CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences , Bei Yi Jie 2, Zhong Guan Cun, Beijing 100190, China.
School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences , Beijing 100049, China.
J Am Chem Soc. 2018 Jan 10;140(1):211-218. doi: 10.1021/jacs.7b08900. Epub 2017 Dec 28.
The abnormal expression of tumor-associated proteases and lowered extracellular pH are important signatures strongly associated with cancer invasion, progression, and metastasis. However, their malignant effects were mainly identified using cell and tissue studies. To noninvasively visualize the heterogeneous distribution of these abnormal indicators in vivo and further disclose their collective behaviors, a target-triggered fluorescent nanoprobe composed of a ratiometric pH-sensitive dye, a near-infrared dye (Cy5.5), and biocompatible FeO nanoparticles was constructed. The pH-sensitive dye was linked through a peptide substrate of matrix metalloprotease-9 (MMP-9) with FeO nanoparticles to establish a Förster resonance energy transfer (FRET) system for sensing the pH of the tumor microenvironment. Cy5.5 served as an internal reference for forming a secondary ratiometric fluorescent system together with the activated pH dye to enable the visualization of protease activities in vivo. Extensive imaging studies using a mouse model of human colon cancer revealed that the overexpression of MMP-9 and abnormal microenvironmental pH quantitatively visualized by this dual-ratiometric probe are spatially heterogeneous and synergistically guide the tumor invasion in vivo.
肿瘤相关蛋白酶的异常表达和细胞外 pH 值降低是与癌症侵袭、进展和转移密切相关的重要特征。然而，这些恶性效应主要是通过细胞和组织研究来确定的。为了非侵入性地可视化这些异常指标在体内的不均匀分布，并进一步揭示它们的集体行为，构建了一种由比率型 pH 敏感染料、近红外染料（Cy5.5）和生物相容性 FeO 纳米粒子组成的靶向触发荧光探针。pH 敏感染料通过基质金属蛋白酶-9（MMP-9）的肽底物与 FeO 纳米粒子连接，建立了用于感测肿瘤微环境 pH 值的Förster 共振能量转移（FRET）系统。Cy5.5 作为内部参考，与激活的 pH 染料一起形成二次比率荧光系统，从而能够在体内可视化蛋白酶活性。使用人结肠癌的小鼠模型进行的广泛成像研究表明，MMP-9 的过表达和这种双比率探针定量可视化的异常微环境 pH 值在空间上是不均匀的，并协同指导体内肿瘤侵袭。
