Imaging-based evaluation of nanoparticle targeting mechanisms in experimental atherosclerosis

Purpose: Nanomedicine holds great promise for the treatment of atherosclerosis, as it offers an innovative way to specifically target drugs to atherosclerotic lesions (1). Yet, nanoparticle targeting principles in atherosclerosis are poorly understood and need to be systematically investigated. Methods: Atherosclerotic rabbits were imaged with novel black-blood 3D Dynamic Contrast Enhanced (DCE)-MRI, which allows the examination of permeability within the atherosclerotic vessel wall. Rabbits were injected with fluorescently (Cy7) labeled nanoparticles (NPs), which circulated different time points. Before sacrifice rabbits were injected with Evans Blue (EB), a fluorescent molecule that binds to albumin and extravasates at sites with enhanced permeability. Ex vivo fluorescence imaging was performed with an IVIS optical imaging system allowing to differentiate between EB and Cy7. Results: DCE-MRI revealed heterogeneous permeability of atherosclerotic lesions (A), which was corroborated with IVIS showing similar distributions of both EB (B,D) and Cy7 (D,E). The correlation between EB and Cy7 is shown in F, which was excellent after a ½ hour (r2=0.8, p<0.0001) and decreased after 6 (r2=0.47, p=0.007) and 24 hours (r2=0.08, p=0.33), signifying initial accumulation of NPs through permeable endothelium and diffusion through the lesions afterwards, as total accumulation remained uniform (G). Permeability-imaging and NP correlation Conclusions: Here we show that NPs accumulate at lesions with increased permeability with both in vivo and ex vivo techniques. We also show that 3D DCE-MRI can investigate permeability of atherosclerotic lesions and might serve as a predictor of atherosclerotic lesions that are amenable to NP therapy. Reference: 1. Tabas I, Glass CK, Science 2013, Anti-inflammatory therapy in chronic disease: challenges and opportunities.