In vitro cytotoxicity of surface modified bismuth nanoparticles

  • Yang Luo
  • Chaoming Wang
  • Yong Qiao
  • Mainul Hossain
  • Liyuan Ma
  • Ming Su
Article
First Online:
Received:
Accepted:

Abstract

This paper describes in vitro cytotoxicity of bismuth nanoparticles revealed by three complementary assays (MTT, G6PD, and calcein AM/EthD-1). The results show that bismuth nanoparticles are more toxic than most previously reported bismuth compounds. Concentration dependent cytotoxicities have been observed for bismuth nanoparticles and surface modified bismuth nanoparticles. The bismuth nanoparticles are non-toxic at concentration of 0.5 nM. Nanoparticles at high concentration (50 nM) kill 45, 52, 41, 34 % HeLa cells for bare nanoparticles, amine terminated bismuth nanoparticles, silica coated bismuth nanoparticles, and polyethylene glycol (PEG) modified bismuth nanoparticles, respectively; which indicates cytotoxicity in terms of cell viability is in the descending order of amine terminated bismuth nanoparticles, bare bismuth nanoparticles, silica coated bismuth nanoparticles, and PEG modified bismuth nanoparticles. HeLa cells are more susceptible to toxicity from bismuth nanoparticles than MG-63 cells. The simultaneous use of three toxicity assays provides information on how nanoparticles interact with cells. Silica coated bismuth nanoparticles can damage cellular membrane yet keep mitochondria less influenced; while amine terminated bismuth nanoparticles can affect the metabolic functions of cells. The findings have important implications for caution of nanoparticle exposure and evaluating toxicity of bismuth nanoparticles.

Keywords

HeLa Cell Bismuth Calcein Iron Oxide Nanoparticles CdSe Nanoparticles 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

Bi

Bare bismuth nanoparticles

Bi–PEG

Polyethylene glycol modified bismuth nanoparticles

Bi@SiO2

Silica encapsulated bismuth nanoparticles

Bi@SiO2–NH2

Amine modified silica encapsulated bismuth nanoparticles

Calcein AM

Calcein acetoxymethyl ester

CdSe/ZnS–COOH

Carboxylic acid modified CdSe/ZnS nanoparticles

EthD-1

Ethidium homodimer-1

Fe3O4–COOH

Carboxylic acid modified iron oxide nanoparticles

Fe3O4–NH2

Amine modified iron oxide nanoparticles

G6PD

Glucose-6-phosphate dehydrogenase

MAA

Mercaptoacetic acid

MTT

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

PEG

Polyethylene glycol

XRF

X-ray fluorescence

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Notes

Acknowledgments

This project has been supported by a research grant (0828466), a CAREER award from National Science Foundation, a Concept Award (W81XWH-10-1-0961) from Lung Cancer Research Program of Department of Defense, a grant from the National Natural Science Foundation of China (30900348), and a fund for the transformation of scientific and technological achievements of the Third Military Medical University (2010XZH08).

References

  1. 1.
    Pamphlett R, Danscher G, Rungby J, Stoltenberg M. Tissue uptake of bismuth from shotgun pellets. Environ Res. 2000;82:258–62.CrossRefGoogle Scholar
  2. 2.
    Larsen A, Martiny M, Stoltenberg M, Danscher G, Rungby J. Gastrointestinal and systemic uptake of bismuth in mice after oral exposure. Pharmacol Toxicol. 2003;93:82–90.Google Scholar
  3. 3.
    Andrews PC, Ferrero RL, Forsyth CM, Junk PC, Maclellan JG, Peiris RM. Bismuth(III) saccharinate and thiosaccharinate complexes and the effect of ligand substitution on their activity against Helicobacter pylori. Organometallics. 2011;30:6283–91.CrossRefGoogle Scholar
  4. 4.
    Gisbert JP. Helicobacter pylori eradication: a new, single-capsule bismuth-containing quadruple therapy. Nat Rev Gastroenterol Hepatol. 2011;8:307–9.CrossRefGoogle Scholar
  5. 5.
    Malfertheiner P, Bazzoli F, Delchier JC, Celinski K, Giguere M, Riviere M, et al. Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: a randomised, open-label, non-inferiority, phase 3 trial. Lancet. 2011;377:905–13.CrossRefGoogle Scholar
  6. 6.
    Rosenblat TL, McDevitt MR, Mulford DA, Pandit-Taskar N, Divgi CR, Panageas KS, et al. Sequential cytarabine and alpha-particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia. Clin Cancer Res. 2010;16:5303–11.CrossRefGoogle Scholar
  7. 7.
    Leussink BT, Baelde HJ, Broekhuizen-van den Berg TM, de Heer E, van der Voet GB, Slikkerveer A, et al. Renal epithelial gene expression profile and bismuth-induced resistance against cisplatin nephrotoxicity. Hum Exp Toxicol. 2003;22:535–40.CrossRefGoogle Scholar
  8. 8.
    Larsen A, Stoltenberg M, West MJ, Danscher G. Influence of bismuth on the number of neurons in cerebellum and hippocampus of normal and hypoxia-exposed mouse brain: a stereological study. J Appl Toxicol. 2005;25:383–92.CrossRefGoogle Scholar
  9. 9.
    Geyikoglu F, Turkez H. Genotoxicity and oxidative stress induced by some bismuth compounds in human blood cells in vitro. Fresenius Environ Bull. 2005;14:854–60.Google Scholar
  10. 10.
    Stoltenberg M, Larsen A, Zhao M, Danscher G, Brunk UT. Bismuth-induced lysosomal rupture in J774 cells. APMIS. 2002;110:396–402.CrossRefGoogle Scholar
  11. 11.
    Turkez H, Geyikoglu F, Keles MS. Biochemical response to colloidal bismuth subcitrate––dose–time effect. Biol Trace Elem Res. 2005;105:151–8.CrossRefGoogle Scholar
  12. 12.
    Stoltenberg M, Hogenhuis JA, Hauw JJ, Danscher G. Autometallographic tracing of bismuth in human brain autopsies. J Neuropathol Exp Neurol. 2001;60:705–10.Google Scholar
  13. 13.
    Kinsella JM, Jimenez RE, Karmali PP, Rush AM, Kotamraju VR, Gianneschi NC, et al. X-ray computed tomography imaging of breast cancer by using targeted peptide-labeled bismuth sulfide nanoparticles. Angew Chem Int Ed. 2011;50:12308–11.CrossRefGoogle Scholar
  14. 14.
    Rabin O, Manuel Perez J, Grimm J, Wojtkiewicz G, Weissleder R. An X-ray computed tomography imaging agent based on long-circulating bismuth sulphide nanoparticles. Nat Mater. 2006;5:118–22.CrossRefGoogle Scholar
  15. 15.
    Ding SN, Shan D, Xue HG, Cosnier S. A promising biosensing-platform based on bismuth oxide polycrystalline-modified electrode: characterization and its application in development of amperometric glucose sensor. Bioelectrochemistry. 2010;79:218–22.CrossRefGoogle Scholar
  16. 16.
    Ma L, Hong Y, Ma Z, Kaittanis C, Perez JM, Su M. Multiplexed highly sensitive detections of cancer biomarkers in thermal space using encapsulated phase change nanoparticles. Appl Phys Lett. 2009;95:043701.CrossRefGoogle Scholar
  17. 17.
    Wang C, Sun Z, Ma L, Su M. Simultaneous detection of multiple biomarkers with over three orders of concentration difference using phase change nanoparticles. Anal Chem. 2011;83:2215–9.CrossRefGoogle Scholar
  18. 18.
    Hossain M, Wang C, Su M. Multiplexed biomarker detection using X-ray fluorescence of composition-encoded nanoparticles. Appl Phys Lett. 2010;97:263704.CrossRefGoogle Scholar
