Skip to main content
SpringerLink
Log in

Delineating the tumor margin with intraoperative surface-enhanced Raman spectroscopy

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

Abstract

The failure of complete tumor resection during cancer surgery is a leading cause of lethal recurrence and metastasis. However, achieving accurate delineation of tumor margins intraoperatively remains extremely difficult because the infiltrated nature of a tumor usually gives an obscure margin and spreading microtumors. Recent studies show that surface-enhanced Raman scattering (SERS) has the potential to depict precisely the actual tumor extent with high sensitivity, specificity, and spatial resolution; thus providing a promising platform to improve the therapeutic efficiency. In this review, we discuss the recent progress in the use of SERS spectroscopy for intraoperative image-guided resection. We highlight key successes in the development of SERS tags and give insights into the design mechanism of rational SERS tags. We also discuss how to improve the performance of intraoperative navigation based on SERS and explore the challenges and future opportunities for the development of a more effective SERS-based platform.

ᅟ

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
Fig. 5

Similar content being viewed by others

References

  1. Sanai N, Berger MS. Surgical oncology for gliomas: the state of the art. Nat Rev Clin Oncol. 2017;15:112–25.

    Article  PubMed  Google Scholar 

  2. Ji M, Lewis S, Camelo-Piragua S, Ramkissoon SH, Snuderl M, Venneti S, et al. Detection of human brain tumor infiltration with quantitative stimulated Raman scattering microscopy. Sci Transl Med. 2015;7(309):309ra163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhang J, Rector J, Lin JQ, Young JH, Sans M, Katta N, et al. Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system. Sci Transl Med. 2017;9(406):eaan3968.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. van Dam GM, Themelis G, Crane LMA, Harlaar NJ, Pleijhuis RG, Kelder W, et al. Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results. Nat Med. 2011;17:1315–20.

    Article  CAS  PubMed  Google Scholar 

  5. Kircher MF, de la Zerda A, Jokerst JV, Zavaleta CL, Kempen PJ, Mittra E, et al. A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle. Nat Med. 2012;18(5):829–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lukianova-Hleb EY, Kim Y-S, Belatsarkouski I, Gillenwater AM, O'Neill BE, Lapotko DO. Intraoperative diagnostics and elimination of residual microtumours with plasmonic nanobubbles. Nat Nanotechnol. 2016;11:525–32.

    Article  CAS  PubMed  Google Scholar 

  7. Petrecca K, Guiot M-C, Panet-Raymond V, Souhami L. Failure pattern following complete resection plus radiotherapy and temozolomide is at the resection margin in patients with glioblastoma. J Neuro-Oncol. 2013;111(1):19–23.

    Article  Google Scholar 

  8. Wang P, Fan Y, Lu L, Liu L, Fan L, Zhao M, et al. NIR-II nanoprobes in-vivo assembly to improve image-guided surgery for metastatic ovarian cancer. Nat Commun. 2018;9:2898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Harmsen S, Teraphongphom N, Tweedle MF, Basilion JP, Rosenthal EL. Optical surgical navigation for precision in tumor resections. Mol Imaging Biol. 2017;19(3):357–62.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Harmsen S, Huang R, Wall MA, Karabeber H, Samii JM, Spaliviero M, et al. Surface-enhanced resonance Raman scattering nanostars for high-precision cancer imaging. Sci Transl Med. 2015;7(271):271ra7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Samanta A, Maiti KK, Soh K-S, Liao X, Vendrell M, Dinish US, et al. Ultrasensitive near-infrared Raman reporters for SERS-based in vivo cancer detection. Angew Chem Int Ed. 2011;50(27):6089–92.

    Article  CAS  Google Scholar 

  12. Harmsen S, Bedics MA, Wall MA, Huang R, Detty MR, Kircher MF. Rational design of a chalcogenopyrylium-based surface-enhanced resonance Raman scattering nanoprobe with attomolar sensitivity. Nat Commun. 2015;6:6570.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mulvaney SP, Musick MD, Keating CD, Natan MJ. Glass-coated, analyte-tagged nanoparticles: a new tagging system based on detection with surface-enhanced Raman scattering. Langmuir. 2003;19(11):4784–90.

