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Smith BR, Zavaleta C, Rosenberg J, et al. High-resolution, serial intravital microscopic imaging of nanoparticle delivery and targeting in a small animal tumor model. Nano Today. 2013;8(2)doi: 10.1016/j.nantod.2013.02.004.
Smith, B. R., Zavaleta, C., Rosenberg, J., Tong, R., Ramunas, J., Liu, Z., Dai, H., & Gambhir, S. S. (2013). High-resolution, serial intravital microscopic imaging of nanoparticle delivery and targeting in a small animal tumor model. Nano today, 8(2), . https://doi.org/10.1016/j.nantod.2013.02.004
Smith, Bryan Ronain, et al. "High-resolution, serial intravital microscopic imaging of nanoparticle delivery and targeting in a small animal tumor model." Nano today vol. 8,2 (2013). doi: https://doi.org/10.1016/j.nantod.2013.02.004
Smith BR, Zavaleta C, Rosenberg J, Tong R, Ramunas J, Liu Z, Dai H, Gambhir SS. High-resolution, serial intravital microscopic imaging of nanoparticle delivery and targeting in a small animal tumor model. Nano Today. 2013 Apr;8(2). doi: 10.1016/j.nantod.2013.02.004. PMID: 24273594; PMCID: PMC3836612.
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Nano Today. 2013 Apr;8(2). doi: 10.1016/j.nantod.2013.02.004.

High-resolution, serial intravital microscopic imaging of nanoparticle delivery and targeting in a small animal tumor model.

Nano today

Bryan Ronain Smith, Cristina Zavaleta, Jarrett Rosenberg, Ricky Tong, John Ramunas, Zhuang Liu, Hongjie Dai, Sanjiv Sam Gambhir

Affiliations

  1. 318 Campus Drive East, E-150, Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA 94305, USA.

PMID: 24273594 PMCID: PMC3836612 DOI: 10.1016/j.nantod.2013.02.004

Abstract

Nanoparticles are under active investigation for the detection and treatment of cancer. Yet our understanding of nanoparticle delivery to tumors is limited by our ability to observe the uptake process on its own scale in living subjects. We chose to study single-walled carbon nanotubes (SWNTs) because they exhibit among the highest levels of tumor uptake across the wide variety of available nanoparticles. We target them using RGD (arginine-glycine-aspartic acid) peptide which directs them to integrins overexpressed on tumor vasculature and on the surface of some tumor cells (e.g., U87MG as used here). We employ intravital microscopy (IVM) to quantitatively examine the spatiotemporal framework of targeted SWNT uptake in a murine tumor model. IVM provided a dynamic microscale window into nanoparticle circulation, binding to tumor blood vessels, extravasation, binding to tumor cells, and tumor retention. RGD-SWNTs bound to tumor vasculature significantly more than controls (P<0.0001). RGD-SWNTs extravasated similarly compared to control RAD-SWNTs, but post-extravasation we observed as RGD-SWNTs eventually bound to individual tumor cells significantly more than RAD-SWNTs (p<0.0001) over time. RGD-SWNTs and RAD-SWNTs displayed similar signal in tumor for a week, but over time their curves significantly diverged (p<0.001) showing increasing RGD-SWNTs relative to untargeted SWNTs. We uncovered the complex spatiotemporal interplay between these competing uptake mechanisms. Specific uptake was delimited to early (1-6 hours) and late (1-4 weeks) time-points, while non-specific uptake dominated from 6 hours to 1 week. Our analysis revealed critical, quantitative insights into the dynamic, multifaceted mechanisms implicated in ligand-targeted SWNT accumulation in tumor using real-time observation.

Keywords: Intravital microscopy; cancer; nanoparticles; serial imaging; single-walled carbon nanotubes; specificity; targeting

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