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Surface-enhanced Raman scattering nanosensors for in vivo detection of nucleic acid targets in a large animal model

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Abstract

Although nanotechnology has led to important advances in in vitro diagnostics, the development of nanosensors for in vivo detection remains very challenging. Here, we demonstrated the proof-of-principle of in vivo detection of nucleic acid targets using a promising type of surface-enhanced Raman scattering (SERS) nanosensor implanted in the skin of a large animal model (pig). The in vivo nanosensor used in this study involves the “inverse molecular sentinel” detection scheme using plasmonics-active nanostars, which have tunable absorption bands in the near infrared region of the “tissue optical window”, rendering them efficient as an optical sensing platform for in vivo optical detection. Ex vivo measurements were also performed using human skin grafts to demonstrate the detection of SERS nanosensors through tissue. In this study, a new core–shell nanorattle probe with Raman reporters trapped between the core and shell was utilized as an internal standard system for self-calibration. These results illustrate the usefulness and translational potential of the SERS nanosensor for in vivo biosensing.

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References

  1. Campion A.; Kambhampati, P. Surface-enhanced Raman scattering. Chem. Soc. Rev. 1998, 27, 241–250.

    Article  Google Scholar 

  2. Schlücker, S. Surface-enhanced Raman spectroscopy: Concepts and chemical applications. Angew. Chem., Int. Ed. 2014, 53, 4756–4795.

    Article  Google Scholar 

  3. Vo-Dinh, T.; Hiromoto, M. Y. K.; Begun, G. M.; Moody, R. L. Surface-enhanced Raman spectrometry for trace organic analysis. Anal. Chem. 1984, 56, 1667–1670.

    Article  Google Scholar 

  4. Vo-Dinh, T. Surface-enhanced Raman spectroscopy using metallic nanostructures. TrAC-Trend. Anal. Chem. 1998, 17, 557–582.

    Article  Google Scholar 

  5. Vo-Dinh, T.; Fales, A. M.; Griffin, G. D.; Khoury, C. G.; Liu, Y.; Ngo, H.; Norton, S. J.; Register, J. K.; Wang, H. N.; Yuan, H. Plasmonic nanoprobes: From chemical sensing to medical diagnostics and therapy. Nanoscale 2013, 5, 10127–10140.

    Article  Google Scholar 

  6. Ng, V. W. K.; Berti, R.; Lesage, F.; Kakkar, A. Gold: A versatile tool for in vivo imaging. J. Mater. Chem. B 2013, 1, 9–25.

    Article  Google Scholar 

  7. Yuan, H.; Khoury, C. G.; Hwang, H.; Wilson, C. M.; Grant, G. A.; Vo-Dinh, T. Gold nanostars: Surfactant-free synthesis, 3D modelling, and two-photon photoluminescence imaging. Nanotechnology 2012, 23, 075102.

    Article  Google Scholar 

  8. Yuan, H.; Fales, A. M.; Khoury, C. G.; Liu, J.; Vo-Dinh, T. Spectral characterization and intracellular detection of surfaceenhanced Raman scattering (SERS)-encoded plasmonic gold nanostars. J. Raman Spectrosc. 2013, 44, 234–239.

    Article  Google Scholar 

  9. Tian, F. R.; Conde, J.; Bao, C. C.; Chen, Y. S.; Curtin, J.; Cui, D. X. Gold nanostars for efficient in vitro and in vivo real-time SERS detection and drug delivery via plasmonictunable Raman/FTIR imaging. Biomaterials 2016, 106, 87–97.

    Article  Google Scholar 

  10. Fales, A. M.; Yuan, H.; Vo-Dinh, T. Development of hybrid silver-coated gold nanostars for nonaggregated surfaceenhanced Raman scattering. J. Phys. Chem. C 2014, 118, 3708–3715.

    Article  Google Scholar 

  11. Souza, G. R.; Levin, C. S.; Hajitou, A.; Pasqualini, R.; Arap, W.; Miller, J. H. In vivo detection of gold-imidazole selfassembly complexes: NIR-SERS signal reporters. Anal. Chem. 2006, 78, 6232–6237.