  19. 19.
    Wang L, Nagesha DK, Selvarasah S, Dokmeci MR, Carrier RL. Toxicity of CdSe nanoparticles in Caco-2 cell cultures. J Nanobiotechnol. 2008;6:11.CrossRefGoogle Scholar
  20. 20.
    Zhao J, Castranova V. Toxicology of nanomaterials used in nanomedicine. J Toxicol Environ Health B Crit Rev. 2011;14:593–632.CrossRefGoogle Scholar
  21. 21.
    Zhang Y, Yu W, Jiang X, Lv K, Sun S, Zhang F. Analysis of the cytotoxicity of differentially sized titanium dioxide nanoparticles in murine MC3T3-E1 preosteoblasts. J Mater Sci Mater Med. 2011;22:1933–45.CrossRefGoogle Scholar
  22. 22.
    Clift MJ, Rothen-Rutishauser B, Brown DM, Duffin R, Donaldson K, Proudfoot L, et al. The impact of different nanoparticle surface chemistry and size on uptake and toxicity in a murine macrophage cell line. Toxicol Appl Pharmacol. 2008;232:418–27.CrossRefGoogle Scholar
  23. 23.
    Zhu ZJ, Carboni R, Quercio MJ Jr, Yan B, Miranda OR, Anderton DL, et al. Surface properties dictate uptake, distribution, excretion, and toxicity of nanoparticles in fish. Small. 2010;6:2261–5.CrossRefGoogle Scholar
  24. 24.
    Hoshino A, Hanada S, Yamamoto K. Toxicity of nanocrystal quantum dots: the relevance of surface modifications. Arch Toxicol. 2011;85:707–20.CrossRefGoogle Scholar
  25. 25.
    Selim KK, Xing ZC, Choi MJ, Chang Y, Guo H, Kang IK. Reduced cytotoxicity of insulin-immobilized CdS quantum dots using PEG as a spacer. Nanoscale Res Lett. 2011;6:528.CrossRefGoogle Scholar
  26. 26.
    Zhang XD, Wu D, Shen X, Liu PX, Yang N, Zhao B, et al. Size-dependent in vivo toxicity of PEG-coated gold nanoparticles. Int J Nanomed. 2011;6:2071–81.CrossRefGoogle Scholar
  27. 27.
    Cho WS, Cho MJ, Jeong J, Choi M, Cho HY, Han BS, et al. Acute toxicity and pharmacokinetics of 13 nm-sized PEG-coated gold nanoparticles. Toxicol Appl Pharmacol. 2009;236:16–24.CrossRefGoogle Scholar
  28. 28.
    Malugin A, Ghandehari H. Cellular uptake and toxicity of gold nanoparticles in prostate cancer cells: a comparative study of rods and spheres. J Appl Toxicol. 2010;30:212–7.Google Scholar
  29. 29.
    Nair S, Sasidharan A, Divya Rani VV, Menon D, Manzoor K, Raina S. Role of size scale of ZnO nanoparticles and microparticles on toxicity toward bacteria and osteoblast cancer cells. J Mater Sci Mater Med. 2009;20(Suppl 1):S235–41.CrossRefGoogle Scholar
  30. 30.
    Wang H, Wingett D, Engelhard MH, Feris K, Reddy KM, Turner P, et al. Fluorescent dye encapsulated ZnO particles with cell-specific toxicity for potential use in biomedical applications. J Mater Sci Mater Med. 2009;20:11–22.CrossRefGoogle Scholar
  31. 31.
    Zhao Y, Lin K, Zhang W, Liu L. Quantum dots enhance Cu2+-induced hepatic L02 cells toxicity. J Environ Sci (China). 2010;22:1987–92.CrossRefGoogle Scholar
  32. 32.
    Mahmoudi M, Simchi A, Imani M, Milani AS, Stroeve P. An in vitro study of bare and poly(ethylene glycol)-co-fumarate-coated superparamagnetic iron oxide nanoparticles: a new toxicity identification procedure. Nanotechnology. 2009;20:225104.CrossRefGoogle Scholar
  33. 33.
    Johnston HJ, Hutchison G, Christensen FM, Peters S, Hankin S, Stone V. A review of the in vivo and in vitro toxicity of silver and gold particulates: particle attributes and biological mechanisms responsible for the observed toxicity. Crit Rev Toxicol. 2010;40:328–46.CrossRefGoogle Scholar
  34. 34.
    Yan M, Zhang Y, Xu K, Fu T, Qin H, Zheng X. An in vitro study of vascular endothelial toxicity of CdTe quantum dots. Toxicology. 2011;282:94–103.CrossRefGoogle Scholar
  35. 35.
    von Recklinghausen U, Hartmann LM, Rabieh S, Hippler J, Hirner AV, Rettenmeier AW, et al. Methylated bismuth, but not bismuth citrate or bismuth glutathione, induces cyto- and genotoxic effects in human cells in vitro. Chem Res Toxicol. 2008;21:1219–28.CrossRefGoogle Scholar
  36. 36.
    Talapin DV, Rogach AL, Kornowski A, Haase M, Weller H. Highly luminescent monodisperse CdSe and CdSe/ZnS nanocrystals synthesized in a hexadecylamine–trioctylphosphine oxide–trioctylphospine mixture. Nano Lett. 2001;1:207–11.CrossRefGoogle Scholar
  37. 37.
    Kirchner C, Liedl T, Kudera S, Pellegrino T, Munoz Javier A, Gaub HE, et al. Cytotoxicity of colloidal CdSe and CdSe/ZnS nanoparticles. Nano Lett. 2005;5:331–8.CrossRefGoogle Scholar
  38. 38.
    Navarro E, Piccapietra F, Wagner B, Marconi F, Kaegi R, Odzak N, et al. Toxicity of silver nanoparticles to chlamydomonas reinhardtii. Environ Sci Technol. 2008;42:8959–64.CrossRefGoogle Scholar
  39. 39.
    Griffitt RJ, Weil R, Hyndman KA, Denslow ND, Powers K, Taylor D, et al. Exposure to copper nanoparticles causes gill injury and acute lethality in zebrafish (Danio rerio). Environ Sci Technol. 2007;41:8178–86.CrossRefGoogle Scholar
  40. 40.
    Pittella F, Zhang M, Lee Y, Kim HJ, Tockary T, Osada K, et al. Enhanced endosomal escape of siRNA-incorporating hybrid nanoparticles from calcium phosphate and PEG-block charge-conversional polymer for efficient gene knockdown with negligible cytotoxicity. Biomaterials. 2011;32:3106–14.CrossRefGoogle Scholar
  41. 41.
    Tiwari DK, Jin T, Behari J. Bio-distribution and toxicity assessment of intravenously injected anti-HER2 antibody conjugated CdSe/ZnS quantum dots in Wistar rats. Int J Nanomed. 2011;6:463–75.Google Scholar
  42. 42.
    Naqvi S, Samim M, Abdin M, Ahmed FJ, Maitra A, Prashant C, et al. Concentration-dependent toxicity of iron oxide nanoparticles mediated by increased oxidative stress. Int J Nanomed. 2010;5:983–9.CrossRefGoogle Scholar
  43. 43.
    Mahmoudi M, Simchi A, Milani AS, Stroeve P. Cell toxicity of superparamagnetic iron oxide nanoparticles. J Colloid Interface Sci. 2009;336:510–8.CrossRefGoogle Scholar
  44. 44.
    Gupta AK, Berry C, Gupta M, Curtis A. Receptor-mediated targeting of magnetic nanoparticles using insulin as a surface ligand to prevent endocytosis. IEEE Trans Nanobiosci. 2003;2:255–61.CrossRefGoogle Scholar
  45. 45.
    Park J, Fong PM, Lu J, Russell KS, Booth CJ, Saltzman WM, et al. PEGylated PLGA nanoparticles for the improved delivery of doxorubicin. Nanomedicine. 2009;5:410–8.CrossRefGoogle Scholar
  46. 46.
    Liu Y, Shipton MK, Ryan J, Kaufman ED, Franzen S, Feldheim DL. Synthesis, stability, and cellular internalization of gold nanoparticles containing mixed peptide-poly(ethylene glycol) monolayers. Anal Chem. 2007;79:2221–9.CrossRefGoogle Scholar
  47. 47.
    Baber O, Jang M, Barber D, Powers K. Amorphous silica coatings on magnetic nanoparticles enhance stability and reduce toxicity to in vitro BEAS-2B cells. Inhal Toxicol. 2011;23:532–43.CrossRefGoogle Scholar
  48. 48.
    Serfontein WJ, Mekel R. Bismuth toxicity in man II. Review of bismuth blood and urine levels in patients after administration of therapeutic bismuth formulations in relation to the problem of bismuth toxicity in man. Res Commun Chem Pathol Pharmacol. 1979;26:391–411.Google Scholar
  49. 49.
    Arata T, Oyama Y, Tabaru K, Satoh M, Hayashi H, Ishida S, et al. Cytotoxic effects of triphenylbismuth on rat thymocytes: comparisons with bismuth chloride and triphenyltin chloride. Environ Toxicol. 2002;17:472–7.CrossRefGoogle Scholar
  50. 50.
    Ribeiro DA, Carlin V, Fracalossi ACC, Oyama LM. Radiopacifiers do not induce genetic damage in murine fibroblasts: an in vitro study. Int Endod J. 2009;42:987–91.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Yang Luo
    • 1
    • 2
  • Chaoming Wang
    • 1
    • 3
  • Yong Qiao
    • 1
  • Mainul Hossain
    • 1
    • 4
  • Liyuan Ma
    • 1
  • Ming Su
    • 1
    • 3
  1. 1.NanoScience Technology CenterUniversity of Central FloridaOrlandoUSA
  2. 2.Department of Laboratory Medicine, Southwest HospitalThird Military Medical UniversityChongqingChina
  3. 3.Department of Mechanical, Materials and Aerospace EngineeringUniversity of Central FloridaOrlandoUSA
  4. 4.School of Electrical Engineering and Computer ScienceUniversity of Central FloridaOrlandoUSA

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