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.
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).



HFn was genetically engineered to express the RGD peptide and Fe3O4nanoparticles 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-Fe3O4or HFn-Fe3O4using a gradient-echo sequence on a whole-body 3T clinical scanner, followed by histological analysis. The nanoparticle accumulation was assessed by the extent of T2*-induced carotid lumen reduction (% lumen loss) or aortic T2*-weighted signal intensity reduction (% SI [signal intensity] loss).



RGD-HFn-Fe3O4was taken up more than HFn-Fe3O4in 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-Fe3O4to both vascular macrophages and endothelial cells.



RGD-HFn-Fe3O4enhances 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.



1 J. Magn. Reson. Imaging 2017;45:1144-1153.
Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.|Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.|Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
Toshiro
T
Kitagawa
Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.|Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.|Tsukuba Advanced Imaging Center, Tsukuba, Japan.
Hisanori
H
Kosuge
Department of Chemistry, Indiana University, Bloomington, Indiana, USA.
Masaki
M
Uchida
Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.|Division of Vascular Surgery, Stanford University School of Medicine, Stanford, California, USA.
Yasunori
Y
Iida
Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.|Division of Vascular Surgery, Stanford University School of Medicine, Stanford, California, USA.
Ronald L
RL
Dalman
Department of Chemistry, Indiana University, Bloomington, Indiana, USA.
Trevor
T
Douglas
Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.|Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.|Magnetic Resonance Systems Research Laboratory, Department of Electrical Engineering, Stanford University School of Medicine, Stanford, California, USA.
Michael V
MV
McConnell
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D002339:Carotid Arteries / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D002340:Carotid Artery Diseases / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D005290:Ferric Compounds / Q000378:metabolism; D005293:Ferritins / Q000378:metabolism*; D007249:Inflammation / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D053758:Nanoparticles; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D009842:Oligopeptides / Q000378:metabolism*; D014652:Vascular Diseases / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology
D005290:Ferric Compounds; D009842:Oligopeptides; C000499:ferric oxide; C047981:arginyl-glycyl-aspartic acid; D005293:Ferritins
RGD; aneurysms; angiogenesis; atherosclerosis; iron; nanoparticles
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