Chemistry, Physics and Technology of Surface

ISSN 2518-1238 (Online), ISSN 2079-1704 (Print)

The aim of the work is investigation of cytotoxic influence of the magnetocarried polyfunctional nanocomposites based on single-domain magnetite (Fe₃O₄) and anthracycline antibiotic doxorubicin (DOX) on yeast cells Saccharomyces cerevisiae. Magnetite was synthesized according to the Elmor reaction. For investigations we used a fraction of particles with sizes of 6-23 nm. Specific surface area of the samples studied was S = 105–180 m²/g. Magnetosensitive nanocomposites Fe₃O₄/DOX, Fe₃O₄/SiO₂/DOX, Fe₃O₄/TiO₂/DOX, Fe₃O₄/ hydroxyapatite (HA)/DOX were synthesized. To obtain Fe₃O₄/SiO₂ nanocomposites, we used tetraethoxysilane (TEOS) as a modifying agent. The technique for synthesis of nanocomposites consisting of magnetite modified with silica dioxide involves hydrolysis of TEOS. The coating was 0.2 g of SiO₂ on 1 g of magnetite. Specific surface area of the nanocomposite increases from 105 m²/g (for unmodified magnetite) to 130 m²/g. To obtain Fe₃O₄/TiO₂ nanocomposites, we used n-butylorthotitanate as a modifying agent. The technique based on the reaction of conversion of n-butylorthotitanate on the magnetite surface into ТіО₂. This conversion consists in hydrolysis of n-butylorthotitanate followed by condensation of hydrolysis products with formation of amorphous ТіО ₂. Modification of the surface of nanosized magnetite with hydroxyapatite (obtaining of Fe₃O₄/HА composites) was carried out by the reaction: 10 Са(NO₃)₂ + 6 (NH₄)2HPO₄ + 8 NH₄ ОН → Са₁₀(PO₄)₆( ОН)₂ + 20 NH₄NO₃. We realized immobilization of DOX on the surfaces of magnetite Fe₃O₄ and nanostructures Fe₃O₄/SiO₂, Fe₃O₄/TiO₂, Fe₃O₄/HA by adsorption method from saline environment. Bioactivity of the nanocomposites was determined in the study of viability of cells by a cytochemical method using optical microscopy and Goryaev chamber with registration of concentration change for cells in suspensions containing nanocomposites, yeast cells, minimal synthetic nutrient medium and saline. Fe3O4/DOX, Fe₃O₄/SiO₂/DOX, Fe₃O₄/TiO₂/DOX, Fe₃O₄/HA/DOX nanocomposites had cytotoxic and antiproliferative activity with respect to Saccharomyces cerevisiae cells, which were characteristic for a free form of doxorubicin. Using the chosen objects, we worked out rather effective, reliable, safe and relatively inexpensive technique for control of cytotoxic activity of nanocomposites, which could be actual for use in development of new medical magnetocarried remedies of targeted delivery, in particular, for oncology.

nanosized single-domain magnetite; doxorubicin; nanocomposites Fe3O4/doxorubicin; Fe3O4/SiO2/doxorubicin; Fe3O4/TiO2/doxorubicin; Fe3O4/hydroxyapatite/doxorubicin; yeast cells; cytotoxicity; proliferation

1. Levy L., Sahoo Y., Kim K.-S., Bergey E.J., Prasad P. Synthesis and characterization of multifunctional nanoclinics for biological applications. Chem. Mater. 2002. 14: 3715. https://doi.org/10.1021/cm0203013

2. Shpak A.P., Gorbyk P.P. Nanomaterials and supramolecular structures. Physics chemistry and applications. (Springer, 2009).

3. Gorbyk P.P., Chekhun V.F. Nanocomposites of medicobiologic destination: reality and perspectives for oncology. Functional materials. 2012. 19(2): 145.

4. Gorbyk P.P., Lerman L.B., Petranovska A.L., Turanska S.P. Advances in semiconductor research: physics of nanosystems, spintronics and technological applications. Magnetosensitive nanocomposites with functions of medico-biological nanorobots: synthesis and properties. Chapter 9. (New York: Nova Science Publishers, 2014). P. 161.

