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Objective:In this study, we constructed a dual-modality SPECT/MRI iron oxide nanoparticles probe which simultaneously target to αvβ3 receptors in tumor angiogenesis on non-small cell lung cancer. Methods: The PEG coated USPIO surface was directly conjugated with peptide c(RGDfK) ( Arg-Gly-Asp) .We demonstrated the specificity of the probe to αvβ3 integrin with Prussian blue staining and quantitative analysis of Fe contents in vitro.In vitro cytotoxicity testing was performed with three probes for 12, 24 and 48 hour with three concentrations. Blood clearance and biodistribution of these probes show excellent biocompatibility. T2-weighted MR and small-animal SPECT/CT imaging were acquired in a H1299 cell xenografted lung cancer model. Result: Superparamagnetic nanoparticles were synthesized via the polyol method. The resulting 4.8 nm nanoparticles have low r2/r1 of 3.88 (r1 =15.2 mM-1·s-1, r2 = 59.09 mM-1·s-1), which can be used as T2 contrast agents. On this basis, USPIOs were used as carrier and were applied to conjugate targeting peptide RGD and label 99mTc nuclide. This research built a stable, quick and efficient labeling method to label 99mTc nuclide to the particles surface. The radiochemical purity of 99mTc labeled nanoparticle > 92%, radioactive stability> 95%.The results of Prussian blue staining indicated that three probes can target to H1299 cells.The same results were verified in the Fe contents in each cell. MRI showed the probe can specifically target to tumor and decreased the MR signal intensity. SPECT images showed particles mainly gathered in liver and kidney indicated that the particles were metabolized by urine and faeces. The qualitative and quantitative analysis of SPECT/MRI images kept in good concordance, and suggested that tumor accumulation of dual-targeting probe was more efficient and the most accumulation culminated at 6 hour post injection. Histological studies revealed that αvβ3 integrin was expressed both on the tumor vessel and tumor cells for H1299 tumor. Conclusion: In this study, 99mTc-RGD@USPIO has higher specificity and sensitivity for detecting αvβ3 integrin–expressing H1299 lung cancer cells and xenografted tumor models. The dual-modal probe can be diagnosis for the specific imaging of lung cancer.