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Acidity-triggered TAT-presenting nanocarriers augment tumor retention and nuclear translocation of drugs
Nano Research ( IF 9.5 ) Pub Date : 2018-10-03 , DOI: 10.1007/s12274-017-1925-4
Wei Jiang , Jilong Wang , Jinbin Yang , Zhiwei He , Zhenhui Hou , Yingli Luo , Li Wang , Jing Liu , Houbing Zhang , Yangyang Zhao , Guoqing Zhang , Fang Huang , Xuechang Zhou , Lifeng Yan , Xianzhu Yang , Yucai Wang , Jun Wang

Hierarchical targeting strategy can combat the sequential drug delivery barriers by changing their properties with response to tumor stimuli. Among these strategies, much less attention has been paid to address the issues of rapid tumor clearance and insufficient cellular translocation. In this work, we demonstrate that a transactivator of transcription (TAT)-presenting nanomedicine (DATAT-NP/Pt), apart from improving tumor accumulation and cellular uptake, can simultaneously enhance tumor retention and promote nuclear translocation of encapsulated platinum prodrugs, and thus improve therapeutic efficacy. Specifically, a protecting 2,3-dimethylmaleic anhydride (DA) corona on the nanomedicine prevented the TAT peptide from serum. DATAT-NP/Pt efficiently accumulated at the tumor site through the enhanced permeability and retention (EPR) effect, followed by acid-triggered TAT presenting within the tumor acidic microenvironment (pH ~ 6.8). The exposed TAT peptide augmented tumor retention and nuclear translocation of DATAT-NP/Pt. We used a tumor-on-a-chip microfluidic system to real-time mimic and analyze tumor accumulation and retention at physiological flow conditions and revealed that surface absorption of nanomedicines on tumors was critical in determining their tumor retention and clearance. Furthermore, the TAT peptide rapidly translocated the DATAT-NP/Pt into the perinuclear region, allowing for higher nuclear platinum concentrations and increased Pt-DNA adduct formation in nuclei, which consequently reversed cisplatin resistance. Our work presents a new strategy to overcome pathophysiological barriers of tumor clearance and insufficient cellular translocation and provides new insights for the design of cancer nanomedicines.

中文翻译:

酸性触发的TAT呈递纳米载体可增强药物的肿瘤保留和核转运

分级靶向策略可以通过响应肿瘤刺激改变其性质来对抗顺序给药障碍。在这些策略中,已经很少关注用于解决快速肿瘤清除和细胞移位不足的问题。在这项工作中,我们证明了呈现反转录激活因子(TAT)的纳米药物(DA TAT-NP / Pt),除了改善肿瘤蓄积和细胞摄取外,还可以同时增强肿瘤保留能力并促进胶囊化铂前药的核转运,从而提高治疗效果。具体而言,纳米药物上的保护性2,3-二甲基马来酸酐(DA)电晕可防止TAT肽进入血清。DATAT-NP / Pt通过增强的通透性和保留(EPR)效应有效地积聚在肿瘤部位,随后在酸性酸性微环境(pH〜6.8)中出现酸触发的TAT。暴露的TAT肽增加了DA TAT-NP / Pt的肿瘤保留和核易位。我们使用了单芯片肿瘤微流控系统来实时模拟和分析在生理流动条件下的肿瘤积累和保留,并揭示了纳米药物在肿瘤上的表面吸收对于确定其肿瘤保留和清除率至关重要。此外,TAT肽可快速转移DATAT-NP / Pt进入核周区域,从而允许更高的核铂浓度和增加的核中Pt-DNA加合物形成,从而逆转了顺铂耐药性。我们的工作提出了一种克服肿瘤清除和细胞移位不足的病理生理障碍的新策略,并为癌症纳米药物的设计提供了新的见识。
更新日期:2018-10-03
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