Ultra-small nanoparticles with sizes comparable to those of pores in the cellular membrane possess significant potential for application in the field of biomedicine. Silicon carbide ultra-small nanoparticles with varying surface termination were tested for the biological system represented by different human cells (using a human osteoblastic cell line as the reference system and a monocyte/macrophage cell line as immune cells). The three tested nanoparticle surface terminations resulted in the observation of different effects on cell metabolic activity. These effects were mostly noticeable in cases of monocytic cells, where each type of particle caused a completely different response ('as-prepared' particles, i.e., were highly cytotoxic, -OH terminated particles slightly increased the metabolic activity, while -NH2 terminated particles caused an almost doubled metabolic activity) after 24 h of incubation. Subsequently, the release of cytokines from such treated monocytes and their differentiation into activated cells was determined. The results revealed the potential modulation of immune cell behavior following stimulation with particular ultra-small nanoparticles, thus opening up new fields for novel silicon carbide nanoparticle biomedical applications.

Biomedical Center Faculty of Medicine in Pilsen Charles University 323 00 Pilsen Czech Republic

Department of Atomic Physics Budapest University of Technology and Economics 1111 Budapest Hungary

Department of Chemical Physics and Optics Faculty of Mathematics and Physics Charles University 121 16 Prague Czech Republic

Institute of Pathological Physiology 1st Faculty of Medicine Charles University 128 53 Prague Czech Republic

Wigner Research Centre for Physics 1121 Budapest Hungary

Zobrazit více v PubMed

Lee M.Y., Yang J.A., Jung H.S., Beack S., Choi J.E., Hur W., Koo H., Kim K., Yoon S.K., Hahn S.K. Hyaluronic acid-gold nanoparticle/interferon alpha complex for targeted treatment of hepatitis C virus infection. ACS Nano. 2012;6:9522–9531. doi: 10.1021/nn302538y. PubMed DOI

Slowing I.I., Vivero-Escoto J.L., Wu C.W., Lin V.S. Mesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriers. Adv. Drug Deliv. Rev. 2008;60:1278–1288. doi: 10.1016/j.addr.2008.03.012. PubMed DOI

Dasari B.C., Cashman S.M., Kumar-Singh R. Reducible PEG-POD/DNA Nanoparticles for Gene Transfer In Vitro and In Vivo: Application in a Mouse Model of Age-Related Macular Degeneration. Mol. Ther. Nucleic. Acids. 2017;8:77–89. doi: 10.1016/j.omtn.2017.06.004. PubMed DOI PMC

Ha S.W., Sikorski J.A., Weitzmann M.N., Beck G.R., Jr. Bio-active engineered 50 nm silica nanoparticles with bone anabolic activity: therapeutic index, effective concentration, and cytotoxicity profile in vitro. Toxicol In Vitro. 2014;28:354–364. doi: 10.1016/j.tiv.2013.12.001. PubMed DOI PMC

Zang X., Zhao X., Hu H., Qiao M., Deng Y., Chen D. Nanoparticles for tumor immunotherapy. Eur. J. Pharm. Biopharm. 2017;115:243–256. doi: 10.1016/j.ejpb.2017.03.013. PubMed DOI

Zhu P., Huang S., Li M., Ding N., Peng B., Kong L., Bo Y. A sandwiched biological fluorescent probe for the diagnosis of human ovarian tumor based on TiO2 nanoparticles. J. Fluoresc. 2011;21:179–186. doi: 10.1007/s10895-010-0702-5. PubMed DOI

Costo R., Bello V., Robic C., Port M., Marco J.F., Puerto Morales M., Veintemillas-Verdaguer S. Ultrasmall iron oxide nanoparticles for biomedical applications: improving the colloidal and magnetic properties. Langmuir. 2012;28:178–185. doi: 10.1021/la203428z. PubMed DOI

Cassano D., Mapanao A.-K., Summa M., Vlamidis Y., Giannone G., Santi M., Guzzolino E., Pitto L., Poliseno L., Bertorelli R., et al. Biosafety and Biokinetics of Noble Metals: The Impact of Their Chemical Nature. ACS Appl. Bio Mater. 2019;2:4464–4470. doi: 10.1021/acsabm.9b00630. PubMed DOI

