Molecular magnetic resonance imaging of activated hepatic stellate cells with ultrasmall superparamagnetic iron oxide targeting integrin αvβ3 for staging liver fibrosis in rat model

Abstract

Purpose To evaluate the expression level of integrin α v β 3 on activated hepatic stellate cells (HSCs) at different stages of liver fibrosis induced by carbon tetrachloride (CCl 4 ) in rat model and the feasibility to stage liver fibrosis by using molecular magnetic resonance imaging (MRI) with arginine-glycine-aspartic acid (RGD) peptide modified ultrasmall superparamagnetic iron oxide nanoparticle (USPIO) specifically targeting integrin α v β 3 . Materials and methods All experiments received approval from our Institutional Animal Care and Use Committee. Thirty-six rats were randomly divided into three groups of 12 subjects each, and intraperitoneally injected with CCl 4 for either 3, 6, or 9 weeks. Controls (n=10) received pure olive oil. The change in T2* relaxation rate (ΔR2*) pre- and postintravenous administration of RGD-USPIO or naked USPIO was measured by 3.0T clinical MRI and compared by one-way analysis of variance or the Student’s t -test. The relationship between expression level of integrin α v β 3 and liver fibrotic degree was evaluated by Spearman’s ranked correlation. Results Activated HSCs were confirmed to be the main cell types expressing integrin α v β 3 during liver fibrogenesis. The protein level of integrin α v and β 3 subunit expressed on activated HSCs was upregulated and correlated well with the progression of liver fibrosis ( r =0.954, P <0.001; r =0.931, P <0.001, respectively). After injection of RGD-USPIO, there is significant difference in ΔR2* among rats treated with 0, 3, 6, and 9 weeks of CCl 4 ( P <0.001). The accumulation of iron particles in fibrotic liver specimen is significantly greater for RGD-USPIO than naked USPIO after being injected with equal dose of iron. Conclusion Molecular MRI of integrin α v β 3 expressed on activated HSCs by using RGD-USPIO may distinguish different liver fibrotic stages in CCl 4 rat model and shows promising to noninvasively monitor the progression of the liver fibrosis and therapeutic response to antifibrotic treatment.

Ultrasound molecular imaging with cRGD-PLGA-PFOB nanoparticles for liver fibrosis staging in a rat model

“…In addition, TGF-β1 is considered a key factor in accelerating hepatic fibrosis because it is released from activated HSCs and further stimulates them [ 40 ]. In this study, we found that integrin α v β 3 , α-SMA, and TGF-β1 expression increased with the progression of liver fibrosis, which is similar to previously reported results [ 41 , 42 ]. Moreover, most integrin α v β 3 is expressed in activated HSCs; much less α v β 3 is expressed in qHSCs, hepatocytes, and other non-parenchymal cells [ 11 ].…”

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“…Recent achievements in targeted molecular MR imaging offer new strategies to enhance specificity and contrast for detecting such small lesions[7-11]. One of the most commonly studied HCC-targeted MRI systems utilizes antibody (aptamer)-guided iron oxide nanoparticles as probes, which are intended to bind specifically with unique overexpressed HCC-related antigens or genes, such as alpha-fetoprotein (AFP) or glypican-3 (GPC3)[12-15].…”

Molecular Imaging of Fibrosis in Benign Diseases: An Overview of the State of the Art

“…And the elevated uptake correlated well with the mRNA and protein levels of integrin α v and β 3 . Ultrasmall superparamagnetic iron oxide nanoparticles (USPIO) modified by RGD (RGD-USPIO) were designed as a molecular MR T2 contrast agent and were used for staging liver fibrosis in rat models induced by CCl 4 [ 69 ]. A significant difference was observed in the T2* relaxation rate change (ΔR2*) among rat treatment cohorts receiving CCl 4 for 0, 3, 6, and 9 weeks.…”