Imaging epidermal growth factor receptor expression in vivo: Pharmacokinetic and biodistribution characterization of a bioconjugated quantum dot nanoprobe

Parmeswaran Diagaradjane, Jacobo M. Orenstein-Cardona, Norman E. Colón-Casasnovas, Amit Deorukhkar, Shujun Shentu, Norihito Kuno, David L. Schwartz, Juri G. Gelovani, Sunil Krishnan

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Abstract

Purpose: To develop and validate an optical imaging nanoprobe for the discrimination of epidermal growth factor (EGF) receptor (EGFR)-overexpressing tumors from surrounding normal tissues that also expresses EGFR. Experimental Design: Near-infrared (NIR) quantum dots (QD) were coupled to EGF using thiol-maleimide conjugation to create EGF-QD nanoprobes. In vitro binding affinity of these nanoprobes and unconjugated QDs was evaluated in a panel of cell lines, with and without anti-EGFR antibody pretreatment. Serial optical imaging of HCT116 xenograft tumors was done after systemic injection of QD and EGF-QD. Results: EGF-QD showed EGFR-specific binding in vitro. In vivo imaging showed three distinct phases, tumor influx (∼3 min), clearance (∼60 min), and accumulation (1-6 h), of EGF-QD nanoprobes. Both QD and EGF-QD showed comparable nonspecific rapid tumor influx and clearance followed by attainment of an apparent dynamic equilibrium at ∼60 min. Subsequently (1-6 h), whereas QD concentration gradually decreased in tumors, EGF-QDs progressively accumulated in tumors. On delayed imaging at 24 h, tumor fluorescence decreased to near-baseline levels for both QD and EGF-QD. Ex vivo whole-organ fluorescence, tissue homogenate fluorescence, and confocal microscopic analyses confirmed tumor-specific accumulation of EGF-QD at 4 h. Immunofluorescence images showed diffuse colocalization of EGF-QD fluorescence within EGFR-expressing tumor parenchyma compared with patchy perivascular sequestration of QD. Conclusion: These results represent the first pharmacokinetic characterization of a robust EGFR imaging nanoprobe. The measurable contrast enhancement of tumors 4 h after systemic administration of EGF-QD and its subsequent normalization at 24 h imply that this nanoprobemay permit quantifiable and repetitive imaging of EGFR expression.

Original languageEnglish (US)
Pages (from-to)731-741
Number of pages11
JournalClinical Cancer Research
Volume14
Issue number3
DOIs
StatePublished - Feb 1 2008

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Diagaradjane, P., Orenstein-Cardona, J. M., Colón-Casasnovas, N. E., Deorukhkar, A., Shentu, S., Kuno, N., Schwartz, D. L., Gelovani, J. G., & Krishnan, S. (2008). Imaging epidermal growth factor receptor expression in vivo: Pharmacokinetic and biodistribution characterization of a bioconjugated quantum dot nanoprobe. Clinical Cancer Research, 14(3), 731-741. https://doi.org/10.1158/1078-0432.CCR-07-1958