Integrin αvβ3-targeted IRDye 800CW near-infrared imaging of glioblastoma.
OBJECTIVE
Integrin α(v)β(3) plays an important role in tumor angiogenesis, growth, and metastasis. We have tested a targeted probe to visualize integrin receptor expression in glioblastomas using near-infrared fluorescent (NIRF) imaging.


METHODS
A transgenic glioblastoma mouse model (RCAS-PDGF-driven/tv-a glioblastoma, which mimics the infiltrative growth pattern of human glioblastomas) and two human orthotopic glioblastoma models (U-87 MG with high integrin β(3) expression and TS543 with low integrin β(3) expression) were studied. An integrin-targeting NIRF probe, IRDye 800CW-cyclic-RGD peptide (IRDye 800CW-RGD), was tested by in vivo and ex vivo NIRF imaging.


RESULTS
We show that the IRDye 800CW-RGD peptide: (i) specifically binds to integrin receptors; (ii) is selectively localized to glioblastoma tissue with overexpressed integrin receptors and is retained over prolonged periods of time; (iii) is associated with minimal autofluorescence and photobleaching because of imaging at 800 nm; (iv) provides delineation of tumor tissue with high precision because of a high tumor-to-normal brain fluorescence ratio (79.7 ± 6.9, 31.2 ± 2.8, and 16.3 ± 1.3) in the U-87 MG, RCAS-PDGF, and TS543 models, respectively; P < 0.01); and (v) enables fluorescence-guided glioblastoma resection. Importantly, small foci of residual fluorescence were observed after resection was completed using white light imaging alone, and these fluorescent foci were shown to represent residual tumor tissue by histology.


CONCLUSIONS
NIRF imaging with the IRDye 800CW-RGD probe provides a simple, rapid, low-cost, nonradioactive, and highly translatable approach for improved intraoperative glioblastoma visualization and resection. It also has the potential to serve as an imaging platform for noninvasive cancer detection and drug efficacy evaluation studies.
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Ruimin
R
Huang
Jelena
J
Vider
Joy L
JL
Kovar
D Michael
DM
Olive
Ingo K
IK
Mellinghoff
Philipp
P
Mayer-Kuckuk
Moritz F
MF
Kircher
Ronald G
RG
Blasberg
D000818:Animals; D001557:Benzenesulfonates / Q000737:chemistry*; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000473:pathology / Q000601:surgery; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D039302:Integrin alphaVbeta3 / Q000302:isolation & purification*; D051379:Mice; D008822:Mice, Transgenic; D057054:Molecular Imaging; D009374:Neoplasms, Experimental / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000473:pathology / Q000601:surgery; D009842:Oligopeptides / Q000737:chemistry; D011859:Radiography; D019265:Spectroscopy, Near-Infrared; D014018:Tissue Distribution
D001557:Benzenesulfonates; C562366:IRDye 800CW; D007211:Indoles; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid