A novel anticancer theranostic prodrug, FDU-DB-NO₂, specifically activated by hypoxia for selective two-photon imaging hypoxia status, real-time tracking drug release, and solid tumor therapy was designed. The devised prodrug consists of an anticancer drug floxuridine (FDU), a fluorescence dye precursor 4′-(diethylamino)-1,1′-biphenyl-2-carboxylate (DB), and a hypoxic trigger 4-nitrobenzyl group. In normal cells, FDU-DB-NO₂ is “locked”. Whereas in tumor cells, the prodrug is “unlocked” by hypoxia and results in fluorescent dye 7-(diethylamino)coumarin (CM) generation along with FDU release. The amounts and rates of CM formation and FDU release were controlled by hypoxic status and increased with the decreasing of the O₂ concentration. The hypoxic status, distribution of oxygen, and amount of FDU release in tumor cells, spheroids, and tumor tissue could be visualized by fluorescence. FDU-DB-NO₂ showed high cytotoxicity against hypoxic MCF-7 and MCG-803 cell lines and no cytotoxicity against normoxic BRL-3A cells and exhibited effective inhibition on tumor growth of MCF-7-cell-inoculated xenograft nude mice. This strategy may provide a promising platform for selective two-photon imaging hypoxia status, real-time tracking drug release, and personalized solid tumor treatment.

中文翻译：

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低氧激活的抗癌前药，用于生物成像，药物释放追踪和抗癌应用

设计了一种新型的抗癌治疗药物前体药物FDU-DB-NO ₂，该药物被低氧特异性激活，用于选择性双光子成像的低氧状态，实时跟踪药物释放和实体瘤治疗。设计的前药由抗癌药氟尿苷（FDU），荧光染料前体4'-（二乙氨基）-1,1'-联苯-2-羧酸酯（DB）和低氧触发4-硝基苄基组成。在正常小区中，FDU-DB-NO ₂被“锁定”。而在肿瘤细胞中，前药由于缺氧而“解锁”，并导致荧光染料7-（二乙氨基）香豆素（CM）生成以及FDU释放。缺氧状态控制着CM形成和FDU释放的数量和速率，并且随着O ₂的减少而增加。专注。缺氧状态，氧气分布以及FDU在肿瘤细胞，球状体和肿瘤组织中的释放量可以通过荧光观察。FDU-DB-NO ₂对低氧MCF-7和MCG-803细胞系表现出高细胞毒性，对常氧BRL-3A细胞无细胞毒性，并且对接种MCF-7细胞的异种裸鼠的肿瘤生长表现出有效的抑制作用。该策略可能为选择性的双光子成像缺氧状态，实时跟踪药物释放和个性化实体瘤治疗提供有希望的平台。