Skip to main content
SpringerLink
Log in

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

  • Published:
Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry Aims and scope Submit manuscript

Abstract

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.

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

Similar content being viewed by others

References

  1. Thorpe, P.E., Clin. Cancer Res., 2004, vol. 10, pp. 415–427.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  3. Fenske, D.B. and Cullis, P.R., Expert Opin. Drug Deliv., 2008, vol. 5, pp. 25–44.

    Article  CAS  Google Scholar 

  4. Maeda, H., Sawa, T., and Konno, T., J. Control. Release, 2001, vol. 74, pp. 47–61.

    Article  CAS  Google Scholar 

  5. Lasic, D.D., and Papahadjopoulos, D., Science, 1995, vol. 267, pp. 1275–1276.

    Article  CAS  Google Scholar 

  6. Gabizon, A., Schmeeda, H., and Barenholz, Y., Clin. Pharmacokinet., 2003, vol. 42, pp. 419–436.

    Article  CAS  Google Scholar 

  7. Zucker, D., Marcus, D., Barenholz, Y., and Goldblum, A., J. Control. Release, 2009, vol. 139, pp. 73–80.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  12. Ehrhardt, C., Kneuer, C., and Bakowsky, U., Adv. Drug. Deliv. Rev., 2004, vol. 56, pp. 527–549.

    Article  CAS  Google Scholar 

  13. Tsuruta, W., Tsurushima, H., Yamamoto, T., Suzuki, K., Yamazaki, N., and Matsumura, A., Biomaterials, 2009, vol. 3, pp. 118–125.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  19. Tron, G.C., Pirali, T., Sorba, G., Pagliai, F., Busacca, S., and Genazzani, A., J. Med. Chem., 2006, vol. 49, pp. 3033–3044.

    Article  CAS  Google Scholar 

  20. Lara-Ochoa, F. and Espinosa-Pérez, G., Tetrahedron Lett., 2007, vol. 48, pp. 7007–7010.

    Article  CAS  Google Scholar 

  21. Mayer, L.D., Hope, M.J., and Cullis, P.R., Biochim. Biophys. Acta, 1986, vol. 858, pp. 161–168.

    Article  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  23. Gabizon, A. and Papahadjopoulos, D., Proc. Natl. Acad. Sci. USA, 1988, vol. 85, pp. 6949–6953.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow V-437, GSP, 117997, Russia

    E. V. Moiseeva, N. R. Kuznetsova, E. V. Svirshchevskaya, N. V. Bovin & E. L. Vodovozova

  2. N.I. Lobachevsky Nizhny Novgorod State University, Nizhny Novgorod, Russia

    N. S. Sitnikov & A. Yu. Fedorov

  3. G.A. Razuvaev Institute of Organometallic Chemistry, Russian Academy of Sciences, Nizhny Novgorod, Russia

    A. S. Shavyrin

  4. Department of Chemistry, M.V. Lomonosov Moscow State University, Moscow, Russia

    I. P. Beletskaya

  5. UMR-CNRS 6264, Saint Jerome Department of Sciences, Aix-Marseille University 1 and 2, Marseille, Cedex 20, France

    S. Combes

Authors
  1. E. V. Moiseeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. R. Kuznetsova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. V. Svirshchevskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N. V. Bovin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N. S. Sitnikov
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. S. Shavyrin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. I. P. Beletskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S. Combes
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A. Yu. Fedorov
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. E. L. Vodovozova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. L. Vodovozova.

Additional information

Original Russian Text © 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, 2011, published in Biomeditsinskaya Khimiya.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moiseeva, E.V., Kuznetsova, N.R., Svirshchevskaya, E.V. et al. Liposome formulations of combretastatin A4 and its 4-arylcoumarin analogue prodrugs: The antitumor effect in the mouse model of breast cancer. Biochem. Moscow Suppl. Ser. B 5, 276–283 (2011). https://doi.org/10.1134/S1990750811030073

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1990750811030073

Keywords

Search

Navigation