Controlled release systems with capabilities for direct and real-time monitoring of the release and dynamics of drugs in living systems are of great value for cancer chemotherapy. Herein, we describe a novel dual turn-on fluorescence signal-based controlled release system (CDox), in which the chemotherapy drug doxorubicin (Dox) and the fluorescent dye (CH) are conjugated by a hydrazone moiety, a pH-responsive cleavable linker. CDox itself shows nearly no fluorescence as the fluorescence of CH and Dox is essentially quenched by the C=N isomerization and N-N free rotation. However, when activated under acidic conditions, CDox could be hydrolyzed to afford Dox and CH, resulting in dual turn-on signals with emission peaks at 595 nm and 488 nm, respectively. Notably, CDox exhibits a desirable controlled release feature as the hydrolysis rate is limited by the steric hindrance effect from both the Dox and CH moieties. Cytotoxicity assays indicate that CDox shows much lower cytotoxicity relative to Dox, and displays higher cell inhibition rate to cancer than normal cells. With the aid of the dual turn-on fluorescence at different wavelengths, the drug release dynamics of CDox in living HepG2 and 4T-1 cells was monitored in double channels in a real-time fashion. Importantly, two-photon fluorescence imaging of CDox in living tumor tissues was also successfully performed by high-definition 3D imaging. We expect that the unique controlled release system illustrated herein could provide a powerful means to investigate modes of action of drugs, which is critical for development of much more robust and effective chemotherapy drugs.

中文翻译：

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基于双开启荧光信号的控释系统，用于实时监测活细胞和肿瘤组织中药物释放动力学

具有对生命系统中药物的释放和动态进行直接和实时监控的功能的控释系统，对于癌症化疗具有重要的价值。在这里，我们描述了一种新型的基于双开启荧光信号的控释系统（CDox），其中化疗药物阿霉素（Dox）和荧光染料（CH）通过，部分（pH响应可裂解的连接子）缀合。 。CDox本身几乎不显示荧光，因为CH和Dox的荧光基本上被C = N异构化和NN自由旋转猝灭。但是，当在酸性条件下活化时，CDox可以水解得到Dox和CH导致双开启信号，其发射峰分别在595 nm和488 nm处。值得注意的是，CDox表现出理想的控释特性，因为水解速率受到Dox和CH部分的位阻作用的限制。细胞毒性试验表明，CDox相对于Dox表现出低得多的细胞毒性，并且比正常细胞显示出更高的对癌症的细胞抑制率。借助不同波长的双开启荧光，CDox的药物释放动力学实时监测双通道双活HepG2和4T-1细胞中的HLA含量。重要的是，还通过高清3D成像成功地在活体肿瘤组织中进行了CDox的双光子荧光成像。我们期望本文所述的独特的控释系统可以提供强有力的手段来研究药物的作用方式，这对于开发更健壮和有效的化疗药物至关重要。