МОРФОЛОГИЧЕСКАЯ ОЦЕНКА ПРОТИВООПУХОЛЕВОГО ЭФФЕКТА НАНОСОМАЛЬНОЙ ФОРМЫ ДОКСОРУБИЦИНА В ОТНОШЕНИИ ЭКСПЕРИМЕНТАЛЬНОЙ ГЛИОБЛАСТОМЫ У КРЫС

As shown previously, doxorubicin bound to the biodegradable poly(butyl cyanoacrylate) nanoparticles coated with polysorbate 80 (Dox-NP) significantly enhanced survival in the orthotopic rat 101/8 glioblastoma model; long-term remission was achieved in 20-40% animals. This tumour has been shown to be an adequate model for experimental chemotherapy, its morphological features of the 101/8 glioblastoma (infiltrative growth pattern, high proliferation rate, vascularization, and pronounced necrotization) being similar to human glioblastomas. The objective of the present study was to investigate the morphological parameters of the antitumour effect of the Dox-NP. The tumor-bearing animals were subjected to chemotherapy using doxorubicin in solution (Dox) or Dox-NP injected intravenously on days 2, 5 and 8 post tumor implantation. The antitumor effect was assessed on days 10, 14 and 18 post tumor implantation. Tumors showed signs of malignancy including invasion of brain tissue, brisk mitotic activity, microvascular proliferation, necrosis and increased proliferation resembling human glioblastoma. Dox-NP produced a considerably more pronounced antitumor effect exhibited as a reduced tumor size, lower proliferation, and a decreased necrotic area compared to Dox and to untreated control groups. A drastic effect of Dox-NP on vascularization indicated an antiangiogenic mode of action. References Avcyn A.P., Kondakova L.I., Halanskij A.S. / Vestnik RAMN. 1993. T.7. S. 51-54. Packer R.J. / Curr. Opin. Pediatr. 1995. V.7. P. 64-72. Grossman S.A., Batara J.F. / Semin. Oncol. 2004. V.31. P.635–644. Stupp R., Mason W.P., van den Bent M.J. et al. / N. Engl. J. Med. 2005. V.352. P.987–996. Groothuis D.R. / Neuro-Oncology. 2000. V.2. P. 45-59. Stan A.C., Casares S., Radu D., Walter G.F., Brumeanu T.D. / Anticancer. Res. 1999. V.19. P.941-950. Walter K.A., Tamargo R.J., Olivi A., Burger P.C., Brem H. / Neurosurgery 1995. V.37. P.1128-1145. von Holst H., Knochenhauer E., Blomgren H., Collins V.P., Ehn L., Lindquist M., Noren G., Peterson C. / Acta Neurochir (Wien). 1990. V.104. P.13-16. Garcia-Garcia E., Andrieux K., Gil S., Couvreur P. Int J Pharm. 2005. V.298. P.274-292. Gelperina S. In: Gupta RB, Kompella UB (Eds.) Nanoparticle Technology for Drug Delivery, Drugs and the Pharmaceutical Sciences, V. 159, Marcel Dekker, New York. 2006. P. 273-318. Kreuter J. / J. Nanosci. Nanotechnol. 2004. V.4. P. 484-488. Petri B., Bootz A., Khalansky A., Hekmatara T., Muller R., Uhl R., Kreuter J., Gelperina S. / J. Control. Release. 2007. V.117. №1. P.51-58. Gulyaev A.E., Gelperina S.E., Skidan I.N., Antropov A.S., Kivman G,Y., Kreuter J. / Pharm. Res. 1999. V.16. P.1564–1569. Steiniger C.J., Kreuter J., Khalansky AS, Skidan IN, Bobruskin A.I., Smirnova Z.S., Severin S.E., Uhl R., Kock M., Geiger K.D., Gelperina S.E. / Int. J. Cancer. 2004. V.109. P. 759-767. Vauthier C., Dubernet C., Fattal E., Pinto-Alphandary H., Couvreur P. / Adv. Drug Deliv. Rev. 2003. V.55, No4. P.519-548. Jablonovskaja L.Ja., Spryshkova N.A. / Arh. Patol. 1971. T. 33. №2. S. 6-10. Duyndam M.C., van Berkel M.P., Dorsman J.C., Rockx D.A., Pinedo H.M., Boven E. / Biochem. Pharmacol. 2007. V.74. №2. P.191-201. Lee K., Quan D.Z., Rey S., Wey H., Liu J.O., Semenza G.L. / Proc. Natl. Acad. Sci. USA. 2009. V.106. № 7. P. 2353-2358. Folkman J. / J. Natl. Cancer Inst. 1990. V.82. P.4-6 Brat D.J., Mapstone T.B. / Ann. Intern. Med. 2003. V.138. P.659-668. Kaur B., Kwaja F.M., Severson E.A., Mateny S.L. / Neuro-Oncology. 2005. V.7. P.134-153 Rong Y., Durden D., Van Meir E.G., Brat D.J. / J. Neuropathol. Exp. Neurol. 2006. V. 65. №6. P.529-539. Chernikov V.P., Halanskij A.S., Nikonova E.A., Kakturskij L.V. / Aktual'nye voprosy patologicheskoj anatomii. 2009. T.2. C. 562-563. Donelli M.G., Zuchetti M., D’Incalci M. / Cancer Chemother. Pharmacol. 1992. V. 30. №4. R.251-260. Matsumura Y., Maeda H. / Cancer Res. 1986. V.46. No 12. P. 6387-6392.