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This article is part of the supplement: Abstracts of the 15th Annual SCMR Scientific Sessions: 2012

Open Access Moderated poster presentation

RGD targeting of human ferritin iron-oxide nanoparticles enhances in vivo molecular MRI of experimental aortic aneurysms

Toshiro Kitagawa1*, Hisanori Kosuge1, Masaki Uchida2, Yasunori Iida3, Ronald L Dalman3, Trevor Douglas2 and Michael V McConnell1

  • * Corresponding author: Toshiro Kitagawa

Author Affiliations

1 Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA

2 Chemistry and Biochemistry, Montana State University, Bozeman, MT, USA

3 Vascular Surgery, Stanford University School of Medicine, Stanford, CA, USA

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Journal of Cardiovascular Magnetic Resonance 2012, 14(Suppl 1):M9  doi:10.1186/1532-429X-14-S1-M9


The electronic version of this article is the complete one and can be found online at: http://www.jcmr-online.com/content/14/S1/M9


Published:1 February 2012

© 2012 Kitagawa et al; licensee BioMed Central Ltd.

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background

Both inflammation and angiogenesis contribute to the progression of abdominal aortic aneurysm (AAA) disease. RGD is a peptide binder of the αvβ3 integrin, which is expressed highly on activated macrophages and angiogenic endothelial cells. Human ferritin (HFn) is a nanoscale protein cage with 12nm diameter and 8nm interior cavity, which we have utilized as a platform for molecular/cellular imaging. We can genetically introduce RGD peptide to HFn. The purpose of this study is to evaluate RGD-conjugated HFn iron oxide nanoparticles for enhanced in vivo MRI of murine AAAs.

Methods

1) Mice - Murine AAAs were induced in Apo-E deficient mice by angiotensin II infusion (1µg/kg/min), followed by monitoring of aortic diameter by ultrasound. Control mice were created by saline infusion.

2) RGD-conjugated HFn-iron oxide nanoparticles - HFn was genetically engineered to display 24 copies of an RGD peptide on the exterior surface of the protein cage. Magnetite (Fe3O4) was encapsulated in the interior cavity of RGD-conjugated HFn (RGD+) and non-targeted HFn (RGD-) at loading factors of 5000Fe per cage, giving R2 values of 93 mM-1s-1 (magnetite diameter: 5-7nm). The injected dose was adjusted to 25mgFe/kg in each animal.

3) MRI - All mice were imaged on a whole-body 3T MRI scanner (Signa HDx, GE Healthcare) with a phased array mouse coil (RAPID MR International), using a gradient echo sequence (TR/TE=100ms/10ms, slice thickness=1.0mm, FOV=3cm, matrix=256x256, FA=60, NEX=10). Mice were then injected with either RGD+ or RGD- (6 AAA and 4 control mice for each), followed by MRI at 24 and 48 hours post injection. The nanoparticle accumulation was assessed by measuring the reduction in the T2*-weighted signal intensity of the AAA (or suprarenal aorta in control mice) relative to adjacent normal-size aorta (expressed as % SI loss).

4) Histology - The aortic wall was stained with Perl’s iron (for nanoparticle accumulation), CD-11b (for macrophages), and CD-31 (for endothelial cells).

Results

MRI showed greater T2* signal loss in the AAA with RDG+ than with RDG- (Fig 1(A)), confirmed by quantitative analysis of % SI loss (Fig 1(A) graph, p=0.01). Abdominal aortic diameter on ultrasound correlated more strongly with % SI loss with RDG+ than with RDG- (Fig 2(B)). Perl’s iron staining confirmed greater accumulation of RDG+ in the AAA compared to RGD- (474±51 vs. 277±29 stained cells/cross-sectional area, p=0.01), with colocalization to both macrophages (CD-11b) and endothelial cells (CD-31) within the AAA wall (Fig 2(C)).

Conclusions

HFn iron-oxide nanoparticles with RGD targeting provide a promising MRI approach for comprehensive in vivo detection of inflammation and angiogenesis in high-risk AAAs.

Funding

Dr. McConnell receives research support from GE Healthcare and he is on a scientific advisory board for Kowa, Inc.