0.19) 1.48 (0.57) 2.31 (0.01) 5.00 (0.71) 0.65 (0.21) Micellar Doxorubicin +Sonication 1.50 (0.37) 0.25 (0.16) 0.74 (0.13) 0.24 (0.13) 13.00 (0.29) 0.36 (0.03) induced cardiotoxicity in mice,"Food Chem. Toxicol., vol. 47, 2009, pp. 2425-2430.
[5] A. Fundar, R. Cavalli, A. Bargoni, D. Vighetto, G. P. Zara and M. R. Gasco," Non-stealth and stealth solid lipid nanoparticles (SLN) carrying doxorubicin: pharmacokinetics and tissue distribution after i.v. administration to rats,"Pharmacol. Res, vol. 42, 2003, pp. 337-343.
[6] A. H. Barati, M. Mokhtari-Dizaji, H. Mozdarani, S. Z. Bathaie and Z. M. Hassan,"Effect of exposure parameters on cavitation induced by lowlevel dual-frequency ultrasound," Ultrason. Sonochem, vol. 14, 2007, pp.783-789.
[7] R. Feng, Y. Zhao, C. Zhu and T. J. Mason,"Enhancement of ultrasonic cavitation yield by multi-frequency sonication," Ultrason. Sonochem, vol. 9, 2002, pp. 231-236.
[8] H. Hasanzadeh, M. Mokhtari-Dizaji, S. Z. Bathaie, Z. M. Hassan, V. Nilchiani and H. Goudarzi,"Enhancement and control of acoustic cavitation yield by low level dual frequency sonication: A subharmonic analysis," Ultrason. Sonochem, 2010 to be published.
[9] G. J. R. Charrois and T. M. Allen,"Drug release rate influences the pharmacokinetics, biodistribution, therapeutic activity, and toxicity of pegylated liposomal doxorubicin formulations in murine breast cancer," Biochim. Biophys. Acta, vol. 1663, 2004, pp.167-177.
[10] M. Yokoyama, M. Miyauchi, N. Yamada, T. Okano, Y. Sakurai, K. Kataoka and S. Inoue,"Characterization and anticancer activity of the micelle-forming polymeric anticancer drug adriamycin-conjugated poly (ethylene glycol)-poly (aspartic acid) block copolymer,"Cancer Res, vol. 50, 1990, pp.1693-1700.
[11] M. Yokoyama, M. Miyauchi, N. Yamada, T. Okano, Y. Sakurai, K. Kataoka and Inoue S,"Polymer micelles as novel drug carrier: Adriamycin-conjugated poly (ethylene glycol)-poly (aspartic acid) block copolymer,"J. Control. Release, vol. 11, 1990, pp. 269-278.
[12] Y. I. Jeong, J. W. Nah, H. C. Lee, S. H. Kim and C. S. Cho,"Adriamycin release from flower-type polymeric micelle based on star-block copolymer composed of poly(gamma-benzyl L-glutamate) as the hydrophobic part and poly(ethylene oxide) as the hydrophilic part," Int. J. Pharm, vol. 188, 1991, pp. 49-58.
[13] H. L. Wong, A. M. Rauth, R. and Bendayan, X. Y. Wu,"In vivo evaluation of a new polymer-lipid hybrid nanoparticle (PLN) formulation of doxorubicin in a murine solid tumor model."Eur. J. Pharm. Biopharm, vol. 65, 2007, pp. 300-308.
[14] R. K. Subedi, K. W. Kang and H. K. Choi,"Preparation and characterization of solid lipid nanoparticles loaded with doxorubicin,"Eur. J. Pharm. Sci, vol. 37, 2009, pp. 508-513.
[15] K. Kazunori, S. K. Glenn, Y. Masayuki, O. Teruo and S. Yasuhisa,"Block copolymer micelles as vehicles for drug delivery,"J. Control. Release, vol. 24, 1993, pp.119-132.
[16] M. Yokoyama, T. Okano, Y. Sakurai, H. Ekimoto, C. Shibazaki and K. Kataoka,"Toxicity and antitumor activity against solid tumors of micelle-forming polymeric anticancer drug and its extremely long circulation in blood,"Cancer Res, vol. 51, 1991, pp. 3229-3236.
[17] G. S. Kwon, M. Naito, M. Yokoyama, T. Okano, Y. Sakurai and K. Kataoka,"Physical entrapment of adriamycin in AB block copolymer micelles," Pharm. Res, vol. 12, 1995, pp. 192-195.
[18] Y. I. Jeong, H. S. Na, K. O. Cho, H. C. Lee, J. W. Nah and C. S," Antitumor activity of adriamycin-incorporated polymeric micelles of poly(
[gamma]-benzyl l-glutamate)/poly(ethylene oxide)," Int. J. Pharm, vol. 365, 2009, pp. 150-156.