Li C., Xu L., Liu Z., Li Z., Quan Z., Al Kheraif A.A., Lin J. Current progress in the controlled synthesis and biomedical applications of ultrasmall (<10 nm) NaREF4 nanoparticles. Dalton. Trans. 2018;47:8538–8556. doi: 10.1039/c8dt00258d. PubMed DOI

Frewin C.L., Locke C., Saddow S.E., Weeber E.J. Single-crystal cubic silicon carbide: an in vivo biocompatible semiconductor for brain machine interface devices. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2011;2011:2957–2960. doi: 10.1109/IEMBS.2011.6090582. PubMed DOI

Beke D., Szekrényes Z., Pálfi D., Róna G., Balogh I., Maák P.A., Katona G., Czigány Z., Kamarás K., Rózsa B., et al. Silicon carbide quantum dots for bioimaging. J. Mater. Res. 2012;28:205–209. doi: 10.1557/jmr.2012.296. DOI

Santavirta S., Takagi M., Nordsletten L., Anttila A., Lappalainen R., Konttinen Y.T. Biocompatibility of silicon carbide in colony formation test in vitro. Arch. Orthopaedic Trauma Surgery. 1998;118:89–91. doi: 10.1007/s004020050319. PubMed DOI

Beke D., Szekrényes Z., Balogh I., Veres M., Fazakas É., Varga L.K., Kamarás K., Czigány Z., Gali A. Characterization of luminescent silicon carbide nanocrystals prepared by reactive bonding and subsequent wet chemical etching. Appl. Phys. Lett. 2011;99 doi: 10.1063/1.3663220. DOI

Dravecz G., Janosi T.Z., Beke D., Major D.A., Karolyhazy G., Erostyak J., Kamaras K., Gali A. Identification of the binding site between bovine serum albumin and ultrasmall SiC fluorescent biomarkers. Phys. Chem. Chem. Phys. 2018;20:13419–13429. doi: 10.1039/C8CP02144A. PubMed DOI

Albanese A., Tang P.S., Chan W.C. The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu. Rev. Biomed. Eng. 2012;14:1–16. doi: 10.1146/annurev-bioeng-071811-150124. PubMed DOI

Bhattacharjee S., Rietjens I.M., Singh M.P., Atkins T.M., Purkait T.K., Xu Z., Regli S., Shukaliak A., Clark R.J., Mitchell B.S., et al. Cytotoxicity of surface-functionalized silicon and germanium nanoparticles: the dominant role of surface charges. Nanoscale. 2013;5:4870–4883. doi: 10.1039/c3nr34266b. PubMed DOI PMC

Frohlich E. The role of surface charge in cellular uptake and cytotoxicity of medical nanoparticles. Int. J. Nanomed. 2012;7:5577–5591. doi: 10.2147/IJN.S36111. PubMed DOI PMC

Herd H., Daum N., Jones A.T., Huwer H., Ghandehari H., Lehr C.M. Nanoparticle geometry and surface orientation influence mode of cellular uptake. ACS Nano. 2013;7:1961–1973. doi: 10.1021/nn304439f. PubMed DOI PMC

Monopoli M.P., Aberg C., Salvati A., Dawson K.A. Biomolecular coronas provide the biological identity of nanosized materials. Nat. Nanotechnol. 2012;7:779–786. doi: 10.1038/nnano.2012.207. PubMed DOI

Escamilla-Rivera V., Uribe-Ramirez M., Gonzalez-Pozos S., Lozano O., Lucas S., De Vizcaya-Ruiz A. Protein corona acts as a protective shield against Fe3O4-PEG inflammation and ROS-induced toxicity in human macrophages. Toxicol. Lett. 2016;240:172–184. doi: 10.1016/j.toxlet.2015.10.018. PubMed DOI

