title: Small-Animal SPECT/CT of the Progression and Recovery of Rat Liver Fibrosis by Using an Integrin αvβ3-targeting Radiotracer.
abstract: OBJECTIVE
  To assess the potential utility of an integrin αvβ3-targeting radiotracer, technetium 99m-PEG4-E[PEG4-cyclo(arginine-glycine-aspartic acid-D-phenylalanine-lysine)]2 ((99m)Tc-3PRGD2), for single photon emission computed tomography (SPECT)/computed tomography (CT) for monitoring of the progression and prognosis of liver fibrosis in a rat model.
  
  
  METHODS
  All animal experiments were performed by following the protocol approved by the institutional animal care and use committee. (99m)Tc-3PRGD2 was prepared and longitudinal SPECT/CT was performed to monitor the progression (n = 8) and recovery (n = 5) of liver fibrosis induced in a rat model by means of thioacetamide (TAA) administration. The mean liver-to-background radioactivity per unit volume ratio was analyzed for comparisons between the TAA and control (saline) groups at different stages of liver fibrosis. Data were compared by using Student t and Mann-Whitney tests. Results:of SPECT/CT were compared with those of ex vivo biodistribution analysis (n = 5).
  
  
  RESULTS
  Accumulation of (99m)Tc-3PRGD2 in the liver increased in proportion to the progression of fibrosis and TAA exposure time; accumulation levels were significantly different between the TAA and control groups as early as week 4 of TAA administration (liver-to-background ratio: 32.30 ± 3.39 vs 19.01 ± 3.31; P = .0002). Results of ex vivo immunofluorescence staining demonstrated the positive expression of integrin αvβ3 on the activated hepatic stellate cells, and the integrin αvβ3 levels in the liver corresponded to the results of SPECT/CT (R(2) = 0.75, P < .0001). (99m)Tc-3PRGD2 uptake in the fibrotic liver decreased after antifibrotic therapy with interferon α2b compared with that in the control group (relative liver-to-background ratio: 0.45 ± 0.05 vs 1.01 ± 0.05; P < .0001) or spontaneous recovery (relative liver-to-background ratio: 0.56 ± 0.06 vs 1.01 ± 0.05; P < .0001).
  
  
  CONCLUSIONS
  (99m)Tc-3PRGD2 SPECT/CT was successfully used to monitor the progression and recovery of liver fibrosis and shows potential applications for noninvasive diagnosis of early stage liver fibrosis.
authors.affiliation: From the Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Rd, Beijing 100191, China (X.Y., Y.W., H.L., L.G., S.X., C.Z., J.S., H.Z., B.J., Z.L., F.W.); Interdisciplinary Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (J.S., F.W.); and State Key Laboratory of Natural and Biomimetic Drugs, Center for Molecular and Translational Medicine, Peking University, Beijing, China (F.W.).
authors.forename: Xinhe
authors.initials: X
authors.lastname: Yu
authors.affiliation: From the Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Rd, Beijing 100191, China (X.Y., Y.W., H.L., L.G., S.X., C.Z., J.S., H.Z., B.J., Z.L., F.W.); Interdisciplinary Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (J.S., F.W.); and State Key Laboratory of Natural and Biomimetic Drugs, Center for Molecular and Translational Medicine, Peking University, Beijing, China (F.W.).
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.affiliation: From the Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Rd, Beijing 100191, China (X.Y., Y.W., H.L., L.G., S.X., C.Z., J.S., H.Z., B.J., Z.L., F.W.); Interdisciplinary Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (J.S., F.W.); and State Key Laboratory of Natural and Biomimetic Drugs, Center for Molecular and Translational Medicine, Peking University, Beijing, China (F.W.).
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: From the Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Rd, Beijing 100191, China (X.Y., Y.W., H.L., L.G., S.X., C.Z., J.S., H.Z., B.J., Z.L., F.W.); Interdisciplinary Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (J.S., F.W.); and State Key Laboratory of Natural and Biomimetic Drugs, Center for Molecular and Translational Medicine, Peking University, Beijing, China (F.W.).
authors.forename: Liquan
authors.initials: L
authors.lastname: Gao
authors.affiliation: From the Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Rd, Beijing 100191, China (X.Y., Y.W., H.L., L.G., S.X., C.Z., J.S., H.Z., B.J., Z.L., F.W.); Interdisciplinary Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (J.S., F.W.); and State Key Laboratory of Natural and Biomimetic Drugs, Center for Molecular and Translational Medicine, Peking University, Beijing, China (F.W.).
authors.forename: Xianlei
authors.initials: X
authors.lastname: Sun
authors.affiliation: From the Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Rd, Beijing 100191, China (X.Y., Y.W., H.L., L.G., S.X., C.Z., J.S., H.Z., B.J., Z.L., F.W.); Interdisciplinary Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (J.S., F.W.); and State Key Laboratory of Natural and Biomimetic Drugs, Center for Molecular and Translational Medicine, Peking University, Beijing, China (F.W.).
authors.forename: Chenran
authors.initials: C
authors.lastname: Zhang
authors.affiliation: From the Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Rd, Beijing 100191, China (X.Y., Y.W., H.L., L.G., S.X., C.Z., J.S., H.Z., B.J., Z.L., F.W.); Interdisciplinary Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (J.S., F.W.); and State Key Laboratory of Natural and Biomimetic Drugs, Center for Molecular and Translational Medicine, Peking University, Beijing, China (F.W.).
authors.forename: Jiyun
authors.initials: J
authors.lastname: Shi
authors.affiliation: From the Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Rd, Beijing 100191, China (X.Y., Y.W., H.L., L.G., S.X., C.Z., J.S., H.Z., B.J., Z.L., F.W.); Interdisciplinary Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (J.S., F.W.); and State Key Laboratory of Natural and Biomimetic Drugs, Center for Molecular and Translational Medicine, Peking University, Beijing, China (F.W.).
authors.forename: Huiyun
authors.initials: H
authors.lastname: Zhao
authors.affiliation: From the Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Rd, Beijing 100191, China (X.Y., Y.W., H.L., L.G., S.X., C.Z., J.S., H.Z., B.J., Z.L., F.W.); Interdisciplinary Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (J.S., F.W.); and State Key Laboratory of Natural and Biomimetic Drugs, Center for Molecular and Translational Medicine, Peking University, Beijing, China (F.W.).
authors.forename: Bing
authors.initials: B
authors.lastname: Jia
authors.affiliation: From the Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Rd, Beijing 100191, China (X.Y., Y.W., H.L., L.G., S.X., C.Z., J.S., H.Z., B.J., Z.L., F.W.); Interdisciplinary Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (J.S., F.W.); and State Key Laboratory of Natural and Biomimetic Drugs, Center for Molecular and Translational Medicine, Peking University, Beijing, China (F.W.).
authors.forename: Zhaofei
authors.initials: Z
authors.lastname: Liu
authors.affiliation: From the Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Rd, Beijing 100191, China (X.Y., Y.W., H.L., L.G., S.X., C.Z., J.S., H.Z., B.J., Z.L., F.W.); Interdisciplinary Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (J.S., F.W.); and State Key Laboratory of Natural and Biomimetic Drugs, Center for Molecular and Translational Medicine, Peking University, Beijing, China (F.W.).
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D021621:Imaging, Three-Dimensional; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000000981:diagnostic imaging / Q000378:metabolism*; D008297:Male; D064847:Multimodal Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013670:Sodium Pertechnetate Tc 99m / Q000493:pharmacokinetics*; D015899:Tomography, Emission-Computed, Single-Photon; D036542:Tomography, Spiral Computed
chemical_list: D039302:Integrin alphaVbeta3; D019275:Radiopharmaceuticals; D013670:Sodium Pertechnetate Tc 99m