Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Protocol
  • Published:

Continuous-flow reactor–based synthesis of carbohydrate and dihydrolipoic acid–capped quantum dots

Abstract

A detailed protocol for the large-scale synthesis of carbohydrate and dihydrolipoic acid (DHLA)-coated CdSe/ZnS and CdTe/ZnS nanoparticles using continuous flow reactors is described here. Three continuous flow microreaction systems, operating at three different temperatures, are used for the synthesis of mannose-, galactose- or DHLA-functionalized quantum dots (QDs). In the first step of synthesis, the CdSe and CdTe nanoparticles are prepared. The size and spectral properties of the CdSe core of the nanoparticles are controlled by adjustment of the residence time and the temperature. As a second step, the zinc sulfide capping under homogenous conditions is carried out at a substantially lower temperature than is required for nanoparticle growth in batch processes. Finally, the trioctylphosphine/oleic acid ligand is effectively replaced with either carbohydrate PEG-thiol moieties or DHLA at 60 °C. This new protocol allows the synthesis of biologically active fluorescent QDs in 4 d.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Scheme for the synthesis of mannose-SH (5) and Gal-SH (10) derivatives.
Figure 2
Figure 3: Schematic overview of continuous flow system used for QD synthesis.
Figure 4: Image of CdSe samples under an UV lamp.
Figure 5: Fluorescence spectra of CdSe QDs prepared at different times at 160 °C.
Figure 6: Fluorescence spectra of CdSe QDs prepared at different temperatures.
Figure 7: TEM image of CdSe QDs.
Figure 8: TEM images of nanoparticles.
Figure 9: Kinetics of turbidity.

Similar content being viewed by others

References

  1. Deka, S. et al. CdSe/CdS/ZnS double shell nanorods with high photoluminescence efficiency and their exploitation as biolabeling probes. J. Am. Chem. Soc. 131, 2948–2958 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Weiss, E.A. et al. Size-dependent charge collection in junctions containing single-size and multi-size array of colloidal CdSe quantum dots. J. Am. Chem. Soc. 130, 74–82 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Weiss, E.A. et al. The use of size-selective excitation to study photocurrent through junctions containing single-size and multi-size arrays of colloidal CdSe quantum dots. J. Am. Chem. Soc. 130, 83–92 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Xie, R., Kolb, U., Li, J., Basch, T. & Mews, A. Synthesis and characterization of highly luminescent CdSe-Core CdS/ZnCdS/ZnS multishell nanocrystals. J. Am. Chem. Soc. 127, 7480–7488 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Mattoussi, H. et al. Self assembly of CdSe-ZnS quantum dot bioconjugates using an engineered recombinant protein. J. Am. Chem. Soc. 122, 12142–12150 (2000).

    Article  CAS  Google Scholar 

  6. Babu, P., Sinha, S. & Surolia, A. Sugar-quantum dot conjugates for a selective and sensitive detection of lectins. Bioconjugate Chem. 18, 146–151 (2007).

    Article  CAS  Google Scholar 

  7. Sun, X.L. et al. Chem. Bio. Chem. 5, 1593–1596 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Kim, J. et al. In vivo real-time bioimaging of hyaluronic acid derivatives using quantum dots. Biopolymers 89, 1144–1153 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Robinson, A. et al. Probing lectin and sperm with carbohydrate-modified quantum dots. ChemBioChem 6, 1899–1905 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Niikura, K. et al. Oligosaccharide-mediated nuclear transport of nanoparticles. ChemBioChem 9, 2623–2627 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Higuchi, Y. et al. Mannosylated semiconductor quantum dots for labeling of macrophages. J. Control. Release 125, 131–136 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Jiang, X. et al. Biotinylated glycol-functionalized quantum dots: synthesis, characterization, and cytotoxicity studies. Bioconjugate Chem. 20, 994–1001 (2009).

    Article  CAS  Google Scholar 

  13. Chan, W.C. & Nie, S. Quantum dots bioconjugates for ultrasensitive nonisotopic detection. Science 281, 2016–2018 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Bruchez, M., Moronne, M., Gin, P., Weiss, S. & Alivisatos, A.P. Semiconductor nanocrystal as fluorescent biological labels. Science 281, 2013–2016 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Howarth, M. et al. Targeting quantum dots to surface proteins in living cells with biotin ligase. PNAS 102, 7583–7588 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Kim, S., Fisher, B., Eisler, H.J. & Bawendi, M. Type-II quantum dots: CdTe/CdSe(Core/Shell) and CdSe/ZnTe(Core/Shell) heterostructures. J. Am. Chem. Soc. 125, 11466–11467 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Giepmans, B.N.G., Adams, S.R., Ellisman, M.H. & Tsien, R.Y. The fluorescent toolbox for assessing protein location and function. Science 312, 217–224 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. George, N., Pick, H., Vogel, H., Johnsson, N. & Johnsson, K. Specific labeling of cell surface proteins with chemically diverse compounds. J. Am. Chem. Soc. 126, 8896–8897 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Stroh, M. et al. Quantum dots spectrally distinguish multiple species within the tumor milieu in vivo. Nat. Med. 11, 678–682 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Somers, R.C., Bawendi, M.G. & Nocera, D.G. CdSe nanocrystal based chem.-/bio- sensors. Chem. Soc. Rev. 36, 579–591 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Liu, W. et al. Compact Cystein-coated CdSe(ZnCdS) quantum dots for in vivo applications. J. Am. Chem. Soc. 129, 14530–14531 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Murray, C.B., Norris, D.J. & Bawendi, M.G. Synthesis and characterization of nearly monodisperse CdE (E = sulfur, selenium, tellurium) semiconductor nanocrystallites. J. Am. Chem. Soc. 115, 8706–8715 (1993).

