Abstract：
Triple negative breast cancer (TNBC) is a notoriously difficult disease to treat, and many of the existing TNBC chemotherapeutics lack tumor selectivity and the capability for simultaneously visualizing and monitoring their own activity in the biological context. However, TNBC cells have been known to generate high levels of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2). To this end, three novel small molecule theranostics 1a, 1c, and 2 consisting of both H2O2-responsive nitrogen mustard prodrug and profluorophore character have been designed, synthesized, and evaluated as targeted cancer therapeutics and bioimaging agents. The three theranostics comprise of boronate esters that deactivate nitrogen mustard functional groups and fluorophores but allow their selective activation through H2O2-specific oxidative deboronation for the release of the active drug and fluorophore. The three theranostics demonstrated H2O2-inducible DNA-alkylating capability and fluorescence turn-on properties in addition to selective anticancer activity. They are particularly effective in killing TNBC MDA-MB-468 cells with high H2O2 level while safe to normal epithelial MCF-10A cell. The conjugated boron-masked fluorophores in 1c and 2 are highly responsive towards H2O2, which enabled tracking of the theranostics in living cellular mitochondria and nucleus organelles. The three theranostics 1a, 1c, and 2 are capable of both selective release of the active drug to take effect in H2O2-rich cancer sites and simultaneously monitoring its activity. This single molecule system is of utmost importance to understand the function, efficacy, and mechanism of the H2O2-activated prodrugs and theranostics within the living recipient.
摘要：
三阴性乳腺癌（TNBC）是一种众所周知的难以治疗的疾病，并且许多现有的TNBC化疗剂缺乏肿瘤选择性和在生物学背景下同时可视化和监测其自身活性的能力。然而,已知TNBC细胞会产生高水平的活性氧（ROS），如过氧化氢(H2O2)。为此,三种新型小分子疗法1a，1c,和2由H2O2响应性氮芥前药和前荧光团特性组成，合成，并被评估为靶向癌症治疗剂和生物成像剂。这三种疗法由硼酸酯组成，该硼酸酯使氮芥官能团和荧光团失活，但允许通过H2O2特异性氧化脱硼进行选择性活化，以释放活性药物和荧光团。除了选择性抗癌活性外，这三种疗法还证明了H2O2可诱导的DNA烷基化能力和荧光开启特性。它们在杀死具有高H2O2水平的TNBCMDA-MB-468细胞方面特别有效,同时对正常上皮MCF-10A细胞是安全的。1c和2中的共轭硼掩蔽的荧光团对H2O2具有高度响应，这使得能够在活细胞线粒体和细胞核细胞器中追踪治疗。三个疗法1a，1c,和2能够选择性释放活性药物以在富含H2O2的癌症部位起作用并同时监测其活性。这个单分子系统对于理解功能至关重要，功效,以及活体接受者体内H2O2激活的前药和疗法的机制。
