Disease Model: Abdominal Aortic Aneurysms (AAA)
Current diagnostic imaging modalities provides little insight on the varying degree of ECM degeneration that precedes rupture in AAAs. Targeted delivery of contrast agents such as gold nanoparticles (GNPs) that bind to degraded matrix could prove useful when combined with computed tomography (CT) to provide a non-invasive surrogate marker of AAA rupture potential.
In this study, AAAs were induced by chronic infusion of angiotensin II (AngII) into low density-lipoprotein receptor-deficient (LDLr -/-) mice in combination with a high-fat diet. Abdominal ultrasound was used to monitor disease progression and to assess the circumferential strain throughout the cardiac cycle. At six weeks, GNPs conjugated with an elastin antibody (EL-GNP) were injected retro-orbitally. Mice were euthanized 24 hours after EL-GNP injection, and aortas were explanted and scanned ex-vivo with a micro-CT system. Histological assessment and 3D models of the aneurysms with micro-CT were used to determine the EL-GNPs distribution. Isolated vessel burst pressure testing was performed on each aneurysmal aorta to quantify rupture strength and to assess rupture location.
Figure 5: Hyperspectral mapping of suprarenal aorta tissue targeted by EL-GNPs. Rows from top to bottom correspond to suprarenal aortas with different levels of elastin damage within the aortic walls, from high to low, respectively. A. Brightfield microscopy images (40X) after Verhoeff-van Gieson staining demonstrated different elastin degradation levels in the selected tissue samples; B. Enhanced darkfield microscopy (EDFM, 40X) showed the existence of high contrast degraded elastin targeting gold nanoparticles in the tissues denoted by the white arrows; C. Hyperspectral images (HSI, 40X) and D. hyperspectral images mapped (Mapped) against their respective reference spectrum library as generated with negative controls. These identified a more extensive distribution of degraded elastin targeting gold nanoparticles compared to darkfield microscopy images. Mapped degraded elastin targeting gold nanoparticles quantity increased with elastin damage as shown in the Verhoeff-van Gieson -stain sections. Scale bar =20µm.
Aneurysms were found along the suprarenal aorta in AngII infused mice. Darkfield microscopy indicated EL-GNPs accumulation around the site of degraded elastin while avoiding the healthy and intact elastin fibers. Using nonlinear regression, the micro-CT signal intensity of EL-GNPs along the suprarenal aortas correlated strongly with burst pressures (R2=0.9415) but not the dilation as assessed by ultrasound measurements.
In summary, using an established mouse model of AAA, we successfully demonstrated in vivo targeting of EL-GNPs to damaged aortic elastin and correlated micro-CT-based signal intensities with burst pressures. Thus, we show that this novel targeting technique can be used as a diagnostic tool to predict the degree of elastin damage and therefore rupture potential in AAAs better than the extent of dilation
5.
References
5. Wang, X., Lane, B. A., Eberth, J. F., Lessner, S. M., & Vyavahare, N. R. (2019). Gold nanoparticles that target degraded elastin improve imaging and rupture prediction in an AngII mediated mouse model of abdominal aortic aneurysm. Theranostics, 9(14), 4156.
