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    England, Christopher G. Gobin, André M. and Frieboes, Hermann B. 2015. Evaluation of uptake and distribution of gold nanoparticles in solid tumors. The European Physical Journal Plus, Vol. 130, Issue. 11,

    Kempen, Paul J. Kircher, Moritz F. de la Zerda, Adam Zavaleta, Cristina L. Jokerst, Jesse V. Mellinghoff, Ingo K. Gambhir, Sanjiv S. and Sinclair, Robert 2015. A correlative optical microscopy and scanning electron microscopy approach to locating nanoparticles in brain tumors. Micron, Vol. 68, p. 70.

    Sanders, Aric W. Jeerage, Kavita M. Schwartz, Cindi L. Curtin, Alexandra E. and Chiaramonti, Ann N. 2015. Gold Nanoparticle Quantitation by Whole Cell Tomography. ACS Nano, Vol. 9, Issue. 12, p. 11792.

    Havrdova, M. Polakova, K. Skopalik, J. Vujtek, M. Mokdad, A. Homolkova, M. Tucek, J. Nebesarova, J. and Zboril, R. 2014. Field emission scanning electron microscopy (FE-SEM) as an approach for nanoparticle detection inside cells. Micron, Vol. 67, p. 149.


A Scanning Transmission Electron Microscopy Approach to Analyzing Large Volumes of Tissue to Detect Nanoparticles

  • Paul J. Kempen (a1), Avnesh S. Thakor (a2) (a3), Cristina Zavaleta (a2), Sanjiv S. Gambhir (a1) (a2) (a4) and Robert Sinclair (a1)
  • DOI:
  • Published online: 27 June 2013

The use of nanoparticles for the diagnosis and treatment of cancer requires the complete characterization of their toxicity, including accurately locating them within biological tissues. Owing to their size, traditional light microscopy techniques are unable to resolve them. Transmission electron microscopy provides the necessary spatial resolution to image individual nanoparticles in tissue, but is severely limited by the very small analysis volume, usually on the order of tens of cubic microns. In this work, we developed a scanning transmission electron microscopy (STEM) approach to analyze large volumes of tissue for the presence of polyethylene glycol-coated Raman-active-silica-gold-nanoparticles (PEG-R-Si-Au-NPs). This approach utilizes the simultaneous bright and dark field imaging capabilities of STEM along with careful control of the image contrast settings to readily identify PEG-R-Si-Au-NPs in mouse liver tissue without the need for additional time-consuming analytical characterization. We utilized this technique to analyze 243,000 μm3 of mouse liver tissue for the presence of PEG-R-Si-Au-NPs. Nanoparticles injected into the mice intravenously via the tail vein accumulated in the liver, whereas those injected intrarectally did not, indicating that they remain in the colon and do not pass through the colon wall into the systemic circulation.

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E. Chang , N. Thekkek , W.W. Yu , V.L. Colvin & R. Drezek (2006). Evaluation of quantum dot cytotoxicity based on intracellular uptake. Small 2(12), 14121417.

N.K. Devaraj , E.J. Keliher , G.M. Thurber , M. Nahrendorf & R. Weissleder (2009). 18F labeled nanoparticles for in vivo PET-CT imaging. Bioconjugate Chem 20(2), 397401.

D. Farrell , J. Alper , K. Ptak , N.J. Panaro , P. Grodzinski & A.D. Barker (2010). Recent advances from the national cancer institute alliance for nanotechnology in cancer. ACS Nano 4(2), 589594.

M. Ferrari (2005). Cancer nanotechnology: Opportunities and challenges. Nat Rev Cancer 5(3), 161171.

D. Inderbitzin , M. Gass , G. Beldi , E. Ayouni , A. Nordin , D. Sidler , B. Gloor , D. Candinas & C. Stoupis (2004). Magnetic resonance imaging provides accurate and precise volume determination of the regenerating mouse liver. J Gastrointest Surg 8(7), 806811.

S. Keren , C. Zavaleta , Z. Cheng , A. de la Zerda , O. Gheysens & S.S. Gambhir (2008). Noninvasive molecular imaging of small living subjects using Raman spectroscopy. Proc Natl Acad Sci U S A 105(15), 58445849.

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 & S.S. Gambhir (2012). A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle. Nat Med 18(5), 829834.

J. Kneipp , H. Kneipp , A. Rajadurai , R.W. Redmond & K. Kneipp (2009). Optical probing and imaging of live cells using SERS labels. J Raman Spectrosc 40(1), 15.

A.L. Koh , C.M. Shachaf , S. Elchuri , G.P. Nolan & R. Sinclair (2008). Electron microscopy localization and characterization of functionalized composite organic-inorganic SERS nanoparticles on leukemia cells. Ultramicroscopy 109(1), 111121.

G. Liang , J. Ronald , Y. Chen , D. Ye , P. Pandit , M.L. Ma , B. Rutt & J. Rao (2011). Controlled self-assembling of gadolinium nanoparticles as smart molecular magnetic resonance imaging contrast agents. Angew Chemie, Int Ed 50(28), 62836286.

Z. Liu , S. Tabakman , S. Sherlock , X. Li , Z. Chen , K. Jiang , S. Fan & H. Dai (2010). Multiplexed five-color molecular imaging of cancer cells and tumor tissues with carbon nanotube Raman tags in the near-infrared. Nano Res 3(3), 222233.

C. Loo , A. Lowery , N. Halas , J. West & R. Drezek (2005). Immunotargeted nanoshells for integrated cancer imaging and therapy. Nano Lett 5(4), 709711.

S.P. Mulvaney , M.D. Musick , C.D. Keating & M.J. Natan (2003). Glass-coated, analyte-tagged nanoparticles: A new tagging system based on detection with surface-enhanced raman scattering. Langmuir 19 (11), 47844790.

A.S. Thakor , J. Jokerst , C. Zavaleta , T.F. Massoud , S.S. Gambhir (2011a). Gold nanoparticles: A revival in precious metal administration to patients. Nano Lett 11(10), 40294036.

A.S. Thakor , R. Luong , R. Paulmurugan , F.I. Lin , P. Kempen , C. Zavaleta , P. Chu , T.F. Massoud , R. Sinclair & S.S. Gambhir (2011b). The fate and toxicity of Raman-active silica-gold nanoparticles in mice. Sci Transl Med 3(79), 79ra33.

A.S. Thakor , R. Paulmurugan , P. Kempen , C. Zavaleta , R. Sinclair , T.F. Massoud & S.S. Gambhir (2011c). Oxidative stress mediates the effects of Raman-active gold nanoparticles in human cells. Small 7(1), 126136.

G. von Maltzahn , A. Centrone , J.H. Park , R. Ramanathan , M.J. Sailor , T.A. Hatton & S.N. Bhatia (2009). SERS-coded gold nanorods as a multifunctional platform for densely multiplexed near-infrared imaging and photothermal heating. Adv Mater 21(31), 31753180.

C.L. Zavaleta , B.R. Smith , I. Walton , W. Doering , G. Davis , B. Shojaei , M.J. Natan & S.S. Gambhir (2009). Multiplexed imaging of surface enhanced Raman scattering nanotags in living mice using noninvasive Raman spectroscopy. Proc Natl Acad Sci USA 106(32), 1351113516.

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Microscopy and Microanalysis
  • ISSN: 1431-9276
  • EISSN: 1435-8115
  • URL: /core/journals/microscopy-and-microanalysis
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