Urano Yasuteru, Asanuma Daisuke, Hama Yukihiro, Koyama Yoshinori, Barrett Tristan, Kamiya Mako, Nagano Tetsuo, Watanabe Toshiaki, Hasegawa Akira, Choyke Peter L, Kobayashi Hisataka
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo, Tokyo, Japan.
Nat Med. 2009 Jan;15(1):104-9. doi: 10.1038/nm.1854. Epub 2008 Dec 7.
A long-term goal of cancer diagnosis is to develop tumor-imaging techniques that have sufficient specificity and sensitivity. To achieve this goal, minimizing the background signal originating from nontarget tissues is crucial. Here we achieve highly specific in vivo cancer visualization by using a newly designed targeted 'activatable' fluorescent imaging probe. This agent is activated after cellular internalization by sensing the pH change in the lysosome. Novel acidic pH-activatable probes based on the boron-dipyrromethene fluorophore were synthesized and then conjugated to a cancer-targeting monoclonal antibody. As proof of concept, ex vivo and in vivo imaging of human epidermal growth factor receptor type 2-positive lung cancer cells in mice was performed. The probe was highly specific for tumors with minimal background signal. Furthermore, because the acidic pH in lysosomes is maintained by the energy-consuming proton pump, only viable cancer cells were successfully visualized. The design concept can be widely adapted to cancer-specific, cell surface-targeting molecules that result in cellular internalization.
癌症诊断的一个长期目标是开发出具有足够特异性和灵敏度的肿瘤成像技术。为实现这一目标，将源自非靶组织的背景信号降至最低至关重要。在此，我们通过使用一种新设计的靶向“可激活”荧光成像探针实现了高度特异性的体内癌症可视化。该试剂在细胞内化后通过感知溶酶体中的pH变化而被激活。合成了基于硼二吡咯亚甲基荧光团的新型酸性pH可激活探针，然后将其与靶向癌症的单克隆抗体偶联。作为概念验证，对小鼠体内人表皮生长因子受体2阳性肺癌细胞进行了体外和体内成像。该探针对肿瘤具有高度特异性，背景信号极小。此外，由于溶酶体中的酸性pH由耗能质子泵维持，只有活癌细胞成功实现了可视化。该设计理念可广泛应用于导致细胞内化的癌症特异性、细胞表面靶向分子。