    Article  Google Scholar 

  12. Stuart, D. A.; Yuen, J. M.; Shah, N.; Lyandres, O.; Yonzon, C. R.; Glucksberg, M. R.; Walsh, J. T.; Van Duyne, R. P. In vivo glucose measurement by surface-enhanced Raman spectroscopy. Anal. Chem. 2006, 78, 7211–7215.

    Article  Google Scholar 

  13. Qian, X. M.; Peng, X. H.; Ansari, D. O.; Yin-Goen, Q.; Chen, G. Z.; Shin, D. M.; Yang, L.; Young, A. N.; Wang, M. D.; Nie, S. M. In vivo tumor targeting and spectroscopic detection with surface-enhanced Raman nanoparticle tags. Nat. Biotechnol. 2008, 26, 83–90.

    Article  Google Scholar 

  14. Samanta, A.; Maiti, K. K.; Soh, K. S.; Liao, X. J.; Vendrell, M.; Dinish, U. S.; Yun, S. W.; Bhuvaneswari, R.; Kim, H.; Rautela, S. et al. Ultrasensitive near-infrared Raman reporters for SERS-based in vivo cancer detection. Angew. Chem., Int. Ed. 2011, 50, 6089–6092.

    Article  Google Scholar 

  15. Maiti, K. K.; Dinish, U. S.; Fu, C. Y.; Lee, J. J.; Soh, K. S.; Yun, S. W.; Bhuvaneswari, R.; Olivo, M.; Chang, Y. T. Development of biocompatible SERS nanotag with increased stability by chemisorption of reporter molecule for in vivo cancer detection. Biosens. Bioelectron. 2010, 26, 398–403.

    Article  Google Scholar 

  16. McQueenie, R.; Stevenson, R.; Benson, R.; MacRitchie, N.; McInnes, I.; Maffia, P.; Faulds, K.; Graham, D.; Brewer, J.; Garside, P. Detection of inflammation in vivo by surfaceenhanced Raman scattering provides higher sensitivity than conventional fluorescence imaging. Anal. Chem. 2012, 84, 5968–5975.

    Article  Google Scholar 

  17. Dinish, U. S.; Balasundaram, G.; Chang, Y. T.; Olivo, M. Actively targeted in vivo multiplex detection of intrinsic cancer biomarkers using biocompatible SERS nanotags. Sci. Rep. 2014, 4, 4075.

    Article  Google Scholar 

  18. Zavaleta, C. L.; Smith, B. R.; Walton, I.; Doering, W.; Davis, G.; Shojaei, B.; Natan, M. J.; Gambhir, S. S. Multiplexed imaging of surface enhanced Raman scattering nanotags in living mice using noninvasive Raman spectroscopy. Proc. Natl. Acad. Sci. USA 2009, 106, 13511–13516.

    Article  Google Scholar 

  19. Yigit, M. V.; Zhu, L. Y.; Ifediba, M. A.; Zhang, Y.; Carr, K.; Moore, A.; Medarova, Z. Noninvasive MRI-SERS imaging in living mice using an innately bimodal nanomaterial. ACS Nano 2011, 5, 1056–1066.

    Article  Google Scholar 

  20. Kang, H.; Jeong, S.; Park, Y.; Yim, J.; Jun, B. H.; Kyeong, S.; Yang, J. K.; Kim, G.; Hong, S.; Lee, L. P. et al. Near-infrared SERS nanoprobes with plasmonic Au/Ag hollow-shell assemblies for in vivo multiplex detection. Adv. Funct. Mater. 2013, 23, 3719–3727.

    Article  Google Scholar 

  21. Wang, Y. L.; Seebald, J. L.; Szeto, D. P.; Irudayaraj, J. Biocompatibility and biodistribution of surface-enhanced Raman scattering nanoprobes in zebrafish embryos: In vivo and multiplex imaging. ACS Nano 2010, 4, 4039–4053.

    Article  Google Scholar 

  22. Fales, A. M.; Yuan, H.; Vo-Dinh, T. Silica-coated gold nanostars for combined surface-enhanced Raman scattering (SERS) detection and singlet-oxygen generation: A potential nanoplatform for theranostics. Langmuir 2011, 27, 12186–12190.

    Article  Google Scholar 

  23. Conde, J.; Bao, C. C.; Cui, D. X.; Baptista, P. V.; Tian, F. R. Antibody–drug gold nanoantennas with Raman spectroscopic fingerprints for in vivo tumour theranostics. J. Control. Release 2014, 183, 87–93.

    Article  Google Scholar 

  24. Zhang, Y.; Qian, J.; Wang, D.; Wang, Y. L.; He, S. L. Multifunctional gold nanorods with ultrahigh stability and tunability for in vivo fluorescence imaging, SERS detection, and photodynamic therapy. Angew. Chem., Int. Ed. 2013, 52, 1148–1151.

    Article  Google Scholar 

  25. Liu, Y.; Ashton, J. R.; Moding, E. J.; Yuan, H.; Register, J. K.; Fales, A. M.; Choi, J.; Whitley, M. J.; Zhao, X. G.; Qi, Y. et al. A plasmonic gold nanostar theranostic probe for in vivo tumor imaging and photothermal therapy. Theranostics 2015, 5, 946–960.

    Article  Google Scholar 

  26. Schwarzenbach, H.; Hoon, D. S. B.; Pantel, K. Cell-free nucleic acids as biomarkers in cancer patients. Nat. Rev. Cancer 2011, 11, 426–437.

    Article  Google Scholar 

  27. Anker, P.; Lyautey, J.; Lederrey, C.; Stroun, M. Circulating nucleic acids in plasma or serum. Clin. Chim. Acta 2001, 313, 143–146.

    Article  Google Scholar 

  28. Gormally, E.; Caboux, E.; Vineis, P; Hainaut, P. Circulating free DNA in plasma or serum as biomarker of carcinogenesis: Practical aspects and biological significance. Mutat. Res. Rev. Mutat. Res. 2007, 635, 105–117.

    Article  Google Scholar 

  29. Kopreski, M. S.; Benko, F. A.; Kwak, L. W.; Gocke, C. D. Detection of tumor messenger RNA in the serum of patients with malignant melanoma. Clin. Cancer Res. 1999, 5, 1961–1965.

    Google Scholar 

  30. Mitchell, P. S.; Parkin, R. K.; Kroh, E. M.; Fritz, B. R.; Wyman, S. K.; Pogosova-Agadjanyan, E. L.; Peterson, A.; Noteboom, J.; O’Briant, K. C.; Allen, A. et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl. Acad. Sci. USA 2008, 105, 10513–10518.

    Article  Google Scholar 

  31. Chen, X.; Ba, Y.; Ma, L. J.; Cai, X.; Yin, Y.; Wang, K. H.; Guo, J. G.; Zhang, Y. J.; Chen, J. N.; Guo, X. et al. Characterization of microRNAs in serum: A novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 2008, 18, 997–1006.

    Article  Google Scholar 

  32. Wang, H. N.; Fales, A. M.; Vo-Dinh, T. Plasmonics-based SERS nanobiosensor for homogeneous nucleic acid detection. Nanomed. Nanotech. Biol. Med. 2015, 11, 811–814.

    Article  Google Scholar 

  33. Ngo, H. T.; Wang, H. N.; Fales, A. M.; Nicholson, B. P.; Woods, C. W.; Vo-Dinh, T. DNA bioassay-on-chip using SERS detection for dengue diagnosis. Analyst 2014, 139, 5655–5659.

    Article  Google Scholar 

  34. Wang, H. N.; Crawford, B. M.; Fales, A. M.; Bowie, M. L.; Seewaldt, V. L.; Vo-Dinh, T. Multiplexed detection of microRNA biomarkers using SERS-based inverse molecular sentinel (iMS) nanoprobes. J. Phys. Chem. C 2016, 120, 21047–21055.

