Theranostics 2018; 8(5):1340-1349. doi:10.7150/thno.22806
Desmin- and vimentin-mediated hepatic stellate cell-targeting radiotracer 99mTc-GlcNAc-PEI for liver fibrosis imaging with SPECT
1. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, China.
2. Department of Nuclear Medicine, Zhongshan Hospital affiliated to Xiamen University, Xiamen 361004, Fujian, China.
3. Department of Nuclear Medicine, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China.
4. Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, 20892 USA.
Extracellular matrix (ECM) accumulation in liver fibrosis is caused by the activation of hepatic stellate cells (HSCs). The goal of this study was to develop a 99mTc-labeled N-acetylglucosamine (GlcNAc) that specifically interacts with desmin and vimentin expressed on activated HSCs to monitor the progression and prognosis of liver fibrosis using single-photon emission computed tomography (SPECT) imaging.
Methods: GlcNAc-conjugated polyethylenimine (PEI) was first prepared and radiolabeled with 99mTc. Noninvasive SPECT imaging with 99mTc-GlcNAc-PEI was used to assess liver fibrosis in a carbon tetrachloride (CCl4) mouse model. The liver uptake value (LUV) of 99mTc-GlcNAc-PEI was measured by drawing the region of interest (ROI) of the whole liver as previously suggested. The LUV of the CCl4 groups was compared with that of the olive oil group. Next, we estimated the correlation between the results of SPECT imaging and physiological indexes. After treatment with clodronate liposome, the LUV of 99mTc-GlcNAc-PEI in fibrotic mice was compared with that in control mice.
Results: 99mTc-GlcNAc-PEI is a hydrophilic compound with high radiochemical purity (>98%) and good stability. It could specifically target desmin and vimentin on the surface of activated HSCs with high affinity (the Kd values were 53.75 ± 9.50 nM and 20.98 ± 3.56 nM, respectively). The LUV of 99mTc-GlcNAc-PEI was significantly different between the CCl4 and control groups as early as 4 weeks of CCl4 administration (3.30 ± 0.160 vs 2.34 ± 0.114%/cc; P ˂ 0.05). There was a strong correlation between the LUV and Sirius Red quantification (R = 0.92, P ˂ 0.001). Compared with control, clodronate liposome treatment reduced the LUV of 99mTc-GlcNAc-PEI (4.62 ± 0.352 vs 2.133 ± 0.414%/cc; P ˂ 0.05).
Conclusion: 99mTc-GlcNAc-PEI SPECT/CT was useful in assessing liver fibrosis and monitoring the treatment response.
Keywords: hepatic fibrosis, desmin, vimentin, SPECT imaging, hepatic stellate cells, 99mTc-GlcNAc-PEI
Zhang D, Zhuang R, Guo Z, Gao M, Huang L, You L, Zhang P, Li J, Su X, Wu H, Chen X, Zhang X. Desmin- and vimentin-mediated hepatic stellate cell-targeting radiotracer 99mTc-GlcNAc-PEI for liver fibrosis imaging with SPECT. Theranostics 2018; 8(5):1340-1349. doi:10.7150/thno.22806. Available from http://www.thno.org/v08p1340.htm