We describe biocompatible and nontoxic nanoparticles for in vivo tumor targeting and detection based on pegylated gold nanoparticles and surface-enhanced Raman scattering (SERS). Colloidal gold has been safely used to treat rheumatoid arthritis for 50 years, and has recently been found to amplify the efficiency of Raman scattering by 14–15 orders of magnitude. Here we show that large optical enhancements can be achieved under in vivo conditions for tumor detection in live animals. An important finding is that small-molecule Raman reporters such as organic dyes were not displaced but were stabilized by thiol-modified polyethylene glycols. These pegylated SERS nanoparticles were considerably brighter than semiconductor quantum dots with light emission in the near-infrared window. When conjugated to tumor-targeting ligands such as single-chain variable fragment (ScFv) antibodies, the conjugated nanoparticles were able to target tumor biomarkers such as epidermal growth factor receptors on human cancer cells and in xenograft tumor models.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Alivisatos, P. The use of nanocrystals in biological detection. Nat. Biotechnol. 22, 47–52 (2004).
Ferrari, M. Cancer nanotechnology: Opportunities and challenges. Nat. Rev. Cancer 5, 161–171 (2005).
Niemeyer, C.M. Nanoparticles, proteins, and nucleic acids: Biotechnology meets materials science. Angew. Chem. Int. Ed. 40, 4128–4158 (2001).
Michalet, X. et al. Quantum dots for live cells, in vivo imaging, and diagnostics. Science 307, 538–544 (2005).
Rosi, N.L. & Mirkin, C.A. Nanostructures in biodiagnostics. Chem. Rev. 105, 1547–1562 (2005).
Cao, Y.C., Jin, R.C. & Mirkin, C.A. Nanoparticles with Raman spectroscopic fingerprints for DNA and RNA detection. Science 297, 1536–1540 (2002).
Gao, X. et al. In-vivo molecular and cellular imaging with quantum dots. Curr. Opin. Biotechnol. 16, 63–72 (2005).
Nie, S.M., Xing, Y., Kim, G.J. & Simons, J.W. Nanotechnology applications in cancer. Annu. Rev. Biomed. Eng. 9, 257–288 (2007).
Yezhelyev, M.V. et al. Emerging use of nanoparticles in diagnosis and treatment of breast cancer. Lancet Oncol. 7, 657–667 (2006).
Gao, X., Cui, Y.Y., Levenson, R.M., Chung, L.W.K. & Nie, S.M. In vivo cancer targeting and imaging with semiconductor quantum dots. Nat. Biotechnol. 22, 969–976 (2004).
Liu, Z. et al. In vivo biodistribution and highly efficient tumour targeting of carbon nanotubes in mice. Nat. Nanotechnol. 2, 47–52 (2007).
Weissleder, R., Kelly, K., Sun, E.Y., Shtatland, T. & Josephson, L. Cell-specific targeting of nanoparticles by multivalent attachment of small molecules. Nat. Biotechnol. 23, 1418–1423 (2005).
Lee, E.S., Na, K. & Bae, Y.H. Polymeric micelle for tumor pH and folate-mediated targeting. J. Control. Release 91, 103–113 (2003).
Torchilin, V.P. Micellar nanocarriers: Pharmaceutical perspectives. Pharm. Res. 24, 1–16 (2007).
Moghimi, S.M., Hunter, A.C. & Murray, J.C. Long-circulating and target-specific nanoparticles: Theory to practice. Pharmacol. Rev. 53, 283–318 (2001).
Couvreur, P. & Vauthier, C. Nanotechnology: Intelligent design to treat complex diseases. Pharm. Res. 23, 1417–1450 (2006).
Duncan, R. Polymer conjugate as anticancer nanomedicines. Nat. Rev. Cancer 6, 688–701 (2006).
Hood, J.D. et al. Tumor regression by targeted gene delivery to the neovasculature. Science 296, 2404–2407 (2002).
Harisinghani, M.G. et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N. Engl. J. Med. 348, 2491–2499 (2003).
McCarthy, J.R., Kelly, K.A., Sun, E.Y. & Weissleder, R. Targeted delivery of multifunctional magnetic nanoparticles. Nanomedicine 2, 153–167 (2007).
Wu, X. et al. Immunofluorescent labeling of cancer marker Her2 and other cellular targets with semiconductor QDs. Nat. Biotechnol. 21, 41–46 (2003).
Kim, S. et al. Near-infrared fluorescent type II quantum dots for sentinel lymph node mapping. Nat. Biotechnol. 22, 93–97 (2004).
Rhyner, M.N. et al. Quantum dots and multifunctional nanoparticles: new contrast agents for tumor imaging. Nanomedicine 1, 209–217 (2006).
Xing, Y. et al. Bioconjugated quantum dots for multiplexed and quantitative immunohistochemistry. Nat. Protoc. 2, 1152–1165 (2007).
Woodle, M.C. & Lu, P.Y. Nanoparticles deliver RNAi therapy. NanoToday, 34–41 (8/2005).
Medarova, Z., Pham, W., Farrar, C., Petkova, V. & Moore, A. In-vivo imaging of siRNA delivery and silencing in tumors. Nat. Med. 13, 372–377 (2007).
Merchant, B. Gold, the noble metal and the paradoxes of its toxicology. Biologicals 26, 49–59 (1998).
Root, S.W., Andrews, G.A., Kniseley, R.M. & Tyor, M.P. The distribution and radiation effects of intravenously administered colloidal gold-198 in man. Cancer 7, 856–866 (1954).
Paciotti, G.F., Kingston, D.G.I. & Tamarkin, L. Colloidal gold nanoparticles: a novel nanoparticle platform for developing multifunctional tumor-targeted drug delivery vectors. Drug Dev. Res. 67, 47–54 (2006).
Paciotti, G.F. et al. Colloidal gold: a novel nanoparticle vector for tumor directed drug delivery. Drug Deliv. 11, 169–183 (2004).
James, W.D., Hirsch, L.R., West, J.L., O'Neal, P.D. & Payne, J.D. Application of INAA to the build-up and clearance of gold nanoshells in clinical studies in mice. J. Radioanal. Nucl. Chem. 271, 455–459 (2007).
Connor, E.E., Mwamuka, J., Gole, A., Murphy, C.J. & Wyatt, M.D. Gold nanoparticles are taken up by human cells but do not cause acute cytotoxicity. Small 1, 325–327 (2005).
Shukla, R. et al. Biocompatibility of gold nanoparticles and their endocytotic fate inside the cellular compartment: a microscopic overview. Langmuir 21, 10644–10654 (2005).
Kneipp, K., Kneipp, H., Itzkan, I., Dasari, R.R. & Feld, M.S. Ultrasensitive chemical analysis by Raman spectroscopy. Chem. Rev. 99, 2957–2976 (1999).
Campion, A. & Kambhampati, P. Surface-enhanced Raman scattering. Chem. Soc. Rev. 27, 241–250 (1998).
Nie, S.M. & Emory, S.R. Probing single molecules and single nanoparticles by surface-enhanced Raman scattering. Science 275, 1102–1106 (1997).
Kneipp, K. et al. Single molecule detection using surface enhanced Raman scattering. Phys. Rev. Lett. 78, 1667–1670 (1997).
Michaels, A.M., Nirmal, M. & Brus, L.E. Surface enhanced Raman spectroscopy of individual rhodamine 6G molecules on large Ag nanocrystals. J. Am. Chem. Soc. 121, 9932–9939 (1999).
Tian, J.H. et al. Study of molecular junctions with a combined surface-enhanced Raman and mechanically controllable break junction method. J. Am. Chem. Soc. 128, 14748–14749 (2006).
Moore, B.D. et al. Rapid and ultra-sensitive determination of enzyme activities using surface-enhanced resonance Raman scattering. Nat. Biotechnol. 22, 1133–1138 (2004).
Krug, J.T., Wang, G.D., Emory, S.R. & Nie, S.M. Efficient Raman enhancement and intermittent light emission observed in single gold nanocrystals. J. Am. Chem. Soc. 121, 9208–9214 (1999).
Doering, W.E. & Nie, S.M. Spectroscopic tags using dye-embedded nanoparticles and surface-enhanced Raman scattering. Anal. Chem. 75, 6171–6176 (2003).
Paez, J.G. et al. EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304, 1497–1500 (2004).
Lynch, T.J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004).
Mahmood, U. & Weissleder, R. Near-infrared optical imaging of proteases in cancer. Mol. Cancer Ther. 2, 489–496 (2003).
