Magnetic nanoradiotracers for targeted neutrophil detection in pulmonary arterial hypertension.

Abstract

Pulmonary arterial hypertension (PAH) is a severe disease characterized by elevated blood pressure in the pulmonary artery that can ultimately damage the right ventricle of the heart. PAH is pathophysiologically heterogeneous, which makes early diagnosis and treatment difficult. Inflammation is thought to be an important factor in the development and progression of this disease and may explain some of the observed interindividual differences. In the context of both acute and chronic inflammation, neutrophil recruitment to the lung has been suggested as a potential biomarker for studying PAH progression. However, there are currently no specific probes for its non-invasive in vivo detection. The imaging-based gold standard for assessing inflammation is [18F] fluorodeoxyglucose (18F-FDG), which is not cell specific. This highlights the urgent need for more specific molecular probes to support personalized medicine. This study investigated the potential of magnetic nanoradiotracers based on ultrasmall iron oxide nanoparticles, functionalized with N-cinnamoyl-F-(D)L-F-(D)L-F peptide, to detect increased neutrophil infiltration in vivo in different PAH animal models via positron emission tomography. These nanoprobes target formyl peptide receptor 1, which is abundantly expressed in the cell membrane of neutrophils. To assess the benefit of these nanoprobes, their biodistribution was first assessed via magnetic resonance imaging and histology. Then, their lung uptake was compared by positron emission tomography with that of 18F-FDG in two types of PAH animal models with different profiles of inflammation and neutrophil infiltration: monocrotaline and double-hit Sugen-chronic hypoxia PAH rat models. Our targeted magnetic nanoradiotracer detected an increase in pulmonary neutrophil infiltration in both PAH models and distinguished between them, which was not possible with 18F-FDG PET. This study underscores the importance of targeted imaging in providing an individualized and longitudinal evaluation of heterogeneous and multifactorial diseases such as PAH. The use of targeted multimodal nanoprobes, for magnetic resonance/positron emission tomography imaging has the potential to facilitate the diagnosis and monitoring of diseases, as well as the development of novel therapies.