    Article  CAS  Google Scholar 

  23. Qu, L., Peng, Z.A. & Peng, X. Alternative routes toward high quality CdSe nanocrystals. Nano Lett. 1, 333–337 (2001).

    Article  CAS  Google Scholar 

  24. Li, J.J. et al. Large-scale synthesis of nearly monodisperse CdSe/CdS Core/Shell nanocrystals using air-stable reagents via successive ion layer adsorption and reaction. J. Am. Chem. Soc. 125, 12567–12575 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Ehrfeld, W. et al. Microreactors: New Technology for Modern Chemistry. (Wiley-VCH, 2000).

  26. Hessel, V. et al. Chemical Micro Process Engineering (Wiley-VCH, 2004).

  27. Wiles, C. & Watts, P. Continuous flow reactor, a tool for the modern synthetic chemist. Eur. J. Org. Chem. 1655–1671 (2008).

  28. Mason, B.P. et al. Greener approaches to organic synthesis using Microreactor technology. Chem. Rev. 107, 2300–2318 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Geyer, K., Codée, J.D.C. & Seeberger, P.H. Microreactor as tools for synthetic chemists – the chemists' round-bottomed flask of the 21st century? Chem. Eur. J. 12, 8434–8442 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Marre, S. et al. Supercritical continuous-microflow synthesis of narrow size distribution quantum dots. Adv. Mater. 20, 4830–4834 (2008).

    Article  CAS  Google Scholar 

  31. Yen, B.K.H., Günther, A., Schmidt, M.A., Jensen, K.F. & Bawendi, M.G. A microfabricated gas-liquid segmented flow reactor for high-temperature synthesis: the case of CdSe quantum dots. Angew. Chem. Int. Ed. 44, 5447–5451 (2005).

    Article  CAS  Google Scholar 

  32. de la Fuente, J.M. & Penadés, S. Glyco-quantum dots: a new luminescent system with multivalent carbohydrate display. Tetrahedron: Asymmetry 16, 387–391 (2005).

    Article  CAS  Google Scholar 

  33. Aaron, R.C. et al. Quantum dot-based multiplexed fluorescence resonance energy transfer. J. Am. Chem. Soc. 127, 18212–18221 (2005).

    Article  Google Scholar 

  34. Susumu, K., Mei, B.C. & Mattoussi, H. Multifunctional ligands based on dihydrolipoic acid and polyethylene glycol to promote biocompatibility of quantum dots. Nat. Protoc. 4, 424–436 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Susumu, K. et al. Enhancing the stability and biological functionalities of quantum dots via compact multifunctional ligands. J. Am. Chem. Soc. 129, 13987–13996 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Liu, W. et al. Compact biocompatible quantum dots functionalized for cellular imaging. J. Am. Chem. Soc. 130, 1274–1284 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Carrillo-Carrion, C., Cordenas, S., Simonet, B.M. & Valcarcel, M. Selective quantification of carnitine enantiomers using chiral cysteine-capped CdSe(ZnS) quantum dots. Anal. Chem. 81, 4730–4733 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Kikkeri, R., Laurino, P., Odedra, A. & Seeberger, P.H. Synthesis of carbohydrate-functionalized QDs in Microreactors. Angew. Chem. Int. Ed. 49, 2054–2057 (2010).

    Article  CAS  Google Scholar 

  39. Leutherdale, C.A., Woo, W.-K., Mikulec, F.V. & Bawendi, M.G. On the absorption cross section of CdSe nanocrystal quantum dots. J. Phys. Chem. 106, 7619–7622 (2002).

    Article  Google Scholar 

  40. Weis, W.I. & Drickamer, K. Structural basis of lectin-carbohydrate recognition. Annu. Rev. Biochem. 65, 441–473 (1996).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Generous funding from the Max Planck Society is gratefully acknowledged.

Author information

Authors and Affiliations

Authors

Contributions

P.L. and R.K. carried out the experiments and designed the protocol. P.H.S. designed and supervised the project. P.L., R.K. and P.H.S. wrote the manuscript.

Corresponding author

Correspondence to Peter H Seeberger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Laurino, P., Kikkeri, R. & Seeberger, P. Continuous-flow reactor–based synthesis of carbohydrate and dihydrolipoic acid–capped quantum dots. Nat Protoc 6, 1209–1220 (2011). https://doi.org/10.1038/nprot.2011.357

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nprot.2011.357

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing