Liu Hong-Wen, Hu Xiao-Xiao, Li Ke, Liu Yongchao, Rong Qiming, Zhu Longmin, Yuan Lin, Qu Feng-Li, Zhang Xiao-Bing, Tan Weihong
Molecular Science and Biomedicine Laboratory , State Key Laboratory of Chemo/Biosensing and Chemometrics , College of Chemistry and Chemical Engineering , College of Life Sciences , Aptamer Engineering Center of Hunan Province , Hunan University , Changsha , 410082 , P. R. China . Email:
Key Laboratory of Environmentally Friendly Chemistry and Applications of Ministry of Education , College of Chemistry , XiangtanUniversity , Xiangtan 411105 , P. R. China.
Chem Sci. 2017 Nov 1;8(11):7689-7695. doi: 10.1039/c7sc03454g. Epub 2017 Sep 14.
Nontoxic prodrugs, especially activated by tumor microenvironment, are urgently required for reducing the side effects of cancer therapy. And combination of chemo-photodynamic therapy prodrugs show effectively synergetic therapeutic efficiency, however, this goal has not been achieved in a single molecule. In this work, we developed a mitochondrial-targeted prodrug for near infrared (NIR) fluorescence imaging guided and synergetic chemo-photodynamic precise cancer therapy for the first time. contains a NIR photosensitizer () and an anticancer drug 5'-deoxy-5-fluorouridine (5'-DFUR). These two parts are linked and caged through a bisboronate group, displaying no fluorescence and very low cytotoxicity. In the presence of HO, the bisboronate group is broken, resulting in activation of for NIR photodynamic therapy and activation of 5'-DFUR for chemotherapy. The activated can also provide a NIR fluorescence signal for monitoring the release of activated drug. Taking advantage of the high HO concentration in cancer cells, exhibits higher cytotoxicity to cancer cells than normal cells, resulting in lower side effects. In addition, based on its mitochondrial-targeted ability, exhibits enhanced chemotherapy efficiency compare to free 5'-DFUR. It also demonstrated a remarkably improved and synergistic chemo-photodynamic therapeutic effect for cancer cells. Moreover, exhibits excellent tumor microenvironment-activated performance when intravenously injected into tumor-bearing nude mice, as demonstrated by fluorescence imaging. Thus, is a promising prodrug for cancer therapy based on its tumor microenvironment-activated drug release, synergistic therapeutic effect and "turn-on" NIR imaging guide.
为了降低癌症治疗的副作用，迫切需要无毒前药，尤其是由肿瘤微环境激活的前药。化疗-光动力疗法前药的联合显示出有效的协同治疗效果，然而，这一目标尚未在单个分子中实现。在这项工作中，我们首次开发了一种用于近红外（NIR）荧光成像引导和协同化疗-光动力精确癌症治疗的线粒体靶向前药。它包含一种近红外光敏剂（）和一种抗癌药物5'-脱氧-5-氟尿苷（5'-DFUR）。这两个部分通过双硼酸酯基团连接并被封闭，不显示荧光且细胞毒性非常低。在过氧化氢（HO）存在的情况下，双硼酸酯基团被破坏，导致用于近红外光动力疗法的激活以及用于化疗的5'-DFUR激活。激活的还可以提供近红外荧光信号以监测激活药物的释放。利用癌细胞中高浓度的HO，对癌细胞表现出比正常细胞更高的细胞毒性，从而降低副作用。此外，基于其线粒体靶向能力，与游离的5'-DFUR相比，表现出增强的化疗效率。它还对癌细胞表现出显著改善的协同化疗-光动力治疗效果。此外，当静脉注射到荷瘤裸鼠体内时，通过荧光成像证明，表现出优异的肿瘤微环境激活性能。因此，基于其肿瘤微环境激活的药物释放、协同治疗效果和“开启”近红外成像引导，是一种有前途的癌症治疗前药。