5. Davaran S., Alimirzalu S., Nejati-Koshki K., Nasrabadi H.T., Akbarzadeh A., Khandaghi A.A., Abbasian M., Alimohammadi S. Physicochemical characteristics of Fe₃O₄ magnetic nanocomposites based on poly(N-isopropylacrylamide) for anti-cancer drug delivery. Asian Pac. J. Cancer Prev. 2014. 15(1): 49. https://doi.org/10.7314/APJCP.2014.15.1.49

6. Anirudhan T.S., Sandeep S. Synthesis, characterization, cellular uptake and cytotoxicity of a multi-functional magnetic nanocomposite for the targeted delivery and controlled release of doxorubicin to cancer cells. J. Mater. Chem. 2012. 22: 12888. https://doi.org/10.1039/c2jm31794j

7. Sadighian S., Hosseini-Monfared H., Rostamizadeh K., Hamidi M. pH-Triggered magnetic-chitosan nanogels (MCNs) for doxorubicin delivery: physically vs. chemically cross linking approach. Adv. Pharm. Bull. 2015. 5(1): 115.

8. Prylutska S.V., Didenko G.V., Potebnya G.P., Bogutska K.I., Prylutskyy Yu.I., Ritter U., Scharff P. Toxic effect of C60 fullerene-doxorubicin complex towards normal and tumor cells in vitro. Biopolym. Cell. 2014. 30(5): 372. https://doi.org/10.7124/bc.0008B4

9. Prylutska S., Grynyuk I., Matyshevska O., Prylutskyy Yu., Evstigneev M., Scharff P., Ritter U. C60 fullerene as synergistic agent in tumor-inhibitory doxorubicin treatment. Drugs R D. 2014. 14(4): 333. https://doi.org/10.1007/s40268-014-0074-4

10. Prylutska S.V., Korolovych V.F., Prylutskyy Yu.I., Evstigneev M.P., Ritter U., Scharff P. Tumor-inhibitory effect of C60 fullerene complex with doxorubicin. Nanomed. Nanobiol. 2014. 1(2): 1.

11. Orel V.E., Mitrelias T., Tselepi M., Golovko T., Nikolov N., Romanov A., Rykhalskiy A., Barnes C., Yaroshenko O., Orel I., Supruniuk I., Shchepotin I. Imaging of Guerin carcinoma during magnetic nanotherapy. J. Nanopharmaceutics Drug Delivery. 2014. 2: 1. https://doi.org/10.1166/jnd.2014.1044

12. Panchuk R.R., Prylutska S.V., Chumak V.V., Skorokhyd N.R., Lehka L.V., Evstigneev M.P., Prylutskyy Yu.I., Berger W., Heffeter P., Scharff P., Ritter U., Stoika R.S. Application of C60 fullerene-doxorubicin complex for tumor cell treatment in vitro and in vivo. J. Biomed. Nanotechnol. 2015. 11(7): 1139. https://doi.org/10.1166/jbn.2015.2058

13. Afanasieva K.S., Prylutska S.V., Lozovik A.V., Bogutska K.I., Sivolob A.V., Prylutskyy Yu.I., Ritter U., Scharff P. C60 fullerene prevents genotoxic effect of doxorubicin on human lymphocytes in vitro. Ukr. Biochem. J. 2015. 87(1): 91. https://doi.org/10.15407/ubj87.01.091

14. Prylutska S., Skivka L., Didenko G., Prylutskyy Yu., Evstigneev M., Potebnya G., Panchuk R., Stoika R., Ritter U., Scharff P. Complex of C60 fullerene with doxorubicin as a promising agent in antitumor therapy. Nanoscale Res. Lett. 2015. 10(499): 1. https://doi.org/10.1186/s11671-015-1206-7

15. Orel V., Shevchenko A., Romanov A., Tselepi M., Mitrelias T., Barnes C.H.W., Burlaka C.H.W., Lukin S., Shchepotin I. Magnetic properties and antitumor effect of nanocomplexes of iron oxide and doxorubicin. Nanomed. Nanotechnol. Biol. Med. 2015. 11(1): 47. https://doi.org/10.1016/j.nano.2014.07.007

16. Kule C., Ondrejickova O., Verner K. Doxorubicin, daunorubicin, and mitoxantrone cytotoxicity in yeast. Mol. Pharmacol. 1994. 46(6):1234.

