A sequential enzyme-activated and light-triggered pro-prodrug nanosystem for cancer detection and therapy
A sequential enzyme-activated and light-triggered pro-prodrug nanosystem for cancer detection and therapy
复制标题
用于癌症检测和治疗的连续酶激活和光触发前药纳米系统
DOI：
10.1039/c7tb01989k
复制
发表时间：
2018-05-07
影响因子：
7
通讯作者：
Wu, Shuizhu
中科院分区：
文献类型：
--
作者：
Chen, Zelin;Li, Bowen;Wu, Shuizhu
DT-黄递酶是一种胞质黄素酶，其水平在许多肿瘤类型中强烈升高。在抗癌药物的结构中修饰DT-心肌黄酶的底物可以促进癌症的检测和治疗。在此，我们开发了一种用于癌症检测和治疗的新型前体药物纳米系统，其特征在于酶激活的荧光发射和随后的光触发药物释放。前体前药分子包含抗癌药物甲氨蝶呤（MTX）、酶（DT-心肌黄酶）响应性醌丙酸部分和可光活化的香豆素基。在没有DT-心肌黄酶的情况下，醌丙酸部分通过光诱导电子转移（PET）猝灭香豆素的荧光并阻断光裂解途径。DT-黄递酶可消除PET的荧光效应，恢复香豆素的荧光。该荧光用作评估酶生物标志物水平的报告信号，并区分肿瘤细胞和正常细胞，随后活性药物MTX的光可控释放可以通过单光子或双光子照射激活。这种前体药物纳米系统显示出对癌细胞的强细胞毒性，对正常细胞的影响可以忽略不计。该策略为构建用于癌症检测的纳米系统以及随后通过内部和外部刺激激活按需选择性杀死癌细胞提供了一个新平台。
DT-diaphorase is a cytosolic flavoenzyme whose level is strongly elevated in a number of tumor types. Incorporating a DT-diaphorase's substrate in the structure of anticancer drugs may facilitate cancer detection and therapy. Herein, we developed a novel pro-prodrug nanosystem for cancer detection and therapy, which features enzyme-activated fluorescence emission and subsequent light-triggered drug release. The pro-prodrug molecule comprises an anticancer drug methotrexate (MTX), an enzyme (DT-diaphorase) responsive quinone propionic acid moiety and a light-activatable coumarinyl. In the absence of DT-diaphorase, the quinone propionic acid moiety quenches the fluorescence of coumarin via photoinduced electron transfer (PET) and blocks the photocleavage pathway. DT-diaphorase can annihilate the effect of PET and restore the fluorescence of coumarin. This fluorescence serves as the reporting signal for assessing the enzyme biomarker level and discriminates tumor cells from normal cells, and subsequently photocontrollable release of the active drug, MTX, can be activated via one- or two-photon irradiation. This pro-prodrug nanosystem shows strong cytotoxicity toward cancer cells and a negligible effect on normal cells. This strategy provides a new platform for constructing nanosystems for cancer detection and subsequent on-demand selective killing of cancer cells via both internal- and external-stimuli activation.