Skip to main content
SpringerLink
Log in

Immuno-Nanoparticles for Multiplex Protein Imaging in Cells and Tissues

  • Review Article
  • Published:
BioChip Journal Aims and scope Submit manuscript

Abstract

Simultaneous visualization of numerous proteins in cells and tissues is fundamental for understanding their diversity and dynamics and to address the heterogeneity of human diseases. Despite the many advantages of multiplex analysis, current methods typically rely upon immunohistochemistry, which can only be used to detect a few proteins. The exceptional optical properties of nanoparticles (NPs) have improved multiplex imaging in cells and tissues. Here, we review recent advances in multiplex imaging-based molecular diagnosis using antibody-conjugated NPs (immuno-NPs). With the aim of furthering development, we anticipate that NP-based multiplex imaging techniques will complement classical immunohistochemistry methods and provide insight into the biological diversity of cells and tissues.

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

Similar content being viewed by others

References

  1. Crivat, G. & Taraska, J.W. Imaging proteins inside cells with fluorescent tags. Trends Biotechnol. 30, 8–16 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Beck, M. et al. The quantitative proteome of a human cell line. Mol. Syst. Biol. 7, 549 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Wu, L. et al. Variation and genetic control of protein abundance in humans. Nature 499, 79–82 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Stack, E.C., Wang, C., Roman, K.A. & Hoyt, C.C. Multiplexed immunohistochemistry, imaging, and quantitation: a review, with an assessment of Tyramide signal amplification, multispectral imaging and multiplex analysis. Methods 70, 46–58 (2014).

    Article  CAS  PubMed  Google Scholar 

  5. Elshal, M.F. & McCoy, J.P. Multiplex bead array assays: performance evaluation and comparison of sensitivity to ELISA. Methods 38, 317–323 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sano, T., Smith, C.L. & Cantor, C.R. Immuno-PCR: very sensitive antigen detection by means of specific antibody-DNA conjugates. Science 258, 120–122 (1992).

    Article  CAS  PubMed  Google Scholar 

  7. Gullberg, M. et al. Cytokine detection by antibody- based proximity ligation. Proc. Natl. Acad. Sci. U. S. A. 101, 8420–8424 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang, X., Zhao, M. & Nolte, D.D. Prostate-specific antigen immunoassays on the BioCD. Anal. Bioanal. Chem. 393, 1151–1156 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Nune, S.K. et al. Nanoparticles for biomedical imaging. Expert Opin. Drug Deliv. 6, 1175–1194 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wolfbeis, O.S. An overview of nanoparticles commonly used in fluorescent bioimaging. Chem. Soc. Rev. 44, 4743–4768 (2015).

    Article  CAS  PubMed  Google Scholar 

  11. Chan, W.C. et al. Luminescent quantum dots for multiplexed biological detection and imaging. Curr. Opin. Biotechnol. 13, 40–46 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Kairdolf, B.A. et al. Semiconductor quantum dots for bioimaging and biodiagnostic applications. Annu. Rev. Anal. Chem. 6, 143–162 (2013).

    Article  CAS  Google Scholar 

  13. Navas-Moreno, M. et al. Nanoparticles for live cell microscopy: A surface-enhanced Raman scattering perspective. Sci. Rep. 7, 4471 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Jaiswal, J.K., Goldman, E.R., Mattoussi, H. & Simon, S.M. Use of quantum dots for live cell imaging. Nat. Meth. 1, 73–78 (2004).

    Article  Google Scholar 

  15. Tighe, P.J., Ryder, R.R., Todd, I. & Fairclough, L.C. ELISA in the multiplex era: potentials and pitfalls. Proteomics Clin. Appl. 9, 406–422 (2015).

    Article  CAS  PubMed  Google Scholar 

  16. Azzazy, H.M. & Mansour, M.M. In vitro diagnostic prospects of nanoparticles. Clin. Chim. Acta 403, 1–8 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Park, H., Hwang, M.P. & Lee, K.H. Immunomagnetic nanoparticle-based assays for detection of biomarkers. Int. J. Nanomedicine 8, 4543–4552 (2013).

    PubMed  PubMed Central  Google Scholar 

  18. Wang, L., O’Donoghue, M.B. & Tan, W. Nanoparticles for multiplex diagnostics and imaging. Nanomedicine (Lond) 1, 413–426 (2006).

    Article  CAS  Google Scholar 

  19. Kim, Y.P. & Kim, H.S. Nanoparticles for Use in Enzyme Assays. ChemBiochem 17, 275–282 (2016).

    Article  CAS  PubMed  Google Scholar 

  20. Kim, G.B. & Kim, Y.P. Analysis of Protease Activity Using Quantum Dots and Resonance Energy Transfer. Theranostics 2, 127–138 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gao, X., Cui, Y., Levenson, R.M., Chung, L.W. & Nie, S. In vivo cancer targeting and imaging with semiconductor quantum dots. Nat. Biotechnol. 22, 969–976 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Larson, D.R. et al. Water-soluble quantum dots for multiphoton fluorescence imaging in vivo. Science 300, 1434–1436 (2003).

    Article  PubMed  Google Scholar 

  23. Rosenthal, S.J., Chang, J.C., Kovtun, O., McBride, J.R. & Tomlinson, I.D. Biocompatible quantum dots for biological applications. Chem. Biol. 18, 10–24 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  26. Tikhomirov, G. et al. DNA-based programming of quantum dot valency, self-assembly and luminescence. Nat. Nanotechnol. 6, 485–490 (2011).

    Article  CAS  PubMed  Google Scholar 

  27. Howarth, M. et al. A monovalent streptavidin with a single femtomolar biotin binding site. Nat. Methods 3, 267–273 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Liu, H.Y. & Gao, X. Engineering monovalent quantum dot-antibody bioconjugates with a hybrid gel system. Bioconjug. Chem. 22, 510–517 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. Wu, X. et al. Immunofluorescent labeling of cancer marker Her2 and other cellular targets with semiconductor quantum dots. Nat. Biotechnol. 21, 41–46 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Yezhelyev, M.V. et al. In situ molecular profiling of breast cancer biomarkers with multicolor quantum dots. Adv. Mater. 19, 3146–3151 (2007).

    Article  CAS  Google Scholar 

  31. Tak, Y.K. et al. High-content quantum dot-based subtype diagnosis and classification of breast cancer patients using hypermulticolor quantitative single cell imaging cytometry. Nano Today 7, 231–244 (2012).

    Article  CAS  Google Scholar 

  32. Xu, H. et al. Quantum dot-based, quantitative, and multiplexed assay for tissue staining. ACS Appl. Mater. Interfaces 5, 2901–2907 (2013).

    Article  CAS  PubMed  Google Scholar 

  33. Park, S. et al. Quantum-dot nanoprobes and AOTF based cross talk eliminated six color imaging of biomolecules in cellular system. Anal. Chim. Acta 985, 166–174 (2017).

    Article  CAS  PubMed  Google Scholar 

  34. Schlucker, S. Surface-Enhanced Raman Spectroscopy: Concepts and Chemical Applications. Angew. Chem. Int. Ed. 53, 4756–4795 (2014).

    Article  CAS  Google Scholar 

  35. Wan, X.Y. et al. Real-time light scattering tracking ofgold nanoparticles- bioconjugated respiratory syncytial virus infecting HEp-2 cells. Sci. Rep. 4, 4529 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Truong, P.L., Ma, X. & Sim, S.J. Resonant Rayleigh light scattering of single Au nanoparticles with different sizes and shapes. Nanoscale 6, 2307–2315 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Woo, M.A. et al. Multiplex immunoassay using fluorescent- surface enhanced Raman spectroscopic dots for the detection of bronchioalveolar stem cells in murine lung. Anal. Chem. 81, 1008–1015 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Lee, S. et al. Rapid and sensitive phenotypic marker detection on breast cancer cells using surface-enhanced Raman scattering (SERS) imaging. Biosens. Bioelectron. 51, 238–243 (2014).

    Article  CAS  PubMed  Google Scholar 

  39. Jeong, S. et al. Fluorescence-Raman dual modal endoscopic system for multiplexed molecular diagnostics. Sci. Rep. 5, 9455 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zavaleta, C.L. et al. Multiplexed imaging of surface enhanced Raman scattering nanotags in living mice using noninvasive Raman spectroscopy. Proc. Natl. Acd. Sci. U.S.A. 106, 13511–13516 (2009).

    Article  Google Scholar 

  41. Kennedy, D.C., Hoop, K.A., Tay, L.L. & Pezacki, J.P. Development of nanoparticle probes for multiplex SERS imaging of cell surface proteins. Nanoscale 2, 1413–1416 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Nima, Z.A. et al. Circulating tumor cell identification by functionalized silver-gold nanorods with multicolor, super-enhanced SERS and photothermal resonances. Sci. Rep. 4, article No. 4752 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Samanta, A., Das, R.K., Park, S.J., Maiti, K.K. & Chang, Y.T. Multiplexing SERS nanotags for the imaging of differentiated mouse embryonic stem cells (mESC) and detection of teratoma in vivo. Am. J. Nucl. Med. Mol. Imaging 4, 114–124 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Lin, J.R., Fallahi-Sichani, M. & Sorger, P.K. Highly multiplexed imaging of single cells using a highthroughput cyclic immunofluorescence method. Nat. Commun. 6, 8390 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bodenmiller, B. Multiplexed Epitope-Based Tissue Imaging for Discovery and Healthcare Applications. Cell Syst. 2, 225–238 (2016).

    Article  CAS  PubMed  Google Scholar 

  46. Yun, M. et al. A High-Affinity Repebody for Molecular Imaging of EGFR-Expressing Malignant Tumors. Theranostics 7, 2620–2633 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Wang, J. & Li, G. Aptamers against cell surface receptors: selection, modification and application. Curr. Med. Chem. 18, 4107–4116 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Gedi, V. & Kim, Y.P. Detection and characterization of cancer cells and pathogenic bacteria using aptamerbased nano-conjugates. Sensors 14, 18302–18327 (2014).

    Article  CAS  PubMed  Google Scholar 

  49. Jeon, H., Lee, M., Jang, W. & Kwon, Y. Intein-mediated Protein Engineering for Biosensor Fabrication. BioChip J. 10, 277–287 (2016).

    Article  CAS  Google Scholar 

  50. Zhang, G., Zheng, S., Liu, H. & Chen, P.R. Illuminating biological processes through site-specific protein labeling. Chem. Soc. Rev. 44, 3405–3417 (2015).

    Article  CAS  PubMed  Google Scholar 

  51. Humar, M. & Yun, S.H. Intracellular microlasers. Nat. Photonics 9, 572–576 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Schubert, M. et al. Lasing within Live Cells Containing Intracellular Optical Microresonators for Barcode- Type Cell Tagging and Tracking. Nano Lett. 15, 5647–5652 (2015).

    Article  CAS  PubMed  Google Scholar 

  53. Yi, J. et al. Highly Multiplexed, Super-resolution Imaging of T Cells Using madSTORM. J. Vis. Exp. 124, doi:10.3791/55997 (2017).

  54. Yan, R., Moon, S., Kenny, S.J. & Xu, K. Spectrally Resolved and Functional Super-resolution Microscopy via Ultrahigh-Throughput Single-Molecule Spectroscopy. ACC. Chem. Res. 51, 697–705 (2018).

    Article  CAS  PubMed  Google Scholar 

  55. Strack, R. Highly multiplexed transcriptome imaging. Nat. Meth. 12, 486–487 (2015).

    Article  CAS  Google Scholar 

  56. Chen, K.H., Boettiger, A.N., Moffitt, J.R., Wang, S. & Zhuang, X. RNA imaging. Spatially resolved, highly multiplexed RNA profiling in single cells. Science 348, aaa6090 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lee, S.E. et al. Integrated miRNA and mRNA Expression Profiling in Response to Eriodictyol in Human Endothelial Cells. BioChip J. 11, 188–195 (2017).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Deparment of Life Science, Hanyang University, Seoul, 04763, Republic of Korea

    Hawon Lee & Young-Pil Kim

  2. Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA

    Xiaohu Gao

  3. Research Institute for Natural Sciences, Hanyang University, Seoul, 04763, Republic of Korea

    Young-Pil Kim

  4. Institute of Nano Science and Technology, Hanyang University, Seoul, 04763, Republic of Korea

    Young-Pil Kim

Authors
  1. Hawon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaohu Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Young-Pil Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Xiaohu Gao or Young-Pil Kim.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, H., Gao, X. & Kim, YP. Immuno-Nanoparticles for Multiplex Protein Imaging in Cells and Tissues. BioChip J 12, 83–92 (2018). https://doi.org/10.1007/s13206-018-2201-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13206-018-2201-8

Keywords

Search

Navigation