Lesniak A., Fenaroli F., Monopoli M.P., Aberg C., Dawson K.A., Salvati A. Effects of the presence or absence of a protein corona on silica nanoparticle uptake and impact on cells. ACS Nano. 2012;6:5845–5857. doi: 10.1021/nn300223w. PubMed DOI

Wang F., Yu L., Monopoli M.P., Sandin P., Mahon E., Salvati A., Dawson K.A. The biomolecular corona is retained during nanoparticle uptake and protects the cells from the damage induced by cationic nanoparticles until degraded in the lysosomes. Nanomedicine. 2013;9:1159–1168. doi: 10.1016/j.nano.2013.04.010. PubMed DOI

Erickson H.P. Size and shape of protein molecules at the nanometer level determined by sedimentation, gel filtration, and electron microscopy. Biol. Proced. Online. 2009;11:32–51. doi: 10.1007/s12575-009-9008-x. PubMed DOI PMC

Sukwong P., Kongseng S., Chaicherd S., Yoovathaworn K., Tubtimkuna S., Pissuwan D. Comparison effects of titanium dioxide nanoparticles on immune cells in adaptive and innate immune system. IET Nanobiotechnol. 2017;11:759–765. doi: 10.1049/iet-nbt.2016.0205. DOI

Chen Q., Wang N., Zhu M., Lu J., Zhong H., Xue X., Guo S., Li M., Wei X., Tao Y., et al. TiO2 nanoparticles cause mitochondrial dysfunction, activate inflammatory responses, and attenuate phagocytosis in macrophages: A proteomic and metabolomic insight. Redox. Biol. 2018;15:266–276. doi: 10.1016/j.redox.2017.12.011. PubMed DOI PMC

Hirai T., Yoshioka Y., Izumi N., Ichihashi K., Handa T., Nishijima N., Uemura E., Sagami K., Takahashi H., Yamaguchi M., et al. Metal nanoparticles in the presence of lipopolysaccharides trigger the onset of metal allergy in mice. Nat. Nanotechnol. 2016;11:808–816. doi: 10.1038/nnano.2016.88. PubMed DOI

Cho W.S., Duffin R., Poland C.A., Duschl A., Oostingh G.J., Macnee W., Bradley M., Megson I.L., Donaldson K. Differential pro-inflammatory effects of metal oxide nanoparticles and their soluble ions in vitro and in vivo; zinc and copper nanoparticles, but not their ions, recruit eosinophils to the lungs. Nanotoxicology. 2012;6:22–35. doi: 10.3109/17435390.2011.552810. PubMed DOI

Nemmar A., Albarwani S., Beegam S., Yuvaraju P., Yasin J., Attoub S., Ali B.H. Amorphous silica nanoparticles impair vascular homeostasis and induce systemic inflammation. Int. J. Nanomed. 2014;9:2779–2789. doi: 10.2147/IJN.S52818. PubMed DOI PMC

Caracciolo G., Palchetti S., Colapicchioni V., Digiacomo L., Pozzi D., Capriotti A.L., La Barbera G., Lagana A. Stealth effect of biomolecular corona on nanoparticle uptake by immune cells. Langmuir. 2015;31:10764–10773. doi: 10.1021/acs.langmuir.5b02158. PubMed DOI

Lappas C.M. The immunomodulatory effects of titanium dioxide and silver nanoparticles. Food Chem. Toxicol. 2015;85:78–83. doi: 10.1016/j.fct.2015.05.015. PubMed DOI

Liu Y., Hardie J., Zhang X., Rotello V.M. Effects of engineered nanoparticles on the innate immune system. Semin. Immunol. 2017;34:25–32. doi: 10.1016/j.smim.2017.09.011. PubMed DOI PMC

Beke D., Szekrényes Z., Balogh I., Czigány Z., Kamarás K., Gali A. Preparation of small silicon carbide quantum dots by wet chemical etching. J. Mater. Res. 2012;28:44–49. doi: 10.1557/jmr.2012.223. DOI

Szekrényes Z., Somogyi B., Beke D., Károlyházy G., Balogh I., Kamarás K., Gali A. Chemical Transformation of Carboxyl Groups on the Surface of Silicon Carbide Quantum Dots. J. Phys. Chem. C. 2014;118:19995–20001. doi: 10.1021/jp5053024. DOI

Beke D., Jánosi T.Z., Somogyi B., Major D.Á., Szekrényes Z., Erostyák J., Kamarás K., Gali A. Identification of Luminescence Centers in Molecular-Sized Silicon Carbide Nanocrystals. J. Phys. Chem. C. 2015;120:685–691. doi: 10.1021/acs.jpcc.5b09503. DOI

Hanaor D., Michelazzi M., Leonelli C., Sorrell C.C. The effects of carboxylic acids on the aqueous dispersion and electrophoretic deposition of ZrO2. J. Eur. Ceramic Soc. 2012;32:235–244. doi: 10.1016/j.jeurceramsoc.2011.08.015. DOI

O’Brien R.W., Midmore B.R., Lamb A., Hunter R.J. Electroacoustic studies of moderately concentrated colloidal suspensions. Faraday Discuss. Chem. Soc. 1990;90 doi: 10.1039/dc9909000301. DOI

Flahaut E., Durrieu M.C., Remy-Zolghadri M., Bareille R., Baquey C. Study of the cytotoxicity of CCVD carbon nanotubes. J. Mater. Sci. 2006;41:2411–2416. doi: 10.1007/s10853-006-7069-7. DOI

Sikora A., Shard A.G., Minelli C. Size and ζ-Potential Measurement of Silica Nanoparticles in Serum Using Tunable Resistive Pulse Sensing. Langmuir. 2016;32:2216–2224. doi: 10.1021/acs.langmuir.5b04160. PubMed DOI

Branda F., Silvestri B., Costantini A., Luciani G. The fate of silica based Stober particles soaked into growth media (RPMI and M254): A DLS and zeta-potential study. Colloids Surf B Biointerfaces. 2015;135:840–845. doi: 10.1016/j.colsurfb.2015.03.033. PubMed DOI

Lin J., Alexander-Katz A. Cell membranes open “doors” for cationic nanoparticles/biomolecules: insights into uptake kinetics. ACS Nano. 2013;7:10799–10808. doi: 10.1021/nn4040553. PubMed DOI

Jiang Y., Huo S., Mizuhara T., Das R., Lee Y.W., Hou S., Moyano D.F., Duncan B., Liang X.J., Rotello V.M. The Interplay of Size and Surface Functionality on the Cellular Uptake of Sub-10 nm Gold Nanoparticles. ACS Nano. 2015;9:9986–9993. doi: 10.1021/acsnano.5b03521. PubMed DOI PMC

Ostrovska L., Broz A., Fucikova A., Belinova T., Sugimoto H., Kanno T., Fujii M., Valenta J., Kalbacova M.H. The impact of doped silicon quantum dots on human osteoblasts. RSC Adv. 2016;6:63403–63413. doi: 10.1039/C6RA14430F. DOI

Balek L., Buchtova M., Kunova Bosakova M., Varecha M., Foldynova-Trantirkova S., Gudernova I., Vesela I., Havlik J., Neburkova J., Turner S., et al. Nanodiamonds as “artificial proteins”: Regulation of a cell signalling system using low nanomolar solutions of inorganic nanocrystals. Biomaterials. 2018;176:106–121. doi: 10.1016/j.biomaterials.2018.05.030. PubMed DOI

Belinova T., Vrabcova L., Machova I., Fucikova A., Valenta J., Sugimoto H., Fujii M., Hubalek Kalbacova M. Silicon Quantum Dots and Their Impact on Different Human Cells. Phys. Status Solidi (b) 2018 doi: 10.1002/pssb.201700597. DOI

Tang H.L., Yuen K.L., Tang H.M., Fung M.C. Reversibility of apoptosis in cancer cells. Br. J. Cancer. 2009;100:118–122. doi: 10.1038/sj.bjc.6604802. PubMed DOI PMC

