Dual-function probe for PET and near-infrared fluorescence imaging of tumor vasculature.
To date, the in vivo imaging of quantum dots (QDs) has been mostly qualitative or semiquantitative. The development of a dual-function PET/near-infrared fluorescence (NIRF) probe can allow for accurate assessment of the pharmacokinetics and tumor-targeting efficacy of QDs.


METHODS
A QD with an amine-functionalized surface was modified with RGD peptides and 1,4,7,10-tetraazacyclodocecane-N,N',N'',N'''-tetraacetic acid (DOTA) chelators for integrin alpha(v)beta(3)-targeted PET/NIRF imaging. A cell-binding assay and fluorescence cell staining were performed with U87MG human glioblastoma cells (integrin alpha(v)beta(3)-positive). PET/NIRF imaging, tissue homogenate fluorescence measurement, and immunofluorescence staining were performed with U87MG tumor-bearing mice to quantify the probe uptake in the tumor and major organs.


RESULTS
There are about 90 RGD peptides per QD particle, and DOTA-QD-RGD exhibited integrin alpha(v)beta(3)-specific binding in cell cultures. The U87MG tumor uptake of (64)Cu-labeled DOTA-QD was less than 1 percentage injected dose per gram (%ID/g), significantly lower than that of (64)Cu-labeled DOTA-QD-RGD (2.2 +/- 0.3 [mean +/- SD] and 4.0 +/- 1.0 %ID/g at 5 and 18 h after injection, respectively; n = 3). Taking into account all measurements, the liver-, spleen-, and kidney-to-muscle ratios for (64)Cu-labeled DOTA-QD-RGD were about 100:1, 40:1, and 1:1, respectively. On the basis of the PET results, the U87MG tumor-to-muscle ratios for DOTA-QD-RGD and DOTA-QD were about 4:1 and 1:1, respectively. Excellent linear correlation was obtained between the results measured by in vivo PET imaging and those measured by ex vivo NIRF imaging and tissue homogenate fluorescence (r(2) = 0.93). Histologic examination revealed that DOTA-QD-RGD targets primarily the tumor vasculature through an RGD-integrin alpha(v)beta(3) interaction, with little extravasation.


CONCLUSIONS
We quantitatively evaluated the tumor-targeting efficacy of a dual-function QD-based probe with PET and NIRF imaging. This dual-function probe has significantly reduced potential toxicity and overcomes the tissue penetration limitation of optical imaging, allowing for quantitative targeted imaging in deep tissue.
Cai
Weibo
W
Molecular Imaging Program at Stanford (MIPS), Department of Radiology, and Bio-X Program, Stanford University School of Medicine, Stanford, CA 94305-5484, USA.
Chen
Kai
K
Li
Zi-Bo
ZB
Gambhir
Sanjiv S
SS
Chen
Xiaoyuan
X
D000818:Animals; D045744:Cell Line, Tumor; D002614:Chelating Agents; D003301:Copper Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring / Q000493:pharmacokinetics*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000378:metabolism; D009842:Oligopeptides / Q000493:pharmacokinetics*; D010455:Peptides / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D045663:Quantum Dots; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D019265:Spectroscopy, Near-Infrared; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D002614:Chelating Agents; D003301:Copper Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D039302:Integrin alphaVbeta3; D036341:Intercellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes; D009842:Oligopeptides; D010455:Peptides; D019275:Radiopharmaceuticals; C057986:echistatin; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; C047981:arginyl-glycyl-aspartic acid