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目的:考察新设计合成的一种FAPα酶激活式靶向抗肿瘤新药甘脯酰阿霉素(Z-GP-Dox)对斑马鱼的毒性作用。方法:以阿霉素作为对照,用不同浓度的Z-GP-Dox处理4月龄的成年斑马鱼及其受精后24h(24hpf)的胚胎,观测其死亡率,并通过显微镜观察Z-GP-Dox对斑马鱼胚胎发育的影响,从形态学和电生理学方面评价其对斑马鱼心脏的毒性作用。结果:Dox对照组的斑马鱼死亡率具有明显的浓度依赖性,而经酰化修饰的前药Z-GP-Dox处理组的斑马鱼死亡率相对较低。Dox可导致斑马鱼胚胎发育严重畸形,心脏功能受损;而相同浓度的前药Z-GP-Dox处理组的胚胎发育基本正常,幼鱼的心脏形态和心率与空白对照组差异不显著。然而,当Z-GP-Dox被FAPα酶解后,其毒性则明显增强,与Dox对照组的毒性相当。结论:与Dox相比,经结构改造的前药Z-GP-Dox对斑马鱼的毒性显著降低,且具有FAPα酶激活式靶向释放特性。
OBJECTIVE: To investigate the toxic effects of a newly designed and synthesized FAPα-activated antitumor drug, GP-Dox, on zebrafish. METHODS: Four-month-old adult zebrafish and embryos at 24 h (24hpf) after fertilization were treated with different concentrations of Z-GP-Dox with adriamycin as control. The mortality of Z-GP- The effects of Dox on zebrafish embryo development were evaluated by morphological and electrophysiological studies on the virulence of zebrafish hearts. Results: The mortality of zebrafish in Dox control group was significantly concentration-dependent, while the death rate of zebrafish in Z-GP-Dox treated group was relatively low. Dox could lead to severe deformity and impaired cardiac function in zebrafish embryos. However, embryo development of Z-GP-Dox treated with the same concentration of prodrug was basically normal. There was no significant difference in cardiac morphology and heart rate between juvenile and blank control groups. However, when Z-GP-Dox was enzymatically hydrolyzed by FAPα, the toxicity of Z-GP-Dox was significantly enhanced, which was comparable to that of Dox control group. Conclusion: Compared with Dox, Z-GP-Dox, a structurally modified prodrug, has significantly reduced the toxicity to zebrafish and has the active release of FAPα.