title: Bispecific Antibody Conjugated Manganese-Based Magnetic Engineered Iron Oxide for Imaging of HER2/neu- and EGFR-Expressing Tumors.
abstract: The overexpression of HER2/neu and EGFR receptors plays important roles in tumorigenesis and tumor progression. Targeting these two receptors simultaneously can have a more widespread application in early diagnosis of cancers. In this study, a new multifunctional nanoparticles (MnMEIO-CyTE777-(Bis)-mPEG NPs) comprising a manganese-doped iron oxide nanoparticle core (MnMEIO), a silane-amino functionalized poly(ethylene glycol) copolymer shell, a near infrared fluorescence dye (CyTE777), and a covalently conjugated anti-HER2/neu and anti-EGFR receptors bispecific antibody (Bis) were successfully developed. In vitro T2-weighted MR imaging studies in SKBR-3 and A431 tumor cells incubated with MnMEIO-CyTE777-(Bis)-mPEG NPs showed - 94.8 ± 3.8 and - 84.1 ± 2.8% negative contrast enhancement, respectively. Pharmacokinetics study showed that MnMEIO-CyTE777-(Bis)-mPEG NPs were eliminated from serum with the half-life of 21.3 mins. In vivo MR imaging showed that MnMEIO-CyTE777-(Bis)-mPEG NPs could specifically and effectively target to HER2/neu- and EGFR-expressing tumors in mice; the relative contrast enhancements were 11.8 (at 2 hrs post-injection) and 61.5 (at 24 hrs post-injection) fold higher in SKBR-3 tumors as compared to Colo-205 tumors. T2-weighted MR and optical imaging studies revealed that the new contrast agent (MnMEIO-CyTE777-(Bis)-mPEG NPs) could specifically and effectively target to HER2/neu- and/or EGFR-expressing tumors. Our results demonstrate that MnMEIO-CyTE777-(Bis)-mPEG NPs are able to recognize the tumors expressing both HER2/neu and/or EGFR, and may provide a novel molecular imaging tool for early diagnosis of cancers expressing HER2/neu and/or EGFR.
authors.affiliation: 1. Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu 300, Taiwan.
authors.forename: Shou-Cheng
authors.initials: SC
authors.lastname: Wu
authors.affiliation: 1. Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu 300, Taiwan.
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: 2. Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu 310, Taiwan.
authors.forename: Hsiang-Ching
authors.initials: HC
authors.lastname: Wang
authors.affiliation: 2. Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu 310, Taiwan.
authors.forename: Min-Yuan
authors.initials: MY
authors.lastname: Chou
authors.affiliation: 3. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 350, Taiwan.
authors.forename: Teng-Yuan
authors.initials: TY
authors.lastname: Chang
authors.affiliation: 4. Translational Research Center, Department of Medical Research, and Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Shyng-Shiou
authors.initials: SS
authors.lastname: Yuan
authors.affiliation: 5. Department of Medical Imaging, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
authors.forename: Chiao-Yun
authors.initials: CY
authors.lastname: Chen
authors.affiliation: 6. Cancer Center, Division of General and Gastroenterological Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Hou
authors.affiliation: 1. Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu 300, Taiwan ; 3. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 350, Taiwan.
authors.forename: John Tsu-An
authors.initials: JT
authors.lastname: Hsu
authors.affiliation: 1. Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu 300, Taiwan ; 7. Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Yun-Ming
authors.initials: YM
authors.lastname: Wang
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000493:pharmacokinetics*; D066246:ErbB Receptors / Q000032:analysis*; D005290:Ferric Compounds / Q000493:pharmacokinetics*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008280:Magnetics; D008345:Manganese / Q000493:pharmacokinetics*; D051379:Mice; D009369:Neoplasms / Q000175:diagnosis* / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D013194:Staining and Labeling / Q000379:methods
chemical_list: D018033:Antibodies, Bispecific; D066246:ErbB Receptors; D005290:Ferric Compounds; D008345:Manganese; D018719:Erb-b2 Receptor Tyrosine Kinases; C000499:ferric oxide; C512478:EGFR protein, human; C508053:ERBB2 protein, human
keywords: EGFR.; HER2/neu; MnMEIO; bispecific antibody; magnetic resonance imaging