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Efficient delivery of BRD4 inhibitor by glutathione-sensitive nanoparticle to suppress gallbladder cancer through inhibiting NF-κB signaling
Applied Materials Today ( IF 7.2 ) Pub Date : 2020-10-10 , DOI: 10.1016/j.apmt.2020.100849
Qiongcong Xu , Liying Wang , Tong Tong , Xitai Huang , Chensong Huang , Fuxi Li , Qiao Su , Yichih Tien , Jun Wu , Wei Zhao , Xiaoyu Yin

Gallbladder cancer (GBC) is one of the most common and aggressive biliary tract diseases with limited therapeutic strategies and poor prognosis. Various therapeutic agents have been demonstrated effective in preclinical models, but high dose requirement and toxicity to normal cells limit their clinical applications. Considering the high concentration of glutathione (GSH) in GBC, we developed a GSH-responsive nanoparticle (NP) system based on biodegradable poly(disulfide amide) (Cys-8E Polymer) for targeted delivery of a BRD4 inhibitor (JQ1), which is known as a promising therapeutic agent for GBC treatment. JQ1-loaded Cys-8E nanoparticles (JQ1@Cys-8E NPs) possessed a high JQ1 loading, preferable stability and redox-responsive release behavior. Additionally, the NPs showed good targeted delivery into GBC tumor spheroids and GBC patient-derived xenograft (PDX) tumors. Specifically, the intracellular GSH in tumors could trigger the release of JQ1, which induced the cell cycle arrest and apoptosis of GBC cells. RNA-sequencing analysis revealed that JQ1@Cys-8E NPs enhanced the effect of JQ1 through inhibiting NF-κB pathway. Importantly, JQ1@Cys-8E NPs significantly suppressed GBC tumor growth in the PDX model of early recurrence. No obvious systemic toxicity and organ damages were observed after treatment with JQ1@Cys-8E NPs. Our results demonstrate the promising therapeutic applications of JQ1@Cys-8E NPs for adjuvant therapy in GBC treatment.



中文翻译:

谷胱甘肽敏感纳米颗粒有效递送BRD4抑制剂通过抑制NF-κB信号传导抑制胆囊癌

胆囊癌(GBC)是最常见的侵略性胆道疾病之一,其治疗策略有限且预后较差。已经证明各种治疗剂在临床前模型中是有效的,但是高剂量需求和对正常细胞的毒性限制了它们的临床应用。考虑到GBC中高浓度的谷胱甘肽(GSH),我们开发了一种基于生物可降解的聚二硫酰胺(Cys-8E聚合物)的GSH响应纳米颗粒(NP)系统,用于靶向递送BRD4抑制剂(JQ1),这是被称为GBC治疗的有前途的治疗剂。载有JQ1的Cys-8E纳米颗粒(JQ1 @ Cys-8E NPs)具有较高的JQ1载量,较好的稳定性和氧化还原响应释放行为。另外,NPs表现出良好的靶向递送到GBC肿瘤球体和GBC患者来源的异种移植(PDX)肿瘤的能力。具体而言,肿瘤中的细胞内GSH可能触发JQ1的释放,从而诱导GBC细胞的细胞周期停滞和凋亡。RNA测序分析表明,JQ1 @ Cys-8E NPs通过抑制NF-κB途径增强了JQ1的作用。重要的是,在PDX早期复发模型中,JQ1 @ Cys-8E NP显着抑制了GBC肿瘤的生长。JQ1 @ Cys-8E NPs治疗后未观察到明显的全身毒性和器官损伤。我们的结果证明了JQ1 @ Cys-8E NP在GBC治疗中具有辅助治疗的广阔应用前景。RNA测序分析表明,JQ1 @ Cys-8E NPs通过抑制NF-κB途径增强了JQ1的作用。重要的是,在PDX早期复发模型中,JQ1 @ Cys-8E NP显着抑制了GBC肿瘤的生长。JQ1 @ Cys-8E NPs治疗后未观察到明显的全身毒性和器官损伤。我们的结果证明了JQ1 @ Cys-8E NP在GBC治疗中具有辅助治疗的广阔应用前景。RNA测序分析表明,JQ1 @ Cys-8E NPs通过抑制NF-κB途径增强了JQ1的作用。重要的是,在PDX早期复发模型中,JQ1 @ Cys-8E NP显着抑制了GBC肿瘤的生长。JQ1 @ Cys-8E NPs治疗后未观察到明显的全身毒性和器官损伤。我们的结果证明了JQ1 @ Cys-8E NP在GBC治疗中具有辅助治疗的广阔应用前景。

更新日期:2020-10-10
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