FAPα酶激活式靶向抗肿瘤前药:Z-GP-Dox对斑马鱼的毒性评价

Toxicity Evaluation of a FAPα-activated Targeting Anticancer Prodrug Z-GP-Dox in Zebrafish

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 toxicity in zebrafish of Z-GP-Dox, a novel FAPα-catalyzed activation targeted anticancer drug designed and synthesized previously. Methods： The mortality of 4-month-oldzebrafish and the development of 24hpf （hours post fertilization） embryos were observed after treatment of Z-GP- Dox in different concentrations. The toxic effects of Z-GP-Dox on the zebrafish heart were evaluated with morphological and electrophysiological changes. Doxorubicin was set as a control. Results： The mortality rate of zebrafish in Dox control group showed significant does-dependent manner, while the mortality rate of the structural acylated modification prodrug Z-GP-Dox treated group was much lower. Dox induced malformations of zebrafish embryos and impaired heart function in juvenile. While at the same concentration, there was no significant difference between the Z-GP-Dox treatment group and blank control group in the heart shape and heart rate of the juvenile. When the Z-GP-Dox was hydrolysised by FAPα, its toxicity significantly increased and almost equal to the Dox. Conclusion： When compared with Dox, prodrug Z-GP-Dox toxicity was reduced significantly in zebrafish with characteristics of FAPα enzyme activated targeting release.