RGD targeting of human ferritin iron oxide nanoparticles enhances in vivo MRI of vascular inflammation and angiogenesis in experimental carotid disease and abdominal aortic aneurysm

Purpose: To evaluate Arg-Gly-Asp (RGD)-conjugated human ferritin (HFn) iron oxide nanoparticles for in vivo magnetic resonance imaging (MRI) of vascular inflammation and angiogenesis in experimental carotid disease and abdominal aortic aneurysm (AAA). Materials and Methods: HFn was genetically engineered to express the RGD peptide and Fe₃O₄ nanoparticles were chemically synthesized inside the engineered HFn (RGD-HFn). Macrophage-rich left carotid lesions were induced by ligation in FVB mice made hyperlipidemic and diabetic (n = 14), with the contralateral right carotid serving as control. Murine AAAs were created by continuous angiotensin II infusion in ApoE-deficient mice (n = 12), while control mice underwent saline infusion (n = 8). All mice were imaged before and after intravenous injection with either RGD-HFn-Fe₃O₄ or HFn-Fe₃O₄ using a gradient-echo sequence on a whole-body 3T clinical scanner, followed by histological analysis. The nanoparticle accumulation was assessed by the extent of T^* ₂-induced carotid lumen reduction (% lumen loss) or aortic T^* ₂ -weighted signal intensity reduction (% SI [signal intensity] loss). Results: RGD-HFn-Fe₃O₄ was taken up more than HFn-Fe₃O₄ in both the ligated left carotid arteries (% lumen loss; 69 ± 9% vs. 36 ± 7%, P = 0.01) and AAAs (% SI loss; 47 ± 6% vs. 20 ± 5%, P = 0.01). The AAA % SI loss correlated positively with AAA size (r = 0.89, P < 0.001). Histology confirmed the greater accumulation and colocalization of RGD-HFn-Fe₃O₄ to both vascular macrophages and endothelial cells. Conclusion: RGD-HFn-Fe₃O₄ enhances in vivo MRI by targeting both vascular inflammation and angiogenesis, and provides a promising translatable MRI approach to detect high-risk atherosclerotic and aneurysmal vascular diseases. Level of Evidence: 1. J. Magn. Reson. Imaging 2017;45:1144–1153.