    Article  CAS  Google Scholar 

  14. Wang Y, Yan B, Chen L. SERS tags: novel optical nanoprobes for bioanalysis. Chem Rev. 2013;113(3):1391–428.

    Article  CAS  PubMed  Google Scholar 

  15. Lane LA, Qian X, Nie S. SERS nanoparticles in medicine: from label-free detection to spectroscopic tagging. Chem Rev. 2015;115(19):10489–529.

    Article  CAS  PubMed  Google Scholar 

  16. Cialla-May D, Zheng XS, Weber K, Popp J. Recent progress in surface-enhanced Raman spectroscopy for biological and biomedical applications: from cells to clinics. Chem Soc Rev. 2017;46(13):3945–61.

    Article  CAS  PubMed  Google Scholar 

  17. Liu Y, Ashton JR, Moding EJ, Yuan H, Register JK, Fales AM, et al. A plasmonic gold nanostar theranostic probe for in vivo tumor imaging and photothermal therapy. Theranostics. 2015;5(9):946–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mohs AM, Mancini MC, Singhal S, Provenzale JM, Leyland-Jones B, Wang MD, et al. Hand-held spectroscopic device for in vivo and intraoperative tumor detection: contrast enhancement, detection sensitivity, and tissue penetration. Anal Chem. 2010;82(21):9058–65.

    Article  CAS  PubMed  Google Scholar 

  19. Bohndiek SE, Wagadarikar A, Zavaleta CL, Van de Sompel D, Garai E, Jokerst JV, et al. A small animal Raman instrument for rapid, wide-area, spectroscopic imaging. Proc Natl Acad Sci U S A. 2013;110(30):12408–13.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Zavaleta CL, Garai E, Liu JTC, Sensarn S, Mandella MJ, Van de Sompel D, et al. A Raman-based endoscopic strategy for multiplexed molecular imaging. Proc Natl Acad Sci U S A. 2013;110(25):E2288–97.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Garai E, Sensarn S, Zavaleta CL, Loewke NO, Rogalla S, Mandella MJ, et al. A real-time clinical endoscopic system for intraluminal, multiplexed imaging of surface-enhanced Raman scattering nanoparticles. PLoS One. 2015;10(4):e0123185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Raman CV, Krishnan KS. A new type of secondary radiation. Nature. 1928;121:501–2.

    Article  CAS  Google Scholar 

  23. Laing S, Jamieson LE, Faulds K, Graham D. Surface-enhanced Raman spectroscopy for in vivo biosensing. Nat Rev Chem. 2017;1:0060.

    Article  CAS  Google Scholar 

  24. Fleischmann M, Hendra PJ, McQuillan AJ. Raman spectra of pyridine adsorbed at a silver electrode. Chem Phys Lett. 1974;26(2):163–6.

    Article  CAS  Google Scholar 

  25. Jeanmaire DL, Van Duyne RP. Surface raman spectroelectrochemistry: part I. Heterocyclic, aromatic, and aliphatic amines adsorbed on the anodized silver electrode. J Electroanal Chem Interfacial Electrochem. 1977;84(1):1–20.

    Article  CAS  Google Scholar 

  26. Jermyn M, Mok K, Mercier J, Desroches J, Pichette J, Saint-Arnaud K, et al. Intraoperative brain cancer detection with Raman spectroscopy in humans. Sci Transl Med. 2015;7(274):274ra19.

    Article  CAS  PubMed  Google Scholar 

  27. Qiu Y, Zhang Y, Li M, Chen G, Fan C, Cui K, et al. Intraoperative detection and eradication of residual microtumors with gap-enhanced Raman tags. ACS Nano. 2018;12(8):7974–85.

    Article  CAS  PubMed  Google Scholar 

  28. Zavaleta CL, Smith BR, Walton I, Doering W, Davis G, Shojaei B, et al. Multiplexed imaging of surface enhanced Raman scattering nanotags in living mice using noninvasive Raman spectroscopy. Proc Natl Acad Sci U S A. 2009;106(32):13511–6.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Kircher MF. How can we apply the use of surface-enhanced Raman scattering nanoparticles in tumor imaging? Nanomedicine. 2017;12(3):171–4.

    Article  CAS  PubMed  Google Scholar 

  30. Oseledchyk A, Andreou C, Wall MA, Kircher MF. Folate-targeted surface-enhanced resonance Raman scattering nanoprobe ratiometry for detection of microscopic ovarian cancer. ACS Nano. 2017;11(2):1488–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. von Maltzahn G, Centrone A, Park J-H, Ramanathan R, Sailor MJ, Hatton TA, et al. SERS-coded gold nanorods as a multifunctional platform for densely multiplexed near-infrared imaging and photothermal heating. Adv Mater. 2009;21(31):3175–80.

    Article  CAS  Google Scholar 

  32. Zhang Y, Qian J, Wang D, Wang Y, He S. Multifunctional gold nanorods with ultrahigh stability and tunability for in vivo fluorescence imaging, SERS detection, and photodynamic therapy. Angew Chem Int Ed. 2013;52(4):1148–51.

    Article  CAS  Google Scholar 

  33. Schwartzberg AM, Olson TY, Talley CE, Zhang JZ. Synthesis, characterization, and tunable optical properties of hollow gold nanospheres. J Phys Chem B. 2006;110(40):19935–44.

    Article  CAS  PubMed  Google Scholar 

  34. Zhang Y, Liu Z, Thackray BD, Bao Z, Yin X, Shi F, et al. Intraoperative Raman-guided chemo-photothermal synergistic therapy of advanced disseminated ovarian cancers. Small. 2018. https://doi.org/10.1002/smll.201801022.

  35. Zhou J, Xiong Q, Ma J, Ren J, Messersmith PB, Chen P, et al. Polydopamine-enabled approach toward tailored plasmonic nanogapped nanoparticles: from nanogap engineering to multifunctionality. ACS Nano. 2016;10(12):11066–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Song J, Zhou J, Duan H. Self-assembled plasmonic vesicles of SERS-encoded amphiphilic gold nanoparticles for cancer cell targeting and traceable intracellular drug delivery. J Am Chem Soc. 2012;134(32):13458–69.

    Article  CAS  PubMed  Google Scholar 

  37. Qian X, Li J, Nie S. Stimuli-responsive SERS nanoparticles: conformational control of plasmonic coupling and surface Raman enhancement. J Am Chem Soc. 2009;131(22):7540–1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kang H, Jeong S, Jo A, Chang H, Yang J-K, Jeong C, et al. Ultrasensitive NIR-SERRS probes with multiplexed ratiometric quantification for in vivo antibody leads validation. Adv Healthc Mater. 2018;7(4):1700870.

    Article  CAS  Google Scholar 

  39. Gandra N, Singamaneni S. “Clicked” plasmonic core–satellites: covalently assembled gold nanoparticles. Chem Commun. 2012;48(94):11540–2.

    Article  CAS  Google Scholar 

  40. Maiti KK, Dinish US, Fu CY, Lee JJ, Soh KS, Yun SW, et al. Development of biocompatible SERS nanotag with increased stability by chemisorption of reporter molecule for in vivo cancer detection. Biosens Bioelectron. 2010;26(2):398–403.

    Article  CAS  PubMed  Google Scholar 

  41. Qian X, Peng X-H, Ansari DO, Yin-Goen Q, Chen GZ, Shin DM, et al. In vivo tumor targeting and spectroscopic detection with surface-enhanced Raman nanoparticle tags. Nat Biotechnol. 2008;26(1):83–90.

    Article  CAS  PubMed  Google Scholar 

  42. Jiang C, Wang Y, Wang J, Song W, Lu L. Achieving ultrasensitive in vivo detection of bone crack with polydopamine-capsulated surface-enhanced Raman nanoparticle. Biomaterials. 2017;114:54–61.

    Article  CAS  PubMed  Google Scholar 

  43. Maiti KK, Samanta A, Vendrell M, Soh KS, Olivo M, Chang YT. Multiplex cancer cell detection by SERS nanotags with cyanine and triphenylmethine Raman reporters. Chem Commun. 2011;47(12):3514–6.

    Article  CAS  Google Scholar 

  44. Hu B, Kong F, Gao X, Jiang L, Li X, Gao W, et al. Avoiding thiol compound interference: a nanoplatform based on high-fidelity Au–Se bonds for biological applications. Angew Chem Int Ed. 2018;57(19):5306–9.

    Article  CAS  Google Scholar 

  45. Iacono P, Karabeber H, Kircher MF. A “Schizophotonic” all-in-one nanoparticle coating for multiplexed SE(R)RS biomedical imaging. Angew Chem Int Ed. 2014;53(44):11756–61.

    Article  CAS  Google Scholar 

  46. Zhang Y, Walkenfort B, Yoon JH, Schlücker S, Xie W. Gold and silver nanoparticle monomers are non-SERS-active: a negative experimental study with silica-encapsulated Raman-reporter-coated metal colloids. Phys Chem Chem Phys. 2015;17(33):21120–6.

    Article  CAS  PubMed  Google Scholar 

  47. Darby BL, Le Ru EC. Competition between molecular adsorption and diffusion: dramatic consequences for SERS in colloidal solutions. J Am Chem Soc. 2014;136(31):10965–73.

    Article  CAS  PubMed  Google Scholar 

  48. Zhang Y, Wang Z, Wu L, Zong S, Yun B, Cui Y. Combining multiplex SERS nanovectors and multivariate analysis for in situ profiling of circulating tumor cell phenotype using a microfluidic chip. Small. 2018;14(20):1704433.

    Article  CAS  Google Scholar 

  49. Jokerst JV, Miao Z, Zavaleta C, Cheng Z, Gambhir SS. Affibody-functionalized gold–silica nanoparticles for Raman molecular imaging of the epidermal growth factor receptor. Small. 2011;7(5):625–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Huang R, Harmsen S, Samii JM, Karabeber H, Pitter KL, Holland EC, et al. High precision imaging of microscopic spread of glioblastoma with a targeted ultrasensitive serrs molecular imaging probe. Theranostics. 2016;6(8):1075–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sun T, Zhang YS, Pang B, Hyun DC, Yang M, Xia Y. Engineered nanoparticles for drug delivery in cancer therapy. Angew Chem Int Ed. 2014;53(46):12320–64.

    CAS  Google Scholar 

  52. Song J, Pu L, Zhou J, Duan B, Duan H. Biodegradable theranostic plasmonic vesicles of amphiphilic gold nanorods. ACS Nano. 2013;7(11):9947–60.

    Article  CAS  PubMed  Google Scholar 

  53. Wang YW, Khan A, Som M, Wang D, Chen Y, Leigh SY, et al. Rapid ratiometric biomarker detection with topically applied SERS nanoparticles. Technology. 2014;02(02):118–32.

    Article  Google Scholar 

  54. Wang YW, Khan A, Leigh SY, Wang D, Chen Y, Meza D, et al. Comprehensive spectral endoscopy of topically applied SERS nanoparticles in the rat esophagus. Biomed Opt Express. 2014;5(9):2883–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wang YW, Doerksen JD, Kang S, Walsh D, Yang Q, Hong D, et al. Multiplexed molecular imaging of fresh tissue surfaces enabled by convection-enhanced topical staining with SERS-coded nanoparticles. Small. 2016;12(40):5612–21.

