Skip to main content

Advertisement

SpringerLink
Log in

Nanoparticles as fluorescent labels for optical imaging and sensing in genomics and proteomics

  • Review
  • Published:
Analytical and Bioanalytical Chemistry Aims and scope Submit manuscript

Abstract

Optical labelling reagents (dyes and fluorophores) are an essential component of probe-based biomolecule detection, an approach widely employed in a variety of areas including environmental analysis, disease diagnostics, pharmaceutical screening, and proteomic and genomic studies. Recently, functional nanomaterials, as a new generation of high-value optical labels, have been applied to molecular detection. The great potential of such recent optical labels has paved the way for the development of new biomolecule assays with unprecedented analytical performance characteristics, related to sensitivity, multiplexing capability, sample throughput, cost-effectiveness and ease of use. This review aims to provide an overview of recent advances using different nanoparticles (such as quantum dots, rare earth doped nanoparticles or gold nanoparticles) for analytical genomics and proteomics, with particular emphasis on the outlook for different strategies of using nanoparticles for bioimaging and quantitative bioanalytical applications, as well as possibilities and limitations of nanoparticles in such a growing field.

Nanoparticles for analytical genomics and proteomics, with particular emphasis on bioimaging and quantitative bioanalytical applications of nanoparticles

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

Similar content being viewed by others

References

  1. Waggoner A (2006) Fluorescent labels for proteomics and genomics. Curr Opin Chem Biol 10:62–66

    Article  CAS  Google Scholar 

  2. Sharma P, Brown S, Walter G, Santra S, Moudgil B (2006) Nanoparticles for bioimaging. Adv Colloid Interface Sci 123:471–485

    Article  Google Scholar 

  3. Willard DM (2003) Nanoparticles in bioanalytics. Anal Bioanal Chem 376:284–286

    CAS  Google Scholar 

  4. Gill R, Zayats M, Willner I (2008) Semiconductor quantum dots for bioanalysis. Angew Chem Int Ed Engl 47:7602–7625

    Article  CAS  Google Scholar 

  5. Sperling RA, Rivera Gil P, Zhang F, Zanella M, Parak WJ (2008) Biological applications of gold nanoparticles. Chem Soc Rev 37:1896–1908

    Article  CAS  Google Scholar 

  6. Mirkin CA, Letsinger RL, Mucic RC, Storhoff JJ (1996) A DNA-based method for rationally assembling nanoparticles into macroscopic materials. Nature 382:607–609

    Article  CAS  Google Scholar 

  7. Taton TA, Mirkin CA, Letsinger RL (2000) Scanometric DNA array detection with nanoparticle probes. Science 289(8):1757–1760

    Article  CAS  Google Scholar 

  8. He L, Musick MD, Nicewarner SR, Salinas FG, Benkovic SJ, Natan MJ, Keating CD (2000) Colloidal Au-enhanced surface plasmon resonance for ultrasensitive detection of DNA hybridization. J Am Chem Soc 122:9071–9077

    Article  CAS  Google Scholar 

  9. Elghanian R, Storhoff JJ, Mucic RC, Letsinger RL, Mirkin CA (1997) Selective colorimetric detection of polynucleotides based on the distance-dependent optical properties of gold nanoparticles. Science 277:1078–1081

    Article  CAS  Google Scholar 

  10. Hirsch LR, Jackson JB, Lee A, Halas NJ, West JL (2003) A whole blood immunoassay using gold nanoshells. Anal Chem 75:2377–2381

    Article  CAS  Google Scholar 

  11. Wang H, Huff TB, Zweifel DA, He W, Low PS, Wei A, Cheng J (2005) In vitro and in vivo two-photon luminescence imaging of single gold nanorods. PNAS 102:15752–15756

    Article  CAS  Google Scholar 

  12. He H, Xie C, Ren J (2008) Nonbleaching fluorescence of gold nanoparticles and its applications in cancer cell imaging. Anal Chem 80:5951–5957

    Article  CAS  Google Scholar 

  13. Wu X, Ming T, Wang X, Wang P, Wang J, Chen J (2010) High-photoluminescence-yield gold nanocubes: for cell imaging and photothermal therapy. ACS Nano 4:113–120

    Article  CAS  Google Scholar 

  14. Lin CJ, Yang T, Lee C, Huang SH, Sperling RA, Zanella M, Li JK, Shen J, Wang H, Yeh H, Parak WJ, Chang WH (2009) Synthesis, characterization, and bioconjugation of fluorescent gold nanoclusters toward biological labeling applications. ACS Nano 3:395–401

    Article  CAS  Google Scholar 

  15. Bruchez M Jr, Moronne M, Gin P, Weiss S, Alivisatos AP (1998) Semiconductor nanocrystals as fluorescent biological labels. Science 281:2013–2016

    Article  CAS  Google Scholar 

  16. Chan WCW, Nie SM (1998) Quantum dot bioconjugates for ultrasensitive nonisotopic detection. Science 281:2016–2018

    Article  CAS  Google Scholar 

  17. Wagner MK, Li F, Li J, Li X, Le XC (2010) Use of quantum dots in the development of assays for cancer biomarkers. Anal Bioanal Chem 397:3213–3224

    Article  CAS  Google Scholar 

  18. Am S, Ruan G, Rhyner MN, Nie S (2006) Engineering luminescent quantum dots for in vivo molecular and cellular imaging. Ann Biomed Eng 34:3–14

    Article  Google Scholar 

  19. Wang C, Gao X, Su X (2010) In vitro and in vivo imaging with quantum dots. Anal Bioanal Chem 397:1397–1415

    Article  CAS  Google Scholar 

  20. Wu XY, Liu HJ, Liu JQ, Haley KN, Treadway JA, Larson JP, Ge NF, Peale F, Bruchez MP (2002) Immunofluorescent labeling of cancer marker Her2 and other cellular targets with semiconductor quantum dots. Nat Biotechnol 21:41–46

    Article  Google Scholar 

  21. Aswathy RG, Yoshida Y, Maekawa T, Kumar DS (2010) Near infrared quantum dots for deep tissue imaging. Anal Bioanal Chem 397:1417–1435

    Article  CAS  Google Scholar 

  22. Delehanty JB, Bradburne CE, Boeneman K, Susumu K, Farrell D, Mei BC, Blanco-Canosa JB, Dawson G, Dawson PE, Mattoussi H, Medintz IL (2010) Delivering quantum dot-peptide bioconjugates to the cellular cytosol: escaping from the endolysosomal system. Integr Biol 2:265–277

    Article  CAS  Google Scholar 

  23. Smith AM, Duan H, Mohs AM, Nie S (2008) Bioconjugated quantum dots for in vivo molecular and cellular imaging. Adv Drug Deliv Rev 60:1226–1240

    Article  CAS  Google Scholar 

  24. Kobayashi H, Hama Y, Koyama Y, Barrett T, Regino CAS, Urano Y, Choyke PL (2007) Simultaneous multicolor imaging of five different lymphatic basins using quantum dots. Nano Lett 7:1711–1716

    Article  CAS  Google Scholar 

  25. Hikage M, Gonda K, Takeda M, Kamei T, Kobayashi M, Kumasaka M, Watanabe M, Satomi S, Ohuchi N (2010) Nano-imaging of the lymph network structure with quantum dots. Nanotechnology 21:185103 (8pp)

    Article  Google Scholar 

  26. Peng CW, Li Y (2010) Application of quantum dots-based biotechnology in cancer diagnosis: current status and future perspectives. J Nanomater 676839 (11pp)

  27. Åkerman ME, Chan WCW, Laakkonen P, Bhatia SN, Ruoslahti E (2002) Nanocrystal targeting in vivo. Proc Natl Acad Sci U S A 99:12617–12621

    Article  Google Scholar 

  28. Dubertret B, Skourides P, Norris DJ, Noireaux V, Brivanlou AH, Libchaber A (2002) In vivo imaging of quantum dots encapsulated in phospholipid micelles. Science 298:1759–1762

    Article  CAS  Google Scholar 

  29. Gao X, Cui Y, Levenson RM, Chung LWK, Nie S (2004) In vivo cancer targeting and imaging with semiconductor quantum dots. Nat Biotechnol 22(8):969–976

    Article  CAS  Google Scholar 

  30. Yang L, Mao H, Wang YA, Cao Z, Peng X, Wang X, Duan H, Ni C, Yuan Q, Adams G, Smith MQ, Wood WC, Gao X, Nie S (2009) Single chain epidermal growth factor receptor antibody conjugated nanoparticles for in vivo tumor targeting and imaging. Small 5:235–243

    Article  CAS  Google Scholar 

  31. Yu X, Chen L, Li K, Li Y, Luo S, Liu J, Deng L, Pang D, Wang (2007) Immunofluorescence detection with quantum dot bioconjugates for hepatoma in vivo. J Biomed Opt 12:014008

    Article  Google Scholar 

  32. Liu J, Lau SK, Varma VA, Moffitt RA, Caldwell M, Liu T, Young AN, Petros JA, Osunkoya AO, Krogstad T, Leyland-Jones B, Wang MD, Nie S (2010) Molecular mapping of tumor heterogeneity on clinical tissue specimens with multiplexed quantum dots. ACS Nano 4:2755–2765

    Article  CAS  Google Scholar 

  33. Kuno M, Fromm DP, Hamann HF, Gallagher A, Nesbitt DJ (2000) Hydrolysis of sulfur trioxide to form sulfuric acid in small water clusters. J Chem Phys 112:3117–3120

    Article  CAS  Google Scholar 

  34. Chatterjee DK, Rufaihah AJ, Zhang Y (2008) Upconversion fluorescence imaging of cells and small animals using lanthanide doped nanocrystals. Biomaterials 29:937–943

    Article  CAS  Google Scholar 

  35. Wang H, Nann T (2009) Monodisperse upconverting nanocrystals by microwave-assisted synthesis. ACS Nano 3:3804–3808

    Article  CAS  Google Scholar 

  36. Kobayashi H, Kosaka N, Ogawa M, Morgan NY, Smith PD, Murray CB, Ye X, Collins J, Kumar GA, Belld H, Choyke PL (2009) In vivo multiple color lymphatic imaging using upconverting nanocrystals. J Mater Chem 19:6481–6484

    Article  CAS  Google Scholar 

  37. Hilderbrand SA, Shao F, Salthouse C, Mahmoodb U, Weissleder R (2009) Upconverting luminescent nanomaterials: application to in vivo bioimaging. Chem Commum 4188–4190

  38. Ungun B, Prud’homme RK, Budijono SJ, Shan J, Lim SF, Ju Y, Austin R (2009) Nanofabricated upconversion nanoparticles for photodynamic therapy. Opt Express 17:80–86

    Article  CAS  Google Scholar 

  39. Chen Z, Che H, Hu H, Yu M, Li F, Zhang Q, Zhou Z, Yi T, Huang C (2008) Versatile synthesis strategy for carboxylic acid functionalized with upconverting nanophosphors as biological labels. J Am Chem Soc 130:3023–3029

    Article  CAS  Google Scholar 

  40. Sun Y, Zhou B, Lin Y, Wang W, Fernando KAS, Pathak P, Meziani MJ, Harruff BA, Wang X, Wang H, Luo PG, Yang H, Kose ME, Chen B, Veca LM, Xie S (2006) Quantum-sized carbon dots for bright and colorful photoluminescence. J Am Chem Soc 128:7756–7757

    Article  CAS  Google Scholar 

  41. Cao L, Wang X, Meziani MJ, Lu F, Wang H, Luo PG, Lin Y, Harruff BA, Veca LM, Murria D, Xie S, Sun Y (2007) Carbon dots for multiphoton bioimaging. J Am Chem Soc 129:11318–11319

    Article  CAS  Google Scholar 

  42. Yang S, Wang X, Wang H, Lu F, Luo PG, Cao L, Meziani MJ, Liu J, Liu Y, Chen M, Huang Y, Sun Y (2009) Carbon dots as nontoxic and high-performance fluorescence imaging agents. J Phys Chem C 113:18110–18114

    Article  CAS  Google Scholar 

  43. Yang S, Cao L, Luo PG, Lu F, Wang X, Wang H, Meziani MJ, Liu Y, Qi G, Sun Y (2007) Carbon dots for optical imaging in vivo. J Am Chem Soc 131:11308–11309

