Detection of Lymph Node Metastases with SERRS Nanoparticles
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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.
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.
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.
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 wordsSurface-enhanced resonance Raman scattering Raman imaging Prostate cancer Lymph node metastasis Intraoperative imaging
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
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.
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.
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