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Nanotheranostics 2022; 6(3):256-269. doi:10.7150/ntno.67362 This issue Cite

Research Paper

Visualizing surface marker expression and intratumoral heterogeneity with SERRS-NPs imaging

Lara K. Rotter^1,2,3,4, Naxhije Berisha^2,5,6,7, Hsiao-Ting Hsu², Kathleen H. Burns⁸, Chrysafis Andreou^2,9,10✉, Moritz F. Kircher^2,11,12,13

1. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute and Harvard University Medical School, Boston, MA, USA
2. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
3. Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
4. Department of Diagnostic and Interventional Neuroradiology, School of Medicine, Technical University Munich, München, Germany
5. PhD Program in Chemistry, The Graduate Center of the City University of New York, New York, NY, USA
6. Department of Nanotechnology, Advanced Science Research Center (ASRC) at the Graduate Center of the City University of New York, New York, NY, USA
7. Department of Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
8. Department of Pathology, Dana-Farber Cancer Institute and Harvard University Medical School, Boston, MA, USA
9. Department of Electrical and Computer Engineering University of Cyprus, Nicosia, Cyprus
10. Emphasis Research Centre, University of Cyprus, Nicosia, Cyprus
11. Molecular Pharmacology Program, Memorial Sloan Kettering Institute, New York, NY, USA
12. Department of Radiology, Weill Cornell Medical College, New York, NY, USA
13. Department of Imaging, Dana-Farber Cancer Institute, Boston, MA, USA

✉ Corresponding author: andreou.chrysafisac.cy

Abstract

Cell surface marker expression in tumors dictates the selection of therapeutics, therapy response, and survival. However, biopsies are invasive, sample only a small area of the tumor landscape and may miss significant areas of heterogeneous expression. Here, we investigated the potential of antibody-conjugated surface-enhanced resonance Raman scattering nanoparticles (SERRS-NPs) to depict and quantify high and low tumoral surface marker expression, focusing on the surface markers epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) in an intracerebral and peripheral setting with an inter- and intratumoral comparison of Raman signal intensities.

Methods: ICR-Prkdc <scid> mice were injected with glioblastoma, epidermoid carcinoma, or breast tumor cell lines intracerebrally and peripherally. SERRS-NPs were functionalized with cetuximab or trastuzumab and administered via tail vein injection. Raman imaging was performed 18 hours post-injection in excised tumors and in vivo through the skull. Tumors were then fixed and processed for immunohistochemical evaluation.

Results: Confirmed by MRI and immunohistochemistry for EGFR and HER2, our results demonstrate that antibody-conjugated SERRS-NPs go beyond the delineation of a tumor and offer clear and distinct Raman spectra that reflect the distribution of the targeted surface marker. The intensity of the SERRS-NP signal accurately discriminated high- versus low-expressing surface markers between tumors, and between different areas within tumors.

Conclusion: Biopsies can be highly invasive procedures and provide a limited sample of molecular expression within a tumor. Our nanoparticle-based Raman imaging approach offers the potential to provide non-invasive and more comprehensive molecular imaging and an alternative to the current clinical gold standard of immunohistochemistry.

Keywords: SERRS, Raman imaging, Raman Nanoparticles, Raman Spectroscopy, Brain tumor, Glioblastoma multiforme, Breast Cancer, Breast Cancer Metastasis, Tumor Heterogeneity, Surface marker expression, EGFR, HER2.

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