Ministry of Health and Social Development of the Russian Federation State Educational Institution Of Higher Professional Education Saratov State Medical University named after V.I. Razumovsky

Authors’ of research Saratov State Medical University n.a. V.I. Razumovsky N.A. Navolokin, A.B. Bucharskya, G.N. Maslyakova, Saratov State University D.A. Gorin D.A., S.V. German

Actuality of research Nanoparticles become widespread in the environment and ingest by breathing, with food, through the skin and by intravenous administration (Oberdörster G. et al., 2005). Nanoparticles can have adverse health effects (Seaton A., Donaldson K., 2005; Shvedova AA, Kisin ER, 2005). Medical products with nanomaterials can be dangerous for the healths (Peters K., Unger RE, 2004).

The medical results often are ignored if they testify to the toxicity of nanomaterials used in medicine (Moghimi SM et al., 2005). Scientific works about toxicity of nanoparticles by morphological methods are rare in the literature.

The purpose of the study to investigate the morphological changes in organs and transplanted tumors of laboratory animals with parenteral methods of administration Fe nanoparticles.

Materials and methods Fe nanoparticles (20 nm ± 10) Zp = 30 mv covered by citrate shell White outbred male rats Transplanted tumor of liver cancer PC-1 Morphological methods: Standard hematoxylin- eosin, histochemical techniques MRI

Design of experiment White outbred half-year-old male rats inoculated with liver cancer PC-1, citrate coated iron nanoparticles (Fe3O4, 20 nm ± 10), Zp = -30 mv, were used in the study. Animal experiments were performed in accordance with the guidance «International Guiding principles for Biomedical Research Involving Animals» (2012). Animals with tumor transplanted liver cancer PC-1 were divided into 3 groups (10 rats were in each group). In the first group the nanoparticle solution was administered once intravenously at a dosage of 0.2 mg / kg; in the second group the nanoparticle solution was administered in a dosage of 16 mg/kg. The third group (comparison group) received a single intravenous injection of 1 ml saline.

Parenteral administration Liver Spleen BrainHeart

The increase of liver and kidney weight was observed macroscopically after administration of Fe nanoparticles, due to the higher degree of venous congestion, the development of vascular and degenerative processes in hepatocytes and epithelial cells of the convoluted tubules. Dystrophic and necrotic processes may depend on disturbance of blood circulation due circulation of iron nanoparticles in the lumen of blood vessels, and due to the toxic influence of the tumor itself. Accumulations of iron nanoparticles and hemosiderin were not found by this method and the duration of administration. Administration of Fe nanoparticles: results

Morphological changes in the tumor and MRT

Statistically significant thinning of interalveolar septa and emphysema with increasing blood supply vessels were occured in the lungs. Clusters of nanoparticles were not revealed, but a significant increase in the area of peribronchial lymphoid infiltrates was noted, which indicates body’s immune response to the introduction of foreign particles. The prevalence of predominance full-blooded pulp compared over white pulp was noted in spleen after intravenous administration. The bright active centers were detected in follicules, which indicated the activation of B-lymphocytes differenciation and their blast-transformation. A statistically significant increase in the thickness of the mantle zone was observed indicating the increasing in cooperation of T- and B- lymphocyte and accumulation of B-lymphocytes of memory. Thus, the citrate stabilized nanoparticles of iron causes the immune stimulation in spleen.

Morphometric changes in organs at intravenous administration of iron nanoparticles Organs parameter control group comparison group Dosage NP Fe 20 mg / kg Dosage NP Fe 16 mg / kg L iver Kupffer cells and Ito8.37±2.78.9± ± ±0.89 ** lymphocytes 3.1± ± ±0.31 ** 1.09±0.33 ** necrotic hepatocytes0.87±0.73.5± ±0.818 ** 14.36±1.7 ** Lung S infiltrates (mm2) 0.017± ± ±0.161 ** 0.21±0.02 ** Interalveolar septa thickness (mm) ± ± ± *** 0.011± * Kidney S glomeruli (mm2) ± ± ± *** ± *** Epithelial height (mm) ± ± ± *** 0.017± *** Spleen S follicles (mm2)0.107± ± ± ±0.027 *** The thickness of the marginal zone (mm) 8.37± ± ± * 0.03±0.039 ***

Conclusions The intravenous administration of citrate - stabilized iron nanoparticles in a dosage of 20 mkg/kg leads to disruption of blood supply to the organs, mainly due to the plethora, while marked dystrophic cell damage is observed in two main detoxification organs: in the liver and kidneys. The immunostimulatory effects of iron on the white pulp of the spleen and peribronchial lymphoid follicles were established. Particles were detected in the heart and brain, and their accumulation in the tumor was significantly noted. This data indicates that the selected dose is sufficient for accumulation of the iron nanoparticles in tumor.

Bibliography 1. Losic D, Rosengarten G, Mitchell JG, et al. Porearchitecture of diatom frustules: potential nanostructuredmembranes for molecular and particle separations. J NanosciNanotechnol 2006; 6: 982–9. 2. Koger N. Prescribing diatom morphology: towardsgenetic engineering of biological nanomaterials. Curr OpinChem Biol 2007; 11: 662–9. 3. Vo-Dinh T, eds. Protein Nanotechnology, Protocols,Instrumentation, and Applications. Series: Methods in MolecularBiology; Totowa: Humana Press Inc, 2008; 452 p. 4. Zschornack G, Grossmann F, Ovsyannikov VP, et al.Highly charged ions for high-tech applications. German-Ukrainian Symposium on Nanoscience and Nanotechnology,abstract book; Essen, 2008: Kentsch J, Durr M, Schnelle T, et al. Microdevices forseparation, accumulation and analysis of biological micro- andnanoparticles. IEE Proc Nanobiotechnol 2003; 150: 82–9. 6. Neugebauer S, Muller U, Lochmuller T, et al. Characterizationof nanopore electrode structures as basis for amplifiedelectro chemical assays. Electroanalysis 2006; 18: 1929– Greulich C, Kittler S, Epple M, et al. Studies on thebiocompatibility and the interaction of silver nanoparticles with human mesenchymal stem cells (hMSCs). Langenbecks Arch Surg 2009; 394: 495– Saleem M, Meyer MC, Breitenstein D, et al. Thesurfactant peptide KL4 in lipid monolayers: phase behavior, topography and chemical distribution. J Biol Chem 2008;283: 5195– Chekhun VF, Kulik GI, Todor IN, et al. The influenceof ferromagnetic nanoparticles on antitumor effect of doxorubicinin Ehrlich ascitic carcinoma-bearing mice. German-Ukrainian Symposium on Nanoscience and Nanotechnology,abstract book; Essen, 2008: Bilyy R, Podhorodecki A, Nyk M, et al. Utilizationof GaN:Eu3+ nanocrystals for the detection of programmedcell death. Physica E: Low-Dimentional Systems and Nanostructures 2008; 40: 2096– Arruebo M, Galan M, Navascues N, et al. Development of magnetic nanostructured silica-based materials as potential vector for drug-delivery application. Chem Materials 2006; 18: 1911–9.