Background <p>Pulmonary delivery of agents to lung is an effective method for the diagnosis and therapy of lung cancer.</p> Purpose <p>To demonstrate that pulmonary delivery of perfluorocarbon (PFC) nanoparticles for orthotopic lung tumor model is better than intravenous injection for subcutaneous tumor, and to confirm that the nanoparticles can be uptaked by tumor tissue which showed by ¹⁹F MR imaging and tissue staining.</p> Methods <p>We detected the targeted ability of folate receptor (FR) targeted PFC nanoparticles with H460 cells <i>in vitro</i>. Subcutaneous and orthotopic lung cancer models were established. When the tumors could be detected by MR after two weeks, PFC nanoparticles were administrated intratracheally in orthotopic group and intravenously in subcutaneous group. ¹⁹F MR scanning was performed in mice models at before and different time points (4, 24, and 48&#xa0;h) after delivery. Mice were euthanized after MR imaging, and tumor tissues were taken out, HE and fluorescent staining were performed respectively. In addition, orthotopic tumor tissue was obtained for transmission electron microscopy (TEM) examination.</p> Results <p>The orthotopic tumor model showed a significant ¹⁹F MRI enhancement effect in the tumor region after PFC nanoparticles delivered intratracheally than subcutaneous model. As time went on, the accumulation of nanoparticles in the tumor area increased, and the ¹⁹F signal increased gradually. The ¹⁹F SNR in the tumor region of orthotopic group was significantly higher than that of subcutaneous group at 24 and 48&#xa0;h after delivery (<i>p</i> &lt; 0.001). Histological experiments showed that PFC nanoparticles accumulated in the tumor region especially in orthotopic group.</p> Conclusion <p>Pulmonary delivery of PFC nanoparticles is a novel and effective method for orthotopic lung cancer xenograft model, and the PFC nanoparticles can be detected by ¹⁹F MR imaging <i>in vivo</i>.</p>