Molecular Imaging and Biology

, Volume 18, Issue 5, pp 677–685 | Cite as

Detection of Lymph Node Metastases with SERRS Nanoparticles

  • Massimiliano Spaliviero
  • Stefan Harmsen
  • Ruimin Huang
  • Matthew A. Wall
  • Chrysafis Andreou
  • James A. Eastham
  • Karim A. Touijer
  • Peter T. Scardino
  • Moritz F. Kircher
Research Article

Abstract

Purpose

The accurate detection of lymph node metastases in prostate cancer patients is important to direct treatment decisions. Our goal was to develop an intraoperative imaging approach to distinguish normal from metastasized lymph nodes. We aimed at developing and testing gold-silica surface-enhanced resonance Raman spectroscopy (SERRS) nanoparticles that demonstrate high uptake within normal lymphatic tissue and negligible uptake in areas of metastatic replacement.

Procedures

We evaluated the ability of SERRS nanoparticles to delineate lymph node metastases in an orthotopic prostate cancer mouse model using PC-3 cells transduced with mCherry fluorescent protein. Tumor-bearing mice (n = 6) and non-tumor-bearing control animals (n = 4) were injected intravenously with 30 fmol/g SERRS nanoparticles. After 16–18 h, the retroperitoneal lymph nodes were scanned in situ and ex vivo with a Raman imaging system and a handheld Raman scanner and data corroborated with fluorescence imaging for mCherry protein expression and histology.

Results

The SERRS nanoparticles demonstrated avid homing to normal lymph nodes, but not to metastasized lymph nodes. In cases where lymph nodes were partially infiltrated by tumor cells, the SERRS signal correctly identified, with sub-millimeter precision, healthy from metastasized components.

Conclusions

This study serves as a first proof-of-principle that SERRS nanoparticles enable high precision and rapid intraoperative discrimination between normal and metastasized lymph nodes.

Key words

Surface-enhanced resonance Raman scattering Raman imaging Prostate cancer Lymph node metastasis Intraoperative imaging 

Notes

Acknowledgments

The authors would like to thank Vladimir Ponomarev, PhD (MSKCC), for providing the SFG-click beetle luciferase-IRES-mCherry plasmid; the Electron Microscopy and Molecular Cytology Core Facility at MSKCC; Julie White, PhD, from the Tri-Institutional Laboratory of Comparative Pathology for interpreting the histological results; Matthew B. Brendel from the Molecular Cytology Core Facility at MSKCC for providing assistance with image analysis and quantification; and Andrew Cho and Marc Levine for critical review of the manuscript.

Compliance with Ethical Standards

Funding

NIH R01 EB017748 (M.F.K.); NIH K08 CA16396 (M.F.K.); M.F.K. is a Damon Runyon-Rachleff Innovator supported (in part) by the Damon Runyon Cancer Research Foundation (DRR-29-14); Pershing Square Sohn Prize by the Pershing Square Sohn Cancer Research Alliance (M.F.K.). MSKCC Center for Molecular Imaging and Nanotechnology (CMINT) Grant, Technology Development Grant, The Center for Experimental Therapeutics of Memorial Sloan Kettering Cancer Center, and Molecularly Targeted Intra-Operative Imaging Grant (M.F.K.); Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research; Geoffrey Beene Cancer Research Center at MSKCC Grant Award and Shared Resources Award (M.F.K.); Bayer HealthCare Pharmaceuticals/RSNA Research Scholar Grant (M.F.K.). M.S. received salary support by the Department of Surgery of MSKCC (Chair: P.T.S). M.A.W. was supported by a National Science Foundation Integrative Graduate Education and Research Traineeship Grant (NSF, IGERT 0965983 at Hunter College). This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748.

Author Contributions

The project was conceptualized and supervised by M.F.K. The study was designed by M.F.K., M.S., S.H., and R.H. Data acquisition was performed by M.S., S.H, R.H., and M.S., S.H, R.H., C.A., M.A.W., J.A.E., K.A.T., P.T.S., and M.F.K. participated in the design and/or interpretation of the reported experiments or results. C.A. performed data analysis. M.S., S.H, R.H., and M.F.K. wrote the manuscript, which was reviewed and approved by all authors.

Conflict of Interest

S.H., M.A.W., and M.F.K. are inventors on pending patents regarding the SERRS nanoparticle design and synthesis procedures. M.F.K. is the inventor of an additional pending patent regarding a wide-field Raman scanner and is a co-founder of RIO Imaging, Inc.

References

  1. 1.
    Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65:5–29CrossRefPubMedGoogle Scholar
  2. 2.
    Yossepowitch O, Eggener SE, Serio AM et al (2008) Secondary therapy, metastatic progression, and cancer-specific mortality in men with clinically high-risk prostate cancer treated with radical prostatectomy. Eur Urol 53:950–959CrossRefPubMedGoogle Scholar
  3. 3.
    Allaf ME, Palapattu GS, Trock BJ et al (2004) Anatomical extent of lymph node dissection: impact on men with clinically localized prostate cancer. J Urol 172:1840–1844CrossRefPubMedGoogle Scholar
  4. 4.
    Bader P, Burkhard FC, Markwalder R, Studer UE (2002) Is a limited lymph node dissection an adequate staging procedure for prostate cancer? J Urol 168:514–518CrossRefPubMedGoogle Scholar
  5. 5.
    Godoy G, von Bodman C, Chade DC et al (2012) Pelvic lymph node dissection for prostate cancer: frequency and distribution of nodal metastases in a contemporary radical prostatectomy series. J Urol 187:2082–2086CrossRefPubMedGoogle Scholar
  6. 6.
    Heidenreich A, Varga Z, Von Knobloch R (2002) Extended pelvic lymphadenectomy in patients undergoing radical prostatectomy: high incidence of lymph node metastasis. J Urol 167:1681–1686CrossRefPubMedGoogle Scholar
  7. 7.
    von Bodman C, Godoy G, Chade DC et al (2010) Predicting biochemical recurrence-free survival for patients with positive pelvic lymph nodes at radical prostatectomy. J Urol 184:143–148CrossRefGoogle Scholar
  8. 8.
    Bader P, Burkhard FC, Markwalder R, Studer UE (2003) Disease progression and survival of patients with positive lymph nodes after radical prostatectomy. Is there a chance of cure? J Urol 169:849–854CrossRefPubMedGoogle Scholar
  9. 9.
    Godoy G, Chong KT, Cronin A et al (2011) Extent of pelvic lymph node dissection and the impact of standard template dissection on nomogram prediction of lymph node involvement. Eur Urol 60:195–201CrossRefPubMedGoogle Scholar
  10. 10.
    Feifer AH, Elkin EB, Lowrance WT et al (2011) Temporal trends and predictors of pelvic lymph node dissection in open or minimally invasive radical prostatectomy. Cancer 117:3933–3942CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Kawakami J, Meng MV, Sadetsky N et al (2006) Changing patterns of pelvic lymphadenectomy for prostate cancer: results from CaPSURE. J Urol 176:1382–1386CrossRefPubMedGoogle Scholar
  12. 12.
    Abdollah F, Sun M, Thuret R et al (2010) Decreasing rate and extent of lymph node staging in patients undergoing radical prostatectomy may undermine the rate of diagnosis of lymph node metastases in prostate cancer. Eur Urol 58:882–892CrossRefPubMedGoogle Scholar
  13. 13.
    Silberstein JL, Laudone VP (2015) Pelvic lymph node dissection. In: Eastham JA, Schaeffer EM (eds) Radical prostatectomy. Springer, New York, pp 57–74Google Scholar
  14. 14.
    Cagiannos I, Karakiewicz P, Eastham JA et al (2003) A preoperative nomogram identifying decreased risk of positive pelvic lymph nodes in patients with prostate cancer. J Urol 170:1798–1803CrossRefPubMedGoogle Scholar
  15. 15.
    Abdollah F, Sun M, Suardi N et al (2012) National Comprehensive Cancer Network practice guidelines 2011: need for more accurate recommendations for pelvic lymph node dissection in prostate cancer. J Urol 188:423–428CrossRefPubMedGoogle Scholar
  16. 16.
    Nepple KG, Rosevear HM, Stolpen AH et al (2013) Concordance of preoperative prostate endorectal MRI with subsequent prostatectomy specimen in high-risk prostate cancer patients. Urol Oncol 31:601–606CrossRefPubMedGoogle Scholar
  17. 17.
    Meinhardt W, Valdes Olmos RA et al (2008) Laparoscopic sentinel node dissection for prostate carcinoma: technical and anatomical observations. BJU Int 102:714–717CrossRefPubMedGoogle Scholar
  18. 18.
    van der Poel HG, Buckle T, Brouwer OR et al (2011) Intraoperative laparoscopic fluorescence guidance to the sentinel lymph node in prostate cancer patients: clinical proof of concept of an integrated functional imaging approach using a multimodal tracer. Eur Urol 60:826–833CrossRefPubMedGoogle Scholar
  19. 19.
    Weissleder R, Elizondo G, Wittenberg J et al (1990) Ultrasmall superparamagnetic iron oxide: an intravenous contrast agent for assessing lymph nodes with MR imaging. Radiology 175:494–498CrossRefPubMedGoogle Scholar
  20. 20.
    Harisinghani MG, Barentsz J, Hahn PF et al (2003) Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 348:2491–2499CrossRefPubMedGoogle Scholar
  21. 21.
    Kircher MF, Willmann JK (2012) Molecular body imaging: MR imaging, CT, and US. Part I. Principles. Radiology 263:633–643CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kircher MF, Willmann JK (2012) Molecular body imaging: MR imaging, CT, and US. Part II. Applications. Radiology 264:349–368CrossRefPubMedGoogle Scholar
  23. 23.
    Andreou C, Kishore SA, Kircher MF (2015) Surface-enhanced Raman spectroscopy: a new modality for cancer imaging. J Nucl Med 56:1295–1299CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kircher MF, de la Zerda A, Jokerst JV et al (2012) A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle. Nat Med 18:829–834CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Karabeber H, Huang R, Iacono P et al (2014) Guiding brain tumor resection using surface-enhanced Raman scattering nanoparticles and a hand-held Raman scanner. ACS Nano 8:9755–9766CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Harmsen S, Huang R, Wall MA et al (2015) Surface-enhanced resonance Raman scattering nanostars for high-precision cancer imaging. Sci Transl Med 7:271–277CrossRefGoogle Scholar
  27. 27.
    Kaighn ME, Narayan KS, Ohnuki Y et al (1979) Establishment and characterization of a human prostatic carcinoma cell line (PC-3). Invest Urol 17:16–23PubMedGoogle Scholar
  28. 28.
    Sobel RE, Sadar MD (2005) Cell lines used in prostate cancer research: a compendium of old and new lines—part 1. J Urol 173:342–359CrossRefPubMedGoogle Scholar
  29. 29.
    Huang R, Vider J, Serganova I, Blasberg RG (2011) ATP-binding cassette transporters modulate both coelenterazine- and D-luciferin-based bioluminescence imaging. Mol Imaging 10:215–226PubMedPubMedCentralGoogle Scholar
  30. 30.
    Horsnell J, Stonelake P, Christie-Brown J et al (2010) Raman spectroscopy—a new method for the intra-operative assessment of axillary lymph nodes. Analyst 135:3042–3047CrossRefPubMedGoogle Scholar
  31. 31.
    Horsnell JD, Smith JA, Sattlecker M et al (2012) Raman spectroscopy—a potential new method for the intra-operative assessment of axillary lymph nodes. Surgeon 10:123–127CrossRefPubMedGoogle Scholar
  32. 32.
    Grimm J, Kircher MF, Weissleder R (2007) Cell tracking: principles and applications. Radiologe 47:25–33CrossRefPubMedGoogle Scholar
  33. 33.
    Harisinghani MG, Saini S, Weissleder R et al (1999) MR lymphangiography using ultrasmall superparamagnetic iron oxide in patients with primary abdominal and pelvic malignancies: radiographic-pathologic correlation. AJR Am J Roentgenol 172:1347–1351CrossRefPubMedGoogle Scholar
  34. 34.
    Wunderbaldinger P, Josephson L, Bremer C et al (2002) Detection of lymph node metastases by contrast-enhanced MRI in an experimental model. Magn Reson Med 47:292–297CrossRefPubMedGoogle Scholar
  35. 35.
    Cheng L, Bergstralh EJ, Cheville JC et al (1998) Cancer volume of lymph node metastasis predicts progression in prostate cancer. Am J Surg Pathol 22:1491–1500CrossRefPubMedGoogle Scholar
  36. 36.
    Andreou C, Kishore SA, Kircher MF (2015) Surface-enhanced Raman spectroscopy: a new modality for cancer imaging. J Nucl Med 56:1295–1299Google Scholar
  37. 37.
    Harmsen S, Bedics MA, Wall MA et al (2015) Rational design of a chalcogenopyrylium-based surface-enhanced resonance Raman scattering nanoprobe with attomolar sensitivity. Nat Commun 6:6570CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Thakor AS, Luong R, Paulmurugan R et al (2011) The fate and toxicity of Raman-active silica-gold nanoparticles in mice. Sci Transl Med 3:79–33CrossRefGoogle Scholar
  39. 39.
    Thakor AS, Gambhir SS (2013) Nanooncology: the future of cancer diagnosis and therapy. CA Cancer J Clin 63:395–418CrossRefPubMedGoogle Scholar

Copyright information

© World Molecular Imaging Society 2016

Authors and Affiliations

  • Massimiliano Spaliviero
    • 1
    • 2
  • Stefan Harmsen
    • 1
  • Ruimin Huang
    • 1
  • Matthew A. Wall
    • 1
    • 3
    • 4
  • Chrysafis Andreou
    • 1
  • James A. Eastham
    • 2
  • Karim A. Touijer
    • 2
  • Peter T. Scardino
    • 2
  • Moritz F. Kircher
    • 1
    • 5
    • 6
  1. 1.Department of RadiologyMemorial Sloan Kettering Cancer CenterNew YorkUSA
  2. 2.Urology Service, Department of SurgerySidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer CenterNew YorkUSA
  3. 3.Department of ChemistryHunter College of the City University of New YorkNew YorkUSA
  4. 4.Department of ChemistryThe Graduate Center of the City University of New YorkNew YorkUSA
  5. 5.Center for Molecular Imaging and Nanotechnology (CMINT), Memorial Sloan Kettering Cancer CenterNew YorkUSA
  6. 6.Department of RadiologyWeill Cornell Medical CollegeNew YorkUSA

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