Analytical and Bioanalytical Chemistry

, Volume 407, Issue 9, pp 2383–2391 | Cite as

Quantitative analysis of Gd@C82(OH)22 and cisplatin uptake in single cells by inductively coupled plasma mass spectrometry

  • Ling-Na Zheng
  • Meng Wang
  • Lei-Chao Zhao
  • Bao-Yun Sun
  • Bing Wang
  • Han-Qing Chen
  • Yu-Liang Zhao
  • Zhi-Fang Chai
  • Wei-Yue FengEmail author
Research Paper
Part of the following topical collections:
  1. Spectrochemical Plasmas for Clinical and Biochemical Analysis


Cisplatin is a commonly used chemotherapeutic drug in cancer treatment, whereas Gd@C82(OH)22 is a new nanomaterial anti-tumor agent. In this study, we determined intracellular Gd@C82(OH)22 and cisplatin after treatment of Hela and 16HBE cells by single cell inductively coupled plasma-mass spectrometry (SC-ICP-MS), which could provide quantitative information at a single-cell level. The cell digestion method validated the accuracy of the SC-ICP-MS. The concentrations of Gd@C82(OH)22 and cisplatin in cells at different exposure times and doses were studied. The SC-ICP-MS is a promising complement to available methods for single cell analysis and is anticipated to be applied further to biomedical research.

Graphical Abstract

The quantitative results of Gd@C82(OH)22 in single cells determined by SC-ICP-MS and acid digestion method, respectively


Cisplatin Gd@C82(OH)22 Single cell ICP-MS Quantitative analysis 



This work was supported by the National Basic Research Program (973 Program: 2011CB933403) and the National Natural Science Foundation of China (21175136, 11275214, and 11375211).


  1. 1.
    Fichtinger-Schepman AMJ, van Oosterom AT, Lohman PHM, Berends F (1987) cis-Diamminedichloroplatinum(II)-induced DNA adducts in peripheral leukocytes from seven cancer patients: quantitative immunochemical detection of the adduct induction and removal after a single dose of cis-diamminedichloroplatinum(II). Cancer Res 47:3000–3004Google Scholar
  2. 2.
    Reed E, Ozols RF, Tarone R, Yuspa SH, Poirier MC (1988) The measurement of cisplatin-DNA adduct levels in testicular cancer patients. Carcinogenesis 9:1909–1911CrossRefGoogle Scholar
  3. 3.
    Reed E, Ostchega Y, Steinberg SM, Yuspa SH, Young RC, Ozols RF, Poirier MC (1990) Evaluation of platinum-DNA adduct levels relative to known prognostic variables in a cohort of ovarian cancer patients. Cancer Res 50:2256–2260Google Scholar
  4. 4.
    Harder HC, Rosenberg B (1970) Inhibitory effects of anti-tumor platinum compounds on DNA, RNA, and protein syntheses in mammalian cells in vitro. Int J Cancer 6:207–216CrossRefGoogle Scholar
  5. 5.
    Howle JA, Gale GR (1970) CIS-dichlorodiammineplatinum (II): persistent and selective inhibition of deoxyribonucleic acid synthesis in vivo. Biochem Pharmacol 19:2757–2762CrossRefGoogle Scholar
  6. 6.
    Dhar S, Gu FX, Langer R, Farokhzad OC, Lippard SJ (2008) Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA–PEG nanoparticles. Proc Natl Acad Sci U S A 105:17356–17361CrossRefGoogle Scholar
  7. 7.
    Hamelers IHL, Staffhorst RWHM, Voortman J, de Kruijff B, Reedijk J, van Bergen en Henegouwen PMP, de Kroon AIPM (2009) High cytotoxicity of cisplatin nanocapsules in ovarian carcinoma cells depends on uptake by caveolae-mediated endocytosis. Clin Cancer Res 15:1259–1268CrossRefGoogle Scholar
  8. 8.
    Gately DP, Howell SB (1993) Cellular accumulation of the anticancer agent cisplatin: a review. Br J Cancer 67:1171–1176CrossRefGoogle Scholar
  9. 9.
    Ali BH, Al Moundhri MS (2006) Agents ameliorating or augmenting the nephrotoxicity of cisplatin and other platinum compounds: a review of some recent research. Food Chem Toxicol 44:1173–1183CrossRefGoogle Scholar
  10. 10.
    Page R, Matus RE, Leifer CE, Loar A (1985) Cisplatin, a new antineoplastic drug in veterinary medicine. J Am Vet Med Assoc 186:288–290Google Scholar
  11. 11.
    Schilsky RL, Anderson T (1979) Hypomagnesemia and renal magnesium wasting in patients receiving cisplatin. Ann Intern Med 90:929–931CrossRefGoogle Scholar
  12. 12.
    Riehemann K, Schneider SW, Luger TA, Godin B, Ferrari M, Fuchs H (2009) Nanomedicine-challenge and perspectives. Angew Chem Int Ed Engl 48:872–897CrossRefGoogle Scholar
  13. 13.
    Henley SJ, Hatton RA, Chen GY, Gao C, Zeng H, Kroto HW, Silva SRP (2007) Enhancement of polymer luminescence by excitation-energy transfer from multi-walled carbon nanotubes. Small 3:1927–1933CrossRefGoogle Scholar
  14. 14.
    Curl RF, Smalley RE (1988) Probing C60. Science 242:1017–1022CrossRefGoogle Scholar
  15. 15.
    Gao YX, Liu NQ, Chen CY, Luo YF, Li YF, Zhang ZY, Zhao YL, Zhao BL, Iida A, Chai ZF (2008) Mapping technique for biodistribution of elements in a model organism, Caenorhabditis elegans, after exposure to copper nanoparticles with microbeam synchrotron radiation X-ray fluorescence. J Anal At Spectrom 23:1121–1124CrossRefGoogle Scholar
  16. 16.
    Nakamura E, Isobe H (2003) Functionalized fullerenes in water. The first 10 years of their chemistry, biology, and nanoscience. Acc Chem Res 36:807–815CrossRefGoogle Scholar
  17. 17.
    Meng J, Liang XJ, Chen XY, Zhao YL (2013) Biological characterizations of [Gd@C82(OH)22]n nanoparticles as fullerene derivatives for cancer therapy. Integr Biol 5:43–47CrossRefGoogle Scholar
  18. 18.
    Qu L, Cao WB, Xing GM, Zhang J, Yuan H, Tang J, Cheng Y, Zhang B, Zhao YL, Lei H (2006) Study of rare earth encapsulated carbon nanomolecules for biomedical uses. J Alloy Compd 408(412):400–404CrossRefGoogle Scholar
  19. 19.
    Xing GM, Yuan H, He R, Gao XY, Jing L, Zhao F, Chai ZF, Zhao YL (2008) The strong MRI relaxivity of paramagnetic nanoparticles. J Phys Chem B 112:6288–6291CrossRefGoogle Scholar
  20. 20.
    Chen CY, Xing GM, Wang JX, Zhao YL, Li B, Tang J, Jia G, Wang TC, Sun J, Xing L, Yuan H, Gao Y, Meng H, Chen Z, Zhao F, Chai ZF, Fang XH (2005) Multihydroxylated [Gd@C82(OH)22]n nanoparticles: antineoplastic activity of high efficiency and low toxicity. Nano Lett 5:2050–2057CrossRefGoogle Scholar
  21. 21.
    Yin JJ, Lao F, Fu PP, Wamer WG, Zhao Y, Wang PC, Qiu Y, Sun B, Xing G, Dong J, Liang XJ, Chen C (2009) The scavenging of reactive oxygen species and the potential for cell protection by functionalized fullerene materials. Biomaterials 30:611–621CrossRefGoogle Scholar
  22. 22.
    Meng H, Xing GM, Sun BY, Zhao F, Lei H, Li W, Song Y, Chen Z, Yuan H, Wang XX, Long J, Chen CY, Liang XJ, Zhang N, Chai ZF, Zhao YL (2010) Potent angiogenesis inhibition by the particulate form of fullerene derivatives. ACS Nano 4:2773–2783CrossRefGoogle Scholar
  23. 23.
    Tsang CN, Ho KS, Sun H, Chan WT (2011) Tracking bismuth antiulcer drug uptake in single Helicobacter pylori cells. J Am Chem Soc 133:7355–7357CrossRefGoogle Scholar
  24. 24.
    Yang D, Zhao YL, Guo H, Li Y, Tewary P, Xing GM, Hou W, Oppenheim JJ, Zhang N (2010) [Gd@C82(OH)22]n nanoparticles induce dendritic cell maturation and activate Th1 immune responses. ACS Nano 4:1178–1186CrossRefGoogle Scholar
  25. 25.
    Zhang WD, Sun BY, Zhang LZ, Bl Z, Nie GJ, Zhao YL (2011) Biosafety assessment of Gd@C82(OH)22 nanoparticles on Caenorhabditis elegans. Nanoscale 3:2636–2641CrossRefGoogle Scholar
  26. 26.
    Wang J, Chen CY, Li B, Yu HW, Zhao YL, Sun J, Li YF, Xing GM, Yuan H, Tang J, Chen Z, Meng H, Gao YX, Ye C, Chai ZF, Zhu CF, Ma BC, Fang XH, Wan LJ (2006) Antioxidative function and biodistribution of [Gd@C82(OH)22]n nanoparticles in tumor-bearing mice. Biochem Pharmacol 71:872–881CrossRefGoogle Scholar
  27. 27.
    Coussens LM, Fingleton B, Matrisian LM (2002) Matrix metalloproteinase inhibitors and cancer-trials and tribulations. Science 295:2387–2392CrossRefGoogle Scholar
  28. 28.
    Meng J, Xing JM, Wang YZ, Lu J, Zhao YL, Gao XY, Wang PC, Jia L, Liang XJ (2011) Epigenetic modulation of human breast cancer by metallofullerenol nanoparticles: in vivo treatment and in vitro analysis. Nanoscale 3:4713–4719CrossRefGoogle Scholar
  29. 29.
    Meng J, Wang DL, Wang PC, Jia L, Chen C, Liang XJ (2010) Biomedical activities of endohedral metallofullerene optimized for nanopharmaceutics. J Nanosci Nanotechnol 10:8610–8616CrossRefGoogle Scholar
  30. 30.
    Liang XJ, Meng H, Wang YZ, He HY, Meng J, Lu J, Wang PC, Zhao YL, Gao XY, Sun BY, Chen CY, Xing GM, Shen DW, Gottesman MM, Wu Y, Yin JJ, Jia L (2010) Metallofullerene nanoparticles circumvent tumor resistance to cisplatin by reactivating endocytosis. Proc Natl Acad Sci U S A 107:7449–7454CrossRefGoogle Scholar
  31. 31.
    Szpunar J (2005) Advances in analytical methodology for bioinorganic speciation analysis: metallomics, metalloproteomics and heteroatom-tagged proteomics and metabolomics. Analyst 130:442–465CrossRefGoogle Scholar
  32. 32.
    Wang M, Feng WY, Zhao YL, Chai ZF (2010) ICP-MS-Based strategies for protein quantification. Mass Spectrom Rev 29:326–348CrossRefGoogle Scholar
  33. 33.
    Sanz-Medel A, Montes-Bayón M, Rosario Fernández de la Campa M, Encinar J, Bettmer J (2008) Elemental mass spectrometry for quantitative proteomics. Anal Bioanal Chem 390:3–16CrossRefGoogle Scholar
  34. 34.
    Zheng LN, Wang M, Wang HJ, Wang B, Li B, Li JJ, Zhao YL, Chai ZF, Feng WY (2011) Quantification of proteins using lanthanide labeling and HPLC/ICP-MS detection. J Anal At Spectrom 26:1233–1236CrossRefGoogle Scholar
  35. 35.
    Wang M, Feng WY, Lu WW, Li B, Wang B, Zhu MT, Wang Y, Yuan H, Zhao YL, Chai ZF (2007) Quantitative analysis of proteins via sulfur determination by HPLC coupled to isotope dilution ICP-MS with a hexapole collision cell. Anal Chem 79:9128–9134CrossRefGoogle Scholar
  36. 36.
    Jiang XM, Huang K, Deng DY, Xia H, Hou XD, Zheng CB (2012) Nanomaterials in analytical atomic spectrometry. TrAC Trends Anal Chem 39:38–59CrossRefGoogle Scholar
  37. 37.
    Ho KS, Chan WT (2010) Time-resolved ICP-MS measurement for single-cell analysis and on-line cytometry. J Anal At Spectrom 25:1114–1122CrossRefGoogle Scholar
  38. 38.
    Pace HE, Rogers NJ, Jarolimek C, Coleman VA, Higgins CP, Ranville JF (2011) Determining transport efficiency for the purpose of counting and sizing nanoparticles via single particle inductively coupled plasma mass spectrometry. Anal Chem 83:9361–9369CrossRefGoogle Scholar
  39. 39.
    Li F, Armstrong DW, Houk RS (2005) Behavior of bacteria in the inductively coupled plasma: atomization and production of atomic ions for mass spectrometry. Anal Chem 77:1407–1413CrossRefGoogle Scholar
  40. 40.
    Bandura DR, Baranov VI, Ornatsky OI, Antonov A, Kinach R, Lou X, Pavlov S, Vorobiev S, Dick JE, Tanner SD (2009) Mass cytometry: technique for real time single cell multitarget immunoassay based on inductively coupled plasma time-of-flight mass spectrometry. Anal Chem 81:6813–6822CrossRefGoogle Scholar
  41. 41.
    Shigeta K, Koellensperger G, Rampler E, Traub H, Rottmann L, Panne U, Okino A, Jakubowski N (2013) Sample introduction of single selenized yeast cells (Saccharomyces cerevisiae) by micro droplet generation into an ICP-sector field mass spectrometer for label-free detection of trace elements. J Anal At Spectrom 28:637–645CrossRefGoogle Scholar
  42. 42.
    Zheng LN, Wang M, Wang B, Chen HQ, Ouyang H, Zhao YL, Chai ZF, Feng WY (2013) Determination of quantum dots in single cells by inductively coupled plasma mass spectrometry. Talanta 116:782–787CrossRefGoogle Scholar
  43. 43.
    Wang HL, Wang B, Wang M, Zheng LN, Chen HQ, Chai ZF, Zhao YL, Feng WY (2015) Time-resolved ICP-MS analysis of mineral element contents and distribution patterns in single cells. Analyst. 140:523–531Google Scholar
  44. 44.
    Tardito S, Isella C, Medico E, Marchiò L, Bevilacqua E, Hatzoglou M, Bussolati O, Franchi-Gazzola R (2009) The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem 284:24306–24319CrossRefGoogle Scholar
  45. 45.
    Minagawa Y, Kigawa J, Itamochi H, Kanamori Y, Shimada M, Takahashi M, Terakawa N (1999) Cisplatin-resistant HeLa cells are resistant to apoptosis via p53-dependent and -independent pathways. Jpn J Cancer Res 90:1373–1379CrossRefGoogle Scholar
  46. 46.
    Wu W, Yan CL, Gan T, Chen ZH, Lu XH, Duerksen-Hughes PJ, Zhu XQ, Yang J (2010) Nuclear proteome analysis of cisplatin-treated HeLa cells. Mutat Res 691:1–8CrossRefGoogle Scholar
  47. 47.
    Gale GR, Morris CR, Atkins LM, Smith AB (1973) Binding of an antitumor platinum compound to cells as influenced by physical factors and pharmacologically active agents. Cancer Res 33:813–818Google Scholar
  48. 48.
    Li YY, Tian YH, Nie GJ (2012) Antineoplastic activities of Gd@C82(OH)22 nanoparticles: tumor microenvironment regulation. Sci China Life Sci 55:884–890CrossRefGoogle Scholar
  49. 49.
    Wang M, Zheng LN, Wang B, Chen HQ, Zhao YL, Chai ZF, Reid HJ, Sharp BL, Feng WY (2014) Quantitative analysis of gold nanoparticles in single cells by laser ablation inductively coupled plasma-mass spectrometry. Anal Chem 86:10252–10256CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Ling-Na Zheng
    • 1
  • Meng Wang
    • 1
  • Lei-Chao Zhao
    • 1
    • 2
  • Bao-Yun Sun
    • 1
  • Bing Wang
    • 1
  • Han-Qing Chen
    • 1
  • Yu-Liang Zhao
    • 1
    • 3
  • Zhi-Fang Chai
    • 1
  • Wei-Yue Feng
    • 1
    Email author
  1. 1.CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy PhysicsChinese Academy of SciencesBeijingChina
  2. 2.School of Materials Science and EngineeringHebei University of TechnologyTianjinChina
  3. 3.CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of ChinaChinese Academy of SciencesBeijingChina

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