17. Patel S., Sprung A.U., Keller B.A., Heaton V.J., Fisher L.M. Identification of yeast DNA topoisomerase II mutants resistant to the antitumor drug doxorubicin: implications for the mechanisms of doxorubicin action and cytotoxicity. Mol. Pharmacol. 1997. 52(4): 658.

18. Saenko Yu.V., Shutov A.M., Rastorgueva E.V. Doxorubicin and menadione reduce cell proliferation of Saccharomyces cerevisiae by different mechanisms. Cytology. 2010. 52(5): 407 [in Russian].

19. Petranovska A.L., Abramov M.V., Turanska S.P., Gorbyk P.P., Kusyak A.P. Magnetic fluids based on magnetite and doxorubicin for targeted delivery of drug. Him. Fiz. Tehnol. Poverhni. 2015. 6(3): 343 [in Ukrainian].

20. Kusyak A.P., Turanska S.P., Petranovska A.L., Gorbyk P.P. Adsorption of cis-dichlorodiammineplatinum by magnetosensitive nanocomposites Fe₃O₄/SiO₂ (TiO₂, Al₂O₃). Novel ways to solve actual problems of basic fields, ecology, energy and resource preservation. In: Kazantip-Eco-2014. XXII international conf. (Khar'kov, 2014). 1: 37 [in Ukrainian].

21. Semko L.S., Gorbyk P.P., Storozhuk L.P., Dz'ubenko L.S., Dubrovin I.V., Oranska O.I. Modification of magnetite with silicon dioxide. Physics and Chemistry of Solid State. 2007. 8(3): 526 [in Ukrainian].

22. Kovalenko A.S., Grin' S.V., Il'in V.G. Peculiarities of template synthesis of mesoporous materials based on titano-silicic ethers. Theor. Exp. Chem. 2004. 40(1): 52. https://doi.org/10.1023/B:THEC.0000020766.31010.2c

23. Semko L.S., Gorbyk P.P., Chuiko O.O., Storozhuk L.P., Dubrovin I.V., Oranska O.I., Revo S.L. Modification of magnetite with titanium dioxide and properties of the obtained nanocomposites. Reports of NAS of Ukraine. 2007. 2: 150 [in Ukrainian].

24. Turov V.V., Gorbik S.P. Determination of adhesion powers at cell/water interface from the data of H NMR spectroscopy. Ukrainian chemical journal. 2003. 69(6): 80 [in Russian].

25. Turov V.V., Gorbik S.P., Chuiko A.A. Influence of dispersed silica on bound water in frozen cellular suspensions. Cryobiology problems. 2002. 3: 16 [in Russian].

26. Gorbyk P.P., Turov V.V. Nanomaterials and nanocomposites in medicine, biology, ecology. (Kyiv: Naukova dumka, 2011) [in Russian].

27. Babaeva I.P., Chernov I.Yu. Yeast biology. (T-vo of scien. edit. KMK, 2004) [in Russian].

28. Medical chemistry and clinical application of silicon dioxide. (Ed. Chuiko A.A.). (Kyiv: Naukova dumka, 2003) [in Russian].

29. Turov V.V., Gun'ko V.M. Clustered water and ways of its using. (Kyiv: Naukova dumka, 2011) [in Russian].

30. Turanska S.P., Turov V.V., Gun'ko V.M., Bogatyrev V.M. Water associates in partly dehydrated yeast and on hydrophobic silica surface. Coll. Chemistry, Physics and Technology of Surface. (Kyiv: Vyd. dim «KM Academy», 2004). 10: 207 [in Ukrainian].

31. Turov V.V., Gun'ko V.M., Bogatyrev V.M., Zarko V.I., Gorbik S.P., Pakhlov E.M., Leboda R., Shulga O.V., Chuiko A.A. Structured water in partially dehydrated yeast cells and at partially hydrophobized fumed silica surface. J. Colloid Interface Sci. 2005. 283: 329. https://doi.org/10.1016/j.jcis.2004.09.046