| Autor: |
Imura R; Research Center for Advanced Science and Technology, The University of Tokyo, Meguro, Tokyo 153-8904, Japan.; Isotope Science Center, The University of Tokyo, Bunkyo, Tokyo 113-0032, Japan.; JFE Engineering Corporation, Yokohama, Kanagawa 230-8611, Japan., Jang J; Isotope Science Center, The University of Tokyo, Bunkyo, Tokyo 113-0032, Japan., Ozeki AN; Isotope Science Center, The University of Tokyo, Bunkyo, Tokyo 113-0032, Japan., Takahashi H; Institute of Engineering Innovation, School of Engineering, The University of Tokyo, Bunkyo, Tokyo 113-8656, Japan., Ida H; JFE Engineering Corporation, Yokohama, Kanagawa 230-8611, Japan., Wada Y; Research Center for Advanced Science and Technology, The University of Tokyo, Meguro, Tokyo 153-8904, Japan.; Isotope Science Center, The University of Tokyo, Bunkyo, Tokyo 113-0032, Japan., Kumakura Y; Isotope Science Center, The University of Tokyo, Bunkyo, Tokyo 113-0032, Japan.; Department of Diagnostic Radiology and Nuclear Medicine, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama 350-8550, Japan., Akimitsu N; Isotope Science Center, The University of Tokyo, Bunkyo, Tokyo 113-0032, Japan. |
| Abstrakt: |
There have been predictions that the use of the macrocyclic chelating agent 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) in zirconium-89 ( 89 Zr) immuno-positron emission tomography ( 89 Zr-immunoPET) could enhance the in vivo stability of 89 Zr radioimmunoconjugates. However, conjugating [ 89 Zr]Zr-DOTA to a monoclonal antibody (mAb) remains a challenge as the heat treatment required for [ 89 Zr]Zr-DOTA chelation can lead to thermal denaturation of the mAb moieties. We developed a method for synthesizing [ 89 Zr]Zr-DOTA-mAb based on a tetrazine (Tz)-conjugated bifunctional DOTA derivative 2,2',2″-(10-(1-(4-(1,2,4,5-tetrazin-3-yl)phenyl)-3,21,26-trioxo-6,9,12,15,18-pentaoxa-29-carboxy-2,22,25-triazanonacosane-29-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DOTAGA-Tz) and the inverse electron-demand Diels-Alder (IEDDA) click chemistry reaction where trans -cyclooctene-modified mAbs are conjugated to [ 89 Zr]Zr-DOTAGA without being exposed to heat. The stability of IEDDA-derived [ 89 Zr]Zr-DOTAGA-trastuzumab was confirmed by in vitro, ex vivo, and in vivo testing and comparative analysis against the conventional deferoxamine (DFO) counterpart [ 89 Zr]Zr-DFO-trastuzumab. The in vivo immunoPET imaging using [ 89 Zr]Zr-DOTAGA-trastuzumab clearly visualized human epidermal growth factor receptor 2-positive malignancies in murine xenograft models. Greater tumor contrast was observed from [ 89 Zr]Zr-DOTAGA-trastuzumab at a 72-h delayed scan compared with [ 89 Zr]Zr-DFO-trastuzumab. These findings suggest that our IEDDA ligation approach can be an effective means of synthesizing [ 89 Zr]Zr-DOTA-mAb and can enhance the theranostic potential of 89 Zr-immunoPET in DOTA-mediated radioimmunotherapy. |
