title: Molecular imaging reveals trastuzumab-induced epidermal growth factor receptor downregulation in vivo.
abstract: Previous in vitro studies demonstrated that treating tumors expressing both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 with trastuzumab resulted in increased EGFR homodimerization and subsequent rapid downregulation of EGFR. We investigated whether molecular imaging using near-infrared fluorescence (NIRF) imaging and PET probes could sensitively detect trastuzumab-induced EGFR downregulation in vivo.
  
  
  METHODS
  The F(ab')2 antibody fragment PaniF(ab')2 was generated by digesting the anti-EGFR monoclonal antibody panitumumab. PaniF(ab')2 was labeled with either a NIRF dye or (68)Ga, and optical imaging and small-animal PET imaging of Dye-PaniF(ab')2 and (68)Ga-PaniF(ab')2, respectively, were performed in HT-29 tumor-bearing nude mice treated with trastuzumab or untreated control.
  
  
  RESULTS
  Longitudinal NIRF imaging studies revealed significantly reduced tumor uptake of Dye-PaniF(ab')2 on days 5 and 7 in trastuzumab-treated HT-29 tumors, compared with control. Western blotting confirmed the downregulation of EGFR after treatment with trastuzumab. Small-animal PET on day 5 after trastuzumab treatment also demonstrated decreased (68)Ga-PaniF(ab')2 uptake in trastuzumab-treated HT-29 tumors. The tumor uptake value of (68)Ga-PaniF(ab')2 obtained from PET imaging had an excellent linear correlation with the uptake value measured using biodistribution.
  
  
  CONCLUSIONS
  The downregulation of EGFR induced by trastuzumab treatment could be detected noninvasively using optical and PET imaging. This molecular imaging strategy could provide a dynamic readout of changes in the tumor signaling and may facilitate the noninvasive monitoring of the early tumor response to drug treatment.
authors.affiliation: Medical Isotopes Research Center, Peking University, Beijing, China Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing, China; and.
authors.forename: Teng
authors.initials: T
authors.lastname: Ma
authors.affiliation: Medical Isotopes Research Center, Peking University, Beijing, China Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing, China; and.
authors.forename: Xianlei
authors.initials: X
authors.lastname: Sun
authors.affiliation: Medical Isotopes Research Center, Peking University, Beijing, China Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing, China; and.
authors.forename: Liyang
authors.initials: L
authors.lastname: Cui
authors.affiliation: Medical Isotopes Research Center, Peking University, Beijing, China Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing, China; and.
authors.forename: Liquan
authors.initials: L
authors.lastname: Gao
authors.affiliation: Medical Isotopes Research Center, Peking University, Beijing, China Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing, China; and.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Medical Isotopes Research Center, Peking University, Beijing, China Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing, China; and.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Medical Isotopes Research Center, Peking University, Beijing, China Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing, China; and.
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.affiliation: Medical Isotopes Research Center, Peking University, Beijing, China Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing, China; and liuzf@bjmu.edu.cn.
authors.forename: Zhaofei
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004396:Coloring Agents / Q000737:chemistry; D015536:Down-Regulation / Q000187:drug effects*; D066246:ErbB Receptors / Q000378:metabolism*; D005710:Gallium Radioisotopes; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D061848:Optical Imaging; D000077544:Panitumumab; D049268:Positron-Emission Tomography; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004396:Coloring Agents; D066246:ErbB Receptors; D005710:Gallium Radioisotopes; D007140:Immunoglobulin Fab Fragments; D000077544:Panitumumab; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: EGFR; HER2; immunotherapy; molecular imaging; tumor response