TY - JOUR
T1 - Imaging epidermal growth factor receptor expression in vivo
T2 - Pharmacokinetic and biodistribution characterization of a bioconjugated quantum dot nanoprobe
AU - Diagaradjane, Parmeswaran
AU - Orenstein-Cardona, Jacobo M.
AU - Colón-Casasnovas, Norman E.
AU - Deorukhkar, Amit
AU - Shentu, Shujun
AU - Kuno, Norihito
AU - Schwartz, David L.
AU - Gelovani, Juri G.
AU - Krishnan, Sunil
PY - 2008/2/1
Y1 - 2008/2/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-07-1958
DO - 10.1158/1078-0432.CCR-07-1958
M3 - Article
C2 - 18245533
AN - SCOPUS:38949102704
SN - 1078-0432
VL - 14
SP - 731
EP - 741
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 3
ER -