Wuelfing, W.P., Gross, S.M., Miles, D.T. & Murray, R.W. Nanometer gold clusters protected by surface-bound monolayers of thiolated poly(ethylene glycol) polymer electrolyte. J. Am. Chem. Soc. 120, 12696–12697 (1998).
Jiang, J.D., Burstein, E. & Kobayashi, H. Resonant raman-scattering by crystal-violet molecules adsorbed on a smooth gold surface — Evidence for a charge-transfer excitation. Phys. Rev. Lett. 57, 1793–1796 (1986).
Gobin, A.M. et al. Near-infrared resonant nanoshells for combined optical imaging and photothermal cancer therapy. Nano Lett. 7, 1929–1934 (2007).
Herbst, R.S. & Shin, D.M. Monoclonal antibodies to target epidermal growth factor receptor-positive tumors — A new paradigm for cancer therapy. Cancer 94, 1593–1611 (2002).
Reuter, C.W.M., Morgan, M.A. & Eckardt, A. Targeting EGF-receptor-signalling in squamous cell carcinomas of the head and neck. Br. J. Cancer 96, 408–416 (2007).
Ntziachristos, V., Bremer, C. & Weissleder, R. Fluorescence imaging with near-infrared light: new technological advances that enable in vivo molecular imaging. Eur. Radiol. 13, 195–208 (2003).
Jain, R.K. Transport of molecules, particles, and cells in solid tumors. Annu. Rev. Biomed. Eng. 1, 241–263 (1999).
Matsumura, Y. & Maeda, H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 46, 6387–6392 (1986).
Huang, X., El-Sayed, I.H., Qian, W. & El-Sayed, M.A. Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods. J. Am. Chem. Soc. 128, 2115–2120 (2006).
Zhang, H.F., Maslov, K., Stoica, G. & Wang, L.H.V. Functional photoacoustic microscopy for high-resolution and noninvasive in vivo imaging. Nat. Biotechnol. 24, 848–851 (2006).
Ntziachristos, V., Ripoll, J., Wang, L.H.V. & Weissleder, R. Looking and listening to light: the evolution of whole-body photonic imaging. Nat. Biotechnol. 23, 313–320 (2005).
Hirsch, L.R. et al. Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance. Proc. Natl. Acad. Sci. USA 100, 13549–13554 (2003).
We are grateful to Gregory Adams at Fox Chase Cancer Center for providing the ScFv B10 plasmid construct, to H.Z. Zhang for tumor cell injection, and to Hong Yi for assistance with TEM. This work was supported by grants from the US Air Force Office Multi-University Research Initiative, the National Cancer Institute Centers of Cancer Nanotechnology Excellence (CCNE) Program (U54CA119338 to S.N.), and the National Cancer Institute SPORE Program in Head and Neck Cancer (P50CA128613 to D.M.S.). Four of us (M.D.W., G.Z.C., D.M.S. and S.N.) also acknowledge the Georgia Cancer Coalition (GCC) for distinguished cancer scholar awards. The human carcinoma cells line Tu686 was kindly provided by Peter G. Sacks (New York University College of Dentistry, New York, NY).
About this article
Cite this article
Qian, X., Peng, XH., Ansari, D. et al. In vivo tumor targeting and spectroscopic detection with surface-enhanced Raman nanoparticle tags. Nat Biotechnol 26, 83–90 (2008). https://doi.org/10.1038/nbt1377
Accessing BCG in infected macrophages by antibody-mediated drug delivery system and tracking by surface-enhanced Raman scattering spectroscopy
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2021)
Numerical investigation of bidirectionally tunable, nanometer-precise, and compact tweezers for screening gold nanoparticles
Journal of the Optical Society of America B (2021)
Optical and Structural Properties of the Gold Nanoparticles Ablated by Laser Ablation in Ethanol for Biosensors
Journal of Physics: Conference Series (2021)
Green synthesis of mono and bimetallic alloy nanoparticles of gold and silver using aqueous extract of Chlorella acidophile for potential applications in sensors
Preparative Biochemistry & Biotechnology (2021)
Plexciton in tip-enhanced resonance Stokes and anti-Stokes Raman spectroscopy and in propagating surface plasmon polaritons
Optics Communications (2021)