Intraperitoneal Injection Improves the Uptake of Nanoparticle Labeled HDL to Atherosclerotic Plaques Compared to Intravenous Injection: A Multimodal Imaging Study in ApoE-/- Mice

Background —The aim of this study was to assess high density lipoprotein (HDL) labeled with superparamagnetic iron oxide nanoparticles (SPIOs) and quantum dots (QDs) for the detection of atherosclerotic lesions in mice after intravenous (iv) and intraperitoneal (ip) injection by multimodal imaging. Methods and Results —Nanoparticle labeled HDLs (NP-HDL) were characterized in vitro by dynamic light scattering and size exclusion chromatography with subsequent cholesterol and fluorescence measurements. For biodistribution and blood clearance studies, radiolabeled NP-HDL SPIOs with 59 Fe (NP-HDL 59Fe-SPIOs ) were injected iv or ip into ApoE -/- mice (n=6) and radioactivity was measured using a γ-counter. NP-HDL accumulation within atherosclerotic plaques in vivo and ex vivo was estimated by magnetic resonance imaging (MRI) at 7 Tesla, ex vivo confocal fluorescence microscopy (CFM), x-ray fluorescence microscopy (XRF) and histological analysis (n=3). Statistical analyses were performed using a two-tailed Student9s t-test. In vitro characterization of NP-HDL confirmed properties similar to endogenous HDL. Blood concentration time curves showed a biexponential decrease for the iv injection, while a slow increase followed by a steady state was noted for ip injection. Radioactivity measurements showed predominant accumulation in the liver and spleen after both application approaches. NP-HDL 59Fe-SPIOs uptake into atherosclerotic plaques increased significantly after ip compared to iv injection (p<0.01). In vivo MRI showed an increased uptake of NP-HDL into atherosclerotic lesions after ip injection, which was confirmed by ex vivo MRI, XRF, CFM and histological analysis. Conclusions —In vivo MRI and ex vivo multimodal imaging of atherosclerotic plaque using NP-HDL is feasible and ip application improves uptake within vessel wall lesions compared to iv injection.