Skip to main content
SpringerLink
Log in

Modifications of nano-titania surface for in vitro evaluations of hemolysis, cytotoxicity, and nonspecific protein binding

  • Research Paper
  • Published:
Journal of Nanoparticle Research Aims and scope Submit manuscript

Abstract

In the past decade, a variety of drug carriers based on mesoporous silica nanoparticles has been extensively reported. However, their biocompatibility still remains debatable, which motivated us to explore the porous nanostructures of other metal oxides, for example titanium dioxide (TiO2), as potential drug delivery vehicles. Herein, we report the in vitro hemolysis, cytotoxicity, and protein binding of TiO2 nanoparticles, synthesized by a sol–gel method. The surface of the TiO2 nanoparticles was modified with hydroxyl, amine, or thiol containing moieties to examine the influence of surface functional groups on the toxicity and protein binding aspects of the nanoparticles. Our study revealed the superior hemocompatibility of pristine, as well as functionalized TiO2 nanoparticles, compared to that of mesoporous silica, the present gold standard. Among the functional groups studied, aminosilane moieties on the TiO2 surface substantially reduced the degree of hemolysis (down to 5%). Further, cytotoxicity studies by MTT assay suggested that surface functional moieties play a crucial role in determining the biocompatibility of the nanoparticles. The presence of NH2– functional groups on the TiO2 nanoparticle surface enhanced the cell viability by almost 28% as compared to its native counterpart (at 100 μg/ml), which was in agreement with the hemolysis assay. Finally, nonspecific protein adsorption on functionalized TiO2 surfaces was examined using human serum albumin and it was found that negatively charged surface moieties, like –OH and –SH, could mitigate protein adsorption to a significant extent.

ᅟ

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Aisaka Y, Kawaguchi R, Watanabe S (2008) Hemolysis caused by titanium dioxide particles. Inhal Toxicol 20:891–893

    Article  Google Scholar 

  • Avgoustakis K (2004) Pegylated poly(lactide) and poly(lactide-coglycolide) nanoparticles: preparation, properties and possible applications in drug delivery. Curr Drug Delivery 1:321–333

    Article  Google Scholar 

  • Cai R, Kubota Y, Shuiyn T, Sakai H, Hashimoto K, Fujishima A (1992) Induction of cytotoxicity by photoexcited TiO2 particles. Cancer Res 52:2346–2348

    Google Scholar 

  • Chen J, Dong X, Zhao J, Tang G (2009) In vivo acute toxicity of titanium dioxide nanoparticles to mice after intraperitoneal injection. J Appl Toxicol 29:330–337

    Article  Google Scholar 

  • Du J, Gebicki JM (2004) Proteins are major initial cell targets of hydroxyl free radicals. Int J Biochem Cell Biol 36:2334–2343

    Article  Google Scholar 

  • Ehrlich V, Darroudi F, Uhl M, Steinkellner S, Zsivkovits M, Knasmeuller S (2002) Fumonisin B1 is genotoxic in human derived hepatoma (HepG2) cells. Mutagenesis 17:257–260

    Article  Google Scholar 

  • Fogh-Andersen N, Bjerrum PJ, Siggaard-Andersen O (1993) Ionic binding, net charge, and Donnan effect of human serum albumin as a function of pH. Clin Chem 39:48–52

    Google Scholar 

  • Ghosh M, Chakraborty A, Mukherjee A (2013) Cytotoxic, genotoxic and the hemolytic effect of titanium dioxide (TiO2) nanoparticles on human erythrocyte and lymphocyte cells in vitro. J Appl Toxicol 33:1097–1110

    Article  Google Scholar 

  • Ghosh S, Majumder D, Sen A, Roy S (2014) Facile sonochemical synthesis of zinc oxide nanoflakes at room temperature. Mater Lett 130:215–217

    Article  Google Scholar 

  • Gogniat G, Thyssen M, Denis M, Pulgarin C, Dukan S (2006) The bactericidal effect of TiO2 photocatalysis involves adsorption onto catalyst and the loss of membrane integrity. FEMS Microbiol Lett 258:18–24

    Article  Google Scholar 

  • Han W, Wag Y, Zheng Y (2009) In vivo biocompatibility studies of nano TiO2 materials. Adv Mater Res 79-82:389–392

