Robert Sinclair, Yitian Zeng and Steven Madsen

Department of Materials Science and Engineering, Stanford University, Stanford, CA 94305, United States


There are various ways in which nanotechnology can assist in early cancer detection, oftentimes utilizing sensitive physical properties of nanomaterials to detect them attached to tumors or circulating cancer cells [1]. The group with whom we collaborate has successfully employed gold nanoparticles contained within a silica shell as a triple modality detection agent [2]. One of the properties utilized is surface-enhanced Raman spectroscopy (SERS) whereby the gold nano-spheres significantly enhance the Raman signal from an organic dye when exposed to an illuminating laser beam, which has been incorporated into a working endoscopic system [3]. While this works well, to our knowledge there has never been any systematic study as to the influence of nanomaterial structure parameters such as size, shape, seperation, coating etc. on the strength of the Raman signal, and hence its utility in detecting small tumors. It is recognized that surface plasmons in noble metal nanoparticles directly contribute to the Raman signal [4], and that the surface plasmon energy is in turn determined by the nanomaterial parameters mentioned above [5]. In this paper, we describe an approach to study the effect of these parameters in order to establish the optimum conditions to generate the highest possible Raman signal.

An array of gold nanoparticles of various size, shape and separation is fabricated from a vapor-deposited gold thin film utilizing standard electron lithographic processes. When a Raman dye is spread over the array, Raman imaging shows the variations of signal and hence the parameters giving rise to maximum signal. Nanoparticle size is seem to be a critical feature. The plasmon resonances and energies are then determined across the array using electron energy loss spectroscopy (EELS) in a scanning TEM (STEM) [6] and the individual spectra are then correlated with the Raman signal from the exact same nanoparticle structures. By this procedure we can establish the critical parameters which yield the highest Raman signal, which leads to the systematic design of the most effective SERS nanoparticles.

This work was supported by the Center for Cancer Nanotechnology Excellence for Translational Diagnostics (CCNE-TD) at Stanford University through an award (grant No:  U54 CA199075) from the National Cancer Institute (NCI) of the National Institutes of Health (NIH). The inspirational contributions and advice from our principle investigators Drs. Sam Gambhir and Shan Wang are most appreciated.


[1] H. Arami, C. B. Patel, S. J. Madsen, P. J. Dickinson, R. M. Davis, Y. Zeng, B. K. Sturges, K. D. Woolard, F. G. Habte, D. Akin, R. Sinclair, and S. S. Gambhir. “Nanomedicine for Spontaneous Brain Tumors: A Companion Clinical Trial”, ACS Nano, 13 (3), 2858-2869 (2019).

[2] M. F. Kircher, A. de la Zerda, J. V. Jokerst, C. L. Zavaleta, P. J. Kempen, E. Mittra, K. Pitter, R. Huang, C. Campos, F. Habte, R. Sinclair, C. W. Brennan, I. K. Mellinghoff, E. C. Holland and S. S. Gambhir. “A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle”, Nature Medicine, 18, 829-834 (2012).

[3] A. S. Thakor, R. Luong, R. Paulmurugan, F. I. Lin, P. Kempen, C. Zavaleta, P. Chu, T. F. Massoud, R. Sinclair, and S. S. Gambir. “The Fate and Toxicity of Raman-Active Silica-Gold Nanoparticles in Mice” Sci Transl Med, 3 (79), 79ra33 (2011).

[4] K. Kneipp, H. Kneipp, I. Itzkan, R. R. Dasari and M. S. Feld. “Surface-enhanced Raman scattering and biophysics“, J. Phys. Condens. Matter 14, R597-R624 (2002).

[5] M. Bosman, V. J. Keast, M. Watanabe, A. I. Maaroof and M. B. Cortie. “Mapping surface plasmons at the nanometre scale with an electron beam“, Nanotechnology 18, 165505 (2007).

[6] S.J. Madsen, M. Esfandyarpour, M.L. Brongersma and R. Sinclair. “Observing Plasmon Damping Due to Adhesion Layers in Gold Nanostructures Using Electron Energy Loss Spectroscopy“, ACS Photonics 4, 268-274 (2017).