title: Assessing activation of hepatic stellate cells by (99m)Tc-3PRGD2 scintigraphy targeting integrin αvβ3: a feasibility study.
abstract: OBJECTIVE
  Hepatic stellate cell (HSC) activation, which is accompanied by increased expression of integrin αvβ3, is an important factor in liver fibrogenesis. Molecular imaging targeting the integrin αvβ3 could provide a non-invasive method for evaluating the expression and the function of the integrin αvβ3 on the activated HSCs (aHSCs) in the injured liver, and then provide important prognostic information. (99m)Tc-3PRGD2 is such a radiotracer specific for integrin αvβ3. In this study, we aimed to compare the differences in liver uptake and retention of the (99m)Tc-3PRGD2 between normal liver and injured liver to evaluate the feasibility of (99m)Tc-3PRGD2 scintigraphy for this purpose.
  
  
  METHODS
  We used planar scintigraphy to assess changes in integrin αvβ3 binding of intravenously-administered (99m)Tc-3PRGD2 in the livers of rats with thioacetamide (TAA)-induced liver fibrosis compared with the controls. We co-injected cold c(RGDyK) with (99m)Tc-3PRGD2 to assess the specific binding of the radiotracer. We performed Sirius red staining to assess liver fibrosis, immunofluorescent colocalization to identify the location of integrin αvβ3 expressed in the fibrotic liver, and we measured protein and messenger RNA expression of integrin αvβ3 and alpha smooth muscle actin (α-SMA) in the control and fibrotic livers.
  
  
  RESULTS
  The fibrotic livers showed enhanced (99m)Tc-3PRGD2 uptake and retention. The radiotracer was demonstrated to bind specifically with the integrin αvβ3 mainly expressed on the aHSCs. The liver-to-heart ratio at 30 min post-injection was higher in the fibrotic livers than in the control livers (TAA, 1.98±0.08 vs. control, 1.50±0.12, p<0.01). The liver t1/2 was longer than in the controls (TAA, 27.07±10.69 min vs. control, 12.67±4.10 min, p<0.01). The difference of heart t1/2 between the two groups was not statistically significant (TAA, 3.13±0.63 min vs. control, 3.41±0.77 min, p=0.94).
  
  
  CONCLUSIONS
  (99m)Tc-3PRGD2 molecular imaging can provide a non-invasive method for assessing activation of HSCs.
authors.affiliation: Department of Radiology and Nuclear Medicine, Shengjing Hospital of China Medical University, Shenyang, China. Electronic address: zhangxin_2003@163.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Radiology and Nuclear Medicine, Shengjing Hospital of China Medical University, Shenyang, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xin
authors.affiliation: Department of Radiology and Nuclear Medicine, Shengjing Hospital of China Medical University, Shenyang, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Radiology and Nuclear Medicine, Shengjing Hospital of China Medical University, Shenyang, China.
authors.forename: Weina
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Radiology and Nuclear Medicine, Shengjing Hospital of China Medical University, Shenyang, China.
authors.forename: Shupeng
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Radiology and Nuclear Medicine, Shengjing Hospital of China Medical University, Shenyang, China.
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Radiology and Nuclear Medicine, Shengjing Hospital of China Medical University, Shenyang, China.
authors.forename: Changping
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Radiology and Nuclear Medicine, Shengjing Hospital of China Medical University, Shenyang, China.
authors.forename: Li
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Radiology and Nuclear Medicine, Shengjing Hospital of China Medical University, Shenyang, China. Electronic address: guoqiyong_2003@163.com.
authors.forename: Qiyong
authors.initials: Q
authors.lastname: Guo
mesh_terms: D000818:Animals; D001692:Biological Transport; D005240:Feasibility Studies; D055166:Hepatic Stellate Cells / Q000000981:diagnostic imaging* / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D015609:Organotechnetium Compounds / Q000378:metabolism; D010456:Peptides, Cyclic / Q000378:metabolism; D011877:Radionuclide Imaging; D051381:Rats; D017208:Rats, Wistar
chemical_list: D039302:Integrin alphaVbeta3; D015609:Organotechnetium Compounds; D010456:Peptides, Cyclic; C561921:technetium 99m (HYNIC-3PRGD(2))(tricine)(TPPTS)
keywords: (99m)Tc-3PRGD2; Hepatic stellate cell; Integrin αvβ3; Liver fibrosis; Scintigraphy