    Article  CAS  PubMed  Google Scholar 

  56. Kang S, Wang Y, Reder NP, Liu JT. Multiplexed molecular imaging of biomarker-targeted SERS nanoparticles on fresh tissue specimens with channel-compressed spectrometry. PLoS One. 2016;11(9):e0163473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Karabeber H, Huang R, Iacono P, Samii JM, Pitter K, Holland EC, et al. Guiding brain tumor resection using surface-enhanced Raman scattering nanoparticles and a hand-held raman scanner. ACS Nano. 2014;8(10):9755–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Stone N, Kerssens M, Lloyd GR, Faulds K, Graham D, Matousek P. Surface enhanced spatially offset Raman spectroscopic (SESORS) imaging - the next dimension. Chem Sci. 2011;2(4):776–80.

    Article  CAS  Google Scholar 

  59. Neuschmelting V, Harmsen S, Beziere N, Lockau H, Hsu HT, Huang R, et al. Dual-modality surface-enhanced resonance Raman scattering and multispectral optoacoustic tomography nanoparticle approach for brain tumor delineation. Small. 2018;14(23):e1800740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Amendola V, Scaramuzza S, Litti L, Meneghetti M, Zuccolotto G, Rosato A, et al. Magneto-plasmonic Au-Fe alloy nanoparticles designed for multimodal SERS-MRI-CT imaging. Small. 2014;10(12):2476–86.

    Article  CAS  PubMed  Google Scholar 

  61. Qian J, Jiang L, Cai F, Wang D, He S. Fluorescence-surface enhanced Raman scattering co-functionalized gold nanorods as near-infrared probes for purely optical in vivo imaging. Biomaterials. 2011;32(6):1601–10.

    Article  CAS  PubMed  Google Scholar 

  62. Wall MA, Shaffer TM, Harmsen S, Tschaharganeh D-F, Huang C-H, Lowe SW, et al. Chelator-free radiolabeling of SERRS nanoparticles for whole-body PET and intraoperative Raman imaging. Theranostics. 2017;7(12):3068–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gao Y, Li Y, Chen J, Zhu S, Liu X, Zhou L, et al. Multifunctional gold nanostar-based nanocomposite: synthesis and application for noninvasive MR-SERS imaging-guided photothermal ablation. Biomaterials. 2015;60(0):31–41.

    Article  CAS  PubMed  Google Scholar 

  64. Thakor AS, Paulmurugan R, Kempen P, Zavaleta C, Sinclair R, Massoud TF, et al. Oxidative stress mediates the effects of Raman-active gold nanoparticles in human cells. Small. 2011;7(1):126–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Zavaleta CL, Hartman KB, Miao Z, James ML, Kempen P, Thakor AS, et al. Preclinical evaluation of Raman nanoparticle biodistribution for their potential use in clinical endoscopy imaging. Small. 2011;7(15):2232–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Thakor AS, Luong R, Paulmurugan R, Lin FI, Kempen P, Zavaleta C, et al. The fate and toxicity of Raman-active silica-gold nanoparticles in mice. Sci Transl Med. 2011;3(79):79ra33.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study received financial support from the National Natural Science Foundation of China (No. 21703230, 21635007, 21721003).

Author information

Authors and Affiliations

  1. State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, Jilin, China

    Chunhuan Jiang & Lehui Lu

  2. School of Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China

    Ying Wang

  3. State Key Laboratory of Supramolecular Structure and Materials, Jilin University, Changchun, 130012, Jilin, China

    Wei Song

Authors
  1. Chunhuan Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lehui Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lehui Lu.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Published in the topical collection New Insights into Analytical Science in China with guest editors Lihua Zhang, Hua Cui, and Qiankun Zhuang.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jiang, C., Wang, Y., Song, W. et al. Delineating the tumor margin with intraoperative surface-enhanced Raman spectroscopy. Anal Bioanal Chem 411, 3993–4006 (2019). https://doi.org/10.1007/s00216-019-01577-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00216-019-01577-9

Keywords

Search

Navigation