    Article  Google Scholar 

  • He Q, Zhang J, Shi J, Zhu Z, Zhang L, Bu W, Guo L, Chen Y (2010) The effect of PEGylation of mesoporous silica nanoparticles on nonspecific binding of serum proteins and cellular responses. Biomaterials 31:1085–1092

    Article  Google Scholar 

  • Hoffmann MR, Martin ST, Choi W, Bahnemann DW (1995) Environmental applications of semiconductor photocatalysis. Chem Rev 95:69–96

    Article  Google Scholar 

  • Huang N, Yang P, Leng YX, Chen JY, Sun H, Wang J, Wang GJ, Ding PD, Xi TF, Leng Y (2003) Hemocompatibility of titanium oxide films. Biomaterials 24:2177–2187

    Article  Google Scholar 

  • Jacobs JF, Poel I, Osseweijer P (2010) Sunscreens with titanium dioxide (TiO2) nanoparticles: a societal experiment. NanoEthics 4:103–113

    Article  Google Scholar 

  • Jin CY, Zhu BS, Wang XF, Lu QH (2008) Cytotoxicity of titanium dioxide nanoparticles in mouse fibroblast cells. Chem Res Toxicol 21:1871–1877

    Article  Google Scholar 

  • Kluson P, Kacer P, Cajthaml T, Kalajic M (2001) Preparation of titania mesoporous materials using a surfactant-mediated sol–gel method. J Mater Chem 11:644–651

    Article  Google Scholar 

  • Lin YS, Haynes CL (2010) Impacts of mesoporous silica nanoparticle size, pore ordering, and pore integrity on hemolytic activity. J Am Chem Soc 132:4834–4842

    Article  Google Scholar 

  • Méndez-vivar J, Mendoza-Serna R, Gómez-Lara J, Gaviño R (1997) Spectroscopic study of SiO2-TiO2 sols prepared using stabilizing agents. J Sol-Gel Sci Technol 8:235–241

    Google Scholar 

  • Murashov V, Harper M, Demchuk E (2006) Impact of silanol surface density on the toxicity of silica aerosols measured by erythrocyte haemolysis. J Occup Environ Hyg 3:718–723

    Article  Google Scholar 

  • Nobuo U (1971) Isoelectric points and conformation of proteins: effect of urea on the behavior of some proteins in isoelectric focusing. BBA-Protein Struct 229:567–581

    Article  Google Scholar 

  • Otsuka H, Nagasaki Y, Kataoka K (2003) PEGylated nanoparticles for biological and pharmaceutical applications. Adv Drug Deliv Rev 55:403–419

    Article  Google Scholar 

  • Owens DE, Peppas NA (2006) Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm 307:93–102

    Article  Google Scholar 

  • Patil S, Sandberg A, Heckert E, Self W, Seal S (2007) Protein adsorption and cellular uptake of cerium oxide nanoparticles as a function of zeta potential. Biomaterials 28:4600–4607

    Article  Google Scholar 

  • Popov AP, Priezzhev AV, Lademann J, Myllylä R (2005) TiO2 nanoparticles as an effective UV-B radiation skin-protective compound in sunscreens. J Phys D Appl Phys 38:2564

    Article  Google Scholar 

  • Prencipe G, Tabakman SM, Welsher K, Liu Z, Goodwin AP, Zhang L, Henry J, Dai H (2009) PEG branched polymer for functionalization of nanomaterials with ultralong blood circulation. J Am Chem Soc 131:4783–4787

    Article  Google Scholar 

  • Reeves JF, Davies SJ, Dodd NJF, Jha AN (2008) Hydroxyl radicals (*OH) are associated with titanium dioxide (TiO2) nanoparticle-induced cytotoxicity and oxidative DNA damage in fish cells. Mutat Res-Fund Mol M 640:113–122

    Article  Google Scholar 

  • Salgin S, Takac S, Ozdamar TH (2006) Adsorption of bovine serum albumin on polyether sulfone ultrafiltration membranes: determination of interfacial interaction energy and effective diffusion coefficient. J Membr Sci 278:251–260

    Article  Google Scholar 

  • Selloni A, Vittadini A, Gratzel M (1998) The adsorption of small molecules on the TiO2 anatase (101) surface by first-principles molecular dynamics. Surf Sci 402-404:219–222

    Article  Google Scholar 

  • Shi H, Magaye R, Castranova V, Zhao J (2013) Titanium dioxide nanoparticles: a review of current toxicological data. Part Fibre Toxicol 10:15

