ABSTRACT
The purpose of this study was to validate an integrin αvß3-targeted magnetic resonance contrast agent, PEG-G3-(Gd-DTPA)6-(cRGD-DTPA)2, for its ability to detect tumor angiogenesis and assess early response to antiangiogenic therapy using dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). Integrin αvß3-positive U87 cells and control groups were incubated with fluorescein-labeled cRGD-conjugated dendrimer, and the cellular attachment of the dendrimer was observed. DCE MRI was performed on mice bearing KB xenograft tumors using either PEG-G3-(Gd-DTPA)6-(cRGD-DTPA)2 or PEG-G3-(Gd-DTPA)6-(cRAD-DTPA)2. DCE MRI was also performed 2 hours after anti-integrin αvß3 monoclonal antibody treatment and after bevacizumab treatment on days 3 and 6t. Using DCE MRI, the 30-minute contrast washout percentage was significantly lower in the cRGD-conjugate injection groups. The enhancement patterns were different between the two contrast injection groups. In the antiangiogenic therapy groups, a rapid increase in 30-minute contrast washout percentage was observed in both the LM609 and bevacizumab treatment groups, and this occurred before there was an observable decrease in tumor size. The integrin αvß3 targeting ability of PEG-G3-(Gd-DTPA)6-(cRGD-DTPA)2 in vitro and in vivo was demonstrated. The 30-minute contrast washout percentage is a useful parameter for examining tumor angiogenesis and for the early assessment of antiangiogenic treatment response.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Contrast Media , Dendrimers , Gadolinium DTPA , Integrin alphaVbeta3/metabolism , Magnetic Resonance Imaging , Neoplasms/blood supply , Polyethylene Glycols , Angiogenesis Inhibitors/pharmacology , Animals , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Bevacizumab , Cell Adhesion , Cell Line, Tumor , Dendrimers/chemical synthesis , Gadolinium DTPA/chemical synthesis , Humans , Immunohistochemistry , Male , Mice, Nude , Neoplasms/diagnostic imaging , Neoplasms/drug therapy , Neoplasms/pathology , Neovascularization, Pathologic , Polyethylene Glycols/chemical synthesis , RNA, Small Interfering/metabolism , Radionuclide Imaging , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
PURPOSE: The purpose of this study is to validate a folate-receptor (FR)-targeted dendrimer, PEG-G3-(Gd-DTPA)11-(folate)5, for its ability to detect FR-positive tumors, by using dynamic contrast-enhanced MRI. PROCEDURES: KB cells, FR siRNA knockdown KB cells, and FR negative HT-1080 cells, were incubated with fluorescein-labeled dendrimer and their cellular uptake was observed. Dynamic contrast-enhanced MRI was performed on mice-bearing KB and HT-1080 tumors and the enhancement patterns and parameters were analyzed. RESULTS: Green fluorescence was found in the KB cells in the cellular uptake experiment, but was not seen in other settings. In the dynamic contrast-enhanced MRI, the 30-min washout percentage was -4 +/- 18% in the KB tumors and 39 +/- 23% in the HT-1080 tumors. A 17% cut-off point gave a sensitivity of 94.4% and a specificity of 93.8%. CONCLUSIONS: We have demonstrated the targeting ability of PEG-G3-(Gd-DTPA)11-(folate)5 in vitro and in vivo. A 17% cut-off point for a 30-min washout percentage can be a useful parameter for the diagnosis of FR-positive tumors.
