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CX-5461-loaded nucleolus-targeting nanoplatform for cancer therapy through induction of pro-death autophagy
Acta Biomaterialia ( IF 9.4 ) Pub Date : 2018-08-30 , DOI: 10.1016/j.actbio.2018.08.035
Yanhong Duo , Min Yang , Zhenya Du , Chuhan Feng , Chen Xing , Yanping Wu , Zhenhua Xie , Fang Zhang , Laiqiang Huang , Xiaowei Zeng , Hongbo Chen

Various drugs have been designed in the past to act on intracellular targets. For the desired effects to be exerted, these drugs should reach and accumulate in specific subcellular organelles. CX-5461 represents a potent small-molecule inhibitor of rRNA synthesis that specifically inhibits the transcription driven by RNA polymerase (Pol) I and induces tumor cell death through triggering a pro-death autophagy. In the current study an innovative kind of CX-5461-loaded mesoporous silica nano-particles enveloped by polyethylene glycol (PEG), polydopamine (PDA) and AS-1411 aptamer (MSNs-CX-5461@PDA-PEG-APt) with the aim of treating cancer cells was constructed, in which the high-surface-area MSNs allowed for high drug loading, PDA acted as gatekeeper to prevent the leakage of CX-5461 from MSNs, PEG grafts on PDA surfaces increased the stable and biocompatible property in physiological condition, and AS-1411 aptamer promoted the nucleolar accumulation of CX-5461. MSNs-CX-5461@PDA-PEG-APt was characterized regarding releasing characteristics, steadiness, encapsulation of drugs, phase boundary potential as well as sizes of particles. Expectedly, In vitro assays showed that aptamer AS-1411 significantly increased the nucleolar accumulation of CX-5461. The aptamer-tagged CX-5461-loaded MSNs demonstrated to be more cytotoxic to cervical cancer cells compared to the control MSNs, due to relatively strong inhibition of rRNA transcription and induction of pro-death autophagy. The in vivo treatment with AS-1411-tagged CX-5461-loaded MSNs showed a stronger distribution in tumor tissues by animal imaging assay and a significantly higher inhibition effect on the growth of HeLa xenografts compared to AS-1411-untagged CX-5461-loaded MSNs. In addition, histology analysis indicated that MSNs-CX-5461@PDA-PEG-APt did not exhibit any significant toxicity on main organs. These results collectively suggested that MSNs-CX-5461@PDA-PEG-APt represents both a safe and potentially nucleolus-targeting anti-cancer drug.

Statement of significance

Many drugs function in specific subcellular organelles. CX-5461 is a specific inhibitor of nucleolar rRNA synthesis. Here, we reported a novel aptamer-tagged nucleolus-targeting CX-5461-loaded nanoparticle, which specifically accumulated in nucleoli and significantly inhibited the tumor growth in vitro and in vivo through inhibiting rRNA transcription and triggering a pro-death autophagy.



中文翻译:

诱导死亡自噬的CX-5461靶向核仁的纳米平台用于癌症治疗

过去已经设计了多种药物来作用于细胞内靶标。为了发挥所需的作用,这些药物应到达并积聚在特定的亚细胞器中。CX-5461代表rRNA合成的有效小分子抑制剂,可特异性抑制RNA聚合酶(Pol)I驱动的转录并通过触发促死亡自噬诱导肿瘤细胞死亡。在本研究中,一种创新型的载有CX-5461的介孔二氧化硅纳米粒子被聚乙二醇(PEG),聚多巴胺(PDA)和AS-1411适体(MSNs-CX-5461 @ PDA-PEG-APt)包裹,建立了治疗癌细胞的目标,其中高表面积MSN允许高载药量,PDA充当网守以防止CX-5461从MSN泄漏,PDA表面的PEG接枝增加了生理条件下的稳定性和生物相容性,而AS-1411适体促进了CX-5461的核仁积累。MSNs-CX-5461 @ PDA-PEG-APt的特征在于释放特性,稳定性,药物包封,相界电势以及颗粒尺寸。预计,体外试验表明,适体AS-1411显着增加了CX-5461的核仁积累。与对照MSN相比,带有适体标签的CX-5461负载的MSN被证明对宫颈癌细胞具有更高的细胞毒性,这是由于rRNA转录相对较强的抑制作用以及促死亡前自噬的诱导。在体内与没有AS-1411的CX-5461标记的MSNs相比,采用AS-1411的CX-5461标记的MSNs进行的动物显像分析显示,在肿瘤组织中的分布更强,并且对HeLa异种移植物的生长具有明显更高的抑制作用。此外,组织学分析表明MSNs-CX-5461 @ PDA-PEG-APt对主要器官没有任何明显的毒性。这些结果共同表明,MSNs-CX-5461 @ PDA-PEG-APt代表了安全的和潜在的靶向核仁的抗癌药。

重要声明

许多药物在特定的亚细胞器中起作用。CX-5461是核仁rRNA合成的特异性抑制剂。在这里,我们报道了一种新型的适体标记的靶向核仁的CX-5461负载纳米颗粒,该纳米颗粒特异性地积聚在核仁中,并通过抑制rRNA转录并触发促死自噬而在体内外显着抑制肿瘤生长。

更新日期:2018-08-30
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