    Article  Google Scholar 

  • Sigal GB, Mrksich M, Whitesides GM (1998) Effect of surface wettability on the adsorption of proteins and detergents. J Am Chem Soc 120(14):3464–3473

    Article  Google Scholar 

  • US Food and Drug Administration (2014) CFR-Code of Federal Regulations, Title 21, vol 1 and 5. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=73.575. Revised as of 1 Apr 2014

  • Vallet-Regí M, Balas F, Arcos D (2007) Mesoporous materials for drug delivery. Angew Chem 46:7548–7558

    Article  Google Scholar 

  • Wang J, Zhou G, Chen C, Yu H, Wang T, Ma Y, Jia G, Gao Y, Li B, Sun J, Li Y, Jiao F, Zhao Y, Chai Z (2007) Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration. Toxicol Lett 168:176–185

    Article  Google Scholar 

  • Weir A, Westerhoff P, Fabricius L, Hristovski K, Goetz N (2012) Titanium dioxide nanoparticles in food and personal care products. Environ Sci Technol 46:2242–2250

    Article  Google Scholar 

  • Yang HG, Zeng HC (2004) Creation of intestine-like interior space for metal-oxide nanostructures with a quasi-reverse emulsion. Angew Chem Int Ed 43:5206–5209

    Article  Google Scholar 

  • Ye L, Mao J, Liu J, Jiang Z, Peng T, Zan L (2013) Synthesis of anatase TiO2 nanocrystals with {101}, {001} or {010} single facets of 90% level exposure and liquid-phase photocatalytic reduction and oxidation activity orders. J Mater Chem A 1:10532–10537

    Article  Google Scholar 

  • Yildirim A, Demirel GB, Erdem R, Senturk B, Tekinay T, Bayindir M (2013a) Pluronic polymer capped biocompatible mesoporous silica nanocarriers. Chem Commun 49:9782–9784

    Article  Google Scholar 

  • Yildirim A, Ozgurab E, Bayindir M (2013b) Impact of mesoporous silica nanoparticle surface functionality on hemolytic activity, thrombogenicity and non-specific protein adsorption. J Mater Chem B 1:1909–1920

    Article  Google Scholar 

  • Yin JJ, Liu J, Ehrenshaft M, Roberts JE, Fu PP, Mason RP, Zhao BZ (2012) Phototoxicity of nano titanium dioxides in HaCaT keratinocytes—generation of reactive oxygen species and cell damage. Toxicol Appl Pharmacol 263:81–88

    Article  Google Scholar 

  • Yokoyama M, Okano T, Sakurai Y, Ekimoto H, Shibazaki C, Kataoka K (1991) Toxicity and antitumor activity against solid tumors of micelle-forming polymeric anticancer drug and its extremely long circulation in blood. Cancer Res 51:3229–3236

    Google Scholar 

  • Zhang Y, Kohler N, Zhang M (2002) Surface modification of superparamagnetic magnetite nanoparticles and their intracellular uptake. Biomaterials 23:1553–1561

    Article  Google Scholar 

  • Zhang X, Bai R, Tong YW (2006) Selective adsorption behaviors of proteins on polypyrrole-based adsorbents. Sep Purif Technol 52:161–169

    Article  Google Scholar 

  • Zhao Y, Sun X, Zhang G, Trewyn BG, Slowing II, Lin VS (2011) Interaction of mesoporous silica nanoparticles with human red blood cell membranes: size and surface effects. ACS Nano 5:1366–1375

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Materials Science and Nanotechnology, Jadavpur University, 188, Raja S.C. Mullick Road, Kolkata, West Bengal, 700032, India

    Aparna Datta

  2. Department of Biochemistry, NRS Medical College and Hospital, 138 A.J.C. Bose Road, Kolkata, West Bengal, 700014, India

    Sayantan Dasgupta

  3. Department of Metallurgical and Material Engineering, Jadavpur University, 188, Raja S.C. Mullick Road, Kolkata, West Bengal, 700032, India

    Siddhartha Mukherjee

Authors
  1. Aparna Datta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sayantan Dasgupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Siddhartha Mukherjee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Aparna Datta.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Datta, A., Dasgupta, S. & Mukherjee, S. Modifications of nano-titania surface for in vitro evaluations of hemolysis, cytotoxicity, and nonspecific protein binding. J Nanopart Res 19, 142 (2017). https://doi.org/10.1007/s11051-017-3835-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11051-017-3835-5

Keywords

Search

Navigation