Targeted Imaging of Lung Cancer with Hyperpolarized (129)Xe MRI Using Surface-Modified Iron Oxide Nanoparticles as Molecular Contrast Agents

SIMPLE SUMMARY: Hyperpolarized (129)Xe (HP (129)Xe) MRI was used to demonstrate the feasibility of targeted imaging of lung cancer using two cancer-specific surface-modified iron oxide nanoparticles (IONPs) as negative contrast agents; polyethylene glycol-coated IONPs (PEG-IONPs), and dextran-coated IONPs conjugating folate on their surface (FA@Dex-IONPs). After the intravenous injection of IONPs, HP (129)Xe signal reductions were observed at cancer sites for both PEG-IONPs and FA@Dex-IONPs administered in mice. By targeted imaging with HP (129)Xe MRI, characteristic differences in pharmacokinetics between PEG-IONPs and FA@Dex-IONPs were successfully monitored. In particular, FA@Dex-IONPs were found to show superior pharmacokinetics for HP (129)Xe MRI in terms of prolonged clearance due to their binding to overexpressed folate receptors in lung cancer cells. ABSTRACT: Hyperpolarized (129)Xe (HP (129)Xe) MRI enables functional imaging of various lung diseases but has been scarcely applied to lung cancer imaging. The aim of this study is to investigate the feasibility of targeted imaging of lung cancer with HP (129)Xe MRI using surface-modified iron oxide nanoparticles (IONPs) as molecular targeting contrast agents. A mouse model of lung cancer (LC) was induced in nine mice by intra-peritoneal injection of urethane. Three months after the urethane administration, the mice underwent lung imaging with HP (129)Xe MRI at baseline (0 h). Subsequently, the LC group was divided into two sub-groups: mice administered with polyethylene glycol-coated IONPs (PEG-IONPs, n = 4) and folate-conjugated dextran-coated IONPs (FA@Dex-IONPs, n = 5). The mice were imaged at 3, 6, and 24 h after the intravenous injection of IONPs. FA@Dex-IONPs mice showed a 25% reduction in average signal intensity at cancer sites at 3 h post injection, and a 24% reduction at 24 h post injection. On the other hand, in PEG-IONPs mice, while a signal reduction of approximately 28% was observed at cancer sites at 3 to 6 h post injection, the signal intensity was unchanged from that of the baseline at 24 h. Proton MRI of LC mice (n = 3) was able to detect cancer five months after urethane administration, i.e., later than HP (129)Xe MRI (3 months). Furthermore, a significant decrease in averaged (1)H T2 values at cancer sites was observed at only 6 h post injection of FA@Dex-IONPs (p < 0.05). As such, the targeted delivery of IONPs to cancer tissue was successfully imaged with HP (129)Xe MRI, and their surface modification with folate likely has a high affinity with LC, which causes overexpression of folate receptors.