Liposome formulations of combretastatin A4 and its 4-arylcoumarin analogue prodrugs: The antitumor effect in the mouse model of breast cancer

  • E. V. Moiseeva
  • N. R. Kuznetsova
  • E. V. Svirshchevskaya
  • N. V. Bovin
  • N. S. Sitnikov
  • A. S. Shavyrin
  • I. P. Beletskaya
  • S. Combes
  • A. Yu. Fedorov
  • E. L. Vodovozova


The antimitotic agent combretastatin A-4 (CA-4) has been recently proposed as an antivascular agent for anticancer therapy. In order to reduce systemic toxicity by means of administration in liposome formulations, new lipophilic prodrugs, oleic derivatives of CA-4 and its 4-arylcoumarin analogue (CA4-Ole and ArC-Ole, respectively), have been synthesized in this study. Liposomes with mean diameter of 100 nm prepared on the basis of egg phosphatidylcholine and baker’s yeast phosphatidylinositol quantitatively included up to 15 mol% of CA4-Ole, or 7 mol% of ArC-Ole. To achieve targeting to neovascular endothelium prodrug bearing liposomes decorated with the tetrasaccharide selectin ligand Sialyl Lewis X (SiaLeX) have been also prepared. The antitumor activity was studied in vivo using the model of slow-growing mouse breast cancer. Under the dose used (22 mg/kg) and the administration protocol (four injections, one per a week, starting from the appearance of palpable tumors) cytostatic CA-4 did not reveal any anticancer effect; moreover, it even stimulated tumor growth. The liposome formulations of CA4-Ole did not demonstrate such stimulation. However, to achieve a pronounced antitumor effect, the number of injections of liposomes should be apparently increased. The cytotoxic activity of a novel antimitotic agent ArC was one order of magnitude lower in the human breast carcinoma cell culture in vitro. Nevertheless, in vivo in the mouse model of breast cancer the antitumor effect of this compound corresponded to the double equivalent dose of CA-4. The results demonstrate perspectives of SiaLeX-liposomes loaded with ArC-Ole: the preparation partially inhibited tumor growth already after the second injection. Thus, subsequent optimization of doses and regimens of administration both for ArC and liposomal ArC-Ole formulations are needed.


combretastatin A-4 4-arylcoumarins lipophilic prodrugs liposomes Sialyl Lewis X breast cancer 


  1. 1.
    Thorpe, P.E., Clin. Cancer Res., 2004, vol. 10, pp. 415–427.CrossRefGoogle Scholar
  2. 2.
    Grosios, K., Holwell, S.E., McGown, A.T., Pettit, G.R., and Bibby, M.C., Br. J. Cancer, 1999, vol. 81, pp. 1318–1327.CrossRefGoogle Scholar
  3. 3.
    Fenske, D.B. and Cullis, P.R., Expert Opin. Drug Deliv., 2008, vol. 5, pp. 25–44.CrossRefGoogle Scholar
  4. 4.
    Maeda, H., Sawa, T., and Konno, T., J. Control. Release, 2001, vol. 74, pp. 47–61.CrossRefGoogle Scholar
  5. 5.
    Lasic, D.D., and Papahadjopoulos, D., Science, 1995, vol. 267, pp. 1275–1276.CrossRefGoogle Scholar
  6. 6.
    Gabizon, A., Schmeeda, H., and Barenholz, Y., Clin. Pharmacokinet., 2003, vol. 42, pp. 419–436.CrossRefGoogle Scholar
  7. 7.
    Zucker, D., Marcus, D., Barenholz, Y., and Goldblum, A., J. Control. Release, 2009, vol. 139, pp. 73–80.CrossRefGoogle Scholar
  8. 8.
    Vodovozova, E.L., Kuznetsova, N.R., Kadykov, V.A., Khutsyan, S.S., Gaenko, G. P., and Molotkovsky, J.G., Nanotechnologies in Russia, 2008, vol. 3, no. 3–4, pp. 228–239.CrossRefGoogle Scholar
  9. 9.
    Kuznetsova, N., Kandyba, A., Vostrov, I., Kadykov, V., Gaenko, G., Molotkovsky, J., and Vodovozova, E., J. Drug Deliv. Sci. Techn., 2009, vol. 19, pp. 51–59.Google Scholar
  10. 10.
    Kozlov, A.M., Korchagina, E.Yu., Vodovozova, E.L., Bovin, N.V., Molotkovsky, J.G., and Syrkin, A.B., Byul. Eksper. Biol. Med., 1997, vol. 123, pp. 439–441.CrossRefGoogle Scholar
  11. 11.
    Vodovozova, E.L., Moiseeva, E.V., Grechko, G.K., Gayenko, G.P., Nifant’ev, N.E., Bovin, N.V., and Molotkovsky, J.G., Eur. J. Cancer, 2000, vol. 36, pp. 942–949.CrossRefGoogle Scholar
  12. 12.
    Ehrhardt, C., Kneuer, C., and Bakowsky, U., Adv. Drug. Deliv. Rev., 2004, vol. 56, pp. 527–549.CrossRefGoogle Scholar
  13. 13.
    Tsuruta, W., Tsurushima, H., Yamamoto, T., Suzuki, K., Yamazaki, N., and Matsumura, A., Biomaterials, 2009, vol. 3, pp. 118–125.CrossRefGoogle Scholar
  14. 14.
    Pattillo, C.B., Venegas, B., Donelson, F.J., Valle, L.D., Knight, L.C., Chong, P.L.G., and Kiani, M.F., Pharm. Res., 2009, vol. 26, pp. 1093–1100.CrossRefGoogle Scholar
  15. 15.
    Nallamothu, R., Wood, G., Pattillo, C.B., Scott, R.C., Kiani, M.F., Moore, B.M., and Thoma, L.A., AAPS PharmSciTech., 2006, vol. 7, no. 2, pp. E1–E10.CrossRefGoogle Scholar
  16. 16.
    Bailly, C., Bal, C., Barbier, P., Combes, S., Finet, J.-P., Hildebrand, M.-P., Peyrot, V., and Wattez, N., J. Med. Chem., 2003, vol. 46, pp. 5437–5444.CrossRefGoogle Scholar
  17. 17.
    Ganina, O.G., Daras, E., Bourgarel-Rey, V., Peyrot, V., Andresyuk, A.N., Finet, J.-P., Fedorov, A.Yu., Beletskaya, I.P., and Combes, S., Bioorg. Med. Chem., 2008, vol. 16, pp. 8806–8812.CrossRefGoogle Scholar
  18. 18.
    Rappl, C., Barbier, P., Bourgarel-Rey, V., Gregoire, C., Gilli, R., Carre, M., Combes, S., Finet, J.-P., and Peyrot, V., Biochemistry, 2006, vol. 45, pp. 9210–9218.CrossRefGoogle Scholar
  19. 19.
    Tron, G.C., Pirali, T., Sorba, G., Pagliai, F., Busacca, S., and Genazzani, A., J. Med. Chem., 2006, vol. 49, pp. 3033–3044.CrossRefGoogle Scholar
  20. 20.
    Lara-Ochoa, F. and Espinosa-Pérez, G., Tetrahedron Lett., 2007, vol. 48, pp. 7007–7010.CrossRefGoogle Scholar
  21. 21.
    Mayer, L.D., Hope, M.J., and Cullis, P.R., Biochim. Biophys. Acta, 1986, vol. 858, pp. 161–168.CrossRefGoogle Scholar
  22. 22.
    Funaki, N.O., Tanaka, J., Kohmoto, M., Sugiyama, T., Ohshio, G., Nonaka, A., Yotsumoto, F., Takeda, Y., and Imamura, M., Oncol. Rep., 2001, vol. 8, pp. 527–532.Google Scholar
  23. 23.
    Gabizon, A. and Papahadjopoulos, D., Proc. Natl. Acad. Sci. USA, 1988, vol. 85, pp. 6949–6953.CrossRefGoogle Scholar
  24. 24.
    Romberg, B., Metselaar, J.M., Baranyi, L., Snel, C.J., Bunger, R., Hennink, W.E., Szebeni, J., and Storm, G., Int. J. Pharm., 2007, vol. 331, pp. 186–189.CrossRefGoogle Scholar
  25. 25.
    Bonetti, A., Zaninelli, M., Rodella, S., Molino, A., Sperotto, L., Piubello, Q., Bonetti, F., Nortilli, R., Turazza, M., and Cetto, G.L., Breast Cancer Res. Treat., 1996, vol. 38, pp. 289–297.CrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2011

Authors and Affiliations

  • E. V. Moiseeva
    • 1
  • N. R. Kuznetsova
    • 1
  • E. V. Svirshchevskaya
    • 1
  • N. V. Bovin
    • 1
  • N. S. Sitnikov
    • 2
  • A. S. Shavyrin
    • 3
  • I. P. Beletskaya
    • 4
  • S. Combes
    • 5
  • A. Yu. Fedorov
    • 2
  • E. L. Vodovozova
    • 1
  1. 1.Shemyakin-Ovchinnikov Institute of Bioorganic ChemistryRussian Academy of SciencesMoscow V-437, GSPRussia
  2. 2.N.I. Lobachevsky Nizhny Novgorod State UniversityNizhny NovgorodRussia
  3. 3.G.A. Razuvaev Institute of Organometallic ChemistryRussian Academy of SciencesNizhny NovgorodRussia
  4. 4.Department of ChemistryM.V. Lomonosov Moscow State UniversityMoscowRussia
  5. 5.UMR-CNRS 6264, Saint Jerome Department of SciencesAix-Marseille University 1 and 2Marseille, Cedex 20France

Personalised recommendations