Wei X., Jiang W., Yu J., Ding L., Hu J., Jiang G. Effects of SiO2 nanoparticles on phospholipid membrane integrity and fluidity. J. Hazard. Mater. 2015;287:217–224. doi: 10.1016/j.jhazmat.2015.01.063. PubMed DOI

Lankoff A., Arabski M., Wegierek-Ciuk A., Kruszewski M., Lisowska H., Banasik-Nowak A., Rozga-Wijas K., Wojewodzka M., Slomkowski S. Effect of surface modification of silica nanoparticles on toxicity and cellular uptake by human peripheral blood lymphocytes in vitro. Nanotoxicology. 2013;7:235–250. doi: 10.3109/17435390.2011.649796. PubMed DOI

Guller A.E., Generalova A.N., Petersen E.V., Nechaev A.V., Trusova I.A., Landyshev N.N., Nadort A., Grebenik E.A., Deyev S.M., Shekhter A.B., et al. Cytotoxicity and non-specific cellular uptake of bare and surface-modified upconversion nanoparticles in human skin cells. Nano Res. 2015;8:1546–1562. doi: 10.1007/s12274-014-0641-6. DOI

Bernas T., Dobrucki J. Mitochondrial and nonmitochondrial reduction of MTT: interaction of MTT with TMRE, JC-1, and NAO mitochondrial fluorescent probes. Cytometry. 2002;47:236–242. doi: 10.1002/cyto.10080. PubMed DOI

Berridge M.V., Tan A.S. Characterization of the cellular reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT): subcellular localization, substrate dependence, and involvement of mitochondrial electron transport in MTT reduction. Arch. Biochem. Biophys. 1993;303:474–482. doi: 10.1006/abbi.1993.1311. PubMed DOI

Freemerman A.J., Johnson A.R., Sacks G.N., Milner J.J., Kirk E.L., Troester M.A., Macintyre A.N., Goraksha-Hicks P., Rathmell J.C., Makowski L. Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. J. Biol. Chem. 2014;289:7884–7896. doi: 10.1074/jbc.M113.522037. PubMed DOI PMC

Palsson-McDermott E.M., O’Neill L.A. The Warburg effect then and now: from cancer to inflammatory diseases. Bioessays. 2013;35:965–973. doi: 10.1002/bies.201300084. PubMed DOI

Choi J., Zhang Q., Reipa V., Wang N.S., Stratmeyer M.E., Hitchins V.M., Goering P.L. Comparison of cytotoxic and inflammatory responses of photoluminescent silicon nanoparticles with silicon micron-sized particles in RAW 264.7 macrophages. J. Appl. Toxicol. 2009;29:52–60. doi: 10.1002/jat.1382. PubMed DOI

Gomez D.M., Urcuqui-Inchima S., Hernandez J.C. Silica nanoparticles induce NLRP3 inflammasome activation in human primary immune cells. Innate. Immun. 2017;23:697–708. doi: 10.1177/1753425917738331. PubMed DOI

Chou C.C., Chen W., Hung Y., Mou C.Y. Molecular Elucidation of Biological Response to Mesoporous Silica Nanoparticles in Vitro and in Vivo. ACS Appl. Mater. Interfaces. 2017;9:22235–22251. doi: 10.1021/acsami.7b05359. PubMed DOI

Li A., Dubey S., Varney M.L., Dave B.J., Singh R.K. IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J. Immunol. 2003;170:3369–3376. doi: 10.4049/jimmunol.170.6.3369. PubMed DOI

Himly M., Mills-Goodlet R., Geppert M., Duschl A. Nanomaterials in the Context of Type 2 Immune Responses-Fears and Potentials. Front. Immunol. 2017;8:471. doi: 10.3389/fimmu.2017.00471. PubMed DOI PMC

Kishimoto T.K., Maldonado R.A. Nanoparticles for the Induction of Antigen-Specific Immunological Tolerance. Front. Immunol. 2018;9:230. doi: 10.3389/fimmu.2018.00230. PubMed DOI PMC

Lakshman R., Finn A. Neutrophil disorders and their management. J. Clin. Pathol. 2001;54:7–19. doi: 10.1136/jcp.54.1.7. PubMed DOI PMC