    Article  Google Scholar 

  35. Wabuyele, M. B.; Vo-Dinh, T. Detection of human immunodeficiency virus type 1DNA sequence using plasmonics nanoprobes. Anal. Chem. 2005, 77, 7810–7815.

    Article  Google Scholar 

  36. Wang, H. N.; Vo-Dinh, T. Multiplex detection of breast cancer biomarkers using plasmonic molecular sentinel nanoprobes. Nanotechnology 2009, 20, 065101.

    Article  Google Scholar 

  37. Gandra, N.; Hendargo, H. C.; Norton, S. J.; Fales, A. M.; Palmer, G. M.; Vo-Dinh, T. Tunable and amplified Raman gold nanoprobes for effective tracking (TARGET): In vivo sensing and imaging. Nanoscale 2016, 8, 8486–8494.

    Article  Google Scholar 

  38. Tian, L. M.; Gandra, N.; Singamaneni, S. Monitoring controlled release of payload from gold nanocages using surface enhanced Raman scattering. ACS Nano 2013, 7, 4252–4260.

    Article  Google Scholar 

  39. Choi, S. W.; Zhang, Y.; Xia, Y. N. A temperature-sensitive drug release system based on phase-change materials. Angew. Chem., Int. Ed. 2010, 49, 7904–7908.

    Article  Google Scholar 

  40. Moon, G. D.; Choi, S. W.; Cai, X.; Li, W. Y.; Cho, E. C.; Jeong, U.; Wang, L. V.; Xia, Y. N. A new theranostic system based on gold nanocages and phase-change materials with unique features for photoacoustic imaging and controlled release. J. Am. Chem. Soc. 2011, 133, 4762–4765.

    Article  Google Scholar 

  41. Register, J. K.; Fales, A. M.; Wang, H. N.; Norton, S. J.; Cho, E. H.; Boico, A.; Pradhan, S.; Kim, J.; Schroeder, T.; Wisniewski, N. A. et al. In vivo detection of SERS-encoded plasmonic nanostars in human skin grafts and live animal models. Anal. Bioanal. Chem. 2015, 407, 8215–8224.

    Article  Google Scholar 

  42. Martinez, K.; Estevez, M. C.; Wu, Y. R.; Phillips, J. A.; Medley, C. D.; Tan, W. H. Locked nucleic acid based beacons for surface interaction studies and biosensor development. Anal. Chem. 2009, 81, 3448–3454.

    Article  Google Scholar 

  43. Ansari, A.; Kuznetsov, S. V. Is hairpin formation in singlestranded polynucleotide diffusion-controlled? J. Phys. Chem. B 2005, 109, 12982–12989.

    Article  Google Scholar 

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Acknowledgements

This work was sponsored by the Defense Advanced Research Projects Agency (No. HR0011-13-2-0003). The content of the information does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred.

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Author notes

  1. Hsin-Neng Wang, Janna K. Register and Andrew M. Fales contributed equally to this work.

Authors and Affiliations

  1. Departments of Biomedical Engineering, Duke University, Durham, NC, 27708, USA

    Hsin-Neng Wang, Janna K. Register, Andrew M. Fales, Naveen Gandra & Tuan Vo-Dinh

  2. Fitzpatrick Institute for Photonics, Duke University, Durham, NC, 27708, USA

    Hsin-Neng Wang, Janna K. Register, Andrew M. Fales, Naveen Gandra & Tuan Vo-Dinh

  3. Medical Center, Duke University, Durham, NC, 27710, USA

    Eugenia H. Cho, Alina Boico, Gregory M. Palmer & Bruce Klitzman

  4. Departments of Chemistry, Duke University, Durham, NC, 27708, USA

    Tuan Vo-Dinh

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  1. Hsin-Neng Wang
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Correspondence to Tuan Vo-Dinh.

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Wang, HN., Register, J.K., Fales, A.M. et al. Surface-enhanced Raman scattering nanosensors for in vivo detection of nucleic acid targets in a large animal model. Nano Res. 11, 4005–4016 (2018). https://doi.org/10.1007/s12274-018-1982-3

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  • DOI: https://doi.org/10.1007/s12274-018-1982-3

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