    Article  Google Scholar 

  44. Li L, Song J, Li S, Fan C (2009) Biomolecular sensing via coupling DNA-based recognition with gold nanoparticles. J Phys D Appl Phys 42:203001–203012

    Article  Google Scholar 

  45. Wang W, Chen C, Qian M, Zhao X (2008) Aptamer biosensor using gold nanoparticles. Anal Bioanal Chem 373:213–219

    CAS  Google Scholar 

  46. Huang CC, Chiang K, Lin ZH, Lee KH, Chang HT (2008) Bioconjugated gold nanodots and nanoparticles for protein assays based on photoluminescence quenching. Anal Chem 80:1497–1504

    Article  CAS  Google Scholar 

  47. Mendintz IL, Mattoussi H (2009) Quantum dot-based resonance energy transfer and its growing appliaction in biology. Phys Chem Chem Phys 11:17–45

    Article  Google Scholar 

  48. Medintz IL, Clapp AR, Mattoussi H, Goldman ER, Fisher B, Mauro JM (2003) Self-assembled nanoscale biosensors based on quantum dot FRET donors. Nat Mater 2:630–638

    Article  CAS  Google Scholar 

  49. Dong H, Gao W, Yan F, Ji H, Ju H (2010) Fluorescence resonance energy transfer between quantum dots and graphene oxide for sensing biomolecules. Anal Chem 82:5511–5517

    Article  CAS  Google Scholar 

  50. Medintz IL, Clapp AR, Brunel FM, Tiefenbrunn T, Uyeda HT, Chang EL, Deschamps JR, Dawson PE, Mattoussi H (2006) Proteolytic activity monitored by fluorescence resonance energy transfer through quantum-dot-peptide conjugates. Nat Mater 5:581–589

    Article  CAS  Google Scholar 

  51. Suzuki M, Husimi Y, Komatsu H, Suzuki K, Douglas KT (2008) Quantum dot FRET biosensors that respond to pH, to proteolytic or nucleolytic cleavage, to DNA synthesis, or to a multiplexing combination. J Am Chem Soc 130:5720–5725

    Article  CAS  Google Scholar 

  52. Geissler D, Charbonniere LJ, Ziessel RF, Butlin NG, Löhmannsröben H-G, Hildebrandt N (2010) Quantum dot biosensors for ultrasensitive multiplexed diagnostics. Angew Chem Int Ed Engl 49:1396–1401

    CAS  Google Scholar 

  53. Zhang C-Y, Yeh H-C, Kuroki MT, Wang T (2005) Single quantum dot-based DNA nanosensor. Nat Mater 4:826–831

    Article  Google Scholar 

  54. Price CP, Newman DJ (1997) Principles and practice of immunoassay. Stockton, New York

    Google Scholar 

  55. Soman CP, Giorgio TD (2008) Quantum dot self-assembly for protein detection with sub-picomolar sensitivity. Langmuir 24:4399–4404

    Article  CAS  Google Scholar 

  56. Goldman ER, Clapp AR, Anderson GP, Uyeda HT, Mauro JM, Medintz IL, Mattoussi H (2004) Multiplexed toxin analysis using four colors of quantum dot fluororeagents. Anal Chem 76:684–688

    Article  CAS  Google Scholar 

  57. Yang LJ, Li YB (2006) Simultaneous detection of Escherichia coli O157:H7 and Salmonella Typhimurium using quantum dots as fluorescence labels. Analyst 131:394–401

    Article  CAS  Google Scholar 

  58. Wei Q, Lee M, Yu X, Lee EK, Seong GH, Choo J, Cho YW (2006) Development of an open sandwich fluoroimmunoassay based on fluorescence resonance energy transfer. Anal Biochem 358:31–37

    Article  CAS  Google Scholar 

  59. Wang Z, Levy R, Fernig DG, Mathias Brust M (2006) Kinase-catalyzed modification of gold nanoparticles: a new approach to colorimetric kinase activity screening. J Am Chem Soc 128:2214–2215

    Article  CAS  Google Scholar 

  60. Choi Y, Ho N-H, Tung C-H (2007) Sensing phosphatase activity by using gold nanoparticles. Angew Chem Int Ed Engl 46:707–709

    Article  CAS  Google Scholar 

  61. Zhao W, Chiuman W, Lam JCF, Brook MA, Li Y (2007) Simple and rapid colorimetric enzyme sensing assays using non-crosslinking gold nanoparticle aggregation. Chem Commun 3729–3731

  62. Maier I, Morgan MRA, Lindner W, Pittner F (2008) Optical resonance-enhanced absorption-based near-field immunochip biosensor for allergen detection. Anal Chem 80:2694–2703

    Article  CAS  Google Scholar 

  63. Algar WR, Krull UJ (2007) Towards multi-colour strategies for the detection of oligonucleotide hybridization using quantum dots as energy donors in fluorescence resonance energy transfer (FRET). Anal Chim Acta 581:193–201

    Article  CAS  Google Scholar 

  64. Eastman PS, Ruan WM, Doctolero M, Nuttall R, Feo GD, Park JS, Chu JFS, Cooke P, Gray JW, Li S, Chen FQF (2006) Qdot nanobarcodes for multiplexed gene expression analysis. Nano Lett 6:1059–1064

    Article  CAS  Google Scholar 

  65. Tombelli S, Minunni M, Mascini M (2007) Aptamers-based assays for diagnostics, environmental and food analysis. Biomol Eng 24:191–200

    Article  CAS  Google Scholar 

  66. Wang G, Wang Y, Chen L, Choo J (2010) Nanomaterials-assisted aptamers for optical sensing. Biosens Bioelectron 25:1859–1868

    Article  CAS  Google Scholar 

  67. De M, Ghosh PS, Rotello VM (2008) Applications of nanoparticles in biology. Adv Mater 20:4225–4241

    Article  CAS  Google Scholar 

  68. Mairal T, Özalp VC, Lozano-Sánchez P, Mir M, Katakis I, O’Sullivan CK (2008) Aptamers: molecular tools for analytical applications. Anal Bioanal Chem 390:989–1007

    Article  CAS  Google Scholar 

  69. Han MS, Lytton-Jean AKR, Oh BK, Heo J, Mirkin CA (2006) Colorimetric screening of DNA-binding molecules with gold nanoparticles probes. Angew Chem Int Ed Engl 45:1807–1810

    Article  CAS  Google Scholar 

  70. Pavlov V, Xiao Y, Shlyahovsky B, Willner I (2004) Aptamer-functionalized Au nanoparticles for the amplified optical detection of thrombin. J Am Chem Soc 126:11768–11769

    Article  CAS  Google Scholar 

  71. Becker RC, Spencer FA (1998) Thrombin: structure, biochemistry, measurement, and status in clinical medicine. J Thromb Thrombolys 5:215–229

    Article  CAS  Google Scholar 

  72. Jana NR, Ying JY (2008) Synthesis of functionalized Au nanoparticles for protein detection. Adv Mater 20:430–434

    Article  CAS  Google Scholar 

  73. Zhen SJ, Huang CZ, Wang J, Li YF (2009) End-to-end assembly of gold nanorods on the basis of aptamer-protein. J Phys Chem C 113:21543–21547

    Article  CAS  Google Scholar 

  74. Huang CC, Huang YF, Cao Z, Tan W, Chang HT (2005) Aptamer-modified gold nanoparticles for colorimetric determination of platelet-derived growth factors and their receptors. Anal Chem 77:5735–5741

    Article  CAS  Google Scholar 

  75. Wu ZS, Lu HX, Liu XP, Hu R, Zhou H, Shen G, Yu RQ (2010) An inhibitory effect of target binding on hairpin aptamer sticky-end pairing-induced gold nanoparticles assembly for light-up colorimetric protein assay. Anal Chem 82:3890–3898

    Article  CAS  Google Scholar 

  76. Medley CD, Smith JE, Tang Z, Wu Y, Bamrungsap S, Tan W (2008) Gold nanoparticle-based colorimetric assay for the direct detection of cancerous cells. Anal Chem 80:1067–1072

    Article  CAS  Google Scholar 

  77. Zhang J, Wang L, Zhang H, Boey F, Song S, Fan C (2010) Aptamer-based multicolour fluorescent gold nanoprobes for multiplex detection in homogeneous solution. Small 6:201–204

    Article  CAS  Google Scholar 

  78. Levi M, Cater SF, Ellington AD (2005) Quantum-dot aptamer beacons for the detection of proteins. Chembiochem 6:2163–2166

    Article  Google Scholar 

  79. Cheng AKH, Su H, Wang YA, Yu HZ (2009) Aptamer-based detection of epithelial tumor marker Mucin 1 with quantum dot-based fluorescence readout. Anal Chem 81:6130–6139

    Article  CAS  Google Scholar 

  80. Dyakyusha L, Yin H, Jaiswal S, Brown T, Baumberg JJ, Booy FP, Melvin T (2005) Quenching of CdSe quantum dot emission, a new approach for biosensing. Chem Commun 3201–3203

  81. Oh E, Hong MY, Lee D, Nam SH, Yoon HC, Kim HS (2005) Inhibition assay of biomolecules based on fluorescence resonance energy transfer (FRET) between quantum dots and gold nanoparticles. J Am Chem Soc 127:3270–3271

    Article  CAS  Google Scholar 

  82. Oh E, Lee D, Kim YP, Cha SY, Oh DB, Kang HA, Kim J, Kim HS (2006) Nanoparticle-based energy transfer for rapid and simple detection of protein glycosylation. Angew Chem Int Ed Engl 45:7959–7963

    Article  CAS  Google Scholar 

  83. Gerion D, Chen F, Kannan B, Fu A, Parak WJ, Chen DJ, Majumdar A, Alivisatos AP (2003) Room-temperature single-nucleotide polymorphism and multiallele DNA detection using fluorescent nanocrystals and microarrays. Anal Chem 75:4766–4772

    Article  CAS  Google Scholar 

  84. Kim JH, Chaudhary S, Ozkan M (2007) Multicolour hybrid nanoprobes of molecular beacon conjugated quantum dots: FRET and gel electrophoresis assisted target DNA detection. Nanotechnology 18:195105

    Article  Google Scholar 

  85. Zhang CY, Johnson LW (2006) Quantum-dot-based nanosensor for RRE IIB RNA−Rev peptide interaction assay. J Am Chem Soc 128:5324–5325

    Article  CAS  Google Scholar 

  86. Fernandez-Argüelles MT, Costa Fernández JM, Pereiro R, Sanz Medel A (2010) Chap. 12, The supramolecular chemistry of organic–inorganic hybrid materials, John Wiley & Sons, Inc

  87. Rurack K, Martínez-Mañez R (2010) Chap. 12, The supramolecular chemistry of organic–inorganic hybrid materials, John Wiley & Sons, Inc., New Jersey

Download references

Acknowledgements

Financial support from project CTQ2006-02309/BQU (Spanish Ministry of Science and Innovation cofinanced by the EU FEDER Programme) is gratefully acknowledged.

Author information

Authors and Affiliations

  1. Department of Physical and Analytical Chemistry, Faculty of Chemistry, University of Oviedo, Julian Clavería, 8, 33006, Oviedo, Spain

    Ana María Coto-García, Emma Sotelo-González, María Teresa Fernández-Argüelles, Rosario Pereiro, José M. Costa-Fernández & Alfredo Sanz-Medel

Authors
  1. Ana María Coto-García
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emma Sotelo-González
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. María Teresa Fernández-Argüelles
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rosario Pereiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. José M. Costa-Fernández
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alfredo Sanz-Medel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alfredo Sanz-Medel.

Additional information

Ana María Coto-García and Emma Sotelo-González contributed equally to this work.

Published in the special issue Nanomaterials for Improved Analytical Processes with Guest Editors Miguel Valcárcel and Bartolomé M. Simonet.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Coto-García, A.M., Sotelo-González, E., Fernández-Argüelles, M.T. et al. Nanoparticles as fluorescent labels for optical imaging and sensing in genomics and proteomics. Anal Bioanal Chem 399, 29–42 (2011). https://doi.org/10.1007/s00216-010-4330-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00216-010-4330-3

